header

Normal Vascular and

Glomerular Anatomy
Arthur H. Cohen
Richard J. Glassock

T
he topic of normal vascular and glomerular anatomy is intro-
duced here to serve as a reference point for later illustrations of
disease-specific alterations in morphology.

CHAPTER

1
1.2 Glomerulonephritis and Vasculitis

FIGURE 1-1
A, The major renal circulation. The renal artery divides into the interlobar arteries (usually
4 or 5 divisions) that then branch into arcuate arteries encompassing the corticomedullary
Interlobar junction of each renal pyramid. The interlobular arteries (multiple) originate from the
artery arcuate arteries. B, The renal microcirculation. The afferent arterioles branch from the
interlobular arteries and form the glomerular capillaries (hemi-arterioles). Efferent arteri-
Arcuate oles then reform and collect to form the post-glomerular circulation (peritubular capillar-
artery Renal ies, venules and renal veins [not shown]). The efferent arterioles at the corticomedullary
artery junction dip deep into the medulla to form the vasa recta, which embrace the collecting
Pelvis
tubules and form hairpin loops. (Courtesy of Arthur Cohen, MD.)
Pyramid

Interlobular Ureter
artery

Afferent
arteriole Interlobular
artery

Glomerulus

Arcuate
artery

Efferent
arteriole
Collecting
tubule
Interlobar
artery
B
 Normal Vascular and Glomerular Anatomy 1.3

FIGURE 1-2 (see Color Plate)

Microscopic view of the normal vascular and glomerular anatomy.
The largest intrarenal arteries (interlobar) enter the kidneys
between adjacent lobes and extend toward the cortex on the side
of a pyramid. These arteries branch dichotomously at the corti-
comedullary junction, forming arcuate arteries that course between
the cortex and medulla. The arcuate arteries branch into a series of
aa ILA interlobular arteries that course at roughly right angles through the
cortex toward the capsule. Blood reaches glomeruli through affer-
ent arterioles, most of which are branches of interlobular arteries,
although some arise from arcuate arteries. ILA—interlobular
artery; aa—afferent arteriole.

FIGURE 1-3
Microscopic view of the juxtaglomerular apparatus. The juxta-
glomerular apparatus (arrow) located immediately adjacent to the
glomerular hilus, is a complex structure with vascular and tubular
components. The vascular component includes the afferent and
efferent arterioles, and the region between them is known as the
lacis. The tubular component consists of the macula densa (arrow-
head). The juxtaglomerular apparatus is an integral component of
the renin-angiotensin system.

FIGURE 1-4
Electron micrograph of the arterioles. Modified smooth muscle
cells of the arterioles of the juxtaglomerular apparatus produce and
secrete renin. Renin is packaged in characteristic amorphous
mature granules (arrow) derived from smaller rhomboid-shaped
immature protogranules (arrowhead).
1.4 Glomerulonephritis and Vasculitis

FP

A B
FIGURE 1-5 (see Color Plate)
Microscopic view of the glomeruli. Glomeruli are spherical mesangial cells (A, arrow) and the matrix (B, arrow). The free
“bags” of capillaries emanating from afferent arterioles and con- wall of glomerular capillaries, across which filtration takes place,
fined within the urinary space, which is continuous with the consists of a basement membrane (arrowheads) covered by viscer-
proximal tubule. The capillaries are partially attached to the al epithelial cells with individual foot processes (FP) and lined by
mesangium, a continuation of the arteriolar wall consisting of endothelial cells.

FIGURE 1-6
Schematic illustration of a glomerulus and adjacent hilar structure.
Note the relationship of mesangial cells to the juxtaglomerular
apparatus and distal tubule (macula densa). Red—mesangial cells;
blue—mesangial matrix; black—basement membrane; green—vis-
ceral and parietal epithelial cells; yellow—endothelial cells. (From
Churg and coworkers [1]; with permission.)

FIGURE 1-7
Electron photomicrograph illustrating a portion of the ultra-
structure of the glomerular capillary wall. The normal width of
the lamina rara externa (LRE) plus the lamina densa (LD) plus
the lamina rara interna (LRI) equals about 250 to 300 nm. The
spaces between the foot processes (FP), having diameters of 20
to 60 nm, are called filtration slit pores. It is believed they are
the path by which filtered fluid reaches the urinary space (U).
The endothelial cells on the luminal aspect of the basement
membrane (BM) are fenestrated, having diameters from 70 to
100 nm (see Fig. 1-9). The BM (LRE plus LD plus LRI) is com-
posed of Type IV collagen and negativity charged proteoglycans
(heparan sulfate). L—lumen. (From Churg and coworkers [1];
with permission.)
 Normal Vascular and Glomerular Anatomy 1.5

FIGURE 1-8
Scanning electron microscopy of the glomerulus. The surface
anatomy of the interdigitating foot processes of normal visceral
epithelial cells (podocytes) is demonstrated. These cells and their
processes cover the capillary, and ultrafiltration occurs between
the fine branches of the cells. (From Churg and coworkers [1];
with permission.)

FIGURE 1-9
Scanning electron microscopy of the glomerulus. The surface
anatomy of endothelial cells of a normal glomerulus is demonstrat-
ed. Note the fenestrated appearance. (From Churg and coworkers
[1]; with permission.)

Reference
1. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and
Atlas of Glomerular Diseases, edn 2. New York: Igaku-Shoin; 1995.
The Primary
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock

T
he primary glomerulopathies are those disorders that affect
glomerular structure, function, or both in the absence of a mul-
tisystem disorder. The clinical manifestations are predominate-
ly the consequence of the glomerular lesion (such as proteinuria,
hematuria, and reduced glomerular filtration rate). The combination
of clinical manifestations leads to a variety of clinical syndromes.
These syndromes include acute glomerulomphritis; rapidly progres-
sive glomerulonephritis; chronic renal failure; the nephrotic syndrome
or “asymptomatic” hematuria, proteinuria, or both.

CHAPTER

2
2.2 Glomerulonephritis and Vasculitis

FIGURE 2-1
CLINICAL SYNDROMES OF GLOMERULAR DISEASE Each of these syndromes arises as a consequence of disturbances of
glomerular structure and function. Acute glomerulonephritis consists
of the abrupt onset of hematuria, proteinuria, edema, and hyperten-
Acute glomerulonephritis sion. Rapidly progressive glomerulonephritis is characterized by
Rapidly progressive glomerulonephritis
features of nephritis and progressive renal insufficiency. Chronic
glomerulonephritis features proteinuria and hematuria with indolent
Chronic glomerulonephritis
progressive renal failure. Nephrotic syndrome consists of massive
Nephrotic syndrome
proteinuria (>3.5 g/d in adults), hypoalbuminemia with edema,
“Asymptomatic” hematuria, proteinuria, or both
lipiduria, and hyperlipidemia. “Asymptomatic” hematuria, protein-
uria, or both is not associated initially with renal failure or edema.
Each of these syndromes may be complicated by hypertension.

FIGURE 2-2
% % %
100 Others
Age-associated prevalence of various
5 glomerular lesions in nephrotic syndrome.
4 Lupus 10.8 This schematic illustrates the age-associat-
2 90 Amyloid
5 5.9
ed prevalence of various diseases and
1 Diabetes 1.6 glomerular lesions among children and
7 80 adults undergoing renal biopsy for evalua-
Other tion of nephrotic syndrome (Guy’s
16.0
70 proliferative Hospital and the International Study of
25.8 Kidney Disease in Children) [1]. Both the
60 MCGN 9.8 systemic and primary causes of nephrotic
syndrome are included. (Diabetes mellitus
50 with nephropathy is underrepresented
because renal biopsy is seldom needed for
Membranous 19.7
76 40
diagnosis.) The bar on the left summarizes
the prevalence of various lesions in chil-
dren aged 0 to 16 years; the bar on the
30 11.8
FSGS
right summarizes the prevalence of vari-
ous lesions in adults aged 16 to 80 years.
20 Note the high prevalence of minimal
change disease in children and the increas-
10 Minimal 22 ing prevalence of membranous glomeru-
changes
lonephritis in the age group of 16 to 60
0 years. FSGS—focal segmental glomeru-
All 5 10 15 20 30 40 50 60 70 80 All osclerosis; MCGN—mesangiocapillary
children Age at onset of NS adults glomerulonephritis. (From Cameron [1];
with permission.)

FIGURE 2-3
PRIMARY GLOMERULAR LESIONS The primary glomerular lesions.

Minimal change disease

Focal segmental glomerulosclerosis with hyalinosis
Membranous glomerulonephritis
Membranoproliferative glomerulonephritis
Mesangial proliferative glomerulonephritis
Crescentic glomerulonephritis
Immunoglobulin A nephropathy
Fibrillary and immunotactoid glomerulonephritis
Collagenofibrotic glomerulopathy
Lipoprotein glomerulopathy
 The Primary Glomerulopathies 2.3

Minimal Change Disease

A B
FIGURE 2-4
Light and electron microscopy in minimal change disease (lipoid Minimal change disease is considered to be the result of glomerular
nephrosis). A, This glomerulopathy, one of many associated with capillary wall damage by lymphokines produced by abnormal T
nephrotic syndrome, has a normal appearance on light microscopy. cells. This glomerulopathy is the most common cause of nephrotic
No evidence of antibody (immune) deposits is seen on immunoflu- syndrome in children (>70%) and also accounts for approximately
orescence. B, Effacement (loss) of foot processes of visceral epithe- 20% of adult patients with nephrotic syndrome. This glomerulopa-
lial cells is observed on electron microscopy. This last feature is the thy typically is a corticosteroid-responsive lesion, and usually has a
major morphologic lesion indicative of massive proteinuria. benign outcome with respect to renal failure.

100
100 12 weeks
8 weeks
Complete remission, cumulative %

80
Cumulative percentage sustained

80
60
remission

60
40
ISKDC children
Prednisone + Cyclophosphamide (11) 40
20
Prednisone (75)
Cyclophosphamide (25)
0 20
0 2 4 8 16 28 0 200 400 600
Weeks from starting treatment Days

FIGURE 2-5 FIGURE 2-6

Therapeutic response in minimal change disease. This graph Cyclophosphamide in minimal change disease. One of several
illustrates the cumulative complete response rate (absence of controlled trials of cyclophosphamide therapy in pediatric patients
abnormal proteinuria) in patients of varying ages in relation to that pursued a relapsing steroid-dependent course is illustrated.
type and duration of therapy [1]. Note that most children with Note the relative freedom from relapse when children were given
minimal change disease respond to treatment within 8 weeks. a 12-week course of oral cyclophosphamide. An 8-week course
Adults require prolonged therapy to reach equivalent response of chlorambucil (0.15–0.2 mg/kg/d) may be equally effective.
rates. Number of patients are indicated in parentheses. (From (From Arbeitsgemeinschaft für pediatrische nephrologie [3];
Cameron [2]; with permission.) with permission.)
2.4 Glomerulonephritis and Vasculitis

FIGURE 2-7
100
Cyclosporine Cyclosporine in minimal change disease. One of several controlled
Cyclophosphamide trials of cyclosporine therapy in this disease is illustrated. Note the
80 relapses that occur after discontinuing cyclosporine therapy (arrow).
Cyclophosphamide was given for 2 months, and cyclosporine for 9
Overall probability

months. Probability—actuarial probability of remaining relapse-free.

60 (From Ponticelli and coworkers [4]; with permission.)

40

20

0
0 90 180 270 360 450 540 630 720
Time, d
Number of patients
Cyclosporine 36 36 36 31
Cyclophosphamide 30 29 28 26

Focal Segmental Glomerulosclerosis

A B
FIGURE 2-8
Light and immunofluorescent microscopy in focal segmental in the deep cortex, is affected. The abnormal glomeruli exhibit
glomerulosclerosis (FSGS). Patients with FSGS exhibit massive segmental obliteration of capillaries by increased extracellular
proteinuria (usually nonselective), hypertension, hematuria, and matrix–basement membrane material, collapsed capillary walls,
renal functional impairment. Patients with nephrotic syndrome or large insudative lesions. These lesions are called hyalinosis
often are not responsive to corticosteroid therapy. Progression to (arrow) and are composed of immunoglobulin M and comple-
chronic renal failure occurs over many years, although in some ment C3 (B, IgM immunofluorescence). The other glomeruli
patients renal failure may occur in only a few years. A, This usually are enlarged but may be of normal size. In some patients,
glomerulopathy is defined primarily by its appearance on light mesangial hypercellularity may be a feature. Focal tubular
microscopy. Only a portion of the glomerular population, initially atrophy with interstitial fibrosis invariably is present.
 The Primary Glomerulopathies 2.5

FIGURE 2-9
Electron microscopy of focal segmental glomerulosclerosis. The elec-
tron microscopic findings in the involved glomeruli mirror the light
microscopic features, with capillary obliteration by dense hyaline
“deposits” (arrow) and lipids. The other glomeruli exhibit primarily
foot process effacement, occasionally in a patchy distribution.

CLASSIFICATION OF FOCAL SEGMENTAL CLASSIFICATION OF MEMBRANOUS

GLOMERULOSCLEROSIS WITH HYALINOSIS GLOMERULONEPHRITIS

Primary (Idiopathic) Primary (Idiopathic)

Classic Secondary
Tip lesion Neoplasia (carcinoma, lymphoma)
Collapsing Autoimmune disease (systemic lupus erythematosus thyroiditis)
Secondary Infectious diseases (hepatitis B, hepatitis C, schistosomiasis)
Human immunodeficiency virus–associated Drugs (gold, mercury, nonsteroidal anti-inflammatory drugs, probenecid, captopril)
Heroin abuse Other causes (kidney transplantation, sickle cell disease, sarcoidosis)
Vesicoureteric reflux nephropathy
Oligonephronia (congenital absence or hypoplasia of one kidney)
Obesity
FIGURE 2-11
Analgesic nephropathy
Hypertensive nephrosclerosis
Most adult patients (75%) have primary or idiopathic disease. Most
children have some underlying disease, especially viral infection. It
Sickle cell disease
is not uncommon for adults over the age of 60 years to have an
Transplantation rejection (chronic)
underlying carcinoma (especially lung, colon, stomach, or breast).
Vasculitis (scarring)
Immunoglobulin A nephropathy (scarring)

FIGURE 2-10
Note that a variety of disease processes can lead to the lesion of
focal segmental glomerulosclerosis. Some of these are the result of
infections, whereas others are due to loss of nephron population.
Focal sclerosis may also complicate other primary glomerular dis-
eases (eg, Immunoglobulin A nephropathy).
2.6 Glomerulonephritis and Vasculitis

A B
FIGURE 2-12
Histologic variations of focal segmental glomerulosclerosis (FSGS). tubule. Some investigators have described a more favorable
Two important variants of FSGS exist. In contrast to the histologic response to steroids and a more benign clinical course.
appearance of the involved glomeruli, with the sclerotic segment in The other variant, known as collapsing glomerulopathy, most
any location in the glomerulus, the glomerular tip lesion (A) is likely represents a virulent form of FSGS. In this form of FSGS,
characterized by segmental sclerosis at an early stage of evolution, most visceral epithelial cells are enlarged and coarsely vacuolated
at the tubular pole (tip) of all affected glomeruli (arrow). and most capillary walls are wrinkled or collapsed (B). These
Capillaries contain monocytes with abundant cytoplasmic lipids features indicate a severe lesion, with a corresponding rapidly pro-
(foam cells), and the overlying visceral epithelial cells are enlarged gressing clinical course of the disease. Integral and concomitant acute
and adherent to cells of the most proximal portion of the proximal abnormalities of tubular epithelia and interstitial edema occur.

100 100
<15 y (138) 90
80 80 Without nephrotic
syndrome
Survival, %

15–59 y (68) 70
60
Survival, %

60
<15 y (62)
40 >60 y (20) 50
>15 y (60) 40
20 Minimal change disease
30
FSGS With nephrotic
0 20
syndrome
0 5 10 15 20 10
Years from onset 0
0 5 10 15 20
Years from onset
FIGURE 2-13
Evolution of focal segmental glomerulosclerosis (FSGS). This graph
compares the renal functional survival rate of patients with FSGS FIGURE 2-14
to that seen in patients with minimal change disease (in adults and The outcome of focal segmental glomerulosclerosis according to the
children). Note the poor prognosis, with about a 50% rate of renal degree of proteinuria at presentation is shown. Note the favorable
survival at 10 years. (From Cameron [2]; with permission.) prognosis in the absence of nephrotic syndrome. Spontaneous or
therapeutically induced remissions have a similar beneficial effect on
long-term outcome. (From Ponticelli, et al. [5]; with permission.)
 The Primary Glomerulopathies 2.7

Membranous Glomerulonephritis

A B

C D
antigen(s) of the immune complexes are unknown. In the remain-
der, membranous glomerulonephritis is associated with well-
defined diseases that often have an immunologic basis (eg, systemic
lupus erythematosus and hepatitis B or C virus infection); some
solid malignancies (especially carcinomas); or drug therapy, such as
gold, penicillamine, captopril, and some nonsteroidal anti-inflam-
matory reagents. Treatment is controversial.
The changes by light and electron microscopy mirror one anoth-
er quite well and represent morphologic progression that is likely
dependent on duration of the disease. A, At all stages immuno-
fluorescence discloses the presence of uniform granular capillary
wall deposits of immunoglobulin G and complement C3. B, In the
early stage the deposits are small and without other capillary wall
changes; hence, on light microscopy, glomeruli often are normal in
appearance. C, On electron microscopy, small electron-dense
E deposits (arrows) are observed in the subepithelial aspects of capillary
walls. D, In the intermediate stage the deposits are partially encircled
FIGURE 2-15 (see Color Plate) by basement membrane material. E, When viewed with periodic
Light, immunofluorescent, and electron microscopy in membra- acid-methenamine stained sections, this abnormality appears as
nous glomerulonephritis. Membranous glomerulonephritis is an spikes of basement membrane perpendicular to the basement
immune complex–mediated glomerulonephritis, with the immune membrane, with adjacent nonstaining deposits. Similar features
deposits localized to subepithelial aspects of almost all glomerular are evident on electron microscopy, with dense deposits and inter-
capillary walls. Membranous glomerulonephritis is the most com- vening basement membrane (D). Late in the disease the deposits
mon cause of nephrotic syndrome in adults in developed countries. are completely surrounded by basement membranes and are under-
In most instances (75%), the disease is idiopathic and the going resorption.
2.8 Glomerulonephritis and Vasculitis

FIGURE 2-16
Evolution of deposits in membranous glomerulonephritis. This
schematic illustrates the sequence of immune deposits in red; base-
ment membrane (BM) alterations in blue; and visceral epithelial cell
changes in yellow. Small subepithelial deposits in membranous
glomerulonephritis (predominately immunoglobulin G) initially
form (A) then coalesce. BM expansion results first in spikes (B) and
later in domes (C) that are associated with foot process effacement,
as shown in gray. In later stages the deposits begin to resorb (dotted
and crosshatched areas) and are accompanied by thickening of the
capillary wall (D). (From Churg, et al. [6]; with permission.)

A B

C D

FIGURE 2-17
100
Natural history of membranous glomerulonephritis. This schematic illustrates the clinical
Dead/ESRD
80 evolution of idiopathic membranous glomerulonephritis over time. Almost half of all patients
Nephrotic syndrome
60 undergo spontaneous or therapy-related remissions of proteinuria. Another group of patients
(25–40%), however, eventually develop chronic renal failure, usually in association with per-
%

Proteinuria
40 sistent proteinuria in the nephrotic range. (From Cameron [2]; with permission.)
20 Remission

0
0 5 10 15
Years of known disease
 The Primary Glomerulopathies 2.9

Membranoproliferative Glomerulonephritis

A B
at all common. The first, known as membranoproliferative
(mesangiocapillary) glomerulonephritis type I, is a primary
glomerulopathy most common in children and adolescents. The
1
same pattern of injury may be observed during the course of many
2 diseases with chronic antigenemic states; these include systemic
3 lupus erythematosus and hepatitis C virus and other infections. In
membranoproliferative glomerulonephritis type I, the glomeruli
4 are enlarged and have increased mesangial cellularity and variably
increased matrix, resulting in lobular architecture. The capillary
5 walls often are thickened with double contours, an abnormality
6 resulting from peripheral migration and interposition of
mesangium (A). Immunofluorescence discloses granular to conflu-
ent granular deposits of C3 (B), immunoglobulin G, and
immunoglobulin M in the peripheral capillary walls and mesangial
regions. The characteristic finding on electron microscopy is in the
C capillary walls. C, Between the basement membrane and endothe-
lial cells are, in order inwardly: (1) epithelial cell, (2) basement
FIGURE 2-18 (see Color Plate) membrane, (3) electron-dense deposits, (4) mesangial cell cyto-
Light, immunofluorescence, and electron microscopy in membra- plasm, (5) mesangial matrix, and (6) endothelial cell. Electron-
noproliferative glomerulonephritis type I. In these types of dense deposits also are in the central mesangial regions.
immune complex–mediated glomerulonephritis, patients often Subepithelial deposits may be present, albeit typically in small
exhibit nephrotic syndrome accompanied by hematuria and numbers. The electron-dense deposits may contain an organized
depressed levels of serum complement C3. The morphology is var- (fibrillar) substructure, especially in association with hepatitis C
ied, with at least three pathologic subtypes, only two of which are virus infection and cryoglobulemia.
2.10 Glomerulonephritis and Vasculitis

A A
B
known as dense deposit disease, the glomeruli may be lobular
or may manifest only mild widening of mesangium. A, The capil-
lary walls are thickened, and the basement membranes are
stained intensely positive periodic acid–Schiff reaction, with a
refractile appearance. B, On immunofluorescence, complement
C3 is seen in all glomerular capillary basement membranes in
a coarse linear pattern. With the use of thin sections, it can be
appreciated that the linear deposits actually consist of two thin
parallel lines. Round granular deposits are in the mesangium.
Coarse linear deposits also are in Bowman’s capsule and the
tubular basement membranes. C, Ultrastructurally, the glomeru-
lar capillary basement membranes are thickened and darkly
stained; there may be segmental or extensive involvement of
the basement membrane. Similar findings are seen in Bowman’s
capsule and tubular basement membranes; however, in the latter,
C the dense staining is usually on the interstitial aspect of that
structure. Patients with dense deposit disease frequently show
FIGURE 2-19 (see Color Plate) isolated C3 depression and may have concomitant lipodystrophy.
Light, immunofluorescence, and electron microscopy in membra- These patients also have autoantibodies to the C3 convertase
noproliferative glomerulonephritis type II. In this disease, also enzyme C3Nef.
 The Primary Glomerulopathies 2.11

SERUM COMPLEMENT CONCENTRATIONS IN GLOMERULAR LESIONS

Serum Concentration
Lesion C3 C4 C’H50 Other
Minimal change disease Normal Normal Normal –
Focal sclerosis Normal Normal Normal –
Membranous glomerulonephritis (idiopathic) Normal Normal Normal –
Immunoglobulin A nephropathy Normal Normal Normal –
Membranoproliferative glomerulonephritis:
Type I Moderate decrease Mild decrease Mild decrease –
Type II Severe decrease Normal Mild decrease C3 nephritic factor+
Acute poststreptococcal glomerulonephritis Moderate decrease Normal Mild decrease Antistreptolysin 0 titer increased
Lupus nephritis:
(World Health Organization Class IV) Moderate to severe Moderate to severe Mild decrease anti–double-stranded DNA antibody+
decrease decrease
(World Health Organization Class V) Normal or mild decrease Normal or mild decrease Normal or mild decrease anti–double-stranded DNA antibody+
Cryoglobulinemia (hepatitis C) Normal or mild decrease Severe decrease Moderate decrease Cryoglobulins; hepatitis C ab
Amyloid Normal Normal Normal –
Vasculitis Normal or increased Normal or increased Normal Antineutrophil cytoplasmic antibody+

C’H50—serum hemolytic complement activity.

FIGURE 2-20
The serum complement component concentration (C3 and C4) and and secondary glomerular lesions are depicted. Note the limited
serum hemolytic complement activity (C’H50) in various primary number of disorders associated with a low C3 or C4 level.

FIGURE 2-21
CLASSIFICATION OF MEMBRANOPROLIFERATIVE Note that although there is the wide variety of underlying causes for
GLOMERULONEPHRITIS TYPE I the lesion of membranoproliferative glomerulonephritis hepatitis C,
with or without cryoglobulinemia, accounts for most cases.

Primary (Idiopathic)
Secondary
Hepatitis C (with or without cryoglobulinemia)
Hepatitis B
Systemic lupus erythematosus
Light or heavy chain nephropathy
Sickle cell disease
Sjögren’s syndrome
Sarcoidosis
Shunt nephritis
Antitrypsin deficiency
Quartan malaria
Chronic thrombotic microangiopathy
Buckley’s syndrome
2.12 Glomerulonephritis and Vasculitis

Mesangial Proliferative Glomerulonephritis

A B
mesangial regions. Little if any increased cellularity is seen, despite
the presence of deposits. In this latter instance, the term mesangial
injury glomerulonephritis is more properly applied. The disorders
are defined on the basis of the immunofluorescence findings, rather
than on the presence or absence of mesangial hypercellularity. There
are numerous disorders with this appearance; some have specific
immunopathologic or clinical features (such as immunoglobulin A
nephropathy, Henoch-Schonlein purpura, and systemic lupus erythe-
matosus). Patients with primary mesangial proliferative glomeru-
lonephritis typically exhibit the disorder in one of four ways:
asymptomatic proteinuria, massive proteinuria often in the nephrot-
ic range, microscopic hematuria, or proteinuria with hematuria. A,
On light microscopy, widening of the mesangial regions is observed,
often with diffuse increase in mesangial cellularity commonly of a
mild degree. No other alterations are present. B, Depending on the
specific entity or lesion, the immunofluorescence is of granular
C mesangial deposits. In the most common of these disorders,
immunoglobulin M is the dominant or sole deposit. Other disorders
FIGURE 2-22 (see Color Plate) are characterized primarily or exclusively by complement C3,
Light, immunofluorescence, and electron microscopy in mesangial immunoglobulin G, or C1q deposits. C, On electron microscopy the
proliferative glomerulonephritis. This heterogeneous group of disor- major finding is of small electron-dense deposits in the mesangial
ders is characterized by increased mesangial cellularity in most of regions (arrow). Foot process effacement is variable, depending on
the glomeruli associated with granular immune deposits in the the clinical syndrome (eg, whether massive proteinuria is present).
 The Primary Glomerulopathies 2.13

Crescentic Glomerulonephritis

A B

C D
FIGURE 2-23 (see Color Plate)
Crescentic glomerulonephritis. A crescent is the accumulation of trophil cytoplasmic antibodies (ANCAs). The clinical manifestations
cells and extracellular material in the urinary space of a glomerulus. are typically of rapidly progressive glomerulonephritis with moder-
The cells are parietal and visceral epithelia as well as monocytes and ate proteinuria, hematuria, oliguria, and uremia. The immunomor-
other blood cells. The extracellular material is fibrin, collagen, and phologic features depend on the basic disease process. On light
basement membrane material. In the early stages of the disease, the microscopy in both AGBM antibody–induced disease and
crescents consist of cells and fibrin. In the later stages the crescents ANCA–associated crescentic glomerulonephritis, the glomeruli with-
undergo organization, with disappearance of fibrin and replacement out crescents often have a normal appearance. It is the remaining
by collagen. Crescents represent morphologic consequences of glomeruli that are involved with crescents. D, Anti-GBM disease is
severe capillary wall damage. A, In most instances, small or large characterized by linear deposits of immunoglobulin G and often
areas of destruction of capillary walls (cells and basement mem- complement C3 in all capillary basement membranes, and in
branes) are observed (arrow), thereby allowing fibrin, other high approximately two thirds of affected patients in tubular basement
molecular weight substances, and blood cells to pass readily from membranes. The ANCA-associated lesion typically has little or no
capillary lumina into the urinary space. B, Immunofluorescence fre- immune deposits on immunofluorescence; hence the term pauci-
quently discloses fibrin in the urinary space. C, The proliferating immune crescentic glomerulonephritis is used. By electron
cells in Bowman’s space ultimately give rise to the typical crescent microscopy, as on light microscopy, defects in capillary wall conti-
shape. Whereas crescents may complicate many forms of glomeru- nuity are easily identified. Both AGBM- and ANCA-associated cres-
lonephritis, they are most commonly associated with either centic glomerulonephritis can be complicated by pulmonary hemor-
antiglomerular basement membrane (AGBM) antibodies or antineu- rhage (see Fig. 2-25).
2.14 Glomerulonephritis and Vasculitis

CLASSIFICATION OF CRESCENTIC GLOMERULONEPHRITIS

Type Serologic Pattern Primary Secondary

I Anti-GBM+ ANCA- Anti-GBM antibody–mediated crescentic glomerular nephritis Goodpasture’s disease
II Anti-GBM- ANCA- Idiopathic crescentic glomerular nephritis (with or without immune Systemic lupus erythematosus, immunoglobulin A, MPGN
complex deposits) cryoimmunoglobulin (with immune complex deposits
III Anti-GBM- ANCA+ Pauci-immune crescentic glomerular nephritis (microscopic polyangiitis) Drug-induced crescentic glomerulonephritis
IV Anti-GBM+ANCA+ Anti-GBM antibody–mediated crescentic glomerular nephritis with ANCA Goodpasture’s syndrome with ANCA

ANCA—antineutrophil cytoplasmic antibody; anti-GBM—glomerular basement membrane antibody;

MPGN— membranoproliferative glomerulonephritis.

FIGURE 2-24
Note that the serologic findings allow for a differentiation of the various forms of
primary and secondary (eg, multisystem disease) forms of crescentic glomerulonephritis.

FIGURE 2-25
Chest radiograph of alveolar hemorrhage. This patient has antiglomerular basement mem-
brane–mediated glomerulonephritis complicated by pulmonary hemorrhage (Goodpasture’s
disease). Note the butterfly appearance of the alveolar infiltrates characteristic of intrapul-
monary (alveolar) hemorrhage. Such lesions can also occur in patients with antineutrophil
cytoplasmic autoantibody–associated vasculitis and glomerulonephritis, lupus nephritis
(SLE), cryoglobulinemia, and rarely in Henoch-Schonlein purpura (HSP).
 The Primary Glomerulopathies 2.15

FIGURE 2-26
↑ Serum creatinine Evaluation of rapidly progressive glomeru-
Proteinuria lonephritis. This algorithm schematically
"Nephritic" sediment
illustrates a diagnostic approach to the
various causes of rapidly progressive
Renal ultrasonography glomerulonephritis (Figure 2-24), Serologic
studies, especially measurement of circulat-
ing antiglomerular basement membrane
Normal or enlarged antibodies, antineutrophil cytoplasmic
Small kidneys Obstruction
kidneys; no obstruction antibodies, antinuclear antibodies, and
serum complement component concentra-
tions, are used for diagnosis. Serologic
Serology*
patterns (A through D)permit categoriza-
tion of probable disease entities.
Pattern type (A) (B) (C) (D)
aGBMA* + – – +
ANCA† – – + +
Goodpasture's disease Type II IC-mediated Microscopic Combined
Type I primary CrGN CGN SLE, HSP, and polyangiitis; type III form; type IV
MPGN CryoIg, type V primary crescentic primary CrGN
primary CrGN CrGN; Wegener's GN;
(idiopathic) drug-induced CrGN

*Antiglomerular basement membrane autoantibody by radioimmunoassay or enzyme-linked

immunosorbent assay
†Antineutrophil cytoplasmic autoantibody by indirect immunofluorescence, confirmed by antigen-specific
assay (anti-MPO, anti-PR3, or both).

FIGURE 2-27 (see Color Plate)

C-ANCA P-ANCA Antineutrophil cytoplasmic autoantibodies
(ANCA). Frequently, ANCA are found in
crescentic glomerulonephritis, particularly
type III (Figure 2-24). Two varieties are
seen (on alcohol-fixed slides). A, C-ANCA
are due to antibodies reacting with cyto-
plasmic granule antigens (mainly pro-
teinase-3). B, P-ANCA are due to antibod-
ies reacting with other antigens (mainly
myeloperoxidase).

A B
2.16 Glomerulonephritis and Vasculitis

Immunoglobulin A Nephropathy

A B

C D
FIGURE 2-28 (see Color Plate)
Light, immunofluorescence, and electron microscopy in immuno- to the term focal proliferative glomerulonephritis. In advanced
globulin A (IgA) nephropathy. IgA nephropathy is a chronic cases, segmental sclerosis often is present and associated with mas-
glomerular disease in which IgA is the dominant or sole component sive proteinuria. During acute episodes, crescents may be present.
of deposits that localize in the mesangial regions of all glomeruli. B, Large round paramesangial fuchsinophilic deposits often are
In severe or acute cases, these deposits also are observed in the identified with Masson’s trichrome or other similar stains (arrows).
capillary walls. This disorder may have a variety of clinical presenta- C, Immunofluorescence defines the disease; granular mesangial
tions. Typically, the presenting features are recurrent macroscopic deposits of IgA are seen with associated complement C3, and IgG
hematuria, often coincident with or immediately after an upper respi- or IgM, or both. IgG and IgM often are seen in lesser degrees of
ratory infection, along with persistent microscopic hematuria and intensity than is IgA. D, On electron microscopy the abnormalities
low-grade proteinuria between episodes of gross hematuria. typically are those of large rounded electron-dense deposits
Approximately 20% to 25% of patients develop end-stage renal (arrows) in paramesangial zones of most if not all lobules.
disease over the 20 years after onset. A, On light microscopy, Capillary wall deposits (subepithelial, subendothelial, or both) may
widening and often an increase in cellularity in the mesangial be present, especially in association with acute episodes. In addi-
regions are observed, a process that affects the lobules of some tion, capillary basement membranes may show segmental thinning
glomeruli to a greater degree than others. This feature gives rise and rarefaction.
 The Primary Glomerulopathies 2.17

FIGURE 2-29
Natural history of immunoglobulin A (IgA) nephropathy. The evolution of IgA nephropa-
thy over time with respect to the occurrence of end-stage renal failure (ESRF) is illustrated.
The percentage of renal survival (freedom from ESRF) is plotted versus the time in years
from the apparent onset of the disease. Note that on average about 1.5% of patients enter
ESRF each year over the first 20 years of this nephropathy. Factors indicating an unfavor-
able outcome include elevated serum creatinine, tubulointerstitial lesions or glomeruloscle-
rosis, and moderate proteinuria (>1.0 g/d). (Modified from Cameron [2].)

Fibrillary and Immunotactoid Glomerulonephritis

A B
entity in which abnormal extracellular fibrils, typically ranging
from 10- to 20-nm thick, permeate the glomerular mesangial
matrix and capillary basement membranes. The fibrils are defined
only on electron microscopy and have an appearance, at first
glance, similar to amyloid. Congo red stain, however, is negative.
Patients with fibrillary glomerulonephritis usually exhibit protein-
uria often in the nephrotic range, with variable hematuria, hyper-
tension, and renal insufficiency. A, On light microscopy the
glomeruli display widened mesangial regions, with variable
increase in cellularity and thickened capillary walls and often with
irregularly thickened basement membranes, double contours, or
both. B, On immunofluorescence, there is coarse linear or conflu-
ent granular staining of capillary walls for immunoglobulin G and
complement C3 and similar staining in the mesangial regions.
Occasionally, monoclonal immunoglobulin G k deposits are identi-
fied; in most instances, however, both light chains are equally rep-
C resented. The nature of the deposits is unknown. C, On electron
microscopy the fibrils are roughly 20-nm thick, of indefinite length,
FIGURE 2-30 (see Color Plate) and haphazardly arranged. The fibrils permeate the mesangial
Light, immunofluorescent, and electron microscopy in nonamyloid matrix and basement membranes (arrow). The fibrils have been
fibrillary glomerulonephritis. Fibrillary glomerulonephritis is an infrequently described in organs other than the kidneys.
2.18 Glomerulonephritis and Vasculitis

A B
FIGURE 2-31 (see Color Plate)
Light, immunofluorescent, and electron microscopy in immunotac-
toid glomerulopathy. Immunotactoid glomerulopathy appears to be
an immune-mediated glomerulonephritis. On electron microscopy
the deposits are composed of multiple microtubular structures in
subepithelial or subendothelial locations, or both, with lesser
involvement of the mesangium. Patients with this disorder typically
exhibit massive proteinuria or nephrotic syndrome. This glomeru-
lopathy frequently is associated with lymphoplasmacytic disorders.
A, On light microscopy the glomerular capillary walls often are
thickened and the mesangial regions widened, with increased cellu-
larity. B, On immunofluorescence, granular capillary wall and
mesangial immunoglobulin G and complement C3 deposits are pre-
sent. The ultrastructural findings are of aggregates of microtubular
structures in capillary wall locations corresponding to granular
deposits by immunofluorescence. C, The microtubular structures
C are large, ranging from 30- to 50-nm thick, or more (arrows).
 The Primary Glomerulopathies 2.19

Collagenofibrotic Glomerulopathy

A B
FIGURE 2-32 (see Color Plate)
Collagenofibrotic glomerulopathy (collagen III glomerulopathy). exhibit proteinuria and mild progressive renal insufficiency.
The collagens normally found in glomerular basement mem- For reasons that are not clear, hemolytic-uremic syndrome has
branes and the mesangial matrix are of types IV (which is domi- evolved in a small number of pediatric patients. A, On light
nant) and V. In collagenofibrotic glomerulopathy, accumulation microscopy the capillary walls are thickened and mesangial
of type III collagen occurs largely in capillary walls in a suben- regions widened by pale staining material. These features are in
dothelial location. It is likely that this disease is hereditary; how- sharp contrast to the normal staining of the capillary basement
ever, because it is very rare, precise information regarding trans- membranes, as evidenced by the positive period acid–Schiff reac-
mission is not known. Collagenofibrotic glomerulopathy origi- tion. With this stain, collagen type III is not stained and there-
nally was thought to be a variant of nail-patella syndrome. fore is much paler. Amyloid stains (Congo red) are negative.
Current evidence suggests little relationship exists between the B, On electron microscopy, banded collagen fibrils are evident
two disorders. Patients with collagen III glomerulopathy often in the subendothelial aspect of the capillary wall.

References
1. Cameron JS, Glassock RJ: The natural history and outcome of the 4. Ponticelli C: Cyclosporine versus cyclophosphamide for patients with
nephrotic syndrome. In The Nephrotic Syndrome. Edited by Cameron steroid-dependent and frequently relapsing idiopathic nephrotic syn-
JS and Glassock RJ. New York: Marcel Dekker, 1987. drome. A multi-center randomized trial. Nephrol Dial Transplant
2. Cameron JS: The long-term outcome of glomerular diseases. In 1993, 8:1326–1332.
Diseases of the Kidney Vol II, edn 6. Edited by Schrier RW, 5. Ponticelli C, Glassock RJ: Treatment of Segmental Glomerulonephritis.
Gottschalk CW. Boston: Little Brown; 1996. Oxford: Oxford Medical Publishers, 1996:110.
3. Arbeitsgemeinschaft für pediatrische nephrologie. Cyclophosphamide 6. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and
treatment of steroid-dependent nephrotic syndrome: comparison of an Atlas of Glomerular Disease, edn 2. New York: Igaku-Shoin; 1995.
eight-week with a 12-week course. Arch Dis Child 1987, 62:1102–1106.
Heredofamilial
and Congenital
Glomerular Disorders
Arthur H. Cohen
Richard J. Glassock

T
he principal characteristics of some of the more common hered-
ofamilial and congenital glomerular disorders are described and
illustrated. Diabetes mellitus, the most common heredofamilial
glomerular disease, is illustrated in Volume IV, Chapter 1. These disor-
ders are inherited in a variety of patterns (X-linked, autosomal domi-
nant, or autosomal recessive). Many of these disorders appear to be
caused by defective synthesis or assembly of critical glycoprotein
(collagen) components of the glomerular basement membrane.

CHAPTER

3
3.2 Glomerulonephritis and Vasculitis

the eyes. The disease is inherited as an X-linked trait; in some fami-

lies, however, autosomal recessive and perhaps autosomal dominant
forms exist. Clinically, the disease is more severe in males than in
females. End-stage renal disease develops in persons 20 to 40 years
of age. In some families, ocular manifestations, thrombocytopenia
with giant platelets, esophageal leiomyomata, or all of these also
occur. In the X-linked form of Alport’s syndrome, mutations occur in
genes encoding the -5 chain of type IV collagen (COL4A5). In the
autosomal recessive form of this syndrome, mutations of either -3
or -4 chain genes have been described. On light microscopy, in the
early stages of the disease the glomeruli appear normal. With pro-
gression of the disease, however, an increase in the mesangial matrix
and segmental sclerosis develop. Interstitial foam cells are common
but are not used to make a diagnosis. Results of immunofluorescence
typically are negative, except in glomeruli with segmental sclerosis in
which segmental immunoglobulin M and complement (C3) are in
the sclerotic lesions. Ultrastructural findings are diagnostic and con-
sist of profound abnormalities of glomerular basement membranes.
FIGURE 3-1 These abnormalities range from extremely thin and attenuated to
Alport’s syndrome. Alport’s syndrome (hereditary nephritis) is a considerably thickened membranes. The thickened glomerular base-
hereditary disorder in which glomerular and other basement mem- ment membranes have multiple layers of alternating medium and
brane collagen is abnormal. This disorder is characterized clinically pale staining strata of basement membrane material, often with
by hematuria with progressive renal insufficiency and proteinuria. incorporated dense granules. The subepithelial contour of the base-
Many patients have neurosensory hearing loss and abnormalities of ment membrane typically is scalloped.

FIGURE 3-2
NC1 100nm Schematic of basement membrane collagen type IV. The postulated
arrangement of type IV collagen chains in a normal glomerular base-
7S ment membrane is illustrated. The joining of noncollagen (NC-1)
and 75 domains creates a lattice (chicken wire) arrangement (A). In
the glomerular basement membrane, 1 and 2 chains predominate
in the triple helix (B), but 3, 4, 5, and 6 chains are also found (not
A shown). Disruption of synthesis of any of these chains may lead to
anatomic and pathologic alternations, such as those seen in Alport’s
syndrome. Arrows indicate fibrils. (From Abrahamson and coworkers
[1]; with permission.)
-S--S-
α1 -S--S- α1

α2 -S--S- α2
-S--S-
α1 -S--S- α1
B -S--S-

FIGURE 3-3
Neurosensory hearing defect in Alport’s syndrome. In patients with adult onset Alport’s
syndrome, classic X-linked sensorineural hearing defects occur. These defects often begin
20 with an auditory loss of high-frequency tone, as shown in this audiogram. The shaded
Hearing loss, dB

area represents normal ranges. (Modified from Gregory and Atkin [2]; with permission.)
40

60

80

100
500 2K 4K 8K 10K 12K 14K 16K 18K
Frequency
 Heredofamilial and Congenital Glomerular Disorders 3.3

FIGURE 3-4
Thin basement membrane nephropathy. Glomeruli with abnormal-
ly thin basement membranes may be a manifestation of benign
familial hematuria. Glomeruli with thin basement membranes
many also occur in persons who do not have a family history of
renal disease but who have hematuria, low-grade proteinuria, or
both. Although the ultrastructural abnormalities have some simi-
larities in common with the capillary basement membranes of
Alport’s syndrome, these two glomerulopathies are not directly
related. Clinically, persistent microscopic hematuria or occasional
episodic gross hematuria are important features. Nonrenal abnor-
malities are absent. On light microscopy, the glomeruli are normal;
no deposits are seen on immunofluorescence. Here, the electron
microscopic abnormalities are diagnostic; all or virtually all
glomerular basement membranes are markedly thin (<200 nm in
adults) without other features such as splitting, layering, or abnor-
mal subepithelial contours.

A B
of the enzyme -galactosidase with accumulation of sphingolipids in
many cells. In the kidney, accumulation of sphingolipids especially
affects glomerular visceral epithelial cells. Deposition of sphin-
golipids in the vascular tree may lead to premature coronary artery
occlusion (angina or myocardial infarction) or cerebrovascular insuf-
ficiency (stroke). Involvement of nerves leads to painful acropares-
thesias and decreased perspiration (anhidrosis). The most common
renal manifestation is that of proteinuria with progressive renal
insufficiency. On light microscopy, the morphologic abnormalities of
the glomeruli primarily consist of enlargement of visceral epithelial
cells and accumulation of multiple uniform small vacuoles in the
cytoplasm (arrow in Panel A). Ultrastructurally, the inclusions are
those of whorled concentric layers appearing as “zebra bodies” or
myeloid bodies representing sphingolipids (B). These structures also
may be observed in mesangial and endothelial cells and in arterial
C and arteriolar smooth muscle cells and tubular epithelia. At consider-
ably higher magnification, the inclusions are observed to consist of
FIGURE 3-5 (see Color Plate) multiple concentric alternating clear and dark layers, with a periodic-
Fabry’s disease. Fabry’s disease, also known as angiokeratoma cor- ity ranging from 3.9 to 9.8 nm. This fine structural appearance (best
poris diffusum or Anderson-Fabry’s disease, is the result of deficiency appreciated at the arrow) is characteristic of stored glycolipids (C).
3.4 Glomerulonephritis and Vasculitis

FIGURE 3-6
Electron microscopy of nail-patella syndrome. This disorder having
skeletal and renal manifestations affects the glomeruli, with accu-
mulation of banded collagen fibrils within the substance of the cap-
illary basement membrane. This accumulation appears as empty
lacunae when the usual stains with electron microscopy (lead cit-
rate and uranyl acetate) are used. However, as here, the fibrils easi-
ly can be identified with the use of phosphotungstic acid stain in
conjunction with or instead of typical stains. Note that this disor-
der differs structurally from collagen type III glomerulopathy in
which the collagen fibrils are subendothelial and not intramembra-
nous in location. Patients with nail-patella syndrome may develop
proteinuria, sometimes in the nephrotic range, with variable pro-
gression to end-stage renal failure. No distinguishing abnormalities
are seen on light microscopy.

FIGURE 3-7
Radiography of nail-patella syndrome. The
skeletal manifestations of nail-patella syn-
drome are characteristic and consist of
absent patella and absent and dystrophic
nails. These photographs illustrate absent
patella (A) and the characteristic nail
changes (B) that occur in patients with the
disorder. (From Gregory and Atkin [2];
with permission.)

A
 Heredofamilial and Congenital Glomerular Disorders 3.5

A B
FIGURE 3-8 (see Color Plate)
Lecithin-cholesterol acyl transferase deficiency. Lipid accumula- membranes are irregularly thickened. Some capillary lumina may
tion occurs in this hereditary metabolic disorder, especially in contain foam cells. Although quite rare, this autosomal recessive
extracellular sites throughout glomerular basement membranes disease has been described in most parts of the world; however,
and the mesangial matrix. A, On electron microscopy the lipid it occurs most commonly in Norway. Patients exhibit proteinuria,
appears as multiple small lacunae, often with small round dense often with microscopic hematuria usually noted in childhood.
granular or membranous structures (arrows). Lipid-containing Renal insufficiency may develop in the fourth or fifth decade of
monocytes may be in the capillary lumina. B, The mesangial life and may progress rapidly. Nonrenal manifestations include
regions are widened on light microscopy, usually with expansion corneal opacification, hemolytic anemia, early atherosclerosis,
of the matrix that stains less intensely than normal. Basement and sea-blue histocytes in the bone marrow and spleen.

A B
FIGURE 3-9 (see Color Plate)
Lipoprotein glomerulopathy. Patients with this rare disease, which mesangial hypercellularity or mesangiolysis may be present. With
often is sporadic (although some cases occur in the same family), immunostaining for -lipoprotein, apolipoproteins E and B are
exhibit massive proteinuria. Lipid profiles are characterized by identified in the luminal masses. B, Electron microscopic findings
increased plasma levels of cholesterol, triglycerides, and very low indicate the thrombi consist of finely granular material with numer-
density lipoproteins. Most patients have heterozygosity for ous vacuoles (lipoprotein). Lipoprotein glomerulopathy may
apolipoprotein E2/3 or E2/4. A, The glomeruli are the sites of mas- progress to renal insufficiency over a long period of time.
sive intracapillary accumulation of lipoproteins, which appear as Recurrence of the lesions in a transplanted organ has been reported
slightly tan masses (thrombi) dilating capillaries (arrows). Segmental infrequently. Lipid-lowering agents are mostly ineffective.
3.6 Glomerulonephritis and Vasculitis

A B
FIGURE 3-10 (see Color Plate)
Nephropathic cystinosis. In older children and young adults, have occasionally enlarged and multinucleated visceral epithelial cells
compared with young children, patients with cystinosis commonly (arrow). As the disease progresses, segmental sclerosis becomes evident
exhibit glomerular involvement rather than tubulointerstitial disease. as in the photomicrograph. B, Crystalline inclusions are identified on
Proteinuria and renal insufficiency are the typical initial manifestations. electron microscopy. The crystals of cysteine are usually dissolved in
A, As the most constant abnormality on light microscopy, glomeruli processing, leaving an empty space as shown here by the arrows.

A B
FIGURE 3-11 (see Color Plate)
Finnish type of congenital nephrotic syndrome. Several disorders the kidneys is varied. Some glomeruli are small and infantile with-
are responsible for nephrotic syndrome within the first few out other alterations, whereas others are enlarged, more mature,
months to first year of life. The most common and important of and have diffuse mesangial hypercellularity. Because of the mas-
these is known as congenital nephrotic syndrome of Finnish type sive proteinuria, some tubules are microcystically dilated, a find-
because the initial descriptions emphasized the more common ing responsible for the older term for this disorder, microcystic
occurrence in Finnish families. This nephrotic syndrome is an disease. Because this syndrome is primarily a glomerulopathy,
inherited disorder in which infants exhibit massive proteinuria the tubular abnormalities are a secondary process and should
shortly after birth; typically, the placenta is enlarged. This disorder not be used to designate the name of the disease. B, On electron
can be diagnosed in utero; increased -fetoprotein levels in amni- microscopy, complete effacement of the foot processes of visceral
otic fluid is a common feature. A, The microscopic appearance of epithelial cells is observed.
 Heredofamilial and Congenital Glomerular Disorders 3.7

hematuria and progressive renal insufficiency. Currently, no evi-

dence exists that this disorder is an inherited process with genetic
linkage. The glomeruli characteristically are small compact mass-
es of extracellular matrix with numerous or all capillary lumina
being obliterated. As here, the visceral epithelial cells typically are
arranged as a corona or crown overlying the contracted capillary
tufts. Earlier stages of glomerular involvement are characterized
by variable increase in mesangial cellularity. Immunofluorescence
is typically negative for immunoglobulin deposits because this
disorder is not immune mediated. In some patients, diffuse
mesangial sclerosis may be part of the triad of the Drash syn-
drome characterized by ambiguous genitalia, Wilms’ tumor, and
diffuse mesangial sclerosis. In some patients, only two of the
three components may be present; however, some investigators
consider all patients with diffuse mesangial sclerosis to be at risk
for the development of Wilms’ tumor even in the absence of geni-
FIGURE 3-12 tal abnormalities. Thus, close observation or bilateral nephrecto-
Diffuse mesangial sclerosis. This disorder is exhibited within the my as prophylaxis against the development of Wilms’ tumor is
first few months of life with massive proteinuria, often with employed occasionally.

References
1. Abrahamson D, Van der Heurel GB, Clapp WL, et al.: Nephritogenic 2. Gregory M, Atkin C: Alport’s syndrome, Fabry disease and nail-patel-
antigens in the glomerular basement membrane. In Immunologic la syndrome. In Diseases of the Kidney, Vol. I. edn 6. Edited by
Renal Diseases. Edited by Nielson EG, Couser, WG. Philadelphia: Schrier RW, Gottschalk CW. Boston: Little Brown, 1995.
Lippincott-Raven, 1997.
Infection-Associated
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock

M
any glomerular diseases may be associated with acute and
chronic infectious diseases of bacterial, viral, fungal, or
parasitic origin. In many instances, the glomerular activa-
tors are transient and of little clinical consequence. In other
instances, distinct clinical syndromes such as acute nephritis or
nephrotic syndrome may be provoked. Some of the more important
infection-related glomerular diseases are illustrated here. Others dis-
eases, including human immunodeficiency virus and hepatitis, are
also discussed in Volume IV.

CHAPTER

4
4.2 Glomerulonephritis and Vasculitis

A B
streptococcus. Typically, patients with glomerulonephritis exhibit
hematuria, edema, proteinuria, and hypertension. Renal function
frequently is depressed, sometimes severely. Most patients recover
spontaneously, and a few go on to rapidly progressive or chronic
indolent disease. A, On light microscopy the glomeruli are enlarged
and hypercellular, with numerous leukocytes in the capillary lumina
and a variable increase in mesangial cellularity. The leukocytes are
neutrophils and monocytes. The capillary walls are single-con-
toured, and crescents may be present. B, On immunofluorescence,
granular capillary wall and mesangial deposits of immunoglobulin
G and complement C3 are observed (starry-sky pattern). Three pre-
dominant patterns occur depending on the location of the deposits;
these include garlandlike, mesangial, and starry-sky patterns.
C, The ultrastructural findings are those of electron-dense deposits,
characteristically but not solely in the subepithelial aspects of the
capillary walls, in the form of large gumdrop or hump-shaped
C deposits (arrow). However, electron-dense deposits also are found
in the mesangial regions and occasionally subendothelial locations.
FIGURE 4-1 (see Color Plate) Endothelial cells often are swollen, and leukocytes are not only
Light, immunofluorescent, and electron microscopy of poststrepto- found in the capillary lumina but occasionally in direct contact
coccal (postinfectious) glomerulonephritis. Glomerulonephritis may with basement membranes in capillary walls with deposits. Similar
follow in the wake of cutaneous or pharyngeal infection with a lim- findings may be observed in glomerulonephritis after infectious
ited number of “nephritogenic” serotypes of group A -hemolytic diseases other than certain strains of Streptococci.
 Infection-Associated Glomerulopathies 4.3

FIGURE 4-2
Infective endocarditis and shunt nephritis. The glomerulonephritis
accompanying infective endocarditis or infected ventriculoatrial
shunts or other indwelling devices is that of a postinfectious
glomerulonephritis or membranoproliferative glomerulonephritis
type I pattern, or both (see Fig. 2-18). In reality, the changes often
are a combination of both. As shown here, this glomerulopathy is
characterized by increased mesangial cellularity, with slight lobular
architecture; occasionally thickened capillary walls, with double
contours (arrow); and leukocytes in some capillary lumina. This
glomerulus also has a small crescent.

A B
(focal segmental) glomerulosclerosis with significant tubular and
interstitial abnormalities. A, In HIVAN, many visceral epithelial
cells are enlarged, coarsely vacuolated, contain protein reabsorp-
tion droplets, and overlay capillaries with varying degrees of wrin-
kling and collapse of the walls (arrows). B, In HIVAN, the tubules
are dilated and filled with a precipitate of plasma protein, and the
tubular epithelial cells display various degenerative features
(arrow). Ultrastructural findings are a combination of those expect-
ed for the glomerulopathy as well as those common to HIV infec-
tion. Thus, the foot processes of visceral epithelial cells are effaced
and often detached from the capillary basement membranes. C,
Common in HIV infection are tubuloreticular structures, modifica-
tions of the cytoplasm of endothelial cells in which clusters of
microtubular arrays are in many cells (arrow). Some evidence sug-
gests that HIV or viral proteins localize in renal epithelial cells and
perhaps are directly or indirectly responsible for the cellular and
C functional damage. HIVAN often has a rapidly progressive down-
hill course, culminating in end-stage renal disease in as few as 4
FIGURE 4-3 (see Color Plate) months. HIVAN has a striking racial predilection; over 90% of
Human immunodeficiency virus (HIV) infection. Many forms of patients are black.
renal disease have been described in patients infected with HIV. The other glomerulopathy that may be an integral feature of HIV
Various immune complex–mediated glomerulonephritides associat- infection is immunoglobulin A nephropathy. In this setting, HIV
ed with complicating infections are known; however, several disor- antigen may be part of the glomerular immune complexes and cir-
ders appear to be directly or indirectly related to HIV itself. culating immune complexes. The morphology and clinical course
Perhaps the more common of these is known as HIV-associated generally are the same as in immunoglobulin A nephropathy occur-
nephropathy (HIVAN). This disease is a form of the collapsing ring in the non-HIV setting.
4.4 Glomerulonephritis and Vasculitis

A B

HT

C D
FIGURE 4-4 (see Color Plate)
Hepatitis C virus infection. The most common glomerulonephri- peripheral granular to confluent granular capillary wall deposits
tis in patients infected with the hepatitis C virus is membra- of immunoglobulin M (IgM) and complement C3; the same
noproliferative glomerulonephritis with, in some instances, immune proteins are in the luminal masses corresponding to
cryoglobulinemia and cryoglobulin precipitates in glomerular hyaline thrombi (arrow). C, Electron microscopy indicates the
capillaries. Thus, the morphology is basically the same as in luminal masses (HT). D, On electron microscopy the deposits
membranoproliferative glomerulonephritis type I (Fig. 2-18A–C). also appear to be composed of curvilinear or annular structures
A, With cryoglobulins, precipitates of protein representing cryo- (arrows). Hepatitis C viral antigen has been documented in the
globulin in the capillary lumina and appearing as hyaline throm- circulating cryoglobulins. Membranous glomerulonephritis with
bi (HT)are observed (arrows), often with numerous monocytes a mesangial component also has been infrequently described in
in most capillaries. B, Immunofluorescence microscopy discloses patients infected with the hepatitis C virus.
 Infection-Associated Glomerulopathies 4.5

A B
the isolation of the hepatitis C virus and its separation from the
hepatitis B virus, membranoproliferative glomerulonephritis was
considered a common immune complex–mediated manifestation
of hepatitis B virus infection. However, more recent data indi-
cate that this form of glomerulonephritis is a feature of hepatitis
C virus infection rather than hepatitis B virus infection. In con-
trast, membranous glomerulonephritis, often with mesangial
deposits and variable mesangial hypercellularity, is the glomeru-
lopathy that is a common accompaniment of hepatitis B virus
infection. Hepatitis B virus surface, core, or e antigens have
been identified in the glomerular deposits. The morphology of
the glomerular capillary walls is similar to the idiopathic form
of membranous glomerulonephritis. A, Some degree of mesan-
gial widening with increased cellularity occurs in most affected
patients. B, Similarly, on immunofluorescence, uniform granular
capillary wall deposits of immunoglobulin G (IgG), complement
C3, and both light chains are disclosed (IgG). It sometimes is
C very difficult to identify mesangial deposits in this setting. C, In
addition to the expected capillary wall changes, electron micro-
FIGURE 4-5 (see Color Plate) scopy discloses deposits in mesangial regions of many lobules
Hepatitis B virus infection. Several glomerulopathies have been (the arrow indicates mesangial deposits; the arrowheads indicate
described in association with hepatitis B viral infection. Until subepithelial deposits).
Vascular Disorders
Arthur H. Cohen
Richard J. Glassock

V
ascular disorders of the kidney comprise a very heterogeneous
array of lesions and abnormalities, depending on the site of the
lesion and underlying pathogenesis. Here, three common dis-
orders are the focus: thrombotic microangiopathies, benign and
malignant nephrosclerosis, and vascular occlusive disease (atheroem-
bolism). Vasculitis and renovascular hypertension are discussed in
other chapters.

CHAPTER

5
5.2 Glomerulonephritis and Vasculitis

A B

C D
thrombocytopenic purpura, malignant hypertension, and renal
disease in progressive systemic sclerosis (scleroderma renal crises).
A, These lesions are characterized primarily by fibrin deposition in
the walls of the glomeruli (fibrin). B, This fibrin deposition is asso-
ciated with endothelial cell swelling (arrow) and thickened capillary
walls, sometimes with a double contour. Variable capillary wall
wrinkling and luminal narrowing occur. Mesangiolysis (dissolution
of the mesangial matrix and cells) is not uncommon and may be
associated with microaneurysm formation. With further endothelial
cell damage, capillary thrombi ensue. C, Arteriolar thrombi also
may be present. In arterioles, fibrin deposits in the walls and lumina
are known as thrombonecrotic lesions, with extension of this
process into the glomeruli on occasion (arrow). The arterial walls
are thickened, with loose concentric intimal proliferation. D, On
electron microscopy, the subendothelial zones of the glomerular
E capillary wall are widened (arrows). Flocculent material accumu-
lates, corresponding to mural fibrin, with associated endothelial cell
FIGURE 5-1 swelling. E, With widespread arterial thrombosis, cortical necrosis is
Light microscopy of thrombotic microangiopathies. This group a common complicating feature. The necrotic cortex consists
of disorders includes hemolytic-uremic syndrome and thrombotic of pale confluent multifocal zones throughout the cortex.
 Vascular Disorders 5.3

FIGURE 5-2 (see Color Plate) FIGURE 5-3 (see Color Plate)
Microangiopathic hemolytic anemia. Bizarrely shaped and Disseminated intravascular coagulation. In disseminated intravas-
fragmented erythrocytes are commonly seen in Wright’s stained cular coagulation, fibrin thrombi are typically found in many
peripheral blood smears from patients with active lesions of glomerular capillary lumina. In contrast to the thrombotic
thrombotic microangiopathy. These abnormally shaped erythro- microangiopathies, in disseminated intravascular coagulation, fib-
cytes presumably arise when the fibrin strands within small rin is not primarily in vessel walls but in the lumina. Consequently,
blood vessels shear the cell membrane, with imperfect resolution the capillary wall thickening, endothelial cell swelling, and fibrin
of the biconcave disk shape. The resultant intravascular hemoly- accumulation in subendothelial locations are not features of this
sis causes anemia, reticulocytosis, and reduced plasma haptoglo- lesion. In the glomerulus illustrated, the fibrin is in many capillary
bin level. lumina and appears as bright fuchsin positive (red) masses.

A B
FIGURE 5-4
Benign and malignant nephrosclerosis. In benign nephrosclerosis lar pole and growing as a collar around the wrinkled ischemic
the artery walls are thickened with intimal fibrosis and luminal tufts. This collagen formation ultimately is associated with tubular
narrowing. Arteriolar walls are thickened with insudative lesions, atrophy and interstitial fibrosis.
a process affecting afferent arterioles almost exclusively. Both In malignant nephrosclerosis the changes are virtually identical
of these processes, which can be quite patchy, result in chronic to those of thrombotic microangiopathies (Fig. 5-1 C). Malignant
ischemia. A, In glomeruli, chronic ischemia is manifested by grad- nephrosclerosis may be seen in essential hypertension, scleroder-
ual capillary wall wrinkling, luminal narrowing, and shrinkage ma, unilateral renovascular hypertension (with a contralateral or
and solidification of the tufts. B, As these processes progress, col- “unprotected” kidney), and as a complicating event in many
lagen forms internal to Bowman’s capsule, beginning at the vascu- chronic renal parenchymal diseases.
5.4 Glomerulonephritis and Vasculitis

A B
instrumentation of patients with severe arteriosclerosis. Most
commonly, aortic plaques are complicated with ulceration and
often adherent fibrin, A. Portions of plaques are dislodged and
travel distally in the aorta. Because the kidneys receive a dispro-
portionately large share of the cardiac output, they are a favored
site of emboli. Typically, the emboli are in small arteries and
arterioles, although glomerular involvement with a few choles-
terol crystals in capillaries is not uncommon. Because of the
size of the crystals, it is sometimes difficult if not impossible
to identify them in glomerular capillaries in paraffin-embedded
sections. In plastic-embedded sections prepared for electron
microscopy, however, the crystals are quite easy to detect. On
light microscopy, cholesterol is represented by empty crystalline
spaces. In the early stages of the disease the crystals lie free in the
vascular lumina. In time, the crystals are engulfed by multinucle-
C ated foreign body giant cells. B, In this light microscopic photo-
graph, a few crystals are evident in the glomerular capillary lumi-
FIGURE 5-5 na and in an arteriole (arrows). C, In the electron micrograph the
Vascular occlusive disease and thrombosis. Atheroemboli (choles- elongated empty space represents dissolved cholesterol. Note that
terol emboli) are most commonly associated with intravascular no cellular reaction is evident.
Renal Interstitium and
Major Features of Chronic
Tubulointerstitial Nephritis
Garabed Eknoyan
Luan D. Truong

A
s a rule, diseases of the kidney primarily affect the glomeruli, vas-
culature, or remainder of the renal parenchyma that consists of
the tubules and interstitium. Although the interstitium and the
tubules represent separate functional and structural compartments, they
are intimately related. Injury initially involving either one of them
inevitably results in damage to the other. Hence the term tubulointersti-
tial diseases is used. Because inflammatory cellular infiltrates of variable
severity are a constant feature of this entity, the terms tubulointerstitial
diseases and tubulointerstitial nephritis have come to be used inter-
changeably. The clinicopathologic syndrome that results from these
lesions, commonly termed tubulointerstitial nephropathy, may pursue
an acute or chronic course. The chronic course is discussed here. The
abbreviation TIN is used to refer synonymously to chronic tubulointer-
stitial nephritis and tubulointerstitial nephropathy.
TIN may be classified as primary or secondary in origin. Primary
TIN is defined as primary tubulointerstitial injury without significant
involvement of the glomeruli or vasculature, at least in the early stages
of the disease. Secondary TIN is defined as secondary tubulointerstitial
injury, which is consequent to lesions initially involving either the
glomeruli or renal vasculature. The presence of secondary TIN is espe-
cially important because the magnitude of impairment in renal function
and the rate of its progression to renal failure correlate better with the CHAPTER
extent of TIN than with that of glomerular or vascular damage.
Renal insufficiency is a common feature of chronic TIN, and its diag-

6
nosis must be considered in any patient who exhibits renal insufficien-
cy. In most cases, however, chronic TIN is insidious in onset, renal insuf-
ficiency is slow to develop, and earliest manifestations of the disease are
those of tubular dysfunction. As such, it is important to maintain a high
6.2 Tubulointerstitial Disease

index of suspicion of this entity whenever any evidence of tubu- the two principal hallmarks of glomerular and vascular diseases
lar dysfunction is detected clinically. At this early stage, removal of the kidney: salt retention, manifested by edema and hyperten-
of a toxic cause of injury or correction of the underlying systemic sion; and proteinuria, which usually is modest and less than 1 to
or renal disease can result in preservation of residual renal func- 2 g/d in TIN. These clinical considerations notwithstanding, a
tion. Of special relevance in patients who exhibit renal insuffi- definite diagnosis of TIN can be established only by morphologic
ciency caused by primary TIN is the absence or modest degree of examination of kidney tissue.

Structure of the Interstitium

FIGURE 6-1
C—Cortex
Diagram of the approximate relative volume composition of tissue compartments at differ-
IS—Inner stripe of outer medulla
OS—Outer stripe of outer medulla
ent segments of the kidney in rats. The interstitium of the kidney consists of peritubular and
IZ—Inner zone of medulla periarterial spaces. The relative contribution of each of these two spaces to interstitial vol-
ume varies, reflecting in part the arbitrary boundaries used in assessing them, but increases
C in size from the cortex to the papilla. In the cortex there is little interstitium because the
peritubular capillaries occupy most of the space between the tubules. The cortical interstitial
OS
cells are scattered and relatively inconspicuous. In fact, a loss of the normally very close
IS
approximation of the cortical tubules is the first evidence of TIN. In the medulla there is a
noticeable increase in interstitial space. The interstitial cells, which are in greater evidence,
IZ have characteristic structural features and an organized arrangement. The ground substance
of the renal interstitium contains different types of fibrils and basementlike material embed-
ded in a glycosaminoglycan-rich substance. (From Bohman [1]; with permission.)

10 50 100%
Extracellular space Interstitial cells
Vessels Tubules

Cortex
FIGURE 6-2
A, Electron micrograph of a rat kidney cortex, where C is the cortex. B, Schematic render-
ing, where the narrow interstitium is shown in black and the wide interstitium is shown by
dots. The relative volume of the interstitium of the cortex is approximately 7%, consisting of
about 3% interstitial cells and 4% extracellular space. The vasculature occupies another
6%; the remainder (ie, some 85% or more) is occupied by the tubules. The cortical intersti-
tial space is unevenly distributed and has been divided into narrow and wide structural
components. The tubules and peritubular capillaries either are closely apposed at several
points, sometimes to the point of sharing a common basement membrane, or are separated
by a very narrow space.
This space, the so-called narrow interstitium, has been estimated to occupy 0.6% of corti-
cal volume in rats. The narrow interstitium occupies about one-half to two-thirds of the
A cortical peritubular capillary surface area. The remainder of the cortical interstitium con-
sists of irregularly shaped clearly discernible larger areas, the so-called wide interstitium.
The wide interstitium has been estimated to occupy 3.4% of cortical volume in rats. The
capillary wall facing the narrow interstitium is significantly more fenestrated than is that
facing the wide interstitium. Functional heterogeneity of these interstitial spaces has been
proposed but remains to be clearly defined. (From Bohman [1]; with permission.)

B
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.3

Medulla
FIGURE 6-3
Scanning electron micrograph of the inner medulla, showing a
prominent collecting duct, thin wall vessels, and abundant inter-
stitium. A gradual increase in interstitial volume from the outer
medullary stripe to the tip of the papilla occurs. In the outer stripe
of the outer medulla, the relative volume of the interstitium is
slightly less than is that of the cortex. This volume has been
estimated to be approximately 5% in rats. It is in the inner stripe
of the outer medulla that the interstitium begins to increase signifi-
cantly in volume, in increments that gradually become larger
toward the papillary tip.
The inner stripe of the outer medulla consists of the vascular bun-
dles and the interbundle regions, which are occupied principally by
tubules. Within the vascular bundles the interstitial spaces are meager,
whereas in the interbundle region the interstitial spaces occupy
some 10% to 20% of the volume. In the inner medulla the differ-
entiation into vascular bundles and interbundle regions becomes
gradually less obvious until the two regions merge. A gradual increase
in the relative volume of the interstitial space from the base of the
inner medulla to the tip of the papilla also occurs. In rats, the
increment in interstitial space is from 10% to 15% at the base to
about 30% at the tip. In rabbits, the increment is from 20% to
25% at the base to more than 40% at the tip.

Cell types

B. RENAL INTERSTITIAL CELLS

Cortex Outer medulla Inner medulla

Fibroblastic cells Fibroblastic cells Pericytes
Mononuclear cells Mononuclear cells Lipid-laden cells
Mononuclear cells

cells are important in antigen presentation. Their cytokines con-

tribute to recruitment of infiltrating cells, progression of injury,
and sustenance of fibrogenesis.
A In the cortex and outer zone of the outer medulla, type I cells are
more common than are type II cells. In the inner zone of the medulla,
FIGURE 6-4 some type I cells form pericytes whereas others evolve into special-
A, High-power view of the medulla showing the wide interstitium ized lipid-laden interstitial cells. These specialized cells increase
and interstitial cells, which are abundant, varied in shape, and in number toward the papillary tip and are a possible source of
arranged as are the rungs of a ladder. B, Renal interstitial cells. medullary prostaglandins and of production of matriceal glyco-
The interstitium contains two main cell types, whose numbers saminoglycans. A characteristic feature of these medullary cells is
increase from the cortex to the papilla. Type I interstitial cells are their connection to each other in a characteristic arrangement,
fibroblastic cells that are active in the deposition and degradation similar to the rungs of a ladder. These cells have a distinct close
of the interstitial matrix. Type I cells contribute to fibrosis in response and regular transverse apposition to their surrounding structures,
to chronic irritation. Type II cells are macrophage-derived mono- specifically the limbs of the loop of Henle and capillaries, but not
nuclear cells with phagocytic and immunologic properties. Type II to the collecting duct cells.
6.4 Tubulointerstitial Disease

Matrix
FIGURE 6-5
Peritubular interstitium in the cortex at the interface of a tubule (T) on the left and a capillary
(C) on the right. The inset shows the same space in cross section, including the basement
membrane (BM) of the two compartments. The extracellular loose matrix is a hydrated
gelatinous substance consisting of glycoproteins and glycosaminoglycans (hyaluronic acid,
heparan sulfate, dermatan sulfate, and chondroitin sulfate) that are embedded within a
fibrillar reticulum. This reticulum consists of collagen fibers (types I, III, and VI) and
unbanded microfilaments. Collagen types IV and V are the principal components of the
basement membrane lining the tubules. Glycoprotein components (fibronectin and laminin)
of the basement membrane connect it to the interstitial cell membranes and to the fibrillar
structures of the interstitial matrix. The relative increase in the interstitial matrix of the
medulla may be important for providing support to the delicate tubular and vascular
structures in this region. (From Lemley and Kriz [2]; with permission.)

Pathologic Features of Chronic TIN

FIGURE 6-6
Primary chronic TIN. The arrow indicates a normal glomerulus.
Apart from providing structural support, the interstitium serves as a
conduit for solute transport and is the site of production of several
cytokines and hormones (erythropoietin and prostaglandins). For the
exchange processes to occur between the tubules and vascular com-
partment, the absorbed or secreted substances must traverse the inter-
stitial space. The structure, composition, and permeability characteris-
tics of the interstitial space must, of necessity, exert an effect on any
such exchange. Although the normal structural and functional corre-
lates of the interstitial space are poorly defined, changes in its compo-
sition and structure in chronic TIN are closely linked to changes in
tubular function. In addition, replacement of the normal delicate
interstitial structures by fibrosclerotic changes of chronic TIN would
affect the vascular perfusion of the adjacent tubule, thereby contribut-
ing to tubular dysfunction and progressive ischemic injury.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.5

Tubular atrophy and dilation comprise a principal feature of

TIN. The changes are patchy in distribution, with areas of atrophic
chronically damaged tubules adjacent to dilated tubules displaying
compensatory hypertrophy. In atrophic tubules the epithelial cells
show simplification, decreased cell height, loss of brush border,
and varying degrees of thickened basement membrane. In dilated
tubules the epithelial cells are hypertrophic and the lumen may
contain hyalinized casts, giving them the appearance of thyroid
follicles. Hence the term thyroidization is used.
The interstitium is expanded by fibrous tissue, in which are inter-
spersed proliferating fibroblasts and inflammatory cells comprised
mostly of activated T lymphocytes and macrophages. Rarely, B
lymphocytes, plasma cells, neutrophils, and even eosinophils may
be present.
The glomeruli, which may appear crowded in some areas owing
to tubulointerstitial loss, usually are normal in the early stages of
the disease. Ultimately, the glomeruli become sclerosed and develop
FIGURE 6-7 periglomerular fibrosis.
Secondary chronic TIN. The arrow indicates a glomerulus with a The large blood vessels are unremarkable in the early phases of
cellular crescent. The diagnosis of TIN can be established only by the disease. Ultimately, these vessels develop intimal fibrosis, medial
morphologic examination of kidney tissue. The extent of the lesions hypertrophy, and arteriolosclerosis. These vascular changes, which
of TIN, whether focal or diffuse, correlates with the degree of also are associated with hypertension, can be present even in the
impairment in renal function. absence of elevated blood pressure in cases of chronic TIN.

CONDITIONS ASSOCIATED WITH PRIMARY CHRONIC TIN

Urinary tract
Immunologic diseases obstructions Hematologic diseases Miscellaneous Hereditary diseases Endemic diseases
Systemic lupus Vesicoureteral reflux Sickle hemoglobinopathies Vascular diseases Medullary cystic disease Balkan nephropathy
erythematosus Mechanical Multiple myeloma Nephrosclerosis Hereditary nephritis Nephropathia epidemica
Sjögren syndrome Lymphoproliferative Atheroembolic disease Medullary sponge kidney
Transplanted kidney disorders Radiation nephritis Polycystic kidney disease
Cryoglobulinemia Aplastic anemia Diabetes mellitus
Goodpasture’s syndrome Sickle hemoglobinopathies
Immunoglobulin A Vasculitis
nephropathy
Amyloidosis
Pyelonephritis
Infections Drugs Heavy metals Metabolic disorders Granulomatous disease Idiopathic TIN
Systemic Analgesics Lead Hyperuricemia- Sarcoidosis
Renal Cyclosporine Cadmium hyperuricosuria Tuberculosis
Bacterial Nitrosourea Hypercalcemia- Wegener’s granulomatosis
Viral Cisplatin hypercalciuria
Fungal Lithium Hyperoxaluria
Mycobacterial Miscellaneous Potassium depletion
Cystinosis

FIGURE 6-8
Tubulointerstitial nephropathy occurs in a motley group of diseases together because of the unifying structural changes associated with
of varied and diverse causes. These diseases are arbitrarily grouped TIN noted on morphologic examination of the kidneys.
6.6 Tubulointerstitial Disease

Pathogenesis of Chronic TIN

FIGURE 6-9
Glomerular disease Schematic presentation of the potential pathways incriminated in
the pathogenesis of chronic TIN caused by primary tubular injury
(dark boxes) or secondary to glomerular disease (light boxes). The
Vascular damage Altered filtration mechanism by which TIN is mediated remains to be elucidated.
Chronic tubular epithelial cell injury appears to be pivotal in the
process. The injury may be direct through cytotoxicity or indirect
Reabsorption by the induction of an inflammatory or immunologic reaction.
Tubular ischemia of noxious Studies in experimental models and humans provide compelling
macromolecules evidence for a role of immune mechanisms. The infiltrating lympho-
cytes have been shown to be activated immunologically. It is the
inappropriate release of cytokines by the infiltrating cells and loss
Chronic tubular cell injury
of regulatory balance of normal cellular regeneration that results in
increased fibrous tissue deposition and tubular atrophy. Another
b-9

Release of cytokines, proteinases potential mechanism of injury is that of increased tubular ammonia-
↑NH3→↑C3b→↑C5

adhesion molecules, growth factors genesis by the residual functioning but hypertrophic tubules. Increased
tubular ammoniagenesis contributes to the immunologic injury by
activating the alternate complement pathway.
↑ Recruitment of Altered glomerular permeability with consequent proteinuria
Fibroblast proliferation appears to be important in the development of TIN in primary
∆Cell balance ↑Matrix deposition antigenically
activated cells glomerular diseases. By the same token, the proteinuria that
develops late in the course of primary TIN may contribute to
the tubular cell injury and aggravate the course of the disease.
Tubular Interstitial Interstitial In primary vascular diseases TIN has been attributed to ischemic
atrophy fibrosis infiltrates injury. In fact, hypertension is probably the most common cause of
TIN. The vascular lesions that develop late in the course of primary
TIN, in turn, can contribute to the progression of TIN. (From
Tubular dysfunction Eknoyan [3]; with permission.)
↓ Capillary perfusion

Progressive loss of renal function

FIGURE 6-10
ROLE OF TUBULAR EPITHELIAL CELLS The infiltrating interstitial cells contribute
to the course TIN. However, increasing
evidence exists for a primary role of the
Chemoattractant Pro-inflammatory tubular epithelial cells in the recruitment
cytokines cytokines Cell surface markers Matrix proteins of interstitial infiltrating cells and in per-
petuation of the process. Injured epithelial
Monocyte chemo- Interleukin-6 (IL-6), IL-8 Human leukocyte antigen Collagen I, III, IV cells secrete a variety of cytokines that
attractant peptide-1 class II have both chemoattractant and pro-inflam-
Platelet-derived growth Laminin, fibronectin
Osteopontin factor- Intercellular adhesion matory properties. These cells express a
molecule-1 number of cell surface markers that enable
Chemoattractant Granulocyte -macrophage
lipids colony-stimulating factor Vascular cell adhesion them to interact with infiltrating cells.
Endothelin-1 Transforming growth
molecule-1 Injured epithelial cells also participate in
factor-1 the deposition of increased interstitial
RANTES matrix and fibrous tissue. Listed are
Tumor necrosis factor-
cytokines, cell surface markers, and matrix
components secreted by the renal tubular
From Palmer [4]; with permission. cell that may play a role in the develop-
ment of tubulointerstitial disease.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.7

Role of Infiltrating Cells

FIGURE 6-11
TIN showing early phase with focal (A) and more severe and diffuse
(B) interstitial inflammatory cell infiltrates. Late phase showing
thickened tubular basement membrane, distorted tubular shape,
and cellular infiltration of the tubules, called tubulitis (C). The
extent and severity of interstitial cellular infiltrates show a direct
correlation with the severity of tubular atrophy and interstitial
fibrosis. Experimental studies show the sequential accumulation of
T cells and monocytes after the initial insult. Accumulation of these
cells implicates their important role both in the early inflammatory
stage of the disease and in the progression of subsequent injury.
Immunohistologic examination utilizing monoclonal antibodies,
coupled with conventional and electron microscopy, indicates that
most of the mononuclear inflammatory cells comprising renal
interstitial infiltrates are T cells. These T cells are immunologically
A activated in the absence of any evidence of tubulointerstitial immune
deposits, even in classic examples of immune complex–mediated
diseases such as systemic lupus erythematosus. The profile of
immunocompetent cells suggests a major role for cell-mediated
immunity in the tubulointerstitial lesions. The infiltrating cells
may be of the helper-inducer subset or the cyotoxic-suppressor
subset, although generally there seems to be a selective prevalence
for the former variety. Lymphocytes that are peritubular and are
seen invading the tubular epithelial cells, so-called tubulitis, are
generally of the cytotoxic (CD8+) variety.
The interstitial accumulation of monocytes and macrophages
involves osteopontin (uropontin). Osteopontin is a secreted cell
attachment glycoprotein whose messenger RNA expression becomes
upregulated, and its levels are increased at the sites of tubular injury
in proportion to the severity of tubular damage. The expression of
other cell adhesion molecules (intercellular adhesion molecule-1,
vascular cellular adhesion molecule-1, and E-selectin) also is increased
B at the sites of tubular injury. This increased expression may contribute
to the recruitment of mononuclear cells and increase the susceptibility
of renal cells to cell-mediated injury.
Fibroblastic (type I) interstitial cells, which normally produce and
maintain the extracellular matrix, begin to proliferate in response
to injury. They increase their well-developed rough endoplasmic
reticulum and acquire smooth muscle phenotype (myofibroblast).
Growth kinetic studies of these cells reveal a significant increase in
their proliferating capacity and generation time, indicating hyper-
proliferative growth.

C
6.8 Tubulointerstitial Disease

Mechanisms Involved in Renal Interstitial Fibrosis

Macrophage

Virus
Protein TNF4
IL 1
TGF–3
PDGF
Lymphocyte GM–CSF
l

IFN
na

IL 4
Sig

IL 2
DO
HLA– DR
Sig

DP
na

Proliferating TH-Cell
l

Proliferating B-cell
Epithelial cell
IL 1
IL1 PDGF
IL6
IL7
IL8 Proliferation ↑↑
ICAM–1 IIFNβ
GM-CSF
G-CSF Differentiation ↓
M-CSF
Factor x MF I – MF III Interstitial fibrosis
Proximal P (30/7.3) PMF IV – PMF VI
Fibroblast
tubulus
Synthesis ↑↑ and Secretion ↑
of collagen

Fibrosin
P 53/6.1

FIGURE 6-12
Expression of human leukocyte antigen class II and adhesion pathways have been proposed to operate at different stages of the
molecules released by injured tubular epithelial cells, as well disease process. Each of these individual pathways usually is part
as by infiltrating cells, modulate and magnify the process to of a recuperative process that works in concert in response to
repair the injury (Figure 6-10). When the process becomes unre- injury. However, it is the loss of their controlling feedback in
sponsive to controlling feedback mechanisms, fibroblasts prolifer- chronic TIN that seems to account for the altered balance and
ate and increase fibrotic matrix deposition. The precise mecha- results in persistent cellular infiltrates, progressive fibrosis, and
nism of TIN remains to be identified. A number of pathogenetic tubular degeneration.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.9

Patterns of Tubular Dysfunction

The tubulointerstitial lesions are localized
either to the cortex or medulla. Cortical
PATTERNS OF TUBULAR DYSFUNCTION IN CHRONIC TIN
lesions mainly affect either the proximal or
distal tubule. Medullary lesions affect the
loop of Henle and the collecting duct. The
Site of injury Cause Tubular dysfunction change in the normal function of each of
Cortex these affected segments then determines the
Proximal tubule Heavy metals Decreased reabsorption of sodium, bicarbonate, glucose, manifestations of tubular dysfunction.
Multiple myeloma uric acid, phosphate, amino acids Essentially, the proximal nephron segment
Immunologic diseases reabsorbs the bulk of bicarbonate, glucose,
Cystinosis amino acids, phosphate, and uric acid.
Distal tubule Immunologic diseases Decreased secretion of hydrogen, potassium Changes in proximal tubular function,
Granulomatous diseases Decreased reabsorption of sodium therefore, result in bicarbonaturia (proximal
Hereditary diseases renal acidosis), 2-microglobinuria, gluco-
Hypercalcemia suria (renal glucosuria), aminoaciduria,
Urinary tract obstruction phosphaturia, and uricosuria.
Sickle hemoglobinopathy
The distal nephron segment secretes
Amyloidosis
hydrogen and potassium and regulates the
Medulla Analgesic nephropathy Decreased ability to concentrate urine final amount of sodium chloride excreted.
Sickle hemoglobinopathy Decreased reabsorption of sodium
Lesions primarily affecting this segment,
Uric acid disorders
Hypercalcemia therefore, result in the distal form of renal
Infection tubular acidosis, hyperkalemia, and salt
Hereditary disorders wasting. Lesions that primarily involve the
Granulomatous diseases medulla and papilla disproportionately
Papilla Analgesic nephropathy Decreased ability to concentrate urine affect the loops of Henle, collecting ducts,
Diabetes mellitus Decreased reabsorption of sodium and the other medullary structures essential
Infection to attaining and maintaining medullary
Urinary tract obstruction hypertonicity. Disruption of these struc-
Sickle hemoglobinopathy tures, therefore, results in different degrees
Transplanted kidney of nephrogenic diabetes insipidus and clini-
cally manifests as polyuria and nocturia.
Although this general framework is use-
ful in localizing the site of injury, consider-
FIGURE 6-13 able overlap may be encountered clinically,
The principal manifestations of TIN are those of tubular dysfunction. Because of the focal with different degrees of proximal, distal,
nature of the lesions that occur and the segmental nature of normal tubular function, the and medullary dysfunction present in the
pattern of tubular dysfunction that results varies, depending on the major site of injury. same individual. Additionally, the ultimate
The extent of damage determines the severity of tubular dysfunction. The hallmarks of development of renal failure complicates
glomerular disease (such as salt retention, edema, hypertension, proteinuria, and hema- the issue further because of the added
turia) are characteristically absent in the early phases of chronic TIN. The type of insult effect of urea-induced osmotic diuresis
determines the segmental location of injury. For example, agents secreted by the organic on tubular function in the remaining
pathway in the pars recta (heavy metals) or reabsorbed in the proximal tubule (light chain nephrons. In this later stage of TIN, the
proteins) cause predominantly proximal tubular lesions. Depositional disorders (amyloidosis absence of glomerular proteinuria and the
and hyperglobulinemic states) cause predominantly distal tubular lesions. Insulting agents more common occurrence of hypertension
that are affected by the urine concentrating mechanism (analgesics and uric acid) or in glomerular diseases can be helpful in
medullary tonicity (sickle hemoglobinopathy) cause medullary injury. the differential diagnosis.
6.10 Tubulointerstitial Disease

Correlates of Tubular Dysfunction

with Severity of Chronic TIN
160 1200
Chronic GN Chronic GN
Acute GN 1100 Acute GN
PTIN PTIN
140 Nephrosclerosis Nephrosclerosis
1000

120 900

800

Maximal osmolality, mOs/kg

100
Inulin clearance, mL/min

700

80 600

500
60
400

300
40

200
20
100

0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
A Interstitial disease (total score) B Interstitial disease (total score)

FIGURE 6-14
1200
Chronic GN Relationship of inulin clearance (A), maximum urine concentration
110 Acute GN (B), and ammonium excretion in response to an acute acid load (C)
PTIN to the severity of tubulointerstitial nephritis. A close correlation
Nephrosclerosis
100 exists between the severity of chronic TIN and impaired renal
tubular and glomerular function. Repeated evaluations of kidney
90 biopsy for the extent of tubulointerstitial lesions have shown a
close correlation with renal function test results in tests performed
80 before biopsy. These tests include those for inulin clearance, maximal
Ammonium excretion, µEq/min

ability to concentrate the urine, and ability to acidify the urine. This
70 correlation has been validated in a variety of renal diseases, including
primary and secondary forms of chronic TIN. (From Shainuck and
60 coworkers [5]; with permission.)

50

40

30

20

10

0
0 1 2 3 4 5 6 7 8 9 10 11 12
C Interstitial disease (total score)
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.11

Correlates of Chronic TIN with Progressive Renal Failure

FIGURE 6-15
100
Probability of maintaining renal function, %

Effect on long-term prognosis of the presence of cortical chronic

tubulointerstitial nephritis in patients with mesangioproliferative
80 Normal interstitium glomerulonephritis (n = 455), membranous nephropathy (n = 334),
and membranoproliferative glomerulonephritis (n = 220). The
60 extent of tubulointerstitial nephritis correlates not only with altered
glomerular and tubular dysfunction at the time of kidney biopsy
40 but also provides a prognostic index of the progression rate to end-
stage renal disease. As shown, the presence of interstitial fibrosis
Interstitial fibrosis
20 on the initial biopsy exerts a significant detrimental effect on the
progression rate of renal failure in a variety of glomerular diseases.
(From Eknoyan [3]; with permission.)
0
0 2 4 6 8 10 12 14 16
Follow-up, y

Drugs
Analgesic Nephropathy
diuresis has provided protection from anal-
Acetaminophen Metabolism gesic-induced renal injury. Relative to plasma
levels, both acetaminophen (paracetamol)
p–phenetidine Meth–hemoglobin
n–OH–p–acetophenetidine
Sulfhemoglobin and its excretory conjugate attain significant
(fourfold to fivefold) concentrations in the
medulla and papilla, depending on the state
Phenactin of hydration of the animal studied. The
p–acetophenetidine toxic effect of these drugs apparently is
related to their intrarenal oxidation to reac-
tive intermediates that, in the absence of
Glucoronide Paracetamol Cytochrome Reactive toxic reducing substances such as glutathione,
sulfate n–acetyl–p–aminophenol P–450 metabolites
become cytotoxic by virtue of their capacity
Glutathione to induce oxidative injury. Salicylates also
are significantly (sixfold to thirteenfold
Covalent binding to Glutathione above plasma levels) concentrated in the
cellular sulfhydryl conjugate
medulla and papilla, where they attain a
level sufficient to uncouple oxidative phos-
Mercapturic
phorylation and compromise the ability of
Cell death cells to generate reducing substances. Thus,
acid
both agents attain sufficient renal medullary
concentration to individually exert a detri-
FIGURE 6-16 mental and injurious effect on cell function,
Metabolism of acetaminophen and its excretion by the kidney. Prolonged exposure to drugs which is magnified when they are present
can cause chronic TIN. Although a number of drugs (eg, lithium, cyclosporine, cisplatin, together. By reducing the medullary tonici-
and nitrosoureas) have been implicated, the more commonly responsible agents are anal- ty, and therefore the medullary concentra-
gesics. As a rule, the lesions of analgesic nephropathy develop in persons who abuse anal- tion of drug attained, water diuresis pro-
gesic combinations (phenacetin, or its main metabolite acetaminophen, plus aspirin, with or tects from analgesic-induced cell injury. A
without caffeine). Experimental evidence indicates that phenacetin, or acetaminophen, plus direct role of analgesic-induced injury can
aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the be adduced from the improvement of renal
lesions can be more readily induced when these drugs are taken together. In all experimental function that can occur after cessation of
studies the extent of renal injury has been dose-dependent and, when examined, water analgesic abuse.
6.12 Tubulointerstitial Disease

FIGURE 6-17
Pathogenesis of renal lesion associated Course of the renal lesions in analgesic nephropathy. The intrarenal
with analgesic abuse
distribution of analgesics provides an explanation for the medullary
location of the pathologic lesions of analgesic nephropathy. The initial
Cortex– normal lesions are patchy and consist of necrosis of the interstitial cells, thin
limbs of the loops of Henle, and vasa recta of the papilla. The col-
Outer medula– patchy tubular damage
a. tubular dilatation
lecting ducts are spared. The quantities of tubular and vascular
b. increased interstitial tissue basement membrane and ground substance are increased. At this
c. casts: pigment stage the kidneys are normal in size and no abnormalities have
Stage I Papilla– possible microscopic changes occurred in the renal cortex. With persistent drug exposure the
changes extend to the outer medulla. Again, the lesions are initially
patchy, involving the interstitial cells, loops of Henle, and vascular
bundles. With continued analgesic abuse, the severity of the inner
Cortex– normal medullary lesions increases with sclerosis and obliteration of the
Outer medula– increase in changes capillaries, atrophy and degeneration of the loops of Henle and
collecting ducts, and the beginning of calcification of the necrotic
Papilla– necrosis and atrophy foci. Ultimately, the papillae become entirely necrotic, with seques-
attached or separated tration and demarcation of the necrotic tissue. The necrotic papillae
Stage II
may then slough and are excreted into the urine or remain in situ,
Cortex– where they atrophy further and become calcified. Cortical scarring,
a. atrophy area overlying characterized by interstitial fibrosis, tubular atrophy, and periglo-
necrotic papilla
merular fibrosis, develops over the necrotic medullary segments.
b. hypertrophy
The medullary rays traversing the cortex are usually spared and
become hypertrophic, thereby imparting a characteristic cortical
Papilla– atrophic, necrotic nodularity to the now shrunken kidneys. Visual observation of these
Stage III configurational changes by computed tomography scan can be
extremely useful in the diagnosis of analgesic nephropathy.

in men and 96 mm in women. Bumpy con-

Size tours are considered to be present if at least
RV three indentations are evident (panels B and
Right kidney RA RA
C). The scan can reveal papillary calcifica-
Left kidney
tions (panels B and D). Visual observation
Spine of the configurational changes illustrated
a a in Figure 6-18 can be extremely useful in
diagnosing the scarred kidney in analgesic
nephropathy. A series of careful studies
A b b C
using CT scans without contrast material
have provided imaging criteria for the diag-
nosis of analgesic nephropathy. Validation
Appearance of these criteria currently is underway by a
Bumpy contours study at the National Institutes of Health.
From studies comparing analgesic abusers
Papillary calcifications
to persons in control groups, it has been
shown that a decrease in kidney size and
bumpy contours of both kidneys provide a
0 1–2 3–5 >5 diagnostic sensitivity of 90% and a specificity
B Number of indentations D of 95%. The additional finding of evidence of
renal papillary necrosis provides a diagnostic
sensitivity of 72% and specificity of 97%, giv-
FIGURE 6-18 ing a positive predictive value of 92%. RA—
Computed tomography (CT) imaging criteria for diagnosing analgesic nephropathy. Renal renal artery; RV— renal vein. (From DeBroe
size (A) is considered decreased if the sum of a and b (panels A and B) is less than 103 mm and Elseviers [6]; with permission.)
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.13

1 2 3
CLINICAL FEATURES
a a a
b b b
c c c
Female predominance, 60–85%
Age, >30 y
Personality disorders: introvert, dependent, anxiety, neurosis, family instability
Addictive habits: smoking, alcohol, laxatives, psychotropics, sedatives a—cortical nephron b—juxta medullary nephron c—midcortical nephron

Causes of analgesic dependency: headache, 40–60%; mood, 6–30%; musculoskeletal

pain, 20–30% FIGURE 6-20
Diagram of cortical and juxtamedullary nephrons in the normal kid-
ney (1). Papillary necrosis (2) and sloughing (3) result in loss of
juxtamedullary nephrons. Cortical nephrons are spared, thereby
FIGURE 6-19 preserving normal renal function in the early stages of the disease.
Certain personality features and clinical findings characterize patients The course of analgesic nephropathy is slowly progressive, and
prone to analgesic abuse. These patients tend to deny analgesic use deterioration of renal function is insidious. One reason for these
on direct questioning; however, their history can be revealing. In all characteristics of the disease is that lesions beginning in the papil-
cases, a relationship exists between renal function and the dura- lary tip affect only the juxtamedullary nephrons, sparing the corti-
tion, intensity, and quantity of analgesic consumed. The magnitude cal nephrons. It is only when the lesions are advanced enough to
of injury is related to the quantity of analgesic ingested chronically affect the whole medulla that the number of nephrons lost is suffi-
over years. In persons with significant renal impairment, the aver- cient to result in a reduction in filtration rate. However, renal
age dose ingested has been estimated at about 10 kg over a mean injury can be detected by testing for sterile pyuria, reduced concen-
period of 13 years. The minimum amount of drug consumption trating ability, and a distal acidifying defect. These features may be
that results in significant renal damage is unknown. It has been evident at levels of mild renal insufficiency and become more pro-
estimated that a cumulative dose of 3 kg of the index compound, nounced and prevalent as renal function deteriorates. Proximal
or a daily ingestion of 1 g/d over 3 years or more, is a minimum tubular function is preserved in patients with mild renal insufficiency
that can result in detectable renal impairment. but can be abnormal in those with more advanced renal failure.

Cyclosporine

A B
FIGURE 6-21
A, Chronic TIN caused by cyclosporine. The arrow indicates the epithelial cell injury. Whereas these early lesions tend to be
characteristic hyaline-type arteriolopathy of cyclosporine nephro- reversible with cessation of therapy, an irreversible interstitial
toxicity. B, Patchy nature of chronic TIN caused by cyclosporine. fibrosis and mononuclear cellular infiltrates develop with pro-
Note the severe TIN on the right adjacent to an otherwise intact longed use of cyclosporine, especially at high doses. The irre-
area on the left. Tubulointerstitial nephritis has emerged as the versible nature of TIN associated with the use of cyclosporine
most serious side effect of cyclosporine. Cyclosporine-mediated and its attendant reduction in renal function have raised concerns
vasoconstriction of the cortical microvasculature has been implicated regarding the long-term use of this otherwise efficient immuno-
in the development of an occlusive arteriolopathy and tubular suppressive agent.
6.14 Tubulointerstitial Disease

Heavy Metals
Lead Nephropathy
exposure to lead are lead-based paints; lead leaked into food dur-
ing storage or processing, particularly in illegal alcoholic beverages
(moonshine); and increasingly, through environmental exposure
(gasoline and industrial fumes). This insidious accumulation of lead
in the body has been implicated in the causation of hyperuricemia,
hypertension, and progressive renal failure. Gout occurs in over
half of cases. Blood levels of lead usually are normal. The diagnosis
is established by demonstrating increased levels of urinary lead
after infusion of 1 g of the chelating agent erthylenediamine
tetraacetic acid (EDTA).
The renal lesions of lead nephropathy are those of chronic TIN.
Cases examined early, before the onset of end-stage renal disease,
show primarily focal lesions of TIN with relatively little interstitial
cellular infiltrates. In more advanced cases the kidneys are fibrotic
and shrunken. On microscopy, the kidneys show diffuse lesions of
TIN. As expected from the clinical features, hypertensive vascular
FIGURE 6-22 changes are prominent.
Lead nephropathy. Arrows indicate the characteristic intranuclear Other heavy metals associated with TIN are cadmium, silicon,
inclusions. Exposure to a variety of heavy metals results in devel- copper, bismuth, and barium. Sufficient experimental evidence and
opment of chronic TIN. Of these metals, the more common and some weak epidemiologic evidence suggest a possible role of organic
clinically important implicated agent is lead. Major sources of solvents in the development of chronic TIN.

Ischemic Vascular Disease

Hypertensive Nephrosclerosis
FIGURE 6-23
Chronic TIN associated with hypertension. The arrows indicate
arterioles and small arteries with thickened walls. Tubular degener-
ation, interstitial fibrosis, and mononuclear inflammatory cell infil-
tration are part of the degenerative process that affects the kidneys
in all vascular diseases involving the intrarenal vasculature with
any degree of severity as to cause ischemic injury. Rarely, if the
insult is sudden and massive (such as in fulminant vasculitis), the
lesions are those of infarction and acute deterioration of renal
function. More commonly, the vascular lesions develop gradually
and go undetected until renal insufficiency supervenes. This chronic
form of TIN accounts for the tubulointerstitial lesions of arteriolar
nephrosclerosis in persons with hypertension. Ischemic vascular
changes also contribute to the lesions of TIN in patients with dia-
betes, sickle cell hemoglobinopathy, cyclosporine nephrotoxicity,
and radiation nephritis.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.15

FIGURE 6-24
Gross appearance of the kidney as a result of arteriolonephroscle-
rosis, showing the granular and scarified cortex.

Obstruction
FIGURE 6-25 (see Color Plate)
Chronic TIN secondary to vesicoureteral reflux (VUR). Clearly
demonstrated is an area that is fairly intact (lower left corner) adja-
cent to one that shows marked damage. Urinary tract obstruction,
whether congenital or acquired, is a common cause of chronic TIN.
Clinically, superimposed infection plays a secondary, adjunctive, and
definitely aggravating role in the progressive changes of TIN. How-
ever, the entire process can occur in the absence of infection.
As clearly demonstrated in experimental models of obstruction,
mononuclear inflammatory cell infiltration is one of the earliest
responses of the kidney to ureteral obstruction. The infiltrating
cells consist of macrophages and suppressor-cytotoxic lymphocytes.
The release of various cytokines by the infiltrating cells of the
hydronephrotic kidney appears to exert a significant modulating
role in the transport processes and hemodynamic changes seen
early in the course of obstruction. With persistent obstruction,
changes of chronic TIN set in within weeks. Fibrosis gradually
becomes prominent.

FIGURE 6-26
Gross appearance of a hydronephrotic kidney caused by
vesicoureteral reflux.
6.16 Tubulointerstitial Disease

Obstructive Nephropathy
FIGURE 6-27
Glomerular lesion of advanced chronic TIN secondary to vesicoureteral
reflux in a patient with massive proteinuria. Note the segmental
sclerosis of the glomerulus and the reactive proliferation of the
visceral epithelial cells. In persons with obstructive nephropathy,
the onset of significant proteinuria (>2g/d) is an ominous sign of
progressive renal failure. As a rule, most of these patients will have
coexistent hypertension, and the renal vasculature will show changes
of hypertensive arteriolosclerosis. The glomerular changes are ischemic
in nature. In those with significant proteinuria, the lesions are those
of focal and segmental glomerulosclerosis and hyalinosis. The
affected glomeruli commonly contain immunoglobulin M and C3
complement on immunofluorescent microscopy. The role of an
immune mechanism remains unclear. Autologous (Tamm-Horsfall
protein and brush-border antigen) or bacterial antigen derivatives
have been incriminated. Adaptive hemodynamic changes (hyperfil-
tration) in response to a reduction in renal mass, by the glomeruli
of remaining intact nephrons of the hydronephrotic kidney, also
have been implicated.

Hematopoietic Diseases
Sickle Hemoglobinopathy
that of chronic TIN. By far more prevalent and severe in patients
with sickle cell disease, variable degrees of TIN also are common
in those with the sickle cell trait, sickle cell–hemoglobin C disease,
or sickle cell–thalassemia disease. The predisposing factors that lead
to a propensity of renal involvement are the physicochemical prop-
erties of hemoglobin S that predispose its polymerization in an
environment of low oxygen tension, hypertonicity, and low pH.
These conditions are characteristic of the renal medulla and therefore
are conducive to the intraerythrocyte polymerization of hemoglobin S.
The consequent erythrocyte sickling accounts for development of
the typical vascular occlusive lesions. Although some of these changes
occur in the cortex, the lesions begin and are predominantly located
in the inner medulla, where they are at the core of the focal scarring
and interstitial fibrosis. These lesions account for the common
occurrence of papillary necrosis.
Examples of tubular functional abnormalities common and detectable
early in the course of the disease are the following: impaired concen-
FIGURE 6-28 trating ability, depressed distal potassium and hydrogen secretion,
The kidney in sickle cell disease. Note the tubular deposition of tubular proteinuria, and decreased proximal reabsorption of phos-
hemosiderin. The principal renal lesion of hemoglobinopathy S is phate, and increased secretion of uric acid and creatinine.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.17

Hematologic Diseases
Plasma Cell Dyscrasias
FIGURE 6-29 (see Color Plate)
A, Myeloma cast nephropathy. The arrow indicates a multinucleated
giant cell. B, Light chain deposition disease. Note the changes indica-
tive of chronic TIN and light chain deposition along the tubular
basement membrane (dark purple). C, Immunofluorescent stain
for  light chain deposition along the tubular basement membrane.
The renal complications of multiple myeloma are a major risk factor
in the morbidity and mortality of this neoplastic disorder. Whereas
the pathogenesis of renal involvement is multifactorial (hypercal-
cemia and hyperuricemia), it is the lesions that result from the
excessive production of light chains that cause chronic TIN. These
lesions are initiated by the precipitation of the light chain dimers in
the distal tubules and result in what has been termed myeloma cast
nephropathy. The affected tubules are surrounded by multinucleated
giant cells. Adjoining tubules show varying degrees of atrophy. The
A propensity of light chains to lead to myeloma cast nephropathy
appears to be related to their concentration in the tubular fluid,
the tubular fluid pH, and their structural configuration. This
propensity accounts for the observation that increasing the flow
rate of urine or its alkalinization will prevent or reverse the casts
in their early stages of formation.
Direct tubular toxicity of light chains also may contribute to
tubular injury.  Light chains appear to be more injurious than are
 light chains. Binding of human  and  light chains to human
and rat proximal tubule epithelial cell brush-border membrane has
been demonstrated. Epithelial cell injury associated with the
absorption of these light chains in the proximal tubules has been
implicated in the pathogenesis of cortical TIN. Another mechanism
relates to the perivascular deposition of paraproteins, either as
amyloid fibrils that are derived from  chains or as fragments of
light chains that are derived from kappa chains, and produce the
so-called light chain deposition disease.
B Of the various lesions, myeloma cast nephropathy appears to be
the most common, being observed at autopsy in one third of cases,
followed by amyloid deposition, which is present in 10% of cases.
Light chain deposition is relatively rare, being present in less than
5% of cases.

C
6.18 Tubulointerstitial Disease

Metabolic Disorders
Hyperuricemia

A B
FIGURE 6-30
A, Intratubular deposits of uric acid. B, Gouty tophus in the renal hyperacidity of their urine caused by an inherent abnormality in
medulla. The kidney is the major organ of urate excretion and a the ability to produce ammonia. The acidity of urine is important
primary target organ affected in disorders of its metabolism. Renal because uric acid is 17 times less soluble than is urate. Therefore,
lesions result from crystallization of urate in the urinary outflow uric acid facilitates precipitation in the distal nephron of persons
tract or the renal parenchyma. Depending on the load of urate, who do not overproduce uric acid but who have a persistently
one of three lesions result: acute urate nephropathy, uric acid acidic urine.
nephrothiasis, or chronic urate nephropathy. Whereas any of these The previous notion that chronic renal disease was common in
lesions produce tubulointerstitial lesions, it is those of chronic patients with hyperuricemia is now considered doubtful in light of
urate nephropathy that account for most cases of chronic TIN. prolonged follow-up studies of renal function in persons with
The principal lesion of chronic urate nephropathy is due to hyperuricemia. Renal dysfunction could be documented only when
deposition of microtophi of amorphous urate crystals in the inter- the serum urate concentration was more than 10 mg/dL in women
stitium, with a surrounding giant-cell reaction. An earlier change, and more than 13 mg/dL in men for prolonged periods. The deteri-
however, probably is due to the precipitation of birefringent uric oration of renal function in persons with hyperuricemia of a lower
acid crystals in the collecting tubules, with consequent tubular magnitude has been attributed to the higher than expected occur-
obstruction, dilatation, atrophy, and interstitial fibrosis. The renal rence of concurrent hypertension, diabetes mellitus, abnormal lipid
injury in persons who develop lesions has been attributed to metabolism, and nephrosclerosis.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.19

Hyperoxaluria

A B
FIGURE 6-31 (see Color Plate)
A, Calcium oxalate crystals (arrow) seen on light microscopy. B, Dark chronic. As a result, interstitial fibrosis, tubular atrophy, and dilation
field microscopy. When hyperoxaluria is sudden and massive (such as result in chronic TIN with progressive renal failure. The propensity
after ethylene glycol ingestion) acute renal failure develops. Other- for recurrent calcium oxalate nephrolithiasis and consequent obstruc-
wise, in most cases of hyperoxaluria the overload is insidious and tive uropathy contribute to the tubulointerstitial lesions.

Granulomatous Diseases
Malacoplakia
hallmark of certain forms of tubulointerstitial
3 5 disease. The best-known form is that of
sarcoidosis. Interstitial granulomatous reac-
tions also have been noted in renal tuberculo-
sis, xanthogranulomatous pyelonephritis,
1 2 7 renal malacoplakia, Wegener’s granulo-
matosis, renal candidiasis, heroin abuse,
hyperoxaluria after jejunoileal bypass
surgery, and an idiopathic form in associa-
tion with anterior uveitis.
The inflammatory lesions of malacoplakia
principally affect the urinary bladder but
may involve other organs, most notably the
kidneys. The kidney lesions may be limited
to one focus or may be multifocal. In three
fourths of cases the renal involvement is
4 6 multifocal, and in one third of cases both
kidneys are involved. The lesions are nodular,
well-demarcated, and variable in size. They
FIGURE 6-32 may coalesce, developing foci of suppura-
Schematic representation of the forms and course of renal involvement by malacoplakia: tion that may become cystic or calcified.
1, normal kidney; 2, enlarged kidney resulting from interstitial nephritis without nodularity; The lesions usually are located in the cortex
3, unifocal nodular involvement; 4, multifocal nodular involvement; 5, abscess formation but may be medullary and result in papillary
with perinephric spread of malacoplakia; 6, cystic lesions; and 7, atrophic multinodular necrosis. (From Dobyan and coworkers [7];
kidney after treatment. Interstitial granulomatous reactions are a rare but characteristic with permission.)
6.20 Tubulointerstitial Disease

Endemic Diseases
in a geographic area bordering the Danube River as it traverses
Romania, Bulgaria, and the former Yugoslavia. The cause of
Balkan nephropathy is unknown; however, it has been attributed
to genetic factors, heavy metals, trace elements, and infectious
agents. The disease evolves in emigrants from endemic regions,
suggesting a role for inheritance or the perpetuation of injury
sustained before emigration.
Initially thought to be restricted to Scandinavian countries, and
thus termed Scandinavian acute hemorrhagic interstitial nephritis,
Nephropathia epidemica has been shown to have a more universal
occurrence. It therefore has been more appropriately renamed hem-
orrhagic fever with renal syndrome. As a rule the disease presents
as a reversible acute tubulointerstitial nephritis but can progress to
a chronic form. It is caused by a rodent-transmitted virus of the
Hantavirus genus of the Bunyaviridae family, the so-called Hantaan
virus. Humans appear to be infected by respiratory aerosols conta-
minated by rodent excreta. Antibodies to the virus are detected in
FIGURE 6-33 the serum, and viruslike structures have been demonstrated in the
Hemorrhagic TIN associated with Hantavirus infection. Two kidneys of persons infected with the virus.
endemic diseases in which tubulointerstitial lesions are a predomi- Tubulointerstitial nephropathy caused by viral infection also has
nant component are Balkan nephropathy and nephropathia epi- been reported in polyomavirus, cytomegalovirus, herpes simplex
demica. Endemic Balkan nephropathy is a progressive chronic virus, human immunodeficiency virus, infectious mononucleosis,
tubulointerstitial nephritis whose occurrence is mostly clustered and Epstein-Barr virus.

Hereditary Diseases
Hereditary Nephritis

A B
FIGURE 6-34
A, Interstitial foam cells in Alport’s syndrome. B, Late phase Alport’s associated epithelial cell proliferation account for cyst formation. It
syndrome showing chronic TIN and glomerular changes in a patient is the continuous growth of cysts and their progressive dilation that
with massive proteinuria. Tubulointerstitial lesions are a prominent cause pressure-induced ischemic injury, with consequent TIN of the
component of the renal pathology of a variety of hereditary diseases adjacent renal parenchyma.
of the kidney, such as medullary cystic disease, familial juvenile Tubulointerstitial lesions also are a salient feature of inherited
nephronophthisis, medullary sponge kidney, and polycystic kidney diseases of the glomerular basement membrane. Notable among
disease. The primary disorder of these conditions is a tubular defect them are those of hereditary nephritis or Alport’s syndrome, in
that results in the cystic dilation of the affected segment in some which a mutation in the encoding gene localized to the X chromo-
patients. Altered tubular basement membrane composition and some results in a defect in the -5 chain of type IV collagen.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.21

Papillary Necrosis

A B
FIGURE 6-35
A, Renal papillary necrosis. The arrow points to the either one or both kidneys. The lesions are bilateral in
region of a sloughed necrotic papilla. B, Whole mount of most patients. In patients with involvement of one kid-
a necrotic papilla. Arrows delineate focal necrosis princi- ney at the time of initial presentation, RPN will devel-
pally affecting the medullary inner stripe. Renal papillary op in the other kidney within 4 years, which is not
necrosis (RPN) develops in a variety of diseases that unexpected because of the systemic nature of the dis-
cause chronic tubulointerstitial nephropathy in which the eases associated with RPN. RPN may be unilateral in
lesion is more severe in the inner medulla. The basic patients in whom predisposing factors (such as infec-
lesion affects the vasculature with consequent focal or tion and obstruction) are limited to one kidney.
diffuse ischemic necrosis of the distal segments of one or Azotemia may be absent even in bilateral papillary
more renal pyramids. In the affected papilla, the sharp necrosis, because it is the total number of papillae
demarcation of the lesion and coagulative necrosis seen involved that ultimately determines the level of renal
in the early stages of the disease closely resemble those of insufficiency that develops. Each human kidney has an
infarction. The fact that the necrosis is anatomically lim- average of eight pyramids, such that even with bilateral
ited to the papillary tips can be attributed to a variety of RPN affecting one papilla or two papillae in each kid-
features unique to this site, especially those affecting the ney, sufficient unaffected renal lobules remain to main-
vasculature. The renal papilla receives its blood supply tain an adequate level of renal function.
from the vasa recta. Measurements of medullary blood As a rule, RPN is a disease of an older age group,
flow notwithstanding, it should be noted that much of the average age of patients being 53 years. Nearly half
the blood flow in the vasa recta serves the countercur- of cases occur in persons over 60 years of age. More
rent exchange mechanism. Nutrient blood supply is pro- than 90% of cases occur in persons over 40 years of
vided by small capillary vessels that originate in each age, except for those caused by sickle cell hemoglo-
given region. The net effect is that the blood supply to binopathy. RPN is much less common in children, in
the papillary tip is less than that to the rest of the medul- whom the chronic conditions associated with papil-
la, hence its predisposition to ischemic necrosis. lary necrosis are rare. However, RPN does occur in
The necrotic lesions may be limited to only a few of children in association with hypoxia, dehydration,
the papillae or may involve several of the papillae in and septicemia.
6.22 Tubulointerstitial Disease

Total Papillary Necrosis

into the pelvis and may be recovered in the
Renal Papillary Necrosis– Papillary Form urine. In most of these cases, however, the
necrotic papillae are not sloughed but are
Lesion Pyelogram
either resorbed or remain in situ, where
Normal they becomes calcified or form the nidus of
Early necrosis, mucosa Normal calyx
normal, papilla swollen. a calculus. In these patients, excretory radio-
logic examination and computed tomogra-
Progressive necrosis, Irregular or phy scanning are diagnostic. Unfortunately,
swelling, mucosal loss. fuzzy calyx these changes may not be evident until the
late stages of RPN, when the papillae
Sequestrian of necrotic Sinus or already are shrunken and sequestered. In
area. "Arc Shadow" fact, even when the papillae are sloughed
out, excretory radiography can be negative.
Sinus formation begins.
The passage of sloughed papillae is
Sinus surrounds "Ring Shadow" associated with lumbar pain, which is
sequestrum. indistinguishable from ureteral colic of
any cause and is present in about half of
Sequestrum extruded "Clubbing" patients. Oliguria occurs in less than 10%
or resorbed. "Clubbed calyx" of patients. A definitive diagnosis of RPN
"Caliectasis" can be made by finding portions of necrotic
papillae in the urine. A deliberate search
Sequestrum calcifies. "Ring Shadow" should be made for papillary fragments in
Obstruction urine collected during or after attacks of
Extruded sequestrum colicky pain of all suspected cases, by
straining the urine through filter paper or a
piece of gauze. The separation and passage
FIGURE 6-36 of papillary tissue may be associated with
Schematic of the progressive stages of the papillary form of renal papillary necrosis and hematuria, which is microscopic in some
their associated radiologic changes seen on intravenous pyelography. Papillary necrosis 40% to 45% of patients and gross in 20%.
occurs in one of two forms. In the medullary form, also termed partial papillary necrosis, The hematuria can be massive, and occa-
the inner medulla is affected; however, the papillary tip and fornices remain intact. In the sionally, instances of exsanguinating hemor-
papillary form, also termed total papillary necrosis, the calyceal fornices and entire papillary rhage requiring nephrectomy have been
tip are necrotic. In total papillary necrosis shown here, the lesion is characterized from the reported. (From Eknoyan and coworkers
outset by necrosis, demarcation, and sequestration of the papillae, which ultimately slough [8]; with permission.)

FIGURE 6-37
Renal Papillary Necrosis – Medullary Form Schematic of the progressive stages of the
medullary form of renal papillary necrosis
Normal Lesion Pyelogram
and their associated radiologic appearance
Early focal, necrosis Normal calyx seen on intravenous pyelography. In par-
of medullary inner tial papillary necrosis the lesion begins as
stripe. focal necrosis within the substance of the
medullary inner stripe. The lesion pro-
Progressive necrosis, Normal calyx gresses by coagulative necrosis to form a
coalescence of necrotic sinus to the papillary tip, with subsequent
areas. Swelling. Mucosa extrusion or resorption of the sequestered
normal. necrotic tissue. The medullary form of
papillary necrosis is commonly encoun-
Mucosal break. Sinus
tered in persons with sickle cell hemoglo-
Sequestration
binopathy. The incidence of radiographi-
and sinus formation.
cally demonstrative papillary necrosis is
Progressive sequestration, Irregular sinus as high as 33% to 65% in such persons.
extrusion, or resorption
of necrotic tissue.

Healing. Irregular Irregular

medullary cavity with medullary
communicating cavity
sinus tract.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.23

avoided in these patients because of dye-induced nephrotoxicity.

When sought, papillary necrosis has been reported in as many as
CONDITIONS ASSOCIATED WITH
25% of cases. Analgesic nephropathy accounts for 15% to 25%
RENAL PAPILLARY NECROSIS
of papillary necrosis in the United States but accounts for as much
as 70% of cases in countries in which analgesic abuse is common.
Papillary necrosis also has been reported in patients receiving non-
Diabetes mellitus
steroidal anti-inflammatory drugs.
Urinary tract obstruction
Sickle hemoglobinopathy is another common cause of papillary
Pyelonephritis necrosis, which, when sought by intravenous pyelography, is detected
Analgesic nephropathy in well over half of cases.
Sickle hemoglobinopathy Infection is usually but not invariably a concomitant finding in
Rejection of transplanted kidney most cases of RPN. In fact, with few exceptions, most patients
Vasculitis with RPN ultimately develop a urinary tract infection, which
Miscellaneous represents a complication of papillary necrosis: that is, the infec-
tion develops after the primary underlying disease has initiated
local injury to the renal medulla, with foci of impaired blood flow
and poor tubular drainage. Infection contributes significantly to
FIGURE 6-38 the symptomatology of RPN, because fever and chills are the pre-
Diabetes mellitus is the most common condition associated with senting symptoms in two thirds of patients and a positive urine
papillary necrosis. The occurrence of capillary necrosis is likely culture is obtained in 70%. However, RPN is not an extension of
more common than is generally appreciated, because pyelography severe pyelonephritis. In most patients with florid acute
(the best diagnostic tool for detection of papillary necrosis) is pyelonephritis, RPN does not occur.

FIGURE 6-39
Spectrum of Renal Papillary Necrosis
Spectrum and overlap of diseases principally associated with renal papillary necrosis
(RPN). Although each disease can cause RPN, it is their coexistence (darkly shaded areas)
that increases the risk, which is even greater after the onset of infection (lightly shaded
Obstruction areas). In most cases of RPN, more than one of the conditions associated with RPN is pre-
sent. Thus, in most cases, the lesion seems to be multifactorial in origin. The pathogenesis
of the lesion may be considered the result of an overlapping phenomenon, in which a com-
bination of detrimental factors appear to operate in concert to cause RPN. As such,
Sickle whereas each of the conditions alone can cause RPN, the coexistence of more than one
Diabetes Infection
Hgb predisposing factor in any one person significantly increases the risk for RPN. The contri-
bution of any one of these factors to RPN would be expected to differ among individuals
and at various periods during the course of the disease. To the extent that the natural
course of RPN itself predisposes patients to development of infection of necrotic foci and
Analgesic obstruction by sloughed papillae, it may be difficult to assign a primary role for any of
abuse
these processes in an individual patient. Furthermore, the occurrence of any of these fac-
tors (necrosis, obstruction, or infection) may itself initiate a vicious cycle that can lead to
another of these factors and culminate in RPN.

References
1. Bohman S: The ultrastructure of the renal interstitium. Contemp 5. Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional
Issues Nephrol 10:1–34, 1983. correlations in renal disease II. The correlations. Hum Pathol 1970,
2. Lemley KV, Kriz W: Anatomy of the renal interstitium. Kidney Int 1:631–641.
1991, 39:370–381. 6. DeBroe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med
3. Eknoyan G: Chronic tubulointerstitial nephropathies. In Diseases of 1998, 338:446–451.
the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: 7. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia reap-
Little Brown; 1997:1983–2015. praised. Am J Kidney Dis 1993, 22:243–252.
4. Palmer BF: The renal tubule in the progression of chronic renal fail- 8. Eknoyan G, Qunibi WY, Grissom RT, et al.: Renal papillary necrosis:
ure. J Invest Med 1997, 45:346–361. an update. Medicine 1982, 61:55–73.
6.24 Tubulointerstitial Disease

Selected Bibliography
Renal Interstitium Drugs
Neilson EG: Symposium on the cell biology of tubulointerstitium. Kidney Boton R, Gaviria M, Battle DC: Prevalence, pathogenesis, and treatment
Int 1991, 39:369–556. of renal dysfunction associated with chronic lithium therapy. Am J
Strutz F, Mueller GA: Symposium on Renal Fibrosis: prevention and pro- Kidney Dis 1990, 10:329–345.
gression. Kidney Int 1996, 49(suppl 54):1–90. Myer BD, Newton L: Cyclosporine induced chronic nephropathy: an obliter-
ative microvascular renal injury. J Am Soc Nephrol 1991, 2(suppl 1):4551.
Chronic Tubulointerstitial Nephritis
Eknoyan G, McDonald MA, Appel D, Truong LD: Chronic tubulointersti- Heavy Metals
tial nephritis: correlation between structural and functional findings. Batuman V: Lead nephropathy, gout, hypertension. Am J Med Sci 1993,
Kidney Int 1990, 38:736–743. 305:241–247.
Jones CL, Eddy AA: Tubulointerstitial nephritis. Ped Nephrol 1992, Batuman V, Maesaka JK, Haddad B et al.: Role of lead in gouty nephropathy.
6:572–586. N Engl J Med 1981, 304:520–523.
Nath KA: Tubulointerstitial changes as a major determinant in progression Fowler BA: Mechanisms of kidney cell injury from metals. Environ Health
of renal damage. Am J Kidney Dis 1992, 20:1–17. Perspec 1993, 100:57–63.
Hu H: A 50-year follow-up of childhood plumbism. Hypertension, renal
Pathogenesis function and hemoglobin levels among survivors. Am J Dis Child 1991,
Bohle A, Muller GA, Wehrmann M et al.: Pathogenesis of chronic renal 145:681–687.
failure in the primary glomerulopathies, renal vasculopathies and
Staessen JA, Lauwerys RR, Buchet JP et al.: Impairment of renal function
chronic interstitial nephritides. Kidney Int 1996, 49(suppl 54):2–9.
with increasing lead concentrations in the general population. N Engl J
Dodd S: The pathogenesis of tubulointerstitial disease and mechanisms of Med 1992, 327:151–156.
fibrosis. Curr Top Pathol 1995, 88:117–143.
Vedeen RP: Environmental renal disease: lead. cadmium, and Balkan
Haggerty DT, Allen DM: Processing and presentation of self and foreign endemic nephropathy. Kidney Int 34(suppl):4–8.
antigens by the renal proximal tubule. J Immunol 1992, 148:2324–2331.
Nath KA: Reshaping the interstitium by platelet-derived growth factor. Impli-
Ischemic Vascular Disease
cations for progressive renal disease. Am J Path 1996, 148:1031–1036.
Freedman BI, Ishander SS, Buckalew VM et al.: Renal biopsy findings in
Sedor JR: Cytokines and growth factors in renal injury. Semin Nephrol presumed hypertensive nephrosclerosis. Am J Nephrol 1994, 14:90–94.
1992, 12:428–440.
Meyrier A, Simon P: Nephroangiosclerosis and hypertension: things are
Wilson CB: Nephritogenic tubulointers-titial antigens. Kidney Int 1991, not as simple as you might think. Nephrol Dial Transplant 1996,
39:501–517. 11:2116–1220.
Yamato T, Noble NA, Miller DE, Border WA: Sustained expression of Schlesinger SD, Tankersley MR, Curtis JJ: Clinical documentation of end
TGF-B1 underlies development of progressive kidney fibrosis. Kidney stage renal disease due to hypertension. Am J Kidney Dis 1994,
Int 1994, 45:916–927. 23:655–660.

Correlation with Renal Failure Obstructive Nephropathy

D’Amico G, Ferrario F, Rastaldi MP: Tubulointerstitial damage in glomerular Arant BS Jr: Vesicoureteric reflux and renal injury. Am J Kidney Dis 1991,
diseases: its role in the progression of renal damage. Am J Kidney Dis 17:491–511.
1995, 26:124–132.
Diamond JR: Macrophages and progressive renal disease in experimental
Eddy AA: Experimental insights into tubulointerstitial disease accompany- hydronephrosis. Am J Kidney Dis 1995, 26:133–140.
ing primary glomerular lesions. J Am Soc Nephrol 1994, 5:1273–1287.
Klahr S: New insight into consequences and mechanisms of renal impair-
Magil AB: Tubulointerstitial lesions in human membranous glomeru-
ment in obstructive nephropathy. Am J Kidney Dis 1991, 18:689–699.
lonephritis: relationship to proteinuria. Amer J Kidney Dis 1995,
25:375–379.
Hematologic Diseases
Allon M: Renal abnormalities in sickle cell disease. Arch Intern Med 1990,
Analgesic Nephropathy 150:501–504.
Henrich WL, Agodoa LE, Barrett B, Bennett WM et al.: Analgesics and the
Kidney. Summary and Recommendations to the Scientific Advisory Falk RJ, Scheinmann JI, Phillips G et al.: Prevalence and pathologic fea-
Board of the National Kidney Foundation. Am J Kidney Dis 1996, tures of sickle cell nephropathy and response to inhibition of
27:162–165 angiotensin converting enzyme. N Engl J Med 1992, 326:910–915.
Nanra RS: Pattern of renal dysfunction in analgesic nephropathy. Comparison Ivanyi B: Frequency of light chain deposition nephropathy relative to renal
with glomerulonephritis. Nephrol Dialysis Transpl 1992, 7:384–390. amyloidosis and Bence Jones cast nephropathy in a necropsy study of
Noels LM, Elseviers NM, DeBroe ME: Impact of legislative measures of patients with myeloma. Arch Pathol Lab Med 1990, 114:986–987.
the sales of analgesics and the subsequent prevalence of analgesic Rota S, Mougenot B, Baudouin M: Multiple myeloma and severe renal
nephropathy: a comparative study in France, Sweden and Belgium. failure: a clinicopathologic study of outcome and prognosis in 34
Nephrol Dial Transplant 1995, 10:167–174. patients. Medicine 1987, 66:126–137.
Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated with Sanders PW, Herrera GA, Kirk KA: Spectrum of glomerular and tubuloint-
the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory erstitial renal lesions associated with monotypical immunoglobulin light
drugs. N Engl J Med 1994, 331:1675–1679. chain deposition. Lab Invest 1991, 64:527–537.
Sandler DP, Burr FR, Weinberg CR: Nonsteroidal anti-inflammatory drugs
and risk of chronic renal failure. Ann Intern Med 1991, 115:165–172.
Sandler DP, Smith JC, Weinberg CR et al.: Analgesic use and chronic renal
disease. N Engl J Med 1989, 320:1238–1243.
 Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.25

Metabolic Disorders Viral Infections

Chaplin AJ: Histopathological occurrence and characterization of calcium Ito M, Hirabayashi N, Uno Y: Necrotizing tubulointerstitial nephritis asso-
oxalate. A review. J Clin Pathol 1977, 30:800–811. ciated with adenovirus infection. Human Pathol 1991, 22:1225–1231.
Foley RJ, Weinman EJ: Urate nephropathy. Am J Med Sci 1984, Papadimitriou M.: Hantavirus nephropathy. Kidney Int 1995, 48:887–902.
288:208–211.
Hanif M, Mobarak MR, Ronan A: Fatal renal failure caused by diethylene Hereditary Diseases
glycol in paracetamol elixir: the Bangladesh epidemic. Br Med J 1995, Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney.
311:88–91. Kidney Int 1994, 46:951–964.
Schneider JA, Lovell H, Calhoun F: Update on nephropathic cystinosis. Gabow PA, Johnson AM, Kaehny VM: Factors affecting the progression
Ped Nephrol 1990, 4:645–653. of renal disease in autosomal-dominant polycystic kidney disease.
Kidney Int 1992, 41:1311–1319.
Zawada ET, Johnson VH, Bergstein J: Chronic interstitial nephritis. Its
Gregory MC, Atkin CL: Alports syndrome, Fabry’s disease and nail patella
occurrence with oxalosis and antitubular basement membrane antibod- syndrome. In Diseases of the Kidney, edn 6. Edited by Schrier RW,
ies after jejunal bypass. Arch Pathol Ub Med 1981, 105:379–383. Gottschalk CW. Boston: Little Brown; 1997:561–590.

Granulomatous Diseases Papillary Necrosis

Mignon F, Mery JP, Mougenot B, et al.: Granulomatous interstitial nephri- Griffin MD, Bergstralk EJ, Larson TS: Renal papillary necrosis. A sixteen
tis. Adv Nephrol 1984, 13:219–245. year clinical experience. J Am Soc Nephrol 1995, 6:248–256.
Viero RM, Cavallo T: Granulomatous interstitial nephritis. Hum Pathol Sabatini S, Eknoyan G, editors: Renal papillary necrosis. Semin Nephrol
1995, 26:1345–1353. 1984, 4:1–106.
Urinary Tract Infection
Alain Meyrier

T
he concern of renal specialists for urinary tract infections
(UTIs) had declined with the passage of time. This trend is now
being reversed, owing to new imaging techniques and to sub-
stantial progress in the understanding of host-parasite relationships,
of mechanisms of bacterial uropathogenicity, and of the inflammatory
reaction that contributes to renal lesions and scarring.
UTIs account for more than 7 million visits to physicians’ offices and
well over 1 million hospital admissions in the United States annually
[1]. French epidemiologic studies evaluated its annual incidence at
53,000 diagnoses per million persons per year, which represents
1.05% to 2.10% of the activity of general practitioners. In the United
States, the annual number of diagnoses of pyelonephritis in females
was estimated to be 250,000 [2].
The incidence of UTI is higher among females, in whom it commonly
occurs in an anatomically normal urinary tract. Conversely, in males
and children, UTI generally reveals a urinary tract lesion that must be
identified by imaging and must be treated to suppress the cause of
infection and prevent recurrence. UTI can be restricted to the bladder
(essentially in females) with only superficial mucosal involvement, or
it can involve a solid organ (the kidneys in both genders, the prostate
in males). Clinical signs and symptoms, hazards, imaging, and treatment
of various types of UTIs differ. In addition, the patient’s background
helps to further categorize UTIs according to age, type of urinary tract
lesion(s), and occurrence in immunocompromised patients, especially
with diabetes or pregnancy. Such various forms of UTI explain the
wide spectrum of treatment modalities, which range from ambulatory,
single-dose antibiotic treatment of simple cystitis in young females, to
rescue nephrectomy for pyonephrosis in a diabetic with septic shock.
This chapter categorizes the various forms of UTI, describes progress
in diagnostic imaging and treatment, and discusses recent data on
bacteriology and immunology. CHAPTER

7
7.2 Tubulointerstitial Disease

Diagnosis
would be the only way of proving it. Urinary tract infection
(UTI) cannot be identified simply by the presence of bacteria in
a voided specimen, as micturition flushes saprophytic urethral
organisms along with the urine. Thus a certain number of colony-
forming units of uropathogens are to be expected in the urine
sample. Midstream collection is the most common method of
urine sampling used in adults. When urine cannot be studied
without delay, it must be stored at 4ºC until it is sent to the
bacteriology laboratory. The urine test strip is the easiest means
of diagnosing UTI qualitatively. This test detects leukocytes and
nitrites. Simultaneous detection of the two is highly suggestive of
UTI. This test is 95% sensitive and 75% specific, and its negative
A B C predictive value is close to 96% [3]. The test does not, however,
detect such bacteria as Staphyloccocus saprophyticus, a strain
responsible for some 3% to 7% of UTIs. Thus, treating UTI sole-
FIGURE 7-1 ly on the basis of test strip risks failure in about 15% of simple
Urine test strips. Normal urine is sterile, but suprapubic aspira- community-acquired infections and a much larger proportion of
tion of the bladder, which is by no means a routine procedure, UTIs acquired in a hospital.

immersed in the urine, shaken, and incu-

Schematic set up of bated overnight.
a dip-slide container Interpretation after 24-hour incubation at 37°C The most specific results, however, are
provided by laboratory analysis, which
Paddle-holding Nonsignificant Significant
stopper
allows precise counting of bacteria and
leukocytes. Normal values for a midstream
specimen are less than or equal to 105
Escherichia coli organisms and 104 leuko-
cytes per milliliter. These classical “Kass cri-
Agar
teria,” however, are not always reliable. In
some cases of incipient cystitis the number
of E. coli per milliliter can be lower, on the
order of 102 to 104 [4]. When fecal conta-
Moist sponge 103 104 105 106 107
mination has been ruled out, growth of
bacteria that are not normally urethral
saprophytes indicates infection. This is the
FIGURE 7-2 case for Pseudomonas, Klebsiella,
Culture interpretation. Urinalysis must examine bacterial and leukocyte counts Enterobacter, Serratia, and Moraxella,
(per milliliter). An approximate way of estimating bacterial counts in the urine uses among others, especially in a hospital set-
a dip-slide method: a plastic paddle covered on both sides with culture medium is ting or after urologic procedures.
 Urinary Tract Infection 7.3

FIGURE 7-3
CAUSES OF ASEPTIC LEUKOCYTURIA Leukocyturia. A significant number of leukocytes (more than 10,000
per milliliter) is also required for the diagnosis of urinary tract infec-
tion, as it indicates urothelial inflammation. Abundant leukocyturia
Self-medication before urine culture can originate from the vagina and thus does not necessarily indicate
Sample contamination by cleansing solution aseptic urinary leukocyturia [1]. Bacterial growth without leukocy-
Vaginal discharge
turia indicates contamination at sampling. Significant leukocyturia
without bacterial growth (aseptic leukocyturia) can develop from
Urinary stone
various causes, among which self-medication before urinalysis is the
Urinary tract tumor
most common.
Chronic interstitial nephritis (especially due to analgesics)
Fastidious microorganisms requiring special culture medium (Ureaplasma urealyticum,
Chlamydia, Candida)

Bacteriology
FIGURE 7-4
A. MAIN MICROBIAL STRAINS RESPONSIBLE Principal pathogens of urinary tract infection (UTI). A and B, Most
FOR URINARY TRACT INFECTION pathogens responsible for UTI are enterobacteriaceae with a high pre-
dominance of Escherichia coli. This is especially true of spontaneous
UTI in females (cystitis and pyelonephritis). Other strains are less
First Episode or Relapse Due to common, including Proteus mirabilis and more rarely gram-positive
Microbial Strain Delayed Relapse Early Reinfection microbes. Among the latter, Staphylococcus saprophyticus deserves
special mention, as this gram-positive pathogen is responsible for 5%
Escherichia coli 71%–79% 60% to 15% of such primary infections, is not detected by the leukocyte
Proteus mirabilis 1.1%–9.7% 15% esterase dipstick, and is resistant to antimicrobial agents that are
Klebsiella — 20% active on gram-negative rods.
Enterobacter 1.0%–9.2% — C, Acute simple pyelonephritis is a common form of upper UTI
Enterococcus 1.0%–3.2% — in females and results from the encounter of a parasite and a host.
Staphylococcus saprophyticus 3%–7% — In the absence of urologic abnormality, this renal infection is most-
Other species 2%–6% 5% ly due to uropathogenic strains of bacteria [5,6], a majority of
cases to community-acquired E. coli. The clinical picture consists
of fever, chills, renal pain, and a general discomfort. Tissue inva-
sion is associated with a high erythrocyte sedimentation rate and
C-reactive protein level well above 2 mg/dL.

100 Minimum
Maximum

Other E. coli
5% 60%
Percent

50

P. mirabilis
15%

Klebsiella
20%
0
E. coli P. mirabilis Klebsiella Enterococcus S. saprophyticus Other
B Enterobacter C
7.4 Tubulointerstitial Disease

Virulence Factors of Uropathogenic Strains

Escherichia coli
Fimbriae P S Type 1

Flagella

Hemolysin
Aerobactin
+
Fe3+ Na+ Na

Erythrocyte

FIGURE 7-6
An electron microscopic view of an Escherichia coli organism
FIGURE 7-5 showing the fimbriae (or pili) bristling from the bacterial cell.
Bacterial uropathogenicity plays a major role in host-pathogen inter-
actions that lead to urinary tract infection (UTI). For Escherichia
coli, these factors include flagella necessary for motility, aerobactin
necessary for iron acquisition in the iron-poor environment of the
urinary tract, a pore-forming hemolysin, and, above all, presence of
adhesins on the bacterial fimbriae, as well as on the bacterial cell
surface. (From Mobley et al. [7]; with permission.)

FIGURE 7-8
Proteus mirabilis Staghorn calculi.
Fimbriae MR/P PMF ATF NAF Ammonium genera-
tion alkalinizes the
urine, creating
Urease
Deaminase [Keto acid]3Fe3+ conditions favorable
Flagella for build-up of
2+
Ni Amino acid
voluminous struvite
Urea NH3+CO2 stones, which can
Na+ progressively invade
IgA protease Hemolysin
the entire pyeloca-
lyceal system, form-
ing staghorn calculi.
These stones are an
Renal epithelial cell endless source of
microbes, and the
urinary tract
obstruction per-
petuates infection.
FIGURE 7-7
Proteus mirabilis is endowed with other nonfimbrial virulence factors,
including the property of secreting urease, which splits urea into NH3
and CO2.
 Urinary Tract Infection 7.5

Fimbrial adhesive structures Nonfimbrial

Type P Fimbriae Type 1 Fimbriae adhesive structure
Adhesin PapG FimH
PapF FimH, FimG
Fibrillum PapE FimF, FimG

FimA
PapK ~100
FimA

Rigid fiber
PapA
Adhesins

PapH

FIGURE 7-10
Pilin
Uropathogenic strains of Escherichia coli readily adhere to epithelial
Minor subunits
Adhesin cells. This figure shows two epithelial cells incubated in urine infected
with E. coli–carrying pap adhesins. Numerous bacteria are scattered
on the epithelial cell membranes. About half of all cases of cystitis are
FIGURE 7-9 due to uropathogenic strains of E. coli–carrying adhesins. Females
Schematic representation of morphology and composition of type P with primary pyelonephritis and no urologic abnormality harbor a
and type 1 adhesive structures. Bacterial adhesins are paramount in uropathogenic strain in almost 100% of cases [5].
fostering attachment of the bacteria to the mucous membranes of the
perineum and of the urothelium. There are several molecular forms
of adhesins. The most studied is the pap G adhesin, which is located
at the tip of the bacterial fimbriae (or pili). This lectin recognizes
binding site conformations provided by oligosaccharide sequences
present on the mucosal surface [8].

FIGURE 7-11
APPROPRIATE ANTIBIOTICS FOR URINARY TRACT INFECTIONS Appropriate antibiotics for urinary tract
infections (UTI). An appropriate antibiotic
for treating UTI must be bactericidal and
Antibiotics General Indications Pregnancy Prophylaxis conform to the following general specifica-
tions: 1) its pharmacology must include, in
Aminoglycosides + +* - case of oral administration, rapid absorp-
Aminopenicillins +† + - tion and attainment of peak serum concen-
Carboxypenicillins + + -
trations; 2) its excretion must be predomi-
Ureidopenicillins + + -
nantly renal; 3) it must achieve high con-
Quinolones +‡ - +
centrations in the renal or prostate tissue;
Fluoroquinolones +§ - +
4) it must cover the usual spectrum of
Cephalosporins
First generation +¶ + +‡ enterobacteria with reasonable chance of
Second generation + + - being effective on an empirical basis.
Third generation + + - Excluding special considerations for child-
Monobactams + + - hood and pregnancy, several classes of
Carbapenem + + - antibiotics fulfill these specifications and
Cotrimoxazole + - +‡ can be used alone or in combination. The
Fosfomycin trometamole +** - - choice also depends on market availability,
Nitroturantoin +†† - +
cost, patient tolerance, and potential for
inducing emergence of resistant strains.
* Aminoglycosides should not be prescribed during pregnancy except for very severe infection and for the shortest
possible duration.
With the exception of amoxicillin plus clavulanic acid, aminopenicillins should not be prescribed as first-line treatment,
owing to the frequency of primary resistance to this class of antibiotics.
‡ According to antibiotic sensitivity tests.
§ Fluoroquinolones carry a risk of tendon rupture (especially Achilles tendon).
¶ Oral administration only.
** Single-dose treatment of cystitis.
†† Simple cystitis; not pyelonephritis or prostatitis.
7.6 Tubulointerstitial Disease

Classification of Urinary Tract Infection

Upper versus lower urinary tract infection
FIGURE 7-12
Cystitis in a female patient. In case of urinary tract infection (UTI), distinguishing between
lower and upper tract infection is classical, but the distinction is also beside the point. The real
point is to determine whether infection is confined to the bladder mucosa, which is the case in
simple cystitis in females, or whether it involves solid organs (ie, prostatitis or pyelonephritis).
The dots in this figure symbolize the presence of bacteria and leukocytes (ie, infection) in the
relevant organ. Here, infection is confined to the bladder mucosa, which can be severely
inflamed and edematous. This could be reflected radiographically by mucosal wrinkling on
the cystogram. In some cases inflammation is severe enough to be accompanied by bladder
purpura, which induces macroscopic hematuria but is not a particular grave sign.

FIGURE 7-13 FIGURE 7-14 FIGURE 7-15

Prostatitis. Anatomically, prostatitis involves Acute prostatitis can be complicated by Pyelonephritis in females. Essentially, this is
the lower urinary tract, but invasion of ascending infection, that is, pyelonephritis. an ascending infection caused by uropatho-
prostate tissue affords easy passage of gens. From the perineum the bacteria gain
pathogens to the prostatic venous system— access to the bladder, ascending to the renal
and, usually, poor penetration by antibi- pelvocalyceal system and thence to the renal
otics. Presence of bacteria in the bladder is medulla, from which they spread toward the
also symbolized in this picture, but owing to cortex. It has been shown that “pyelitis” can-
free communication between bladder urine not be considered a pathologic entity, as renal
and prostate tissue, it can be accepted that pelvis infection is invariably associated with
pure cystitis does not exist in males. nearby contamination of the renal medulla.
 Urinary Tract Infection 7.7

CRITERIA FOR TISSUE INVASION

Clinical
Kidney or prostate infection is marked by fever over 38°C, chills, and pain. The patient appears acutely ill.
Laboratory
Tissue invasion is invariably accompanied by an erythrocyte sedimentation rate over 20 mm/h and serum C-reactive protein
levels over 2.0 mg/dL. Blood cultures grow in 30%–50% of cases, which in an immunocompetent host indicates simply bac-
teremia, not septicemia. This reflects easy permeability between the urinary and the venous compartments of the kidney.
Imaging
When indicated, ultrasound imaging, tomodensitometry, and scintigraphy provide objective evidence of pyelonephritis.
In case of vesicoureteral reflux, urinary tract infection necessarily involves the upper urinary tract.

FIGURE 7-17
Criteria for tissue invasion.
FIGURE 7-16
Renal abscess formation. As specified else-
where, renal abscess due to enterobacteri-
aceae (as opposed to hematogenous renal
abscess, often of staphylococcal origin) can
be considered a severe form of pyelonephritis
with renal tissue liquefaction, ending in a
walled-off cavity.

Primary versus secondary urinary tract infection

FIGURE 7-19
Cystogram of a
65-year-old woman.
A voluminous blad-
der tumor (arrows)
infiltrates the blad-
der floor and the
initial segment of
the urethra.

FIGURE 7-18
An episode of urinary tract infection (UTI) should prompt considera-
tion of whether it involves a normal urinary tract or, alternatively, if
it is a complication of an anatomic malformation. This is especially
true of relapsing UTI in both genders, and this hypothesis should be
systematically raised in males and in children.
Recurrent cystitis in females can be explained by hymeneal scars
that pull open the urethral outlet during intercourse. Although
rarely, other malformations that promote recurrent female cystitis
are occasionally discovered, such as urethral diverticula (arrows).
Finally, it should be recalled that recurrent or chronic cystitis in an
older woman can also reveal an unsuspected bladder tumor.
7.8 Tubulointerstitial Disease

FIGURE 7-20
Urethrocystogram of a man following acute prostatitis. In males,
acute prostatitis may reveal urethral stenosis. Urethral stenosis is a
good explanation for acute prostatitis. The beaded appearance of the
stenosis (arrow) suggests an earlier episode of gonorrheal urethritis.

pyelonephritis, the possibility of VUR should always be considered.

Childhood vesicoureteral reflux is five times more common in girls
than in boys. It has a genetic background: several cases occasionally
occur in the same family. Unless detected and corrected early, espe-
cially the most severe forms of this class and when urine is infected
(one episode of pyelonephritis suffices), childhood VUR is a major
cause of cortical scarring, renal atrophy, and in bilateral cases chronic
renal insufficiency. The International Reflux Study classifies reflux
grades as follows: I) ureter only; II) ureter, pelvis, and calyces, no
dilation, and normal calyceal fornices; III) mild or moderate dilation
or tortuosity of ureter and mild or moderate dilation of renal pelvis
but no or slight blunting of fornices; IV) moderate dilation or tortu-
I II III IV V osity of ureter and moderate dilation of renal pelvis and calyces,
complete obliteration of sharp angle of fornices but maintenance of
papillary impressions in majority of calyces; V) gross dilation and
FIGURE 7-21 tortuosity of ureter, gross dilation of renal pelvis and calyces. Papillary
The severity of vesicoureteral reflux (VUR) as graded in 1981 by impressions are no longer visible in the majority of calyces. (From
the International Reflux Study Committee. When children have International Reflux Study Committee [9]; with permission.)

A B
FIGURE 7-22
Cystogram demonstrating left ureteral reflux (A). The conse- the adjacent renal tissue. The calyceal cavities are very close to the
quences on the left kidney (B) consist of calyceal distension and a renal capsule, indicating complete cortical atrophy. This picture is
clubbed appearance due to the destruction of the papillae and of typical of chronic pyelonephritis secondary to vesicoureteral reflux.
 Urinary Tract Infection 7.9

FIGURE 7-23 FIGURE 7-24

In case of bilateral, neglected vesicoureteral reflux, chronic pyelone- When intravenous pyelography discloses two ureters, the one draining
phritis is bilateral and asymmetric. Here, the right kidney is globally the lower pyelocalyceal system crosses the upper ureter and opens
atrophic. A typical cortical scar is seen on the outer aspect of the left into the bladder less obliquely than normally, allowing reflux of urine
kidney. The lower pole, however, is fairly well-preserved with nearly and explaining repeated attacks of pyelonephritis followed by atrophy
normal parenchymal thickness. of the lower pole of the kidney. Retrograde cystography is indicated
for repeated episodes of pyelonephritis and when intravenous pyelog-
raphy or computed tomography renal examination discovers cortical
scars. In adults, retrograde cystography is obtained by direct catheter-
ization of the bladder.

FIGURE 7-25 FIGURE 7-26

(see Color Plate) In the paraplegic,
In children, isotopic and more generally
cystography allows in patients with
a diagnosis of vesi- spinal disease,
coureteral reflux neurogenic bladder
with much less radi- is responsible for
ation than if cystog- stasis, bladder
raphy were carried distension, and
out with iodinated diverticula. These
contrast medium. functional and
anatomic factors
explain the frequency
of chronic urinary
tract infection
complicated with
bladder and upper
urinary tract
infectious stones.
7.10 Tubulointerstitial Disease

Imaging

FIGURE 7-27
When acute pyelonephritis occurs in a sound, immunocompetent
female with no history of urologic disease, imaging can be limited
to a plain abdominal film (to rule out renal and ureteral stones) and
renal ultrasonography. Ultrasonography typically discloses a swollen FIGURE 7-28
kidney with loss of corticomedullary differentiation, denoting renal The ultrasound procedure occasionally discloses the cavity of a small
inflammatory edema. Images corresponding to the infected zones renal abscess, a common complication of acute pyelonephritis, even
are more dense than normal renal tissue (arrows). in simple forms.

A B
FIGURE 7-29
Computed tomodensitometry. Simple pyelonephritis does not areas in an edematous, swollen kidney. The pathophysiology of
require much imaging; however, it should be remembered that there hypodense images has been elucidated by animal experiments in
is no correlation between the severity of the clinical picture and the the primates [11] which have shown that renal infection with
renal lesions. Therefore, a diagnosis of “simple” pyelonephritis at uropathogenic Escherichia coli induces intense vasoconstriction.
first contact can be questioned when response to treatment is not Computed tomodensitometric images of acute pyelonephritis can
clear after 3 or 4 days. This is an indication for uroradiologic imag- take various appearances. The most common findings consist of
ing, such as renal tomodensitometry followed by radiography of the one or several wedge-shaped or streaky zones of low attenuation
urinary tract while it is still opacified by the contrast medium. extending from papilla to cortex, A. Hypodense images can be
The typical picture of acute pyelonephritis observed after con- round, B. On this figure, the infected zone reaches the renal cortex
trast medium injection [10] consists of hypodensities of the infected and is accompanied with adjacent perirenal edema. Several such
(Continued on next page)
 Urinary Tract Infection 7.11

C D
FIGURE 7-29 (Continued)
images can coexist in the same kidney, C.
Marked juxtacortical, circumscribed hypo-
dense zones, bulging under the renal cap-
sule, D, usually correspond to lesions close
to liquefaction and should be closely fol-
lowed, as they can lead to abscess forma-
tion and opening into the perinephric space,
E and F. (E and F from Talner et al. [10];
with permission.)

E F

FIGURE 7-30
100 Comparative sensitivity of four diagnostic imaging techniques for
acute pyelonephritis. Renal cortical scintigraphy using 99mTc-dimethyl
86
succinic acid (DMSA) or 99mTc-gluconoheptonate (GH) is very sensi-
75 tive for diagnosing acute pyelonephritis. It entails very little irradiation
as compared with conventional radiography using contrast medium.
Some nephrologists consider 99mTc-DMSA cortical scintigraphy as the
Percent

first-line diagnostic imaging method for renal infection in children. It is

50 42
interesting to compare its sensitivity with that of more conventional
imaging methods. (From Meyrier and Guibert [5]; with permission.)
24

0
Renal CT scan Ultrasonography IVP
scintigraphy (intravenous
pyelography)
7.12 Tubulointerstitial Disease

FIGURE 7-31 (see Color Plate)

99mTc-DMSA cortical imaging of simple pyelonephritis in a female.
The clinical signs implicated the right kidney. (Contrary to conven-
tional radiology, the right kidney appears on the right of the image.)
The false colors indicate cortical renal blood supply from red (nor-
mal) to blue (ischemia). The right kidney is obviously involved
with pyelonephritis, especially its poles. However, contrary to
the results of computed tomography, which indicated right-sided
pyelonephritis only, a focus of infection also occupies the lower pole
of the right kidney. This picture illustrates the greater sensitivity of
renal scintigraphy for diagnosing renal infection. It also indicates
that clinically unilateral acute pyelonephritis can, in fact, be bilateral.

A B
FIGURE 7-32
Renal pathology in acute pyelonephritis. Renal pathology of human the diabetes patient whose kidney is shown here. A, The surgically
acute pyelonephritis is quite comparable to what is observed in removed kidney is swollen, and its surface shows whitish zones.
experimental pyelonephritis in primates [11]. However, our knowl- B, A section of the same organ shows white suppurative areas (scat-
edge of renal pathology in this condition in humans is based mainly tered with small abscesses) extending eccentrically from the medulla
on the most catastrophic cases, which required nephrectomy, like to the cortex. There also were sloughed papillae (see Fig. 7-37).

A B
FIGURE 7-33
Histologic appearance of pyelonephritic kidney. A, The renal tissue comprising a majority of polymorphonuclear leukocytes, induces
is severely edematous and interspersed with inflammatory cells and tubular destruction and is accompanied by a typical infectious cast
hemorrhagic streaks. B, On another section, severe inflammation, in a tubular lumen (arrow).
 Urinary Tract Infection 7.13

FIGURE 7-34
Clinical picture compatible A general algorithm for the investigation
with acute pyelonephritis (APN) and treatment of acute pyelonephritis.
Treatment of acute pyelonephritis is based
Urine culture and cytology on antibiotics selected from the list in
ESR CRP Figure 7-11. Preferably, initial treatment is
based on parenteral administration. It is
Renal Negative.
debatable whether common forms of sim-
Positive
scintigraphy Reconsider Initial
ple pyelonephritis initially require both an
and/or CT scan diagnosis of APN work-up aminoglycoside and another antibiotic.
Initial parenteral treatment for an average
No renal lesion. Renal lesions. Previous No previous of 4 days should be followed by about 10
Seek other Maintain history of history of days of oral therapy based on bacterial
infection diagnosis of APN upper UTI upper UTI sensitivity tests. It is strongly recommended
that urine culture be carried out some 30
to 45 days after the end of treatment, to
Abnormal. Yes Possible urinary Plain abdominal verify that bacteriuria has not recurred.
Call urologist IVP tract obstruction radiograph APN—acute pyelonephritis; ESR—erythro-
or stone? Ultrasonography cyte sedimentation rate; CRP—C-reactive
No protein; UTI—urinary tract infection;
Secondary APN Primary APN IVP—intravenous pyelography. (From
Treat Treat Normal Drug therapy only
cause infection Meyrier and Guibert [5]; with permission.)

Day
Start treatment with first-line antibiotics 1

Good clinical Atypical clinical Further Days

response and imaging
lab. Confirmation of response or 2 to
appropriate initial Wrong initial (IVP, CT) 4 or 5
antibiotic choice antibiotic choice

Continue Adapt Normal. Abnormal. Days

same antibiotic Consider drug Call 5 to 15
treatment treatment intolerance urologist

Day
End treatment 15

Recurrence Verify Between

of bacteriuria urine sterility Sterile days
30 and 45

Radiourological work-up. No further

New treatment investigations or treatment
7.14 Tubulointerstitial Disease

FIGURE 7-35 (see Color Plate)

Renal abscess. Like acute pyelonephritis, one third of cases of renal abscess occur in a nor-
mal urinary tract; in the others it is a complication of a urologic abnormality. The clinical
picture is that of severe pyelonephritis. In fact, it can be conceptualized as an unfavorably
developing form of acute pyelonephritis that progresses from presuppurative to suppurative
renal lesions, leading to liquefaction and formation of a walled-off cavity. The diagnosis of
renal abscess is suspected when, despite adequate treatment of pyelonephritis (described in
Fig. 7-34), the patient remains febrile after day 4. Here, necrotic renal tissue is visible close
to the abscess wall. The tubules are destroyed, and the rest of the preparation shows innu-
merable polymorphonuclear leukocytes within purulent material.

A B
FIGURE 7-36
Renal computed tomography (CT). In addition to ultrasound the renal parenchyma, A, or bulge outward under the renal capsule,
examination, CT is the best way of detecting and localizing a risking rupture into Gerota’s space, B.
renal abscess. The abscess cavity can be contained entirely within
 Urinary Tract Infection 7.15

A B
FIGURE 7-37
Urinary tract infection (UTI) in the immunocompromised host. UTI
results from the encounter of a pathogen and a host. Natural defenses
against UTI rest on both cellular and humoral defense mechanisms.
These defense mechanisms are compromised by diabetes, pregnancy,
and advanced age. Diabetic patients often harbor asymptomatic bac-
teriuria and are prone to severe forms of pyelonephritis requiring
immediate hospitalization and aggressive treatment in an intensive
care unit.
A particular complication of upper renal infection in diabetes is
papillary necrosis (see Fig. 7-32). The pathologic appearance of a
sloughing renal papilla, A. The sloughed papilla is eliminated and can
be recovered by sieving the urine, B. In other cases, the necrotic papil-
la obstructs the ureter, causing retention of infected urine and severely
aggravating the pyelonephritis. C, It can lead to pyonephrosis (ie,
C complete destruction of the kidney), as shown on CT.

FIGURE 7-38
Nonpregnant Pregnant
500 Urinary tract infection (UTI) in an immunocompromised host.
IgG Pregnancy is associated with suppression of the host’s immune
response, in the form of reduced cytotoxic T-cell activity and
reduced circulating immunoglobulin G (IgG) levels. Asymptomatic
0
bacteriuria is common during pregnancy and represents a major
1000 risk of ascending infection complicated by acute pyelonephritis.
IgA
(Continued on next page)
Antibody activity, % of control

500

0
1000
IgM

500

0
0 2 0 2
A Time of sampling, wks
7.16 Tubulointerstitial Disease

Nonpregnant Pregnant
>250
IgG
1000 250

200

500

Levels of IL-6, units/mL

Antibody activity, Abs 405 nm

150

0 100
1000
IgA

50

500 20

20
0
0
0
0 2 0 2 Nonpregnant Pregnant Nonpregnant Pregnant
Time of sampling, wks Serum Urine
B C

FIGURE 7-38 (Continued)

Petersson and coworkers [12] recently demonstrated that the suscepti- The last may indicate that pregnant women have a generally reduced
bility of the pregnant woman to acute UTI is accompanied by reduced level of mucosal inflammation. These factors may be crucial for
serum antibody activity (IgG, IgA, IgM), reduced urine antibody activ- explaining the frequency and the severity of acute pyelonephritis
ity (IgG, IgA), and low interleukin 6 (IL-6) response, A–C, respectively. during pregnancy. (From Petersson et al. [12]; with permission.)

FIGURE 7-39
Acute prostatitis as visualized sonographically. Acute prostatitis
is common after urethral or bladder infection (usually by
Escherichia coli or Proteus organisms). Another cause is prostate
hematogenous contamination, especially by Staphylococcus.
Signs and symptoms of acute prostatitis, in addition to fever,
chills, and more generally the signs and symptoms of tissue inva-
sion by infection described above, are accompanied by dysuria,
pelvic pain, and septic urine. Acute prostatitis is an indication
for direct ultrasound (US) examination of the prostate by
endorectal probe. In this case of acute prostatitis in a young
male, US examination disclosed a prostatic abscess (1) compli-
cating acute prostatitis in the right lobe (2). Acute prostatitis is
an indication for thorough radiologic imaging of the whole uri-
nary tract, giving special attention to the urethra. Urethral stric-
ture may favor prostate infection (see Fig. 7-20).
 Urinary Tract Infection 7.17

Special Forms of Renal Infection

A B
FIGURE 7-40 (see Color Plate)
Xanthogranulomatous pyelonephritis (XPN). XPN is a special obstructive renal stone. Nephrectomy was performed. A, The
form of chronic renal inflammation caused by an abnormal obstructive renal stone is shown by an arrowhead. The renal
immune response to infected obstruction [13]. This case in a cavities are dilated. The xanthogranulomatous tissue (arrows)
middle-aged woman with a long history of renal stones is typical. consists of several round, pseudotumoral masses with a typical
For several months she complained of flank pain, fever, fatigue, yellowish color due to presence of lipids. In some instances such
anorexia and weight loss. Laboratory workup found inflammatory xanthogranulomatous tissue extends across the capsule into the
anemia and increased erythrocyte sedimentation rate and C-reactive perirenal fat and fistulizes into nearby viscera such as the colon
protein levels. Urinalysis showed pyuria and culture grew Escherichia or duodenum. B, Microscopic view of the xanthogranulomatous
coli. CT scan of the right kidney showed replacement of the renal tissue. This part of the lesion is made of lipid structures composed
tissue by several rounded, low-density areas and detected an of innumerable clear droplets.

Spectrum of renal malakoplakia

Mononuclear
cells Interstitial
Inflammation
(nonspecific) nephritis

von Hansemann Megalocytic

Persistent cells interstitial
inflammation (prediagnostic) nephritis
Ca2+

Michaelis-Gutmann
Defective
(MG) bodies Malakoplakia
cell function
(diagnostic)

B
Destuctive
granulomas Fibrosis teroid therapy for autoimmune disease. In 13% of the published cases,
xanthogranulomatous "pseudosarcoma" malakoplakia involved a transplanted kidney. The female-male ratio is
pyelonephritis 3:1. Lesions can involve the kidney, the bladder, or the ureter and form
A
pseudotumors. B, Histologically, malakoplakia is distinguished by
large, pale, periodic acid–Schiff–positive macrophages (von Hanse-
FIGURE 7-41 mann cells) containing calcific inclusions (Michaelis-Gutmann bodies).
Malakoplakia. Malakoplakia (or malacoplakia), like xanthogranulo- The larger ones are often free in the interstitium. Malakoplakia, an
matous pyelonephritis, is also a consequence of abnormal macrophage unusual form of chronic tubulointerstitial nephritis, must be recog-
response to gram-negative bacteria, A. Malakoplakia occurs in associ- nized by early renal biopsy and can resolve, provided treatment
ation with chronic UTI [14]. In more than 20% of cases, affected per- consisting of antibiotics with intracellular penetration is applied for
sons have some evidence of immunosuppression, especially corticos- several weeks. (B, Courtesy of Gary S. Hill, MD.)
7.18 Tubulointerstitial Disease

References
1. Stamm WE, Hooton TM: Management of urinary tract infections in 8. Roberts JA, Marklund BI, Ilver D, et al.: The Gal( 1-4)Gal–
adults. N Engl J Med 1993, 329:1328–1334. specific tip adhesin of Escherichia coli P-fimbriae is needed for
2. Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management pyelonephritis to occur in the normal urinary tract. Proc Natl Acad
of acute pyelonephritis in women: A cohort study. Am J Emerg Med Sci USA 1994, 91:11889–11893.
1994, 12:271–278. 9. International Reflux Study Committee: Medical versus surgical
3. Pappas PG: Laboratory in the diagnosis and management of urinary treatment of primary vesicoureteral reflux. J Urol 1981, 125:277.
tract infections. Med Clin North Am 1991, 75:313–325. 10. Talner LB, Davidson AJ, Lebowitz RL, et al.: Acute pyelonephritis:
4. Kunin CM, VanArsdale White L, Tong HH: A reassessment of the Can we agree on terminology? Radiology 1994, 192:297–306.
importance of “low-count” bacteriuria in young women with acute 11. Roberts JA: Etiology and pathophysiology of pyelonephritis.
urinary symptoms. Ann Intern Med 1993, 119:454–460. Am J Kidney Dis 1991, 17:1–9.
5. Meyrier A, Guibert J: Diagnosis and drug treatment of acute 12. Petersson C, Hedges S, Stenqvist K, et al.: Suppressed antibody and
pyelonephritis. Drugs 1992, 44:356–367. interleukin-6 responses to acute pyelonephritis in pregnancy. Kidney
6. Meyrier A: Diagnosis and management of renal infections. Curr Opin Int 1994, 45:571–577.
Nephrol Hypertens 1996, 5:151–157. 13. Case records of the Massachusetts General Hospital. N Engl J Med
7. Mobley HLT, Island MD, Massad G: Virulence determinants of 1995, 332:174–179.
uropathogenic Escherichia coli and Proteus mirabilis. Kidney Int 14. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia
1994, 46(Suppl. 47):S129–S136. reappraised. Am J Kidney Dis 1993, 22:243–252.
Reflux and Obstructive
Nephropathy
James M. Gloor
Vicente E. Torres

R
eflux nephropathy, or renal parenchymal scarring associated
with vesicoureteral reflux (VUR), is an important cause of
renal failure. Some studies have shown that in up to 10% of
adults and 30% of children requiring renal replacement therapy for
end-stage renal disease, reflux nephropathy is the cause of the renal
failure. Reflux nephropathy is thought to result from the combination
of VUR of infected urine into the kidney by way of an incompetent
ureterovesical junction valve mechanism and intrarenal reflux. Acute
inflammatory responses to the infection result in renal parenchymal
damage and subsequent renal scarring. Loss of functioning renal mass
prompt compensatory changes in renal hemodynamics that, over time,
are maladaptive and result in glomerular injury and sclerosis.
Clinically, reflux nephropathy may cause hypertension, proteinuria,
and decreased renal function when the scarring is extensive. The identi-
fication of VUR raises the theoretic possibility of preventing reflux
nephropathy. The inheritance pattern of VUR clearly is suggestive of a
strong genetic influence. Familial studies of VUR are consistent with
autosomal dominant transmission, and linkage to the major histocom-
patibility genes has been reported. Identification of infants with reflux
detected on the basis of abnormalities seen on prenatal ultrasound
examinations before urinary tract infection occurs may provide an
opportunity for prevention of reflux nephropathy. In persons with VUR
detected at the time of diagnosis of a urinary tract infection, avoidance
of further infections may prevent renal injury. Nevertheless, the situa-
tion is far from clear. Most children with reflux nephropathy already CHAPTER
have renal scars demonstrable at the time of the urinary tract infection
that prompts the diagnosis of VUR. Most children found to have VUR

8
do not develop further renal scarring after diagnosis, even after subse-
quent urinary tract infections. Other children may develop renal scars
in the absence of further urinary tract infections. The best treatment of
8.2 Tubulointerstitial Disease

VUR has not yet been firmly established. No clear advantage has usually is accompanied by hydronephrosis, an abnormal dilation
been demonstrated for surgical correction of VUR versus medical of the renal pelvis, and calices. However, because hydronephrosis
therapy with prophylactic antibiotics after 5 years of follow-up can occur without functional obstruction, the terms obstructive
examinations. New surgical techniques such as the submucosal nephropathy and hydronephrosis are not synonymous. Hydro-
injection of bioinert substances may have a role in select cases. nephrosis is found at autopsy in 2% to 4% of cases. Obstructive
The term obstructive nephropathy is used to describe the func- nephropathy is responsible for approximately 4% of end-stage
tional and pathologic changes in the kidney that result from renal failure. Obstruction to the flow of urine can occur anywhere
obstruction to the flow of urine. Obstruction to the flow of urine in the urinary tract and has many different causes.

FIGURE 8-1
CAUSES OF OBSTRUCTIVE NEPHROPATHY Obstructive nephropathy is responsible for
end-stage renal failure in approximately 4%
of persons. Obstruction to the flow of urine
Intraluminal Extrinsic can occur anywhere in the urinary tract.
Calculus, clot, renal papilla, fungus ball Congenital (aberrant vessels): Obstruction can be caused by luminal bod-
Congenital hydrocalycosis
ies; mural defects; extrinsic compression by
Intrinsic vascular, neoplastic, inflammatory, or other
Ureteropelvic junction obstruction
Congenital: processes; or dysfunction of the autonomic
Retrocaval ureter
Calyceal infundibular obstruction nervous system or smooth muscle of the
Neoplastic tumors:
Ureteropelvic junction obstruction urinary tract. The functional and clinical
Benign tumors:
Ureteral stricture or valves consequences of urinary tract obstruction
Benign prostatic hypertrophy
Posterior urethral valves depend on the developmental stage of the
Pelvic lipomatosis kidney at the time the obstruction occurs,
Anterior urethral valves
Cysts severity of the obstruction, and whether the
Urethral stricture
Primary retroperitoneal tumors: obstruction affects one or both kidneys.
Meatal stenosis
Mesodermal origin (eg, sarcoma)
Prune-belly syndrome
neurogenic origin (eg, neurofibroma)
Neoplastic:
Embryonic remnant (eg, teratoma)
Carcinoma of the renal pelvis, ureter, or bladder
Retroperitoneal extension of pelvic or abdominal tumors:
Polyps
Uterus, cervix
Bladder, prostate
Rectum, sigmoid colon
Metastatic tumor:
Lymphoma
Inflammatory:
Retroperitoneal fibrosis
Inflammatory bowel disease
Diverticulitis
Infection or abscess
Gynecologic:
Pregnancy
Uterine prolapse
Surgical disruption or ligation

Functional
Neurogenic bladder
Drugs(anticholinergics, antidepressants, calcium channel
blockers)
 Reflux and Obstructive Nephropathy 8.3

Anatomy of Vesicoureteric Reflux

FIGURE 8-2
Anatomy of the ureterovesical junction. The ureterovesical junction permits free antegrade
urine flow from the upper urinary tract into the bladder and prevents retrograde urinary
reflux from the bladder into the ureter and kidney. Passive compression of the distal sub-
mucosal portion of the ureter against the detrusor muscle as a result of bladder filling
impedes vesicoureteral reflux (VUR). An active mechanism preventing reflux also has been
proposed in which contraction of longitudinally arranged distal ureteral muscle fibers
occludes the ureteral lumen, impeding retrograde urine flow [1–3]. (From Politano [4];
Intramural with permission.)
ureter

Submucosal
ureter

FIGURE 8-3
Bladder wall
Tissue sagittal sections (upper panels) and
cystoscopic appearances (lower panels) of
the ureterovesical junction illustrating vary-
Ureter ing submucosal tunnel lengths. The length of
the submucosal segment of the distal ureter
A B C D E is an important factor in determining the
12 mm 8 mm 5 mm 2 mm 0 mm effectiveness of the ureteral valvular mecha-
nism in preventing vesicoureteral reflux
(VUR). In children without VUR, the ratio
of tunnel length to ureteral diameter is sig-
nificantly greater than in children with VUR
[5,6]. (From Kramer [7]; with permission.)
A' B' C' D' E'
Cytoscopic view

FIGURE 8-4
Simple and compound papillae are illustrated [8,9]. Two types of
renal papillae have been identified. Simple papillae are the most
common type. They have slitlike papillary duct openings on their
convex surface. These papillae are compressed by increases in
pelvic pressure, preventing urine from entering the papillary ducts
(intrarenal reflux). Compound papillae are formed by the fusion of
two or more simple papillae. In compound papillae, some ducts
open onto a flat or concave surface at less oblique angles.
Increased intrapelvic pressure may permit intrarenal reflux.
Compound papillae usually are found in the renal poles.
8.4 Tubulointerstitial Disease

Pathogenesis of Vesicoureteric Reflux

and Reflux Nephropathy

FIGURE 8-6
Experimental vesicoureteric reflux in pigs: cystourethrogram show-
FIGURE 8-5 ing intrarenal reflux. Reflux of radiocontrast medium into the
Experimental vesicoureteric reflux in pigs. This pathology specimen renal parenchyma is seen. The pressure required to produce
demonstrates surgically induced vesicoureteric reflux in a 2-week- intrarenal reflux is lower in young children than it is in older chil-
old male piglet. Note that the submucosal canal of one of the dren or adults, which is consistent with the observation that reflux
ureters has been unroofed. scars occur more commonly in younger children [10].

A B C
FIGURE 8-7
Experimental vesicoureteric reflux in pigs. The polar location of scars. In urinary tract infections, reflux of urine from the renal
acute suppurative pyelonephritis and evolution of parenchymal pelvis into the papillary ducts of compound papillae predominantly
(Continued on next page)
 Reflux and Obstructive Nephropathy 8.5

D E F
FIGURE 8-7 (Continued)
located in the poles (intrarenal reflux) provides bacteria access reflux nephropathy: Hemorrhagic with polymorphonuclear cell
to the renal parenchyma, resulting in suppurative pyelonephritis infiltrate (A, B); white, not retracted, with prominent mononu-
and subsequent polar scarring [11,12]. Intact (A, C, E) and coro- clear cell infiltrate (C, D), and retracted scan with prominent
nally sectioned (B, D, F) kidneys illustrating the three stages of fibrosis (E, F).

FIGURE 8-8 (see Color Plate)

Experimental vesicoureteric reflux (VUR) in pigs: mesangiopathic
lesions. Reflux of infected urine can result in glomerular lesions
characterized by activation of mesangial cells, mesangial expan-
sion, mesangial hypercellularity, and the presence of large granules.
The granules test positive on periodic acid–Schiff reaction and are
located inside cells with the appearance of macrophages. These
glomerulopathic lesions occur by a process that does not require
contiguity with the infected interstitium nor intrarenal reflux.
These lesions are not related to reduction of renal mass. Similar
glomerular lesions have been identified in piglets after intravenous
administration of endotoxin. Whether similar glomerular lesions
occur in infants or young children with VUR and reflux nephropa-
thy is not known [13].

FIGURE 8-9 (see Color Plate)

Experimental vesicoureteric reflux (VUR) in pigs: 99mTechnetium-dimercaptosuccinic acid
(DMSA) scan demonstrating reflux nephropathy. Radionuclide imaging using DMSA has
been found to be safe and effective in investigating reflux nephropathy [14]. DMSA is
localized to the proximal renal tubules of the renal cortex. Parenchymal scars appear as a
defect in the kidney outline, with reduced uptake of DMSA or by contraction of the whole
kidney. Currently, DMSA radionuclide renal scanning is the most sensitive modality used
to detect renal scars relating to reflux. New areas of renal scarring can be seen earlier with
DMSA than with intravenous pyelography [15].
8.6 Tubulointerstitial Disease

FIGURE 8-10
Integrative View of Pathogenetic Mechanisms in Reflux Nephropathy Integrative view of pathogenetic mechanisms in reflux nephropa-
thy. Abnormalities of ureteral embryogenesis may result in a defec-
Defective mesonephric mesoderm tive antireflux mechanism, permitting vesicoureteral reflux (VUR),
(ureteral bud) incomplete bladder emptying, urinary stasis, and infection.
Bacterial virulence factors modify the pathogenicity of different
Abnormal induction of bacterial strains. Bacterial surface appendages such as fimbriae may
metanephric mesoderm interact with epithelial cell receptors of the urinary tract, enhancing
High-voiding bacterial adhesion to urothelium. Endotoxin is capable of inhibit-
VUR pressures
ing ureteral peristalsis, contributing to the extension of the infec-
(In utero) +
tion into the upper urinary tract even in the absence of VUR.
IRR Inoculation of the renal parenchyma with bacteria produces an
+ acute inflammatory response, resulting in the release of inflamma-
Virulent tory mediators into the surrounding tissue. The acute inflammatory
bacterial strain response elicited by the presence of infecting bacteria is responsible
+
for the subsequent renal parenchymal injury. In addition, it is pos-
Immune sible that immune complexes, bacterial fragments, and endotoxin
Susceptible Inhibition
complexes of ureteral resulting from infection may produce a glomerulopathy.
host
Bacterial peristalsis Even in the absence of urinary tract infection, VUR associated
fragments with elevated intravesical pressure is capable of producing renal
Endotoxin
Focal exudative Toxic urine parenchymal scars. The developing kidney appears to be particular-
reaction component ly susceptible. Renal tubular distention resulting from high
Delayed intrapelvic pressure may exert an injurious effect on renal tubular
hypersensitivity epithelium. Compression of the surrounding peritubular capillary
Glomerulopathy
Pyelonephritic network by distended renal tubules may produce ischemia. During
scar micturition, elevated intravesical pressure is transmitted to the
Sterile scar
Back-pressure renal pelvis and renal tubule. This transient pressure elevation may
atrophy produce tubular disruption. Extravasation of urine into the sur-
Reduced nephron
population Diffuse interstitial rounding parenchyma results in an immune-mediated interstitial
Dysplasia fibrosis nephritis and further renal injury.
The reduction in functional renal mass produced by the interaction
Hyperfiltration High-protein diet of the pathogenetic factors listed here induces compensatory hemo-
Hypertension dynamic changes in renal blood flow and the glomerular filtration
Pregnancy rate. Over time, these compensatory changes may be maladaptive,
Glomerulosclerosis may produce hyperfiltration and glomerulosclerosis, and may even-
tuate in renal insufficiency. (From Kramer [16]; with permission.)
Progressive renal insufficiency

FIGURE 8-11
Vesicoureteral reflux and renal dysplasia. An abnormal ureteral
bud resulting from defective ureteral embryogenesis may penetrate
the metanephric blastema at a site other than that required for
optimum renal development, potentially resulting in renal dysplasia
or hypoplasia [17].
 Reflux and Obstructive Nephropathy 8.7

Diagnosis of Vesicoureteric Reflux and Reflux Nephropathy

FIGURE 8-12
International system of radiographic grading of vesicoureteral reflux
(VUR). The severity of VUR is most frequently classified according to
the International Grading System of Vesicoureteral Reflux, using a
standardized technique for performance of voiding cystourethrogra-
phy. The definitions of this system are illustrated in Figure 8-4 and
are as follows. In grade I, reflux only into the ureter occurs. In grade
II, reflux into the ureter, pelvis, and calyces occurs. No dilation
occurs, and the calyceal fornices are normal. In grade III, mild or
moderate dilation, tortuosity, or both of the ureter are observed, with
mild or moderate dilation of the renal pelvis. No or only slight blunt-
ing of the fornices is seen. In grade IV, moderate dilation, tortuosity,
I II III IV V or both of the ureter occur, with moderate dilation of the renal pelvis
and calyces. Complete obliteration of the sharp angle of the fornices
is observed; however, the papillary impressions are maintained in
most calyces. In grade V, gross dilation and tortuosity of the ureter
occur; gross dilation of the renal pelvis and calyces is seen. The papil-
lary impressions are no longer visible in most calyces [18].

International Reflux Study Committee consisting of four grades of

Types of renal scarring severity. In grade 1, mild scarring in no more than two locations is
seen. More severe and generalized scarring is seen in grade 2 but
with normal areas of renal parenchyma between scars. In grade 3, or
so-called backpressure type, contraction of the whole kidney occurs
and irregular thinning of the renal cortex is superimposed on wide-
spread distortion of the calyceal anatomy, similar to changes seen in
obstructive uropathy. Grade 4 is characterized by end-stage renal dis-
ease and a shrunken kidney having very little renal function [19].
Parenchymal scarring detected by radionuclide renal scintigraphy
A Mild B Severe C "Back-pressure" D End-stage is classified similarly. A, In grade 1, no more than two scarred
areas are detected. B, In grade 2, more than two affected areas are
seen, with some areas of normal parenchyma between them. C,
FIGURE 8-13 Grade 3 renal scarring is characterized by general damage to the
Grading of renal scarring associated with vesicoureteral reflux. entire kidney, similar to obstructive nephropathy. D, In grade 4, a
Reflux renal parenchymal scarring detected on intravenous pyelogra- contracted kidney in end-stage renal failure is seen, with less than
phy can be classified according to the system adopted by the 10% of total overall function [14].

FIGURE 8-14
Voiding cystourethrogram demonstrating bilateral grade 5 vesicoureteral reflux. Voiding
cystourethrography is performed by filling the bladder with radiocontrast material and
observing for reflux under fluoroscopy, either during the phase of bladder filling or dur-
ing micturition. Contrast material is infused through a small urethral catheter under
gravity flow.
8.8 Tubulointerstitial Disease

FIGURE 8-15
Radionuclide cystogram demonstrating bilateral vesicoureteral reflux (VUR). This method
using 99mtechnetium pertechnetate is useful in detecting VUR. Advantages of radionuclide
cystography include lower radiation exposure, less interference with overlying bowel con-
tents and bones, and higher sensitivity in detection of VUR. Radionuclide cystography is
useful in follow-up examinations of patients known to have VUR, as a screening test in
asymptomatic siblings of children with reflux and girls with urinary tract infections, and in
serial examinations of children with neuropathic bladders at risk for developing VUR.
Disadvantages of this method include less anatomic detail and inadequacy in evaluating
the male urethra, making it unsuitable for screening boys for urinary tract infections [7].

A B
FIGURE 8-16
A, Intravenous pyelogram and, B, nephrotomogram demonstrating not be visible immediately after renal infection, because scars may
grade 2 reflux nephropathy. Historically, this testing modality has not be fully developed for several years [20]. The advantages of
been the one most commonly used to evaluate reflux nephropathy intravenous pyelography in evaluating reflux nephropathy include
[7]. Irregular renal contour, parenchymal thinning, small renal size, precision in delineating renal anatomic detail and providing base-
and calyceal blunting all are radiographic signs of reflux nephropa- line measurements for future follow-up evaluations, renal growth,
thy on intravenous pyelography [17]. Radiographic changes may and scar formation.

FIGURE 8-17
A, Posterior and, B, anterior views of
99mtechnetium-dimercaptosuccinic acid
(DMSA) renal scan showing bilateral grade
2 reflux nephropathy. This nephropathy is
characterized by focal areas of decreased
radionuclide uptake predominantly affect-
ing the lower renal poles.

A B
 Reflux and Obstructive Nephropathy 8.9

13
Predicted mean
12 95% predicted limits

11
10
9

Renal length, cm
8
7
6
5
4
3
2
0 2 4 6 8 10 12 5 10 15
C Months Years
A
FIGURE 8-18
Prenatal detection of vesicoureteral reflux (VUR). A,
Ultrasonography showing mild fetal hydronephrosis. B, Postnatal
voiding cystourethrogram (VCUG) showing grade 4 VUR. C,
Graph showing small renal size in the same infant. Vesicoureteral
reflux has been identified in neonates in whom prenatal ultra-
sonography examination reveals hydronephrosis [21–28]. Normal
infants do not have VUR, even when born prematurely [29,30].
The severity of reflux often is not predictable on the basis of
appearance on ultrasonography [22,31]. Hydronephrosis greater
than 4 mm and less than 10 mm in the anteroposterior dimension
on ultrasound examination after 20 weeks’ gestational age has
been termed mild fetal hydronephrosis. Mild fetal hydronephrosis
is associated with VUR in a significant percentage of infants
[26,31]. Despite the absence of a previous urinary tract infection,
many kidneys affected prenatally exhibit decreased function
[22,24,32,33]. Unlike the focal parenchymal scars seen in infection-
associated reflux nephropathy, the parenchymal abnormalities seen
in prenatal VUR are most commonly manifested by a generalized
decrease in renal size (reflux nephropathy grade 3 or 4) [34,35].

B
8.10 Tubulointerstitial Disease

FIGURE 8-19
90 83 Male Prenatal detection of vesicoureteral reflux (VUR): gender distribution versus VUR detected
80 77 after urinary tract infection (UTI). VUR detected as part of the evaluation of prenatal
Female
70 hydronephrosis is most commonly identified in boys. In an analysis of six published stud-
60 ies of VUR diagnosed in a total of 124 infants with antenatally detected hydronephrosis,
50 83% of those affected were boys [33]. Conversely, VUR detected after a UTI most com-
%

40 monly affects girls. In the International Reflux Study in Children (IRSC) and Southwest
30 23 Pediatric Nephrology Study Group (SWPNSG) investigations of VUR detected in a total of
20 17
380 children after UTI, 77% of those affected were girls [20,36].
10
0
Prenatally Detected
detected after UTI

Clinical Course of Vesicoureteric Reflux

90
50 50
50 80 Grade 1
Grade 2
70
40 Resolved VUR, % Grade 3
60
30 50
30
%

20 21 40
20 30
20
10
10
0 0
1 2 3 4 5 0 1 2 3 4 5
Vesicoureteral reflux grade Years follow-up

FIGURE 8-20 FIGURE 8-21

Resolution of vesicoureteral reflux (VUR) detected prenatally at fol- Resolution of vesicoureteral reflux (VUR) detected postnatally
low-up examinations over 2 years. Spontaneous resolution of VUR after urinary tract infection: mild to moderate VUR. The Southwest
can occur in infants with reflux detected during the postnatal evalu- Pediatric Nephrology Study Group (SWPNSG) prospectively observed
ation of prenatal urinary tract abnormalities. In an analysis of six 113 patients aged 4 months to 5 years with grades I to III VUR
investigations of VUR detected neonatally with a follow-up period detected after urinary tract infection. The SWPNSG reported on 59
of 2 years, resolution was seen in 50% of infants with grades I and children followed up with serial excretory urograms and voiding cys-
II. High-grade reflux (grades IV to V) resolved in only 20% [33]. tourethrography for 5 years. Mild (grade I and II) VUR resolved after
5 years in the ureters of 80% of these children, and in most cases
within 2 to 3 years. Grade III VUR resolved in only 46% of ureters
in children with VUR [20].

FIGURE 8-22
90 82 80 Grade 1 Resolution of vesicoureteral reflux (VUR) detected postnatally after
80 Grade 2 urinary tract infection at follow-up examinations over 5 years. Mild
70
Patients studied, %

Grade 3
to moderate VUR spontaneously resolves in a significant percentage
60 Grade 4–5 53
of children, whereas high-grade reflux resolves only rarely. The
50 43
40
40 Southwest Pediatric Nephrology Study Group (SWPNSG) found
31 that grades I and II VUR resolved in 80% of children with refluxing
30
20 17 16 18 20 ureters at follow-up examinations over 5 years. In the Birmingham
10 Reflux Study Group (BRSG), International Reflux Study in Children
0 (IRSC), and SWPNSG investigations of high-grade VUR (grades III
Resolution Improvement Unchanged to V) in children, improvement in reflux severity was seen in 30%
to 40% of affected ureters. Spontaneous resolution was rare and
occurred in only 16% to 17% of children with refluxing ureters at
follow-up examinations over 5 years [20,37,38].
 Reflux and Obstructive Nephropathy 8.11

FIGURE 8-23
40
Unilateral Resolution of grades III to V vesicoureteral reflux (VUR) detected
35
Bilateral postnatally after urinary tract infection: bilateral versus unilateral
30 VUR. Spontaneous resolution of high-grade VUR is much more
Resolved VUR, %

25 likely to occur in unilateral reflux. The International Reflux Study

20 in Children (IRSC) showed that grades III to V VUR resolved in
children in whom both kidneys were affected nearly five times as
15
often (39%) as in those in whom VUR was bilateral (8%). In bilat-
10 eral VUR, spontaneous resolution did not occur after 2 years of
5 observation [38].
0
0 3 9 21 33 45 57
Months follow-up

18
IRSC IRSC
60 16
BRSG SWPNSG
14

New scar formation, %

Scarred or thinned, %

50
12
40 10
30 8
6
20
4
10 2
0 0
0 I–II III IV Dilated 0 1 2 3 4 5
Vesicoureteral reflux grade Years follow-up

FIGURE 8-24 FIGURE 8-25

Frequency of parenchymal scarring at the time of diagnosis of vesi- Development of parenchymal scarring after diagnosis of
coureteral reflux (VUR). Many children in whom VUR is detected vesicoureteral reflux (VUR). Parenchymal scarring occurs after
after a urinary tract infection already have evidence of renal diagnosis and initiation of therapy as well. The Southwest
parenchymal scarring. In two large prospective studies the frequen- Pediatric Nephrology Study Group (SWPNSG) followed up 59
cy of scars seen in persons with VUR increased with VUR severity. children with mild to moderate VUR (grades I to III) diagnosed
The International Reflux Study in Children (IRSC) studied 306 after urinary tract infection [20]. None of the children studied
children under 11 years of age with grades III to V VUR [36]. The had parenchymal scarring on intravenous pyelography at the
frequency of parenchymal scarring or thinning increased from 10% time of diagnosis. Parenchymal scars were seen to develop in
in children with nonrefluxing renal units (in children with con- 10% of children over the course of 5 years of follow-up exami-
tralateral VUR) to 60% in those with severely refluxing grade V nations, including some children without documented urinary
kidneys. In another large prospective study, the Birmingham Reflux tract infections during the period of observation. In this group,
Study Group (BRSG) reported renal scarring in 54% of 161 chil- renal scarring occurred nearly three times more commonly in
dren under 14 years of age with severe VUR resulting in ureteral grade 3 VUR than it did in grades 1 and 2 VUR. In the
dilation (greater than grade 3 using the classification system adopt- International Reflux Study in Children (IRSC) (European
ed by the International Reflux Study in Children group) at the time group), a prospective study of high-grade VUR (grades III and
reflux was detected [39]. Participants in these studies were children IV), new scars developed in 16% of 236 children after 5 years’
previously diagnosed as having had urinary tract infection. observation [40].

FIGURE 8-26
Development of new renal scars versus age at diagnosis of vesicoureteral reflux
(VUR). The frequency of new scar formation appears to be inversely related to age.
The International Reflux Study in Children (IRSC) examined children with high-grade
VUR and found that new scars developed in 24% under 2 years of age, 10% from 2
to 4 years of age, and 5% over 4 years of age [40].
8.12 Tubulointerstitial Disease

Treatment of Vesicoureteric Reflux

correcting VUR in 97.5% of 231 reimplanted ureters in 151 chil-
18 dren randomized to surgical therapy. Medical therapy consisted of
Surgical
16 long-term antibiotic uroprophylaxis using nitrofurantoin, trimetho-
Medical
14 prim, or trimethoprim-sulfa. No statistically significant advantage
Renal scarring, %

12 was demonstrable for either treatment modality with respect to

10 new scar formation after 5 years of observation in either study.
8 New scars were identified in 20 of the 116 children treated surgi-
6 cally (17%) and 19 of the 155 children treated medically (16%) at
4 follow-up examinations over 5 years. Those children treated surgi-
2 cally who developed parenchymal scars generally did so within the
0 first 2 years after ureteral repeat implantation, whereas scarring
0 5 10 15 20 25 30 35 40 45 50 55 60 occurred throughout the observation period in the group that did
Months follow-up not have surgery. VUR persisted in 80% of children randomized to
medical treatment after follow-up examinations over 5 years.
The results of the IRSC paralleled the findings of the
FIGURE 8-27 Birmingham Reflux Study Group (BRSG) investigation of medical
Effectiveness of medical versus surgical treatment: new scar forma- versus surgical therapy for VUR in 161 children. After 2 years of
tion at follow-up examinations over 5 years in children with high- observation, progressive or new scar formation was seen in 16% of
grade vesicoureteral reflux (VUR). The International Reflux Study children with refluxing ureters in the group treated surgically and
in Children (IRSC) (European group) was designed to compare the 19% in the group treated medically. In contrast to the IRSC, how-
effectiveness of medical versus surgical therapy of VUR in children ever, new scar formation was rare after 2 years of observation in
diagnosed after urinary tract infection. Surgery was successful in both groups [37,40].

FIGURE 8-28
Effectiveness of medical versus surgical treatment: incidence of uri-
40 38 39 BRSG-Surgical nary tract infections. Vesicoureteral reflux (VUR) predisposes affected
Urinary tract infections, %

35 34 BRSG- Medical persons to urinary tract infection owing to incomplete bladder empty-
IRSC-Medical ing and urinary stasis. Medical therapy with uroprophylactic antibi-
30 28
IRSC-Surgical otics and surgical correction of VUR have as a goal the prevention of
25
21 SWPNSG
20 urinary tract infection. In three prospective studies of 400 children
15 with VUR (Southwest Pediatric Nephrology Study Group [SWPNSG],
International Reflux Study in Children [IRSC], Birmingham Reflux
10
Study Group [BRSG]) treated either medically or surgically and who
5
were observed over 5 years the rate of infection was similar, ranging
0 from 21% to 39%. The rate of infection was no different between the
group treated medically and that treated surgically [20,37,39].

FIGURE 8-29
Nonpyelonephritic
Effectiveness of medical versus surgical treatment: incidence of urinary tract infection ver-
40 UTI sus pyelonephritis in severe vesicoureteral reflux (VUR). Although the incidence of uri-
UTI versus pyelonephritis, %

35 Pyelonephritis nary tract infections (UTIs) is the same in surgically and medically treated children with
30 17 VUR, the severity of infection is greater in those treated medically. The International
25 29
Reflux Study in Children (IRSC) (European group) studied 306 children with VUR and
20 observed them over 5 years; 155 were randomized to medical therapy, and 151 had surgi-
15
cal correction of their reflux. Although the incidence of UTI statistically was no different
21 between the groups (38% in the medical group, 39% in the surgical group), children
10
treated medically had an incidence of pyelonephritis twice as high (21%) as those treated
5 10
surgically (10%) [41].
0
Medical Surgical
therapy therapy
 Reflux and Obstructive Nephropathy 8.13

surgical correction. In children in whom

VUR resolves spontaneously, a high index
VUR detected
of suspicion for urinary tract infection
should be maintained, and urine cultures
Associated GU anomalies
expected to affect VUR? should be obtained at times of febrile illness
without ready clinical explanation.
In persons in whom mild VUR fails to
Yes No resolve after 2 to 3 years of observation,
consideration should be given to voiding pat-
Treat appropriately Severity of VUR tern. A careful voiding history and an evalu-
ation of urinary flow rate may reveal abnor-
malities in bladder function that impede res-
Mild (I-III) Severe (IV-V) olution of reflux. Correction of
dysfunctional voiding patterns may result in
Uroprophylaxis Functional study resolution of VUR. In the absence of dys-
Hygiene education (Radionuclide or ExU) functional voiding, it is controversial
Surveillance urine cultures whether older women with persistent VUR
Annual VCUG are best served by surgical correction or
Nonfunctioning Functioning close observation with uroprophylactic
Urinary tract infections? kidney kidney antibiotic therapy and surveillance urine cul-
tures, especially during pregnancy. Males
with persistent low-grade VUR may be can-
Yes No Consider didates for close observation with surveil-
nephrectomy Uroprophylaxis Surgical
correction lance urine cultures while not receiving
Consider surgery Resolution of VUR after 2 years antibiotic therapy, especially if they are over
Annual VCUG
4 years of age and circumcised. Circumcision
lowers the incidence of urinary tract infec-
Resolution of VUR after 2 years tion. In severe VUR the function of the
Yes No
affected kidney should be evaluated with a
Long term functional study (radionuclide renal scan).
Yes No
followup to Female Male High-grade VUR in nonfunctioning kidneys
detect UTI is unlikely to resolve spontaneously, and
nephrectomy may be indicated to decrease
Consider Consider Consider observation Long term Surgery the risk of urinary tract infection and avoid
surgery surgery off antibiotics followup the need for uroprophylactic antibiotic thera-
py. In patients with functioning kidneys who
have high-grade VUR, the likelihood for res-
FIGURE 8-30 olution should be considered. Severe VUR,
Proposed treatment of vesicoureteral reflux (VUR) in children. This algorithm provides an especially if bilateral, is unlikely to resolve
approach to evaluate and treat VUR in children. In VUR associated with other genitouri- spontaneously. Proceeding directly to repeat
nary anomalies, therapy for reflux should be part of a comprehensive treatment plan implantation may be indicated in some cases.
directed toward correcting the underlying urologic malformation. Children with mild VUR Medical therapy with uroprophylactic antibi-
should be treated with prophylactic antibiotics, attention to perineal hygiene and regular otics and serial VCUG may also be used,
bowel habits, surveillance urine cultures, and annual voiding cystourethrogram (VCUG). reserving surgical therapy for those in whom
Children with recurrent urinary tract infection on this regimen should be considered for resolution fails to occur.

Complications of Reflux Nephropathy

FIGURE 8-31
25
Development of hypertension in 55 normotensive subjects with reflux nephropathy at fol-
20 low-up examinations over 15 years. The incidence of hypertension in persons with reflux
nephropathy increases with age and appears to develop most commonly in young adults
Hypertensive, %

15 within 10 to 15 years of diagnosis. In a cohort of 55 normotensive persons with reflux

nephropathy observed for 15 years, 5% became hypertensive after 5 years. This percent-
10 age increased to 16% at 10 years, and 21% at 15 years. The grading system for severity of
scarring was different from the system adopted by the International Reflux Study
5
Committee. Nevertheless, using this system, 78% of persons in the group could be classi-
0 fied as having reflux nephropathy severity scores between 1 and 4 [42].
0 5 10 15
Years
8.14 Tubulointerstitial Disease

FIGURE 8-32
100
Frequency of hypertension versus severity of parenchymal scarring. The frequency of
80 hypertension in persons with vesicoureteral reflux–related renal scars is higher than in the
normal population. In adults with reflux nephropathy the incidence of hypertension can be
Hypertensive, %

60 correlated with the severity of renal scarring. Adding the individual grade of reflux (0–4)
for the two kidneys results in a scale ranging from 0 (no scars) to 8 (severe bilateral scar-
40 ring). Persons with cumulative scores of parenchymal scarring from 1 to 4 have a 30%
incidence of hypertension, whereas 60% of those with scarring scores ranging from 5 to 8
20
have hypertension [42,43].
0
1–4 5–8
Cumulative reflux scarring severity score

induces compensatory changes in

glomerular and vascular hemodynamics.
These changes initially maintain the
glomerular filtration rate but are mal-
adaptive over time. A–D, Compensatory
hyperfiltration results in renal injury
manifested histologically by glomerular
hypertrophy and FSGS and clinically as
persistent proteinuria [44]. In reflux
nephropathy, proteinuria is a poor prog-
nostic sign, indicating that renal injury
has occurred. The severity of proteinuria
A B is inversely proportional to functioning
renal mass and the glomerular filtration
rate and directly proportional to the
degree of global glomerulosclerosis.
Surgical correction of vesicoureteral
reflux has not been found to prevent
further deterioration of renal function
after proteinuria has developed. Hyper-
filtration resulting from decreased renal
mass continues and produces progressive
glomerulosclerosis and loss of renal func-
tion. Evidence exists that inhibition of the
renin-angiotensin system through the use of
angiotensin-converting enzyme inhibitors
C D decreases the compensatory hemodynamic
changes that produce hyperfiltration
FIGURE 8-33 injury. Thus, these inhibitors may be
Glomerular hypertrophy and focal segmental glomerulosclerosis (FSGS) in severe effective in slowing the progress of renal
reflux nephropathy. Reflux nephropathy resulting in reduced renal functional mass failure in reflux nephropathy.
 Reflux and Obstructive Nephropathy 8.15

Pathogenesis of Obstructive Nephropathy

Birth
FIGURE 8-34
Fetus Neonate Adult
Consequences of urinary tract obstruction for the developing kidney in animals. The
effects of urinary tract obstruction on the developing kidney depend on the time of onset,
location, and degree of obstruction. Ureteral obstruction during early pregnancy results in
Dysplasia disorganization of the renal parenchyma (dysplasia) and a reduction in the number of
nephrons. Partial or complete ureteral obstruction in neonates causes vasoconstriction,
Number of glomerular hypoperfusion, impaired ipsilateral renal growth, and interstitial fibrosis. The
nephrons degree of impairment of the ipsilateral kidney, in the case of partial unilateral ureteral
obstruction, and of compensatory hypertrophy of the contralateral kidney, in the case of
Renal growth partial or complete unilateral ureteral obstruction, is inversely related to the age of the ani-
Compensatory hypertrophy* mal at the time of obstruction. The older the animal, the less the impairment of the ipsilat-
eral kidney and the less the compensatory growth of the contralateral kidney. In addition,
Recovery of function
after relief of obstruction the recovery of renal function after relief of urinary tract obstruction also decreases with
the age of the animal [45].
*When unilateral

FIGURE 8-35
PGE2, PGI2 Renal hemodynamic response to mild partial ureteral obstruction. Renal blood flow and
Angiotensin II the glomerular filtration rate may not change in mild partial ureteral obstruction, despite a
RA RE significant reduction in glomerular capillary ultrafiltration coefficient (Kf). This is due to
PGC
the increase in glomerular capillary hydraulic pressure (PGC) caused by a prostaglandin
E2–induced reduction of afferent arteriolar resistance (RA) and an angiotensin II–induced
Kf elevation of efferent arteriolar resistance (RE). It is likely that other vasoactive factors,
such as thromboxane A2, also play a role, particularly in more severe ureteral obstruction
accompanied by reductions in renal blood flow and glomerular filtration rate [46].
PGE2—prostaglandin E2; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure.

Pt

vascular resistance and an increase in renal blood flow mediated by

2 h post-obstruction 24 h post-obstruction increased production of prostaglandin E2 (PGE2), prostacyclin, and
nitric oxide (NO). The increase in renal blood flow (RBF) and
PGE2, PGI2 Endothelin Angiotensin II
glomerular capillary pressure maintain the glomerular filtration rate
N0 TBX A 2
(GFR) at approximately 80% of normal, despite an increase in
RA PGC RE RA PGC RE intratubular pressure. As the ureteral obstruction persists, activation
(Macrophage of the renin-angiotensin system and increased production of throm-
infiltration)
RBF (120%) RBF (50%) boxane A2 (TBXA2) and endothelin result in progressive vasocon-
GFR (80%) (Activation of GFR (20%) striction, with reductions in renal blood flow and glomerular capil-
renin-angiotensin) lary pressure. The glomerular filtration rate decreases to approxi-
Pt Unilateral Pt mately 20% of baseline, despite normalization of the intratubular
pressures. The hemodynamic changes in the early phase (0–2 h) of
RA PGC RE RA PGC RE bilateral ureteral obstruction are similar to those observed after uni-
+ ANP lateral obstruction. As bilateral obstruction persists, however, there is
RBF (120%) RBF (50%) an accumulation of atrial natriuretic peptide (ANP) that does not
GFR (80%) GFR (20%) occur after unilateral obstruction. The increased ANP levels attenu-
ate the afferent and enhance the efferent vasoconstrictions, with
Pt Bilateral Pt maintenance of normal glomerular capillary and elevated tubular
pressures. Despite these differences in hemodynamic changes
between unilateral and bilateral ureteral obstruction, the reductions
FIGURE 8-36 in renal blood flow and glomerular filtration rate 24 hours after
Acute renal hemodynamic response to unilateral or bilateral com- obstruction are similar [47–49]. PGC—glomerular capillary hydraulic
plete ureteral obstruction. In the first 2 hours after unilateral com- pressure; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure;
plete ureteral obstruction, there is a reduction in preglomerular RA—afferent arteriolar resistance; RE—efferent arteriolar resistance.
8.16 Tubulointerstitial Disease

300
FIGURE 8-37
Intrapelvic pressure Chronic renal hemodynamic response to complete unilateral ureter-
Renal blood flow al obstruction. During complete ureteral obstruction, renal blood
Change from baseline, %

200 Glomerular filtration rate flow progressively decreases. Renal blood flow is 40% to 50% of
normal after 24 hours, 30% at 6 days, 20% at 2 weeks, and 12%
100 at 8 weeks [48].

Baseline
–50

0 1 2 3 4 5 6 7 8
Weeks after obstruction

Cortex Medulla Cortex Medulla

Release of obstruction Release of obstruction
40
40

Leukocytes, 105/g
30
Leukocytes, 105/g

30
20
20
10
10
0
0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
A Control 4 h 12 h 24 h Control 4 h 12 h 24 h C Days Days

FIGURE 8-38
Cortex
Development of interstitial cellular infiltrates in the renal cortex
and medulla after ureteral obstruction. After ureteral obstruction
there is a rapid influx of macrophages and suppressor T lympho-
cytes in the cortex and medulla (A) that is accompanied by an
increase in urinary thromboxane B2 and a decrease in the glomeru-
lar filtration rate. The production of thromboxane A2 by the infil-
trating macrophages (B) contributes to the renal vasoconstriction
of chronic urinary tract obstruction. After release of the obstruc-
tion the cellular infiltration is slowly reversible, requiring several
days to revert to near normal levels (C) [50,51].

Medulla

B
 Reflux and Obstructive Nephropathy 8.17

obstructed kidney. Angiotensin II can

induce the synthesis of transforming growth
Tubular obstruction factor  (TGF-), a cytokine that stimulates
extracellular matrix synthesis and inhibits
its degradation. Obstructive nephropathy
Pt is accompanied by downregulation of the
kallikrein-kinin system and nitric oxide
production that can be reversed by adminis-
Osteopontin Renin, angiotensinogen, EGF tration of a converting enzyme inhibitor or
PDGF Bradykinin of L-arginine. The rapid upregulation of
MCP ACE, AT1 receptor bcl2
chemotactic factors such as monocyte
chemoattractant peptide 1 (MCP-1) and
Macrophages TGF-ß Nitric oxide osteopontin in the tubular epithelial cells,
O–2 in response to increased intratubular pres-
CuZnSOD
H 2O 2 Catalase sure, contributes to the recruitment of
Fibroblasts, TIMP Apoptosis, macrophages. Macrophages produce
myofibroblasts Collagen tubular drop-out fibroblast growth factor and induce fibrob-
last proliferation and myofibroblast trans-
formation. The downregulation of epider-
Tubulointerstitial mal growth factor (EGF), Bcl 2, and antiox-
fibrosis idant enzymes and the increased production
of superoxide and hydrogen peroxide
(H2O2) contribute to an increased rate of
FIGURE 8-39 apoptosis and tubular dropout [51– 57].
Pathogenesis of tubulointerstitial fibrosis in obstructive nephropathy. This pathogenesis PDGF–platelet-derived growth factor;
has been extensively studied. Increased expression of renin, angiotensinogen, angiotensin- SOD—superoxide dismutase; TIMP—tissue
converting enzyme (ACE), and the angiotensin II type 1 (AT1) receptor occurs in the inhibitor of metalloproteinases.

FIGURE 8-40
Obstruction
Recovery of renal function after relief of complete unilateral
100 ureteral obstruction of variable duration. The recovery of the ipsi-
80 lateral glomerular filtration rate after relief of a unilateral com-
plete ureteral obstruction has been best studied in dogs and
60 depends on the duration of the obstruction. Complete recovery
occurs after 1 week of obstruction. The degree of recovery after 2
40 and 4 weeks of obstruction is only of 58% and 36%, respectively.
No recovery occurs after 6 weeks of obstruction [58]. Rare
20
reports of recovery of renal function in patients with longer peri-
0 ods of unilateral ureteral obstruction may represent high-grade
0 2 4 6 8 12 14 16 18 20 22 24 partial obstruction rather than complete obstruction or may
Weeks after obstruction reflect differences in lymphatic drainage and renal anatomy
between the human and canine kidneys [59].
8.18 Tubulointerstitial Disease

Clinical Manifestations of Obstructive Nephropathy

FIGURE 8-41
Functional
Damage to Medullary Na+reabsorption ( Na+/K+ ATPase) Clinical correlates of abnormalities of tubu-
abnormalities
inner medulla blood flow Loop of Henle Collecting duct lar function in obstructive nephropathy.
in obstructed
kidneys Acute ureteral obstruction stimulates tubular
(unilteral or reabsorption, resulting in increased urine
bilateral) Corticomedullary Intraluminal
concentration gradient negative potential osmolality and reduced urine sodium con-
centration [60]. In contrast, obstructive
nephropathy is characterized by a reduced
Resistance Concentration defect Na+ wasting H+ secretion H+-ATPase
to ADH K+ secretion Na+/K+ ATPase ability to concentrate the urine, reabsorb
sodium, and secrete hydrogen ions (H+) and
Consequences potassium. In unilateral obstructive
of bilateral ECFV excess
nephropathy, these functional abnormalities
obstruction do not have a clinical correlate because of
ANP
the reduced glomerular filtration rate and
Osmotic load (urea) immaterial contribution of the obstructed
kidney to total renal function. Hyperkalemic
metabolic acidosis and, when the intake of
Clinical free water is not adequate, hypernatremia
Excessive replacement
correlates can occur in patients with partial bilateral
Hypernatremia Postobstructive diuresis after Hyperkalemic ureteral obstruction or partial ureteral
when free relief of bilateral obstruction metabolic acidosis obstruction in a solitary kidney. Similarly,
water intake is (volume contraction, in partial bilateral postobstructive diuresis can occur only after
inadequate hypomagnesemia, other ureteral obstruction relief of bilateral ureteral obstruction or
electrolyte abnormalities)
ureteral obstruction in a solitary kidney but
not after relief of unilateral obstruction
[61–67]. ADH>\#209>antidiuretic hormone;
ANP—atrial natriuretic peptide; ECFV—
extracellular fluid volume; Na-K ATPase—
sodium-potassium adenosine triphosphatase.

FIGURE 8-42
Urinary tract obstruction Clinical manifestations of obstructive nephropathy. These manifes-
tations depend on the cause of the obstruction, its anatomic loca-
tion, its severity, and its rate of development [61,68,69].
Unilateral Bilateral or solitary kidney

Partial or complete Partial Complete

• Pain (dull aching • Renin-dependent • Polyuria, polydipsia • Anuria • Bladder

renal colic) hypertension • Hypernatremia • Uremia symptoms
• Susceptibility to • Erythrocytosis • Volume contraction • Fluctuating
urinary tract (rare) • Hyperkalemic urine
infection and metabolic acidosis output
nephrolithiasis • Uremia
• Volume-dependent
hypertension
 Reflux and Obstructive Nephropathy 8.19

Diagnosis of Obstructive Nephropathy

1.0
Furosemide Baseline
Saline
0.8
Obstruction Saline + furosemide
Tracer activity

0.6

RI
Hydronephrosis 0.4
without obstruction
0.2
Normal
0.0
A Time B Partial obstruction Contralateral kidney

Nevertheless, obstruction rarely can occur

without hydronephrosis, when the ureter
and renal pelvis are encased in a fibrotic
process and unable to expand. In contrast,
mild dilation of the collecting system of no
functional significance is not unusual. Even
obvious hydronephrosis in some cases may
not be associated with functional obstruc-
tion [70]. Diuresis renography is helpful
when the functional significance of the
dilation of the collecting system is in ques-
tion [71,72]. Renal Doppler ultrasonogra-
phy before and after administration of nor-
mal saline and furosemide also has been
used to differentiate obstructive from
nonobstructive pyelocaliectasis [73]. Other
techniques such as excretory urography,
C D computed tomography, and retrograde or
antegrade ureteropyelography are helpful
FIGURE 8-43 to determine the cause of the urinary tract
Diagnosis of obstructive nephropathy. A, Diuresis renography. B, Doppler ultrasonogra- obstruction. The utility of excretory urog-
phy. C, D, Magnetic resonance urogram utilizing a single shot fast spin echo technique raphy is limited in patients with advanced
with anterior-posterior projection (C) and left posterior oblique projection (D). Images renal insufficiency. In these cases magnetic
demonstrate a widely patent right ureteropelvic junction in a patient with abdominal pain resonance urography can provide coronal
and suspected ureteropelvic junction obstruction. Administration of gadolinium is not imaging of the renal collecting systems and
required for this technique. Note also the urine in the bladder, cerebrospinal fluid in the ureters similar to that of conventional
spinal canal, and fluid in the small bowel. urography without the use of iodinated
Ultrasonography is the procedure of choice to determine the presence or absence of a contrast. RI— resistive index. (C, D,
dilated renal pelvis or calices and to assess the degree of associated parenchymal atrophy. Courtesy of B. F. King, MD.)

FIGURE 8-44
Diagnosis of obstructive nephropathy by postnatal renal ultra-
sonography, showing hydronephrosis in ureteropelvic junction
obstruction. Renal ultrasonography is a sensitive test to detect
hydronephrosis. The absence of ureteral dilation is consistent with
obstruction at the level of the ureteropelvic junction.
8.20 Tubulointerstitial Disease

FIGURE 8-45
Before Furosemide After Furosemide Mercaptoacetyltriglycine-3 renal scan with furosemide in a new-
born with left ureteropelvic junction obstruction. A diuretic renal
scan using 99mtechnetium-mercaptoacetyltriglycine (99mTc-MAG-3)
showing differential renal function (47% right kidney; 53% left
kidney) at 1 to 2 minutes after radionuclide administration is seen.
A significant amount of radionuclide remains in each kidney 15
1 min. minutes after administration. After administration of furosemide,
however, the isotope is seen to disappear rapidly from the right
kidney (t1/2 of radioisotope washout in 4.9 minutes) but persists
in the hydronephrotic left kidney (t1/2 in 50.1 minutes). A t1/2 of
the radioisotope in less than 10 minutes is thought to reflect a lack
of significant obstruction. A t1/2 of over 20 minutes is suggestive
of obstruction. Intermediate values of washout are indeterminate.
The most appropriate therapy for infants with delayed renal pelvic
radioisotope washout and diagnosis of ureteropelvic junction
obstruction is controversial. Some authors advocate pyeloplasty to
alleviate the obstruction based on renal scan results, whereas oth-
5 min. ers advocate withholding surgery unless renal function deteriorates
or hydronephrosis progresses.

10 min.

15 min.

Lt Rt Lt Rt
 Reflux and Obstructive Nephropathy 8.21

Posterior Urethral Valves

FIGURE 8-46
Posterior urethral valves. A, Illustrative
diagram. B, Pathology specimen. Valvular
obstruction at the posterior urethra is the
most common cause of lower urinary tract
obstruction in boys. Anatomically, the
Type I lesion most commonly is comprised of an
oblique diaphragm with a slitlike perfora-
tion arising from the posterior urethra dis-
tal to the verumontanum and inserting at
the midline anterior urethra. (From Kaplan
and Scherz [74]; with permission.)
A

FIGURE 8-47
Excretory urogram of a patient with poste-
rior urethral valves. Bladder outlet obstruc-
tion results in bladder wall thickening, tra-
beculation, and formation of diverticula.
Increased intravesical pressure may result
in vesicoureteral reflux, as is seen on the
left. Obstruction resulting in increased
intrarenal pressure may result in rupture
at the level of a renal fornix, producing a
urinoma, or perirenal collection of urine,
as seen on the right.

FIGURE 8-48
Voiding cystourethrogram (VCUG) demonstrating posterior urethral valves and dilation
of the posterior urethra. Urethral valves are best detected by VCUG. The obstructing
valves are seen as oblique or perpendicular folds with proximal urethral dilation and elon-
gation. Distal to the valves the urinary stream is diminished. Alleviating the bladder outlet
obstruction is indicated, either by lysis of the valves themselves or by way of vesicostomy,
in small infants until sufficient growth occurs to make valve resection technically feasible.
8.22 Tubulointerstitial Disease

Ureterovesical Junction Obstruction

FIGURE 8-49
Excretory urogram showing ureterovesical junction obstruction in a 2-year-old girl.

Retroperitoneal Fibrosis

A B
FIGURE 8-50
A–H, Idiopathic retroperitoneal fibrosis: computed tomography nal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and fibrous
scans of the abdomen before (left panels, note right ureteral stent pseudotumor of the orbit. In the clinical setting, patients with idio-
and mild left ureteropyelocaliectasis) and 7 years after ureterolysis pathic retroperitoneal fibrosis exhibit systemic symptoms such as
(right panels, note omental interposition). Retroperitoneal fibrosis malaise, anorexia and weight loss, and abdominal or flank pain.
is characterized by the accumulation of inflammatory and fibrotic Renal insufficiency is often seen and is caused by bilateral ureteral
tissue around the aorta, between the renal hila and the pelvic brim. obstruction. Laboratory test results usually demonstrate anemia
Most cases are idiopathic; the remainder are associated with and an elevated sedimentation rate. The treatment is directed to the
immune-mediated connective tissue diseases, ingestion of drugs release of the ureteral obstruction, which initially can be achieved
such as methysergide, abdominal aortic aneurysms, or malignancy. by placement of ureteral stents. Administration of corticosteroids is
Idiopathic retroperitoneal fibrosis can be associated with mediasti- helpful to control the systemic manifestations of the disease and
(Continued on next page)
 Reflux and Obstructive Nephropathy 8.23

C D

E F

G H
FIGURE 8-50 (Continued)
often to reduce the bulk of the tumor and relieve the ureteral the ureters from the fibrotic mass, lateralizing them, and wrapping
obstruction. Administration of corticosteroids, however, should be them in omentum to prevent repeat obstruction, is often necessary.
considered only when malignancy and retroperitoneal infection can Other immunosuppressive agents have been used rarely when the
be ruled out. As in other chronic renal diseases, administration of systemic manifestations of the disease cannot be controlled with
corticosteroids should be kept at the minimal level capable of con- safe doses of corticosteroids. In most cases the long-term outcome
trolling symptoms. Surgical ureterolysis, which consists of freeing of idiopathic retroperitoneal fibrosis is satisfactory [75–77].
8.24 Tubulointerstitial Disease

References
1. Roshani H, Dabhoiwala NF, Verbeek FJ, Lamers WH: Functional 24. Anderson PAM, Rickwood AMK: Features of primary vesicoureteric
anatomy of the human ureterovesical junction. Anat Rec 1996, reflux detected by prenatal sonography. Br J Urol 1991, 67:267–271.
245:645–651. 25. Stocks A, Richards D, Frentzen B, Richard G: Correlation of prenatal
2. Noordzij JW, Dabhoiwala NF: A view on the anatomy of the renal pelvic anteroposterior diameter with outcome in pregnancy. J
ureterovesical junction. Scand J Urol Nephrol 1993, 27:371–380. Urol 1996, 155:1050–1052.
3. Thomson AS, Dabhoiwala NF, Verbeek FJ, Lamers WH: The func- 26. Adra AM, Mejides AA, Dennaoui MS, et al.: Fetal pyelectasis: Is it
tional anatomy of the ureterovesical junction. Br J Urol 1994, always “physiological”? [abstract]. Am J Obstet Gynecol 1995,
73:284–291. 172:359.
4. Politano VA: Vesico-ureteral reflux. In Urologic Surgery, edn 2. Edited 27. Morin L, Cendron M, Garmel SH, et al.: Minimal fetal hydronephro-
by Glenn JF. New York: Harper and Row Publishers, 1975:272–293. sis: natural history and implications for treatment. Am J Obstet
5. Paquin AJ: Ureterovesical junction: the description and evaluation of Gynecol 1995, 172:354.
a technique. J Urol 1959, 82:573. 28. Zerin JM, Ritchey MJ, Chang ACH: Incidental vesicoureteral reflux
6. Stephens FD, Lenaghan D: The anatomical basis and dynamics of in neonates with antenatally detected hydronephrosis and other
vesicoureteral reflux. J Urol 1962, 87:669. abnormalities. Radiology 1993, 187:157–160.
7. Kramer, SA: Vesicoureteral reflux. In Clinical Pediatric Urology, edn 29. Peters PC, Johnson DE, Jackson JHJ: The incidence of vesicoureteral
3. Edited by Kelalis PP, King LR, Belman AB. Philadelphia: WB reflux in the premature child. J Urol 1967, 97:259–260.
Saunders Company, 1992:441–499. 30. Lich R Jr, Howerton LW Jr, Goode LS, Davis LA: The ureterovesical
8. Ransley PG, Risdon RA: Renal papillary morphology in infants and junction of the newborn. J Urol 1964, 92:436–438.
young children. Urol Res 1975, 3:111–113. 31. Marra G, Barbieri G, Moioli C, et al.: Mild fetal hydronephrosis indi-
9. Ransley PG, Risdon RA: Renal papillary morphology and intrarenal cating vesicoureteric reflux. Arch Dis Child 1994, 70:F147–150.
reflux in the young pig. Urol Res 1975, 3:105–109. 32. Wallin L, Bajc M: The significance of vesicoureteric reflux on kidney
10. Funston MR, Cremin BJ: Intrarenal reflux-papillary morphology and development assessed by dimercaptosuccinate renal scintigraphy. Br J
pressure relationships in children’s necropsy kidneys. Br J Radiol Urol 1994, 73:607–611.
1978, 51:665–670. 33. Elder JS: Commentary: importance of antenatal diagnosis of vesi-
11. Ransley PG, Risdon RA: Reflux nephropathy: effects of antimicrobial coureteral reflux. J Urol 1992, 148:1750–1754.
therapy on the evolution of the early pyelonephritic scar. Kidney Int 34. Crabbe DCG, Thomas DFM, Gordon AC, et al.: Use of 99mtech-
1981, 20:733–742. netium-dimercaptosuccinic acid to study patterns of renal damage
12. Torres VE, Kramer SA, Holley KE, et al.: Effect of bacterial immu- associated with prenatally detected vesicoureteral reflux. J Urol 1992,
nization on experimental reflux nephropathy. J Urol 1984, 131:772. 148:1229–1231.
13. Torres VE, Kramer SA, Holley KE, et al.: Interaction of multiple risk 35. Sheridan M, Jewkes F, Gough DCS: Reflux nephropathy in the first
factors in the pathogenesis of experimental reflux nephropathy in the year of life: role of infection. Pediatr Surg Int 1991, 6:214–216.
pig. J Urol 1985, 133:131–135. 36. Weiss R, Tamminen-Mobius T, Koskimies O, et al.: Characteristics at
14. Goldraich NP, Goldraich IH, Anselmi OE, Ramos OL: Reflux entry of children with severe primary vesicoureteral reflux recruited
nephropathy: the clinical picture in South Brazilian children. Control for a multicenter international therapeutic trial comparing medical
Nephrol 1984, 39:52–67. and surgical management. J Urol 1992, 148:1644–1649.
15. Scherz HC, Downs TM, Caeser R: The selective use of dimercaptosuc- 37. Taylor CM, White RHR: Prospective trial of operative vs. non-opera-
cinic acid renal scans in children with vesicoureteral reflux. J Urol tive treatment of severe vesicoureteric reflux in children: five years’
1994, 152:628–631. observation. Br Med J 1987, 295:237–241.
16. Kramer SA: Experimental vesicoureteral reflux. Dialogues Pediatr 38. Tamminen-Mobius T, Brunier E, Ebel K-D, et al.: Cessation of vesi-
Urol 1984, 7:1. coureteral reflux for 5 years in infants and children allocated to med-
ical treatment. J Urol 1992, 148:1662–1666.
17. Hinchliffe SA, Chan Y, Jones H, et al.: Renal hypoplasia and postna-
tally acquired cortical loss in children with vesicoureteral reflux. 39. Astley R, Clark RC, Corkery JJ, et al.: Prospective trial of operative
Pediatr Nephrol1992, 6:439–444. vs. non-operative treatment of severe vesicoureteric reflux: two years’
observation in 96 children. Br Med J 1983, 287:171–174.
18. Lebowitz RL, Olbing H, Parkkulainen K, et al.: International system
of radiographic grading of vesicoureteral reflux. Pediatr Radiol 1985, 40. Olbing H, Claesson I, Ebel K-D, et al.: Renal scars and parenchymal
15:105. thinning in children with vesicoureteral reflux: a 5-year report of the
International Reflux Study in Children (European branch). J Urol
19. Smellie JM, Edwards D, Hunter N, et al.: Vesico-ureteric reflux and 1992, 148:1653–1656.
renal scarring. Kidney Int 1975, 8:s65–s72.
41. Jodal U, Koskimies O, Hanson E, et al.: Infection pattern in children
20. Arant BS: Medical management of mild and moderate vesicoureteral with vesicoureteral reflux randomly allocated to operation or long-
reflux: followup studies of infants and young children. A preliminary term antibacterial prophylaxis. J Urol 1992, 148:1650–1652.
report of the Southwest Pediatric Nephrology Study Group. J Urol
1992, 148:1683–1687. 42. Goonasekera CDA, Shah V, Wade A, et al.: 15-year follow-up of renin
and blood pressure in reflux nephropathy. Lancet 1996,
21. Steele BT, Robitaille P, DeMaria J, Grignon A: Follow-up evaluation 347:640–643.
of prenatally recognized vesicoureteric reflux. J Pediatr 1989,
115:95–96. 43. Torres V, Malek RS, Svensson JP: Vesicoureteral reflux in the adult:
nephropathy, hypertension, and stones. J Urol 1983, 130:41–44.
22. Najmaldin A, Burge DM, Atwell JD: Reflux nephropathy secondary
to intrauterine vesicoureteric reflux. J Pediatr Surg 1990, 25:387–390. 44. Torres V, Velosa J, Holley KE, et al.: The progression of vesicoureteral
reflux nephropathy. Ann Intern Med 1980, 92:776–784.
23. Marra G, Barbieri G, Dell’Agnola CA, et al.: Congenital renal damage
associated with primary vesicoureteral reflux detected prenatally in 45. Chevalier RL: Effects of ureteral obstruction on renal growth. Semin
male infants. J Pediatr 1994, 124:726–730. Nephrol 1995, 15:353–360.
 Reflux and Obstructive Nephropathy 8.25

46. Ichikawa I, Brenner BM: Local intrarenal vasoconstrictor-vasodilator 62. Campbell HT, Bello-Reuss E, Klahr S: Hydraulic water permeability
interactions in mild partial ureteral obstruction. Am J Physiol 1979, and transepithelial voltage in the isolated perfused rabbit cortical col-
236:F131–140. lecting tubule following acute unilateral ureteral obstruction. J Clin
47. Dal Canton A: Effects of 24-hour unilateral ureteral obstruction on Invest 1985, 75:219.
glomerular hemodynamics in rat kidney. Kidney Int 1979, 15:457. 63. Hanley MJ, Davidson K: Isolated nephron segments from rabbit mod-
48. Klahr S: Pathophysiology of obstructive nephropathy: a 1991 update. els of obstructive uropathy. J Clin Invest 1982, 69:165.
Semin Nephrol 1991, 11:156. 64. Hwang S: Transport defects of rabbit inner medullary collecting duct
49. Marin-Grez M, Fleming JT: Atrial natriuretic peptide causes pre- cells in obstructive uropathy. Am J Physiol 1993, 264:F808.
glomerular vasodilatation and post-glomerular vasoconstriction in rat 65. Hwang S: Transport defects of rabbit medullary thick ascending limb
kidney. Nature 1986, 324:473. cells in obstructive uropathy. J Clin Invest 1993, 91:21.
50. Schreiner GF, Harris KPG, Purkerson ML, Klahr S: Immunological 66. Kimura H, Mujais SK: Cortical collecting duct Na-K pump in
aspects of acute ureteral obstruction: immune cell infiltrate in the kid- obstructive uropathy. Am J Physiol 1990, 258:F1320.
ney. Kidney Int 1988, 34:487–493. 67. Muto S, Asano Y: Electrical properties of the rabbit cortical collecting
51. Diamond JR: Macrophages and progressive renal disease in experi- duct from obstructed kidneys after unilateral ureteral obstruction. J
mental hydronephrosis. Am J Kidney Dis 1995, 26:133–140. Clin Invest 1994, 94:1846.
52. Chevalier RL: Growth factors and apoptosis in neonatal ureteral 68. Davis BB, Preuss HG, Murdaugh HVJ: Hypomagnesemia following
obstruction. J Am Soc Nephrol 1996, 7:1098–1105. the diuresis of post-renal obstruction and renal transplant. Nephron
53. Ishidoya S, Morrisey J, McCracken R, Klahr S: Delayed treatment 1975, 14:275.
with enalapril halts tubulointerstitial fibrosis in rats with obstructive 69. Landsberg L: Hypernatremia complicating partial urinary tract
uropathy. Kidney Int 1996, 49:1110–1119. obstruction. N Engl J Med 1970, 283:746.
54. Morrisey J, Ishidoya S, McCracken R, Klahr S: Nitric oxide genera- 70. Whitherow RO, Whitaker RH: The predictive accuracy of antegrade
tion ameliorates the tubulointerstitial fibrosis of obstructive nephropa- pressure flow studies in equivocal upper tract obstruction. Br J Urol
thy. J Am Soc Nephrol 1996, 7:2202–2212. 1981, 53:496.
55. Ricardo SD, Ding G, Eufemio M, Diamond JR: Antioxidant expres- 71. Koff SA, Thrall JN, Keyes JW: Diuretic radionuclide urography. A
sion in experimental hydronephrosis: role of mechanical stretch and noninvasive method for evaluating nephroureteral dilatation. J Urol
growth factors. Am J Physiol 1997, 272:F789–F798. 1979, 122:451.
56. Wright EJ, McCaffrey TA, Robertson AP, et al.: Chronic unilateral ureter- 72. Whitfield HN: Furosemide intravenous urography in the diagnosis of
al obstruction is associated with interstitial fibrosis and tubular expression pelviureteric junction obstruction. Br J Urol 1979, 51:445.
of transforming growth factor-beta.Lab Invest 1996, 74:528–537. 73. Shokeir AA, Nijman RJM, El-Azab M, Provoost AP: Partial ureteral
57. Yanagisawa H: Dietary protein restriction normalized eicosanoid pro- obstruction: effect of intravenous normal saline and furosemide on the
duction in isolated glomeruli from rats with bilateral ureteral obstruc- resistive index. J Urol 1997, 157:1074–1077.
tion.Kidney Int 1994, 46:245. 74. Kaplan GW, Scherz HC: Infravesicle obstruction. In Clinical Pediatric
58. Vaughn EDJ, Gillenwater JY: Recovery following complete chronic Urology, edn 3. Edited by Kelalis PP, King LR, Belman AB.
unilateral ureteral occlusion: functional, radiographic and pathologic Philadelphia: WB Saunders Company; 1992:821–864.
alterations. J Urol 1971, 106:27–35. 75. Gilkeson GS, Allen NB: Retroperitoneal fibrosis: a true connective tis-
59. Shapiro SR: Recovery of renal function after prolonged unilateral sue disease. Rheum Dis North Am 1996, 22:23–38.
ureteral obstruction. J Urol 1976, 115:136–40. 76. Kottra JJ, Dunnick NR: Retroperitoneal fibrosis. Radiol Clin North
60. Miller TR: Urinary diagnostic studies in acute renal failure: a prospec- Am 1996, 34:1259–1275.
tive study. Ann Intern Med 1978, 89:47. 77. Massachusetts General Hospital: Case records–case 27–1996: N Engl
61. Batlle DC, Arruda JAL, Kurtzman NA: Hyperkalemic distal renal J Med 1996, 335:650–655.
tubular acidosis associated with obstructive uropathy. N Engl J Med
1981, 304:373.
Cystic Diseases
of the Kidney
Yves Pirson
Dominique Chauveau

A
kidney cyst is a fluid-filled sac arising from a dilatation in any
part of the nephron or collecting duct. A sizable fraction of all
kidney diseases—perhaps 10% to 15%—are characterized by
cysts that are detectable by various imaging techniques. In some, cysts
are the prominent abnormality; thus, the descriptor cystic (or poly-
cystic). In others, kidney cysts are an accessory finding, or are only
sometimes present, so that some question whether they are properly
classified as cystic diseases of the kidney. In fact, the commonly
accepted complement of cystic kidney diseases encompasses a large
variety of disorders of different types, presentations, and courses.
Dividing cystic disorders into genetic and “nongenetic” conditions
makes sense, not only conceptually but clinically: in the former cystic
involvement of the kidney often leads to renal failure and is most often
associated with extrarenal manifestations of the inherited defect,
whereas in the latter cysts rarely jeopardize renal function and gener-
ally are not part of a systemic disease.
In the first section of this chapter we deal with nongenetic (ie,
acquired and developmental) cystic disorders, emphasizing the imaging
characteristics that enable correct identification of each entity. Some
common pitfalls are described. A large part of the section on genetic
disorders is devoted to the most common ones (eg, autosomal-domi-
nant polycystic kidney disease), focusing on genetics, clinical manifes-
tations, and diagnostic tools. Even in the era of molecular genetics, the
diagnosis of the less common inherited cystic nephropathies relies on
proper recognition of their specific renal and extrarenal manifestations. CHAPTER
Most of these features are illustrated in this chapter.

9
9.2 Tubulointerstitial Disease

General Features
FIGURE 9-1
PRINCIPAL CYSTIC DISEASES OF THE KIDNEY Principal cystic diseases of the kidney.
Classification of the renal cystic disorders,
with the most common ones printed in bold
Nongenetic Genetic type. (Adapted from Fick and Gabow [1];
Welling and Grantham [2]; Pirson, et al. [3].)
Acquired disorders Autosomal-dominant
Simple renal cysts (solitary or multiple) Autosomal-dominant polycystic kidney disease
Cysts of the renal sinus (or peripelvic lymphangiectasis) Tuberous sclerosis complex
Acquired cystic kidney disease (in patients with von Hippel-Lindau disease
chronic renal impairment) Medullary cystic disease
Multilocular cyst (or multilocular cystic nephroma) Glomerulocystic kidney disease
Hypokalemia-related cysts Autosomal-recessive
Developmental disorders Autosomal-recessive polycystic kidney disease
Medullary sponge kidney Nephronophthisis
Multicystic dysplastic kidney X-linked
Pyelocalyceal cysts Orofaciodigital syndrome, type I

IMAGING CHARACTERISTICS OF THE MOST COMMON RENAL CYSTIC DISEASES

Disease Kidney Size Cyst Size Cyst Location Liver

Simple renal cysts Normal Variable (mm–10 cm) All Normal
Acquired renal cystic disease Most often small, sometimes large 0.5–2 cm All Normal
Medullary sponge kidney Normal or slightly enlarged mm Precalyceal Normal (most often)
ADPKD Enlarged Variable (mm–10 cm) All Cysts (most often)
ARPKD Enlarged mm increase with age All CHF
NPH Small mm–2 cm (when present) Medullary Normal

FIGURE 9-2
Characteristics of the most common renal cystic diseases detectable in the vast majority of patients. ADPKD—autosomal-dominant
by imaging techniques (ultrasonography, computed tomography, polycystic kidney disease; ARPKD—autosomal-recessive polycystic
magnetic resonance). In the context of family history and clinical kidney disease; CHF—congenital hepatic fibrosis; NPH—
findings, these allow the clinician to establish a definitive diagnosis nephronophthisis.
 Cystic Diseases of the Kidney 9.3

Nongenetic Disorders
FIGURE 9-3
Solitary simple cyst. Large solitary cyst found incidentally at ultra-
sonography (longitudinal scan) in the lower pole of the right kid-
ney. Criteria for the diagnosis of simple cyst include absence of
internal echoes, rounded outline, sharply demarcated, smooth
walls, bright posterior wall echo (arrows). The latter occur because
less sound is absorbed during passage through cyst than through
the adjacent parenchyma. If these criteria are not satisfied, comput-
ed tomography can rule out complications and other diagnoses.

PREVALENCE OF SIMPLE RENAL CYSTS DETECTED BY ULTRASONOGRAPHY

Prevalence, %
≥1 Cyst ≥2 Cysts* ≥3 Cysts* ≥1 Cyst in Each Kidney
Age group, y M F M F M F M F
15–29 0 0 0 0 0 0 0 0
30–49 2 1 0 1 0 1 0 1
50–69 15 7 2 1 1 1 2 1
≥70 32 15 17 8 6 3 9 3

*Unilateral or bilateral. M—male; F—Female.

FIGURE 9-4
Prevalence of simple renal cysts detected by ultrasonography increases with age and is higher in males. Cyst size also increases
according to age in an Australian population of 729 persons with age. Most simple cysts are located in the cortex. (From
prospectively screened by ultrasonography. The prevalence Ravine et al. [4]; with permission.)
9.4 Tubulointerstitial Disease

A B
FIGURE 9-5
A and B, Multiple simple cysts (one 7 cm in diameter in the lower Each cyst exhibits the typical features of an uncomplicated simple
pole of the left kidney and three 4 to 5 cm in diameter in the right cyst on CT: 1) homogeneous low density, unchanged by contrast
kidney) detected by contrast-enhanced computed tomography (CT). medium; 2) rounded outline; 3) very thin (most often indetectable)
Additional millimetric cysts might be suspected in both kidneys. wall; 4) distinct delineation from adjacent parenchyma.

A B
FIGURE 9-6
A, Contrast-enhanced computed tomography (CT) shows a Ultrasonographic appearance mimicked hydronephrosis. Also
simple, 3-cm wide cyst of the renal sinus (arrows) found during known as hilar lymphangiectasis or peripelvic (or parapelvic)
investigation of renal calculi. Note subcapsular hematoma cysts, this acquired disorder consists of dilated hilar lymph
(arrowheads) detected after lithotripsy. B, Contrast-enhanced channels. Its frequency is about 1% in autopsy series. Although
CT shows bilateral multiple cysts of the renal sinus, leading to usually asymptomatic, cysts of the renal sinus can cause severe
chronic compression of the pelvis and subsequent renal atrophy. urinary obstruction, B.
 Cystic Diseases of the Kidney 9.5

A B
FIGURE 9-7
A, Acquired cystic kidney disease (ACKD) detected by contrast- hemodialysis and peritoneal dialysis, respectively [5]. In the early
enhanced computed tomography (CT) in a 71-year-old man on stage, kidneys are small or even shrunken and cysts are usually
hemodialysis for 4 years. A, Note the several intrarenal calcifica- smaller than 0.5 cm. Cyst numbers and kidney volume increase
tions, which are not unusual in dialysis patients. ACKD is charac- with time, as seen on this patient’s scan (B) repeated 8 years into
terized by the development of many cysts in the setting of chronic dialysis. Advanced ACKD can mimic autosomal-dominant polycys-
uremia. It can occur at any age, including childhood, whatever the tic disease. ACKD sometimes regresses after successful transplanta-
original nephropathy. The diagnosis is based on detection of at tion; it can involve chronically rejected kidney grafts. Although
least three to five cysts in each kidney in a patient who has chronic ACKD is usually asymptomatic it may be complicated by bleed-
renal failure but not hereditary cystic disease. The prevalence of ing—confined to the cysts or extending to either the collecting sys-
ACKD averages 10% at onset of dialysis treatment and subse- tem (causing hematuria) or the perinephric spaces—and associated
quently increases, to reach 60% and 90% at 5 and 10 years into with renal cell carcinoma. (Courtesy of M. Jadoul.)

FIGURE 9-8
Age <55 and > 3 years No Screening for acquired cystic kidney disease (ACKD) and renal neoplasms in patients receiv-
on RRT and good No
screening ing renal replacement therapy (RRT). The major clinical concern with ACKD is the risk of
clinical condition?
renal cell carcinoma, often the tubulopapillary type, associated with this disorder: the inci-
Yes dence is 50-times greater than in the general population. Moreover, ACKD-associated renal
No
carcinoma is more often bilateral and multicentric; however, only a minority of them evolve
Echography: into invasive carcinomas or cause metastases [5]. There is no doubt that imaging should be
ACKD? performed when a dialysis patient has symptoms such as flank pain and hematuria, the
Yes question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients
is still being debated. Using decision analysis incorporating morbidity and mortality associ-
No
Suspicion of ated with nephrectomy in dialysis patients, Sarasin and coworkers [6] showed that only the
Biennial echo
renal neoplasm? youngest patients at risk for ACKD benefit from periodic screening. On the basis of this
analysis, it has been proposed that screening be restricted to patients younger than 55 years,
Yes
who have been on dialysis at least 3 years and are in good general condition. Recognized
Enhanced CT: No risk factors for renal cell carcinoma in ACKD are male gender, uremia of long standing,
confirmed neoplasm? large kidneys, and analgesic nephropathy.

Yes
Nephrectomy
and annual
follow-up of
contralateral kidney
9.6 Tubulointerstitial Disease

FIGURE 9-9
Multilocular cyst (or multilocular cystic
nephroma) of the right kidney, detected by
ultrasonography (A) and contrast-enhanced
CT-scan (B). Both techniques show the
characteristic septa (arrow) dividing the
mass into multiple sonolucent locules. This
rare disorder is usually a benign tumor,
though some lesions have been found to
contain foci of nephroblastoma or renal
clear cell carcinoma. The imaging appear-
ance is actually indistinguishable from
those of the cystic forms of Wilms’ tumor
and renal clear cell carcinoma. (Courtesy
of A. Dardenne.)
A B

A B
FIGURE 9-10
A, contrast-enhanced computed tomography (CT) for evaluation
of a left renal stone in a 67-year-old man. A cystic mass was found
at the lower pole of the right kidney. Only careful examination
revealed that the walls of the mass (arrows) were too thick for a
simple cyst (see Fig. 9-5 for comparison). B, The echo pattern of
the mass was very heterogeneous (arrows), clearly different from
the echo-free appearance of a simple cyst (see Fig. 9-3 for compari-
son). C, Magnetic resonance imaging showed thick, irregular
walls and a hyperintense central area (arrows). At surgery, the
mass proved to be a largely necrotic renal cell carcinoma. Thus,
although renal carcinoma is not a true cystic disease, it occasional-
ly has a cystic appearance on CT and can mimic a simple cyst.
C (Courtesy of A. Dardenne.)
 Cystic Diseases of the Kidney 9.7

FIGURE 9-11
Medullary sponge kidney (MSK) diagnosed by intravenous urography in 53-year-old
woman with a history of recurrent kidney stones. Pseudocystic collections of contrast medi-
um in the papillary areas (arrows) are the typical feature of MSK. They result from congen-
ital dilatation of collecting ducts (involving part or all of one or both kidneys), ranging
from mild ectasia (appearing on urography as linear striations in the papillae, or papillary
“blush”) to frank cystic pools, as in this case (giving a spongelike appearance on section of
the kidney). MSK has an estimated prevalence of 1 in 5000 [2]. It predisposes to stone for-
mation in the dilated ducts: on plain films, clustering of calcifications in the papillary areas
is very suggestive of the condition. MSK may be associated with a variety of other congeni-
tal and inherited disorders, including corporeal hemihypertrophy, Beckwith-Wiedemann
syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retarda-
tion), polycystic kidney disease (about 3% of patients with autosomal-dominant polycystic
kidney disease have evidence of MSK), congenital hepatic fibrosis, and Caroli’s disease [7].

FIGURE 9-12
Multicystic dysplastic kidney (MCDK) found incidentally by
enhanced CT in a 34-year-old patient. The dysplastic kidney is
composed of cysts with mural calcifications (arrows). Note the
compensatory hypertrophy of the right kidney and the incidental
simple cysts in it. MCDK consists of a collection of cysts frequently
described as resembling a bunch of grapes and an atretic ureter. No
function can be demonstrated. Only unilateral involvement is com-
patible with life. Usually, the contralateral kidney is normal and
exhibits compensatory hypertrophy. In some 30% of cases, howev-
er, it is also affected by some congenital abnormalities such as dys-
plasia or pelviureterical junction obstruction. In fact, among the
many forms of renal dysplasia, MCDK is thought to represent a
cystic variety.

FIGURE 9-13
Intravenous urography demonstrates multiple calyceal diverticula
(arrows) in a 38-year-old woman who complained of intermittent
flank pain. Previously, the ultrasonographic appearance had sug-
gested the existence of polycystic kidney disease. Although usually
smaller than 1 cm in diameter, pyelocalyceal diverticula occasion-
ally are much larger, as in this case. They predispose to stone for-
mation. Since ultrasonography is the preferred screening tool for
cystic renal diseases, clinicians must be aware of both its pitfalls
(exemplified in this case and in the case of parapelvic cysts; see
Fig. 9-6) and its limited power to detect very small cysts.
9.8 Tubulointerstitial Disease

Genetic disorders
FIGURE 9-14
GENETICS OF ADPKD Genetics of autosomal-dominant polycystic kidney disease
(ADPKD). ADPKD is by far the most frequent inherited kidney dis-
ease. In white populations, its prevalence ranges from 1 in 400 to 1
Gene Chromosome Product Patients with ADPKD, % in 1000. ADPKD is characterized by the development of multiple
renal cysts that are variably associated with extrarenal (mainly
PKD1 16 Polycystin 1 80–90 hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by
PKD2 4 Polycystin 2 10–20 mutations in at least three different genes. PKD1, the gene responsi-
PKD3 ? ? Very few ble in approximately 85% of the patients, located on chromosome
16, was cloned in 1994 [8]. It encodes a predicted protein of 460
kD, called polycystin 1. The vast majority of the remaining cases
are accounted for by a mutation in PKD2, located on chromosome
4 and cloned in 1996 [9]. The PKD2 gene encodes a predicted pro-
tein of 110 kD called polycystin 2. Phenotypic differences between
the two main genetic forms are detailed in Figure 9-19. The exis-
tence of (at least) a third gene is suggested by recent reports.

FIGURE 9-15
NH2 Autosomal-dominant polycystic kidney disease: predicted structure
of polycystin 1 and polycystin 2 and their interaction. Polycystin 1
Cysteine-rich domain
is a 4302-amino acid protein, which anchors itself to cell mem-
Leucine-rich domain branes by seven transmembrane domains [10]. The large extracel-
PKD1 domain lular portion includes two leucine-rich repeats usually involved in
C protein-protein interactions and a C-type lectin domain capable of
C L C-type lectin domain
L B binding carbohydrates. A part of the intracellular tail has the
B capacity to form a coiled-coil motif, enabling either self-assembling
Lipoprotein A domain or interaction with other proteins. Polycystin 2 is a 968-amino acid
R protein with six transmembrane domains, resembling a subunit of
E REJ domain
J voltage-activated calcium channel. Like polycystin 1, the C-termi-
nal end of polycystin 2 comprises a coiled-coil domain and is able
Transmembrane segment
to interact in vitro with PKD2 [11]. This C-terminal part of poly-
cystin 2 also includes a calcium-binding domain. On these grounds,
it has been hypothesized that polycystin 1 acts like a receptor and
Alpha helix coiled-coil signal transducer, communicating information from outside to
inside the cell through its interaction with polycystin 2. This coor-
R
E dinated function could be crucial during late renal embryogenesis.
J It is currently speculated that both polycystins play a role in the
Out
maturation of tubule epithelial cells. Mutation of polycystins could
Membrane
thus impair the maturation process, maintaining some tubular cells
in a state of underdevelopment. This could result in both sustained
In
cell proliferation and predominance of fluid secretion over absorp-
tion, leading to cyst formation (see Fig. 9-16 and references 12 and
NH2 13 for review). (From Hughes et al. [10] and Germino [12].)
HOOC
COOH
Polycystin 1 Polycystin 2
 Cystic Diseases of the Kidney 9.9

allele is required to trigger cyst formation

Thickened tubular (ie, a mechanism similar to that demonstrat-
basement membrane ed for tumor suppressor genes in tuberous
sclerosis complex and von Hippel-Lindau dis-
ease). The hypothesis is supported by both
the clonality of most cysts and the finding of
Fluid loss of heterozygosity in some of them [12].
Accumulation Cell immaturity resulting from mutated
polycystin would lead to uncontrolled
growth, elaboration of abnormal extracellu-
lar matrix, and accumulation of fluid.
Aberrant cell proliferation is demonstrated by
the existence of micropolyps, identification of
Normal tubule Occurrence Monoclonal Isolated cyst mitotic phases, and abnormal expression of
with germinal of somatic proliferation disconnected from proto-oncogenes. Abnormality of extracellu-
PKD1 mutation of the leading to its tubule of lar matrix is evidenced by thickening and
mutation normal PKD1 cyst formation origin lamination of the tubular basement mem-
in each cell allele in one brane; involvement of extracellular matrix
tubular cell
would explain the association of cerebral
(the "second hit")
artery aneurysms with ADPKD. As most
cysts are disconnected from their tubule of
FIGURE 9-16 origin, they can expand only through net
Hypothetical model for cyst formation in autosomal-dominant polycystic kidney disease transepithelial fluid secretion, just the reverse
(ADPKD), relying on the “two-hit” mechanism as the primary event. The observation that of the physiologic tubular cell function [13].
only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors ger- Figure 9-17 summarizes our current knowl-
minal PKD1 mutation, is best accounted for by the two-hit model. This model implies that, in edge of the mechanisms that may be involved
addition to the germinal mutation, a somatic (acquired) mutation involving the normal PKD1 in intracystic fluid accumulation.

FIGURE 9-17
Autosomal-dominant polycystic kidney disease (ADPKD): mecha-
nisms of intracystic fluid accumulation [13,14]. The primary mech-
Basolateral Aden
ylate Apical anism of intracystic fluid accumulation seems to be a net transfer
cycla
se of chloride into the lumen. This secretion is mediated by a
(CFTR) bumetanide-sensitive Na+-K+-2Cl- cotransporter on the basolateral
Na+ cAMP ATP
K+ Cl– side and cystic fibrosis transmembrane regulator (CFTR) chloride
2Cl– channel on the apical side. The activity of the two transporters is
PKA regulated by protein kinase A (PKA) under the control of cyclic
Bumetanide DPC
2K + adenosine monophosphate (AMP). The chloride secretion drives
+ + ATP movement of sodium and water into the cyst lumen through elec-
(Na -K -ATPase) Lumen trical and osmotic coupling, respectively. The pathway for transep-
3Na+ ADP + Pi
ithelial Na+ movement has been debated. In some experimental
H 2O conditions, part of the Na+ could be secreted into the lumen via a
Ouabain
(A P)
Q mispolarized apical Na+-K+-ATPase (“sodium pump”); however, it
H 2O
Na+ is currently admitted that most of the Na+ movement is paracellu-
lar and that the Na+-K+-ATPase is located at the basolateral side.
( AQP)
The movement of water is probably transcellular in the cells that
express aquaporins on both sides and paracellular in others [13,
14]. AQP—aquaporine; DPC—diphenylamine carboxylic acid.
9.10 Tubulointerstitial Disease

0.46
ADPKD: CLINICAL MANIFESTATIONS 1.0 (0.22-0.98)

Odds ratio (95% Cl) PKD2 vs. PKD1

0.47
(0.28-0.81)
0.8
Manifestation Prevalence, % Reference
Renal 0.6 0.28 0.18
Hypertension Increased with age [15] (0.16-0.48) (0.07-0.47)
(80 at ESRD)
Pain (acute and chronic) 60 [3,16] 0.4
Gross hematuria 50 [3,16]
Urinary tract infection Men 20; women 60 [3]
[17] 0.2
Calculi 20
Renal failure 50 at 60 y [18]
Hepatobiliary (see Fig. 9–23) 0.0
Cardiovascular Hypertension Renal infection Subarachnoid Abdominal
Cardiac valvular abnormality 20 [16] history hemorrhage hernia
Intracranial arteries
Aneurysm 8 [3] 80
PKD2 74 75
Dolichoectasia 2 [19]
Rare PKD1 70
? Ascending aorta dissection 70
? Coronary arteries aneurysm Rare
61 60
Other 60
Pancreatic cysts 9 [20]
Arachnoid cysts 8 [21] 50
Hernia Age, y
Inguinal 13 [22]
7 [22] 40
Umbilical 35
Spinal Meningeal Diverticula 0.2 [23]
30

20
FIGURE 9-18
10
Main clinical manifestations of autosomal-dominant polycystic kid-
ney disease (ADPKD). Renal involvement may be totally asympto- 0
matic at early stages. Arterial hypertension is the presenting clinical Clinical End-stage Death
finding in about 20% of patients. Its frequency increases with age. presentation renal failure
Flank or abdominal pain is the presenting symptom in another Median age
20%. The differential diagnosis of acute abdominal is detailed in
Figure 9-22. Gross hematuria is most often due to bleeding into a
cyst, and more rarely to stone. Renal infection, a frequent reason FIGURE 9-19
for hospital admission, can involve the upper collecting system, Autosomal-dominant polycystic kidney disease (ADPKD): pheno-
renal parenchyma or renal cyst. Diagnostic data are obtained by type PKD2 versus PKD1. Families with a PKD2 mutation have a
ultrasonography, excretory urography and CT: use of CT in cyst milder phenotype than those with a PKD1 mutation. In this study
infection is described in Figure 9-21. Frequently, stones are radiolu- comparing 306 PKD2 patients (from 32 families) with 288 PKD1
cent or faintly opaque, because of their uric acid content. The main patients (17 families), PKD2 patients were, for example, less likely
determinants of progression of renal failure are the genetic form of to be hypertensive, to have a history of renal infection, to suffer a
the disease (see Fig. 9-19) and gender (more rapid progression in subarachnoid hemorrhage, and to develop an abdominal hernia. As
males). Hepatobiliary and intracranial manifestations are detailed a consequence of the slower development of clinical manifestations,
in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most PKD2 patients were, on average, 26 years older at clinical presen-
usually asymptomatic. Spinal meningeal diverticula can cause pos- tation, 14 years older when they started dialysis, and 5 years older
tural headache. ESRD—end-stage renal disease. when they died. Early-onset ADPKD leading to renal failure in
childhood has been reported only in the PKD1 variety. (Data from
Hateboer [24].)
 Cystic Diseases of the Kidney 9.11

A B

C D
FIGURE 9-20
Autosomal-dominant polycystic kidney disease (ADPKD): kidney kidneys may be observed, as in this 36-year-old woman. In the early
involvement. Examples of various cystic involvements of kidneys in stage of the disease, making the diagnosis may be more difficult (see
ADPKD. Degree of involvement depends on age at presentation and Fig. 9-28 for the minimal sonographic criteria to make a diagnosis
disease severity. A, With advanced disease as in this 54-year-old of ADPKD in PKD1 families). C, D, Contrast-enhanced CT is more
woman, renal parenchyma is almost completely replaced by innu- sensitive than ultrasonography in the detection of small cysts. The
merable cysts. Note also the cystic involvement of the liver. B, presence of liver cysts helps to establish the diagnosis, as in this 38-
Marked asymmetry in the number and size of cysts between the two year-old man with PKD2 disease and mild kidney involvement.
9.12 Tubulointerstitial Disease

A B
FIGURE 9-21
Autosomal-dominant polycystic kidney disease (ADPKD): kidney antibiotherapy (fluoroquinolone). B, CT repeated 17 days later
cyst infection. Course of severe cyst infection in the right kidney of showed considerable enlargement of the infected cysts (arrows).
a patient with ADPKD who was admitted for fever and acute right Percutaneous drainage failed to control infection, and nephrectomy
flank pain. Blood culture was positive for Escherichia coli. A, CT was necessary. This case illustrates the potential severity of cyst
performed on admission showed several heterogeneous cysts in the infection and the contribution of sequential CT in the diagnosis
right kidney (arrows). Infection did not respond to appropriate and management of complicated cysts.

FIGURE 9-22
ADPKD: SPECIFIC CAUSES OF Autosomal-dominant polycystic kidney disease (ADPKD): specific
ACUTE ABDOMINAL PAIN causes of acute abdominal pain. The most frequent cause of acute
abdominal pain related to ADPKD is intracyst bleeding. Depending
on the amount of bleeding, it may cause mild, transient fever. It may
Cause Frequency Fever or may not cause gross hematuria. Cyst hemorrhage is responsible for
most high-density cysts and cyst calcifications demonstrated by CT.
Renal Spontaneous resolution is the rule. Excretory urography or enhanced
Cyst Bleeding ++++ Mild (<38°C, maximum 2 days) or none CT is needed mostly to locate obstructive, faintly opaque stones.
Stone ++ With pyonephrosis Stones may be treated by percutaneous or extracorporal lithotripsy.
Infection + High; prolonged with cyst involved Renal infection may involve the upper collecting system,
Liver Cyst renal parenchyma, or cyst. Parenchymal infection is evidenced
Infection Rare High, prolonged by positive urine culture and prompt response to antibiotherapy;
Bleeding Very Rare Mild (<38°C, maximum 2 days) or none cyst infection by the development of a new area of renal tenderness,
quite often a negative urine culture (but a positive blood culture),
and a slower response to antibiotherapy. CT demonstrates the het-
erogeneous contents and irregularly thickened walls of infected
cysts. Cyst infection warrants prolonged anti-biotherapy [3]. An
example of severe, intractable cyst infection is shown in Figure 9-21.
 Cystic Diseases of the Kidney 9.13

ADPKD: HEPATOBILIARY MANIFESTATIONS

Finding Frequency
Asymptomatic liver cysts Very common; increased prevalence with
age (up to 80% at age 60)
Symptomatic polycystic liver disease Uncommon (male/female ratio: 1/10)
Complicated cysts (hemorrhage,
infection)
Massive hepatomegaly
Chronic pain/discomfort
Early satiety
Supine dyspnea
Abdominal hernia
Obstructive jaundice
Hepatic venous outflow obstruction
Congenital hepatic fibrosis Rare (not dominantly transmitted)
Idiopathic dilatation of intrahepatic or Very rare
extrahepatic biliary tract
Cholangiocarcinoma Very rare
FIGURE 9-24
Autosomal-dominant polycystic kidney disease (ADPKD): polycys-
tic liver disease. Contrast-enhanced CT in a 32-year-old woman
FIGURE 9-23 with ADPKD, showing massive polycystic liver disease contrasting
Autosomal-dominant polycystic kidney disease (ADPKD): hepato- with mild kidney involvement.
biliary manifestations. Liver cysts are the most frequent extrarenal Massive polycystic liver disease can cause chronic pain, early
manifestation of ADPKD. Their prevalence increases dramatically satiety, supine dyspnea, abdominal hernia, and, rarely, obstructive
from the third to the sixth decade of life, reaching a plateau of 80% jaundice, or hepatic venous outflow obstruction. Therapeutic
thereafter [25, 26]. They are observed earlier and are more numer- options include cyst sclerosis and fenestration, hepatic resection,
ous and extensive in women than in men. Though usually mild and and, ultimately, liver transplantation [25, 26].
asymptomatic, cystic liver involvement occasionally is massive and
symptomatic (see Figure 9-24). Rare cases have been reported of
congenital hepatic fibrosis or idiopathic dilatation of the intrahepatic
or extrahepatic tract associated with ADPKD [25, 26].

A B
FIGURE 9-25
Autosomal-dominant polycystic kidney disease (ADPKD): ICA rupture in ADPKD is ill-defined. ICA rupture entails 30% to
intracranial aneurysm detection. Magnetic resonance angiogra- 50% mortality. It is generally manifested by subarachnoid hemor-
phy (MRA), A, and spiral computed tomography (CT) angiogra- rhage, which usually presents as an excruciating headache. In this
phy, B, in two different patients, both with ADPKD, show an setting, the first-line diagnostic procedure is CT. Management
asymptomatic intracranial aneurysm (ICA) on the posterior com- should proceed under neurosurgical guidance [27].
municating artery (arrow), A, and the anterior communicating Given the severe prognosis of ICA rupture and the possibility
artery (arrow), B, respectively. of prophylactic treatment, screening ADPKD patients for ICA has
The prevalence of asymptomatic ICA in ADPKD is 8%, as been considered. Screening can be achieved by either MRA or spi-
compared with 1.2% in the general population. It reaches 16% ral CT angiography. Current indications for screening are present-
in ADPKD patients with a family history of ICA [27]. The risk of ed in Figure 9-26. (Courtesy of T. Duprez and F. Hammer.)
9.14 Tubulointerstitial Disease

FIGURE 9-26
Age 18–40 years No Autosomal-dominant polycystic kidney disease (ADPKD): intracranial aneurysm (ICA)
and family history No
screening. On the basis of decision analyses (taking into account ICA prevalence, annual
of ICA? screening
risk of rupture, life expectancy, and risk of prophylactic treatment), it is currently pro-
Yes posed to screen for ICA 18 to 40-year-old ADPKD patients with a family history of ICA
[25, 27]. Screening could also be offered to patients in high-risk occupations and those
Brain MR angiography No
or spiral CT scan: Repeat every who want reassurance. Guidelines for prophylactic treatment are the same ones used in
ICA? 5 years the general population: the neurosurgeon and the interventional radiologist opt for either
surgical clipping or endovascular occlusion, depending on the site and size of ICA.
Yes

Conventional
angiography
Discuss management
with neurosurgeon

ADPKD: PRESYMPTOMATIC DIAGNOSIS ADPKD: ULTRASONOGRAPHIC

DIAGNOSTIC CRITERIA

Presymptomatic diagnosis
Is advisable in families when early management of affected patients would be altered Age Cysts
(eg, because of history of intracranial aneurysm)
15–29 2, uni- or bilateral
Should be made available to persons at risk who are 18 years or older who request
the test 30–59 2 in each kidney
Should be preceded by information about the possibility of inconclusive results and ≥60 4 in each kidney
the consequences of the diagnosis:
If negative, reassurance Minimal number of cysts to establish a diagnosis of ADPKD in PKD1 families at risk.
If positive, regular medical follow-up, possible psychological burden,
risk of disqualification from employment and insurances
FIGURE 9-28
Autosomal-dominant polycystic kidney disease (ADPKD): ultra-
sonographic diagnostic criteria. Ultrasound diagnostic criteria for
FIGURE 9-27 the PKD1 form of ADPKD, as established by Ravine’s group on the
Autosomal-dominant polycystic kidney disease (ADPKD): presymp- basis of both a sensitivity and specificity study [4, 28]. Note that
tomatic diagnosis. Presymptomatic diagnosis is aimed at both detect- the absence of cyst before age 30 years does not rule out the diag-
ing affected persons (to provide follow-up and genetic counseling) nosis, the false-negative rate being inversely related to age. When
and reassuring unaffected ones. Until a specific treatment for ADPKD ultrasound diagnosis remains equivocal, the next step should be
is available, presymptomatic diagnosis in children is not advised either contrast-enhanced CT (more sensitive than ultrasonography
except in rare families where early-onset disease is typical. Presymp- in the detection of small cysts) or gene linkage (see Figure 9-29). A
tomatic diagnosis is recommended when a family is planned and similar assessment is not yet available for the PKD2 form. (From
when early management of affected patients would be altered. The Ravine et al. [28]; with permission.)
mainstay of screening is ultrasonography; diagnostic echographic
criteria according to age in PKD1 families are depicted in Figure 9-28,
and diagnosis by gene linkage in Figure 9-29.
 Cystic Diseases of the Kidney 9.15

FIGURE 9-29
Deceased Example of the use of gene linkage to identify ADPKD gene carriers
I ? ? Unaffected among generation IV of a PKD1 family. Two markers flanking the
1 2 Affected PKD1 gene were used. The first one (3’ HVR) has six possible alle-
? Unknown status les (1 through 6) and the other (p 26.6) is biallelic (a, b). In this
family, the haplotype 2a is transmitted with the disease (see affected
persons II5, III1, and III3). Thus, IV4 has a 99% chance of being a
carrier of the mutated PKD1 gene, whereas her sisters (IV1, IV2,
II IV3) have a 99% chance of being disease free.
1 2 3 4 5
Until direct gene testing for PKD1 and PKD2 is readily available,
1 1 genetic diagnosis will rest on gene linkage. Such analysis requires
b b that other affected and unaffected family members (preferably from
III
1 2 3 two generations) be available for study. Use of markers on both
sides of the tested gene is required to limit potential errors due to
2 3 2 5 4 2
a b b a a a recombination events. Linkage to PKD1 is to be tested first, as it
accounts for about 85% of cases.

IV ? ? ? ?
1 2 3 4
2 3 3 2 3 5 2 5
b b b b b a a a

FIGURE 9-30
Life expectancy <5 yrs Autosomal-dominant polycystic kidney disease (ADPKD): renal
or contraindication to surgery Yes replacement therapy. Transplantation nowadays is considered in any
or to immunosuppressants? ADPKD patient with a life expectancy of more than 5 years and
No with no contraindications to surgery or immunosuppression.
Pretransplant workup should include abdominal CT, echocardiogra-
Pretransplant workup: phy, myocardial stress scintigraphy, and, if needed (see Figure 9-26),
Yes Eligibility for transplantation? screening for intracranial aneurysm. Pretransplant nephrectomy is
advised for patients with a history of renal cyst infection, particularly
No if the infections were recent, recurrent, or severe. Patients not eligible
History of No
cyst infection? for transplantation may opt for hemodialysis or peritoneal dialysis.
Very large kidneys Yes Although kidney size is rarely an impediment to peritoneal dialysis,
Yes or abdominal hernia?
this option is less desirable for patients with very large kidneys,
No because their volume may reduce the exchangeable surface area and
Remove the tolerance for abdominal distension. Outcome for ADPKD
kidney(s)? or
patients following renal replacement therapy is similar to that of
matched patients with another primary renal disease [29, 30].
Transplantation Peritoneal dialysis Hemodialysis
9.16 Tubulointerstitial Disease

FIGURE 9-31
CLINICAL FEATURES Tuberous sclerosis complex (TSC): clinical features. TSC is an auto-
somal-dominant multisystem disorder with a minimal prevalence of
1 in 10,000 [30, 31]. It is characterized by the development of mul-
Finding Frequency, % Age at onset, y tiple hamartomas (benign tumors composed of abnormally arranged
and differentiated tissues) in various organs. The most common
Skin manifestations are dermatologic (see Fig. 9-32) and neurologic (see
Hypomelanotic macules 90 Childhood Fig. 9-33). Renal involvement occurs in 60% of cases and includes
Facial angiofibromas 80 5–15
Forehead fibrous plaques 30 ≥5
cysts (see Fig. 9-34). Retinal involvement, occurring in 50% of
“Shagreen patches” (lower back) 30 ≥10 cases, is almost always asymptomatic. Liver involvement, occurring
Periungual fibromas 30 ≥15 in 40% of cases, includes angiomyolipomas and cysts. Involvement
Central nervous system of other organs is much rarer [31, 32].
Cortical tubers 90 Birth
Subependymal tumors 90 Birth
(may be calcified)
focal or generalized seizures 80 0–1
Mental retardation/ 50 0–5
behavioral disorder
Kidney
Angiomyolipomas 60 Childhood
Cysts 30 Childhood
Renal cell carcinoma 2 Adulthood
Eye
Retinal hamartoma 50 Childhood
Retinal pigmentary abnormality 10 Childhood
Liver (angiomyolipomas, cysts) 40 Childhood
Heart (rhabdomyoma) 2 Childhood
Lung (lymphangiomyomatosis; 1 ≥20
affects females)

B
FIGURE 9-32 (see Color Plate)
Tuberous sclerosis complex (TSC): skin involvement. Facial angiofibromas, forehead
plaque, A, and ungual fibroma, B, characteristic of TSC. Previously (and inappropriately)
called adenoma sebaceum, facial angiofibromas are pink to red papules or nodules, often
concentrated in the nasolabial folds. Forehead fibrous plaques appear as raised, soft patch-
es of red or yellow skin. Ungual fibromas appear as peri- or subungual pink tumors; they
are found more often on the toes than on the fingers and are more common in females.
Other skin lesions include hypomelanotic macules and “shagreen patches” (slightly elevated
A patches of brown or pink skin). (Courtesy of A. Bourloud and C. van Ypersele.)
 Cystic Diseases of the Kidney 9.17

FIGURE 9-33
Tuberous sclerosis complex (TSC): central nervous system involvement. Brain CT shows
several subependymal, periventricular, calcified nodules characteristic of TSC. Subependymal
tumors and cortical tubers are the two characteristic neurologic features of TSC. Calcified
nodules are best seen on CT, whereas noncalcified tumors are best detected by magnetic
resonance imaging. Clinical manifestations are seizures (including infantile spasms) occur-
ring in 80% of infants, and varying degrees of intellectual disability or behavioral disorder,
reported in 50% of children [32].

A B
FIGURE 9-34
Tuberous sclerosis complex (TSC): kidney involvement. Contrast- of fat into the tumor, but it is not always possible to distinguish
enhanced CT, A, and gadolinium-enhanced T1 weighted magnetic between AML and renal cell carcinoma. The main complication of
resonance images, B, of a 15-year-old woman with TSC, show AML is bleeding with subsequent gross hematuria or potentially life-
both a large, hypodense, heterogeneous tumor in the right kidney threatening retroperitoneal hemorrhage.
(arrows) characteristic of angiomyolipoma (AML) and multiple Cysts seem to be restricted to the TSC2 variety (see Fig. 9-35)
bilateral kidney cysts. Kidney cysts had been detected at birth. [33]. Their extent varies widely from case to case. Occasionally,
AML is a benign tumor composed of atypical blood vessels, polycystic kidneys are the presenting manifestation of TSC2 in early
smooth muscle cells, and fat tissue. While single AML is the most childhood: in the absence of renal AML, the imaging appearance is
frequent kidney tumor in the general population, multiple and bilat- indistinguishable from ADPKD. Polycystic kidney involvement leads
eral AMLs are characteristic of TSC. In TSC, AMLs develop at a to hypertension and renal failure that reaches end stage before age
younger age in females; frequency and size of the tumors increase 20 years. Though the frequency of renal cell carcinoma in TSC is
with age. Diagnosis of AML by imaging techniques (ultrasonography small, the incidence is increased as compared with that of the gener-
[US], CT, magnetic resonance imagine [MRI]) relies on identification al population. (Courtesy of J. F. De Plaen and B. Van Beers.)
9.18 Tubulointerstitial Disease

VHL: ORGAN INVOLVEMENT

Mean age (range)

HG loci PKD1 TSC2 16 pter
Death Findings Frequency, % at diagnosis, y
Chromosome 16 Central nervous system 30 (9–71)
Hemangioblastoma
Cerebellar 60
FIGURE 9-35 Spinal cord 20
Tuberous sclerosis complex (TSC): genetics. Representative examples Endolymphatic sac tumor Rare
of various contiguous deletions of the PKD1 and TSC2 genes in Eye/Retinal hemangioblastoma 60 25 (8–70)
five patients with TSC and prominent renal cystic involvement (the Kidney
size of the deletion in each patient is indicated). Clear cell carcinoma 40 40 (18–70)
TSC is genetically heterogeneous. Two genes have been identified. Cysts 30 35 (15–60)
The TSC1 gene is on chromosome 9, and TSC2 lies on chromosome Adrenal glands/ 15 20 (5–60)
16 immediately adjacent and distal to the PKD1 gene. Half of affect- Pheochromocytoma
ed families show linkage to TSC1 and half to TSC2. Nonetheless, Pancreas 30 (13–70)
60% of TSC cases are apparently sporadic, likely representing new Cysts 40
mutations (most are found in the TSC2 gene) [34]. The proteins Microcystic adenoma 4
encoded by the TSC1 and TSC2 genes are called hamartin and Islet cell tumor 2
tuberin, respectively. They likely act as tumor suppressors; their pre- Carcinoma 1
cise cellular role remains largely unknown. The diseases caused by
Liver (cysts) Rare ?
type 1 and type 2 TSC are indistinguishable except for renal cysts,
which, so far, have been observed only in TSC2 patients [33], and
for intellectual disability, which is more common in TSC2 patients
[34]. (Adapted from Sampson, et al. [33].)
FIGURE 9-36
Von Hippel-Lindau disease (VHL): organ involvement. VHL is an
autosomal-dominant multisystem disorder with a prevalence rate of
roughly 1 in 40,000 [32, 35]. It is characterized by the development
of tumors, benign and malignant, in various organs. VHL-associated
tumors tend to arise at an earlier age and more often are multicentric
than the sporadic varieties. Morbidity and mortality are mostly relat-
ed to central nervous system hemangioblastoma and renal cell carci-
noma. Involvement of cerebellum, retinas, kidneys, adrenal glands,
and pancreas is illustrated (see Figures 9-37 to 9-41).
The VHL gene is located on the short arm of chromosome 3 and
exhibits characteristics of a tumor suppressor gene. Mutations are
now identified in 70% of VHL families [36].

FIGURE 9-37
Von Hippel-Lindau disease (VHL): central nervous system involve-
ment. Gadolinium-enhanced brain magnetic resonance image of a
patient with VHL, shows a typical cerebellar hemangioblastoma,
appearing as a highly vascular nodule (arrow) in the wall of a cyst
(arrowheads) located in the posterior fossa. Hemangioblastomas are
benign tumors whose morbidity is due to mass effect. Cerebellar
hemangioblastomas may present with symptoms of increased
intracranial pressure. Spinal cord involvement may be manifested
as syringomyelia. (Courtesy of S. Richard.)
 Cystic Diseases of the Kidney 9.19

FIGURE 9-38 (see Color Plate)

Von Hippel-Lindau disease (VHL): retinal
involvement. Ocular fundus, A, and corre-
sponding fluorescein angiography, B, in a
patient with VHL, shows two typical reti-
nal hemangioblastomas. The smaller tumor
(arrow) appears at the fundus as an intense
red spot, whereas the larger (arrow heads)
appears as a pink-orange lake with dilated,
tortuous afferent and efferent vessels. Small
peripheral lesions are usually asympto-
matic, whereas large central tumors can
impair vision. (Courtesy of B. Snyers.)

FIGURE 9-40
Von Hippel-Lindau disease (VHL): adrenal gland involvement.
FIGURE 9-39 Gadolinium-enhanced abdominal magnetic resonance image of a
Von Hippel-Lindau disease (VHL): kidney involvement. Contrast- patient with VHL shows bilateral pheochromocytoma (arrows).
enhanced CT of a patient with VHL, showing the polycystic aspect Renal lesions include cysts and solid carcinomas (arrow heads).
of the kidneys. Renal involvement of VHL includes cysts (simple, Pheochromocytoma may be the first manifestation of VHL. It
atypical, and cystic carcinoma) and renal cell carcinoma [36, 37]. tends to cluster within certain VHL families [36]. (Courtesy of
The latter is the leading cause of death from VHL. Occasionally, H. Neumann.)
polycystic kidney involvement may mimic autosomal-dominant
polycystic kidney disease. Both cystic involvement and sequelae
of surgery can lead to renal failure. Nephron-sparing surgery is
recommended [37].
9.20 Tubulointerstitial Disease

FIGURE 9-41
Von Hippel-Lindau disease (VHL): pancreas involvement. Contrast-
enhanced abdominal CT in a patient with VHL shows multiple cysts
in both pancreas (especially the tail, arrows) and kidneys. The major-
ity of pancreatic cysts are asymptomatic. When they are numerous
and large, they can induce diabetes mellitus or steatorrhea. Other,
rare pancreatic lesions include microcystic adenoma, islet cell tumor,
and carcinoma.

FIGURE 9-42
VHL: SCREENING PROTOCOL Von Hippel-Lindau disease. As most manifestations of VHL are
potentially treatable, periodic examination of affected patients is
strongly recommended. Though genetic testing is now very useful
Study Affected persons Relatives at risk for presymptomatic identification of affected persons, it must be
remembered that a mutation in the VHL gene currently is detected
Physical examination Annual Annual in only 70% of families. For persons at risk in the remaining families,
24-h Urine collection for Annual Annual a screening program is also proposed.
metadrenaline and
normetadrenaline
Funduscopy Annual Annual (age 5 to 60)
Gadolinium MRI brain scan Every 3 y (from age 10) Every 3 y (age 15 to 60)
Abdomen Annual gadolinium MRI Annual echography or
gadolinium MRI
(age 15 to 60)

FIGURE 9-43
Medullary cystic disease (MCD). Contrast-enhanced CT in a 35-
year-old man with MCD. Multiple cysts are seen in the medullary
area. Two daughters were also found to be affected. MCD is a very
rare autosomal-dominant disorder characterized by medullary cysts
detectable by certain imaging techniques (preferably computed
tomography) and progressive renal impairment leading to end-
stage disease between 20 and 40 years of age. Dominant inheri-
tance and early detection of kidney cysts distinguish MCD from
autosomal-recessive nephronophthisis (see Fig. 9-48), even though
the two may be indistinguishable on histologic examination.
 Cystic Diseases of the Kidney 9.21

THERE IS A WHITE
BOX PLACED OVER
HANDWRITTEN
TYPE.
A

B
multiple cysts, typically small cortical ones. This cystic pattern was
verified in the nephrectomy specimen, B, obtained 8 months later
at the time of kidney transplantation, and GCKD was confirmed
by histopathologic examination with Masson’s trichrome stain.
C, Cysts consisted of a dilatation of Bowman’s space surrounding
a primitive-looking glomerulus.
C GCKD may be sporadic or genetically dominant. Among the
familial cases, some patients are infants who have early-onset auto-
FIGURE 9-44 somal-dominant polycystic disease. In others (children or adults) the
Glomerulocystic kidney disease (GCKD). Contrast-enhanced CT, A, disease is unrelated to PKD1 and PKD2 and may or not progress to
in a 23-year-old woman with the sporadic form of GCKD shows end-stage renal failure [38]. (Courtesy of D. Droz.)

FIGURE 9-45
ARPKD: CLINICAL MANIFESTATIONS Autosomal-recessive polycystic kidney disease (ARPKD): clinical man-
ifestations. ARPKD is characterized by the development of cysts origi-
nating from collecting tubules and ducts, invariably associated with
Renal congenital hepatic fibrosis. Its prevalence is about 1 in 40,000 [39].
Antenatal (ultrasonographic changes) In the most severe cases, with marked oligohydramnios and an empty
Oligohydramnios with empty bladder
bladder, the diagnosis may be suspected as early as the 12th week of
Increased renal volume and echogenicity
gestation. Some neonates die from either respiratory distress or renal
failure. In most survivors, the disease is recognized during the first
Neonatal period
year of life. The ultrasonographic (US) kidney appearance is depicted
Dystocia and oligohydramnios
in Figure 9-46. Excretory urography shows medullary striations
Enlarged kidneys
owing to tubular ectasia. Kidney enlargement may regress with time.
Renal failure
End-stage renal failure develops before age 25 in 70% of patients.
Respiratory distress with pulmonary hypoplasia (possibly fatal)
Liver involvement consists of portal fibrosis (see Fig. 9-47) and
Infancy of childhood
intrahepatic bilary ectasia, frequently resulting in portal hypertension
Nephromegaly (may regress with time)
(leading to hypersplenism and esophageal varices) and less often in
Hypertension (often severe in the first year of life) cholangitis, respectively. US may show dilatation of the biliary ducts,
Chronic renal failure (slowly progressive, with a 60% probability of renal survival at and even cysts. The respective severity of kidney and liver involve-
15 years of age and 30% at 25 years of age)
ment vary widely between families and even in a single kindred.
Hepatic
A comparison of the diagnostic features of autosomal-dominant
Portal fibrosis
polycystic kidney disease (ADPKD) and ARPKD is summarized in
Intrahepatic biliary tract ectasia
Figure 9-2. Renal US of the parents of a child with ARPKD is, of
course, normal. It should be noted that congenital hepatic fibrosis is
found in rare cases of ADPKD with early-onset renal disease. The
gene responsible for ARPKD has been mapped to chromosome 6.
There is no evidence of genetic heterogeneity [40].
9.22 Tubulointerstitial Disease

FIGURE 9-46
A and B, Autosomal-recessive polycystic
kidney disease (ARPKD): renal imaging. On
ultrasonography of a child with ARPKD
the kidneys appear typically enlarged and
uniformly hyperechogenic (owing to the
presence of multiple small cysts), and
demarcations of cortex, medulla, and sinus
are lost. The ultrasonographic appearance
is different in older children, because cysts
can grow and become round; then they
resemble the appearance of ADPKD. Figure
9-2 describes how to differentiate the two
conditions. (Courtesy of P. Niaudet.)

A B

FIGURE 9-47 FIGURE 9-48

Autosomal-recessive polycystic kidney disease (ARPKD): liver his- Nephronophthisis (NPH): renal involvement. Kidney biopsy specimen
tology. Liver biopsy specimen from a child with ARPKD shows visualized by light microscopy with periodic acid–Schiff stain, in a
typical congenital hepatic fibrosis (hematoxylin eosin safran [HES] patient with juvenile NPH of an early stage. Note the typical thicken-
stain). This portal space is enlarged by fibrosis, and the number of ing and disruption of the tubular basement membrane (appearing
biliary channels is increased, many of them being enlarged and all in red); the histiolymphocytic infiltration present at this stage is pro-
being irregular in outline. (Courtesy of S. Gosseye.) gressively replaced by interstitial fibrosis.
NPH is an autosomal recessive disorder, accounting for 10% to
15% of all children admitted for end-stage renal failure. Although
classified as a renal cystic disorder, NPH is characterized by chronic
diffuse tubulointerstitial nephritis; the presence of cysts at the corti-
comedullary boundary (thus, the alternative term “medullary cystic
disease,” now preferably reserved for the autosomal-dominant form;
see Fig. 9-43) is a late manifestation of the disease. Clinical features
include early polyuria-polydypsia, unremarkable urinalysis, frequent
absence of hypertension, and eventually, end-stage renal failure at a
median age of 13 (range 3 to 23) years. Ultrasonographic features
are summarized in Figure 9-2; medullary cysts are sometimes detected.
Associated disorders are detailed in Figure 9-49. A gene called NPH1
that has been identified on chromosome 2 accounts for about 80%
of cases [41, 42]. In two thirds of them, a large homozygous dele-
tion is detected in this gene [43]. (Courtesy of P. Niaudet.)
 Cystic Diseases of the Kidney 9.23

FIGURE 9-49
NPH: EXTRARENAL INVOLVEMENT Nephronophthisis (NPH): extrarenal involvement. Extrarenal involve-
ment occurs in 20% of NPH cases. The most frequent finding is
tapetoretinal degeneration (known as Senior-Loken syndrome), which
Retinitis pigmentosa (Senior-Loken syndrome) often results in early blindness or progressive visual impairment.
Multiple organ involvement, including Other rare manifestations include liver (hepatomegaly, hepatic fibro-
Liver fibrosis
sis), bone (cone-shaped epiphysis), and central nervous system (mental
retardation, cerebellar ataxia) abnormalities, quite often in association.
Other rare features
Skeletal changes (cone-shaped epiphyses)
Cerebellar ataxia
Mental retardation

A B
FIGURE 9-50
Orofaciodigital syndrome (OFD). Contrast-enhanced CT, Characteristic dysmorphic features include oral (hyperplastic
A, and the hands, B, of a 26-year-old woman with OFD type 1 frenulum, cleft tongue, cleft palate or lip, malposed teeth), facial
(OFD1) [43]. Multiple cysts involve both kidneys. Note that (asymmetry, broad nasal root), and digit (syn-brachy-polydacty-
they are smaller and more uniform than in ADPKD and that ly) abnormalities. Mental retardation is present in about half the
renal contours are preserved. Some cysts were also detected in cases. Kidneys may be involved by multiple (usually small) cysts,
liver and pancreas (arrow). Syndactyly was surgically corrected, mostly of glomerular origin; renal failure occurs between the
and the digits of the hands are shortened (brachydactyly). second and the seventh decade of life. Recognition of the dys-
OFD1 is a rare X-linked, dominant disorder, diagnosed morphic features is the key to the diagnosis [44, 45]. (Courtesy
almost exclusively in females, as affected males die in utero. of F. Scolari.)

References
1. Fick GM, Gabow PA: Hereditary and acquired cystic disease of the 6. Sarasin FP, Wong JB, Levey AS, Meyer KB: Screening for acquired
kidney. Kidney Int 1994, 46:951–964. cystic kidney disease: A decision analytic perspective. Kidney Int
2. Welling LW, Grantham JJ: Cystic and developmental diseases of the 1995, 48:207–219.
kidney. In The Kidney. Edited by Brenner M. Philadelphia:WB 7. Hildebrandt F, Jungers P, Grünfeld JP: Medullary cystic and medullary
Saunders Company; 1996:1828–1863. sponge renal disorders. In Diseases of the Kidney. Edited by Schrier
RW, Gottschalk CW. Boston: Little Brown; 1997:499–520.
3. Pirson Y, Chauveau D, Grünfeld JP: Autosomal dominant polycystic
kidney disease. In Oxford Textbook of Clinical Nephrology. Edited 8. The European Polycystic Kidney Disease Consortium: The polycystic
kidney disease 1 gene encodes a 14 kb transcript and lies within a
by Davison AM, Cameron JS, Grünfeld JP, et al. Oxford:Oxford duplicated region on chromosome 16. Cell 1994, 77:881–894.
University Press; 1998:2393–2415.
9. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic
4. Ravine D, Gibson RN, Donlan J, Sheffield LJ: An ultrasound renal kidney disease that encodes an integral membrane protein. Science
cyst prevalence survey: Specificity data for inherited renal cystic dis- 1996, 272:1339–1342.
eases. Am J Kidney Dis 1993, 22:803–807. 10. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1
5. Levine E: Acquired cystic kidney disease. Radiol Clin North Am (PKD1) gene encodes a novel protein with multiple cell recognition
1996, 34:947–964. domains. Nature Genet 1995, 10:151–160.
9.24 Tubulointerstitial Disease

11. Qian F, Germino FJ, Cai Y, et al.: PKD1 interacts with PKD2 through 30. Culleton B, Parfrey PS: Management of end-stage renal failure and
a probable coiled-coil domain. Nature Genet 1997, 16:179–183. problems of transplantation in autosomal dominant polycystic kidney
12. Germino GG: Autosomal dominant polycystic kidney disease: a two- disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres
hit model. Hospital Pract 1997, 81–102. VE. Oxford:Oxford University Press; 1996:450–461.
13. Grantham JJ: The etiology, pathogenesis, and treatment of autosomal 31. Torres VE: Tuberous sclerosis complex. In Polycystic Kidney Disease.
dominant polycystic kidney disease: Recent advances. Am J Kidney Edited by Watson ML, Torres VE. Oxford:Oxford University Press;
Dis 1996, 28:788–803. 1996:283–308.
14. Devuyst O, Beauwens R: Ion transport and cystogenesis: The para- 32. Huson SM, Rosser EM: The Phakomatoses. In Principles and Practice
digm of autosomal dominant polycystic kidney disease. Adv Nephrol of Medical Genetics. Edited by Rimoin DL, Connor JM, Pyeritz RE.
1998, (in press). New York:Churchill Livingstone; 1997: 2269–2302.
15. Parfrey PS, Barrett BJ: Hypertension in autosomal dominant polycys- 33. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic dis-
tic kidney disease. Curr Opin Nephrol Hypertens 1995, 4:460–464. ease in tuberous sclerosis: Role of the polycystic kidney disease 1
gene. Am J Human Genet 1997, 61:843–851.
16. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J
Med 1993, 329:332–342. 34. Jones AC, Daniells CE, Snell RG, et al.: Molecular genetic and pheno-
typic analysis reveals differences between TSC1 and TSC2 associated
17. Torres WE, Wilson DM, Hattery RR, Segura JW: Renal stone disease
familial and sporadic tuberous sclerosis. Hum Molec Genet 1997,
in autosomal dominant polycystic kidney disease. Am J Kidney Dis
6:2155–2161.
1993, 22:513–519.
35. Michels V: Von Hippel-Lindau disease. In Polycystic Kidney Disease.
18. Choukroun G, Itakura Y, Albouze G, et al.: Factors influencing pro-
Edited by Watson ML, Torres VE. Oxford:Oxford University Press;
gression of renal failure in autosomal dominant polycystic kidney dis-
1996:309–330.
ease. J Am Soc Nephrol 1995, 6:1634–1642.
36. Neumann HPH, Zbar B: Renal cysts, renal cancer and von Hippel-
19. Schievink WI, Torres VE, Wiebers DO, Huston J III: Intracranial arterial
Lindau disease. Kidney Int 1997, 51:16–26.
dolichoectasia in autosomal dominant polycystic kidney disease. J Am
Soc Nephrol 1997, 8:1298–1303. 37. Chauveau D, Duvic C, Chretien Y, et al.: Renal involvement in von
Hippel-Lindau disease. Kidney Int 1996, 50:944–951.
20. Torra R, Nicolau C, Badenas C, et al.: Ultrasonographic study of pan-
creatic cysts in autosomal dominant polycystic kidney disease. Clin 38. Sharp CK, Bergman SM, Stockwin JM, et al.: Dominantly transmitted
Nephrol 1997, 47:19–22. glomerulocystic kidney disease: A distinct genetic entity. J Am Soc
Nephrol 1997, 8:77–84.
21. Schievink WI, Huston J III, Torres VA, Marsh WR: Intracranial cysts
in autosomal dominant polycystic kidney disease. J Neurosurg 1995, 39. Gagnadoux MF, Broyer M: Polycystic kidney disease in children. In
83:1004–1007. Oxford Textbook of Clinical Nephrology. Edited by Davison AM,
Cameron JS, Grünfeld JP, et al. Oxford:Oxford University Press;
22. Gabow PA: Autosomal dominant polycystic kidney disease—more
1998:2385–2393.
than a renal disease. Am J Kidney Dis 1990, 16:403–413.
40. Zerres K, Mücher G, Bachner L, et al.: Mapping of the gene for auto-
23. Schievink WI, Torres VE: Spinal meningeal diverticula in autosomal
somal recessive polycystic kidney disease (ARPKD) to chromosome
dominant polycystic kidney disease. Lancet 1997, 349:1223–1224.
6p21-cen. Nature Genet 1994, 7:429–432.
24. Hateboer N, Dijk M, Torra R, et al.: Phenotype PKD2 vs. PKD1;
41. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juve-
results from the European concerted action. J Am Soc Nephrol 1997,
nile nephronophthisis (recessive medullary cystic kidney disease) maps
8:373A.
to chromosome 2p. Nature Genet 1993, 3:342–345.
25. Chauveau D, Pirson Y, Le Moine A, et al.: Extrarenal manifestations
42. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an
in autosomal dominant polycystic kidney disease. Adv Nephrol 1997,
SH3 domain protein is mutated in nephronophthisis type 1. Nature
26:265–289.
Genet 1997, 17:149–153.
26. Torres VE: Polycystic liver disease. In Polycystic Kidney Disease.
43. Konrad M, Saunier S, Heidet L, et al.: Large homozygous deletions of
Edited by Watson ML, Torres VE. Oxford: Oxford University Press;
the 2q13 region are a major cause of juvenile nephronophthisis. Hum
1996:500–529.
Molec Genet 1996, 5: 367–371.
27. Pirson Y, Chauveau D: Intracranial aneurysms in autosomal dominant
44. Scolari F, Valzorio B, Carli O, et al.: Oral-facial-digital syndrome type
polycystic kidney disease. In Polycystic Kidney Disease. Edited by
I: An unusual cause of hereditary cystic kidney disease. Nephrol Dial
Watson ML, Torres VE. Oxford:Oxford University Press;
Transplant 1997, 12:1247–1250.
1996:530–547.
45. Feather SA, Winyard PJD, Dodd S, Woolf AS: Oral-facial-digital syn-
28. Ravine D, Gibson RN, Walker RG, et al.: Evaluation of ultrasono-
drome type 1 is another dominant polycystic kidney disease: Clinical,
graphic diagnostic criteria for autosomal dominant polycystic kidney
radiological and histopathological features of a new kindred. Nephrol
disease 1. Lancet 1994, 343:824–827.
Dial Transplant 1997, 12:1354–1361.
29. Pirson Y, Christophe JL, Goffin E: Outcome of renal replacement
therapy in autosomal dominant polycystic kidney diseases. Nephrol
Dial Transplant 1996, 11 (suppl. 6):24–28.
Toxic Nephropathies
Jean-Louis Vanherweghem

T
ubular interstitial structures of the kidney are particularly vul-
nerable in face of toxic compounds. High concentration of the
toxics in de medulla as well as medullary hypoxia and renal
hypoperfusion could explain this particularity. Clinical nephrotoxici-
ty involves toxins of diverse origin. The culprits are often registered
and non registered drugs either prescribed or purchased over the
counter. Other major causes result from occupational and industrial
exposures. Sometimes, the identification of the nephrotoxin requires
astuteness and long investigations especially in cases of environmental
toxins or prolonged intake of unregulated drugs or natural products.
A correct diagnosis of the causes is, however, the key for future pre-
vention of renal diseases. The diagnosis of “chronic interstitial nephri-
tis of unknown origin” should, therefore, no longer be used.

CHAPTER

10
10.2 Tubulointerstitial Disease

Exposure to Nephrotoxins
FIGURE 10-1
TOXIC CAUSES OF CHRONIC Chronic exposure to drugs, occupational hazards, or environmental
TUBULOINTERSTITIAL RENAL DISEASES toxins can lead to chronic interstitial renal diseases. The following
are the major causes of chronic interstitial renal diseases: occupation-
al exposure to heavy metals; abuse of over-the-counter analgesics;
Metals (Environmental or Occupational Exposure) misuse of germanium; chronic intake of mesalazine for intestinal dis-
Lead orders, lithium for depression, and cyclosporine in renal and nonre-
Cadmium
nal diseases; and environmental or iatrogenic exposure to fungus or
plant nephrotoxins (ochratoxins, aristolochic acids).
Drugs or Additives (Use, Misuse, or Abuse)
Lithium
Germanium
Analgesics
Cyclosporine
Mesalazine
Fungus and Plant Toxins (Environmental or Iatrogenic Exposure)
Ochratoxins
Aristolochic acids

Exposure to Metals
FIGURE 10-2
30
Occupational exposure to metals and risks for chronic renal fail-
25 ure. Comparison of the occupational histories of 272 patients with
(95% confidence intervals)

chronic renal failure with those of a matched control group having

20
normal renal function has shown an increased risk of chronic renal
Odds ratio

15 failure after exposure to mercury, tin, chromium, copper, and lead.

In this study the increased risk with exposure to cadmium was not
10 statistically significant. Squares indicate odds ratios; circles indicate
5 CIs. (Adapted from Nuyts and coworkers [1]; with permission.)

0
Mercury Tin Chromium Copper Lead Cadmium

Odds ratio C1 > C1 <

Mercury 5130 1020 25,700
Tin 3720 1220 11,300
Chromium 2770 1210 6330
Copper 2540 1160 5530
Lead 2110 1230 4360
Cadmium 2200 900 8250
 Toxic Nephropathies 10.3

Lead nephropathy

CAUSES OF LEAD NEPHROPATHY CLINICAL MANIFESTATIONS OF LEAD NEPHROPATHY

Environmental Gout
Eating paint from lead-painted furniture, woodwork, and toys in children Arterial hypertension
Lead-contaminated flour Renal failure (interstitial type)
Home lead-contaminated drinking water from lead pipes
Drinking of moonshine whiskey
Occupational
Lead-producing plants: lead smelters, battery plants FIGURE 10-4
Gout and hypertension are the major clinical manifestations of lead
nephropathy. The prominent feature of early hyperuricemia in lead
nephropathy may explain the confusion between lead nephropathy
FIGURE 10-3 and gout nephropathy. Lead urinary excretion after ethylenedi-
Lead nephropathy associated with environmental and occupational amine tetraacetic acid (EDTA)–lead mobilization testing may help
exposure. Epidemiologic observations have established the relation- with the correct diagnosis [3].
ship between lead exposure and renal failure in association with
children eating lead paint in their homes, chronic ingestion of lead-
contaminated flour, lead-loaded drinking water in homes, and
drinking of illegal moonshine whiskey [2,3]. Occupational expo-
sure in lead-producing industries also has been associated with a
higher incidence of renal dysfunction.

FIGURE 10-5
Days 1 2 3 Ethylenediamine tetraacetic acid (EDTA)–lead mobilization test in lead nephropathy.
EDTA (calcium disodium acetate) for detecting lead nephropathy. This test consists of a
24-hour urinary lead excretion over 3 consecutive days after administration of 2 g of EDTA
by intramuscular route on the first day in divided doses 12 hours apart. Persons without
8 AM 8 PM excessive lead exposure excrete less than 0.6 mg of lead during the day after receiving 2 g
of EDTA parenterally. In the presence of renal failure, the excretion is delayed; however,
EDTA 1 g 1g the cumulative total remains less than 0.6 mg over 3 days (From Batuman and coworkers
[3]; with permission.)
IM IM
Urinary Lead,
collection mg

Excessive lead exposure:

No < 0.6
Yes >0.6

FIGURE 10-6
120 I II 1500 Ethylenediamine tetraacetic acid (EDTA)–
Creatinine clearance, mL/min

IV lead mobilization test in chronic renal

100
failure of uncertain origin (A–C). In a
80 study of 296 patients without history of
1000
Lead, mg/72 h

60 V lead exposure, the results of this test were

III
IV III abnormal in 15.4% (II) of patients with
40
II hypertension and normal renal function
20 500 and in 56.1% of patients with renal fail-
I V
0 ure of uncertain origin (in 44.1% of the
Blood pressure N patients without associated gout (III) and
A Gout + B 0 in 68.7% of the patients with associated
gout (IV), respectively).
(Continued on next page)
10.4 Tubulointerstitial Disease

FIGURE 10-6 (Continued)

The EDTA–lead mobilization test was normal in normotensive subjects with normal renal
IV function and in patients with chronic renal failure (I) of well-known origin (V). (Adapted
Patients with abnormal test

from Sanchez-Fructuoso and coworkers [4].)

results, %

50 III

II

C 0

Cadmium nephropathy
FIGURE 10-7
110 Decrease in renal function after 25-year exposure to cadmium (Cd). In workers exposed to
Glomerular filtration rate,

105 cadmium for an average time of 25 years, a progressive decrease in renal function occurs
mL/min/1.73 m2

100 during a 5-year follow-up period, despite removal from cadmium exposure 10 years earlier.
95 On average, the glomerular filtration rate was shown to be decreased to 31 mL/min/1.73
90 m2 after 5 years instead of the expected age-related value of 5 mL/min/1.73 m2. (Adapted
85 from Roels and coworkers [5].)
80
Expected values
75 Cd exposure
70
5 6 7 8 9 10 11
Removal from Cd exposure, y

Graph values
I II III IV
NEP 43 53 50 76
CC16 16 17 25 124
RBP 80 122 132 594
ß2-m 73 112 102 834

FIGURE 10-8
* Tubular markers in cadmium workers. Impairment of renal proximal
NEP 834
800 CC16
tubular epithelium induced by cadmium can be documented by an
RBP
increase in urinary excretion of urinary neutral endopeptidase 24.11
Creatinine, µg/g

ß2–m *
594
(NEP), an enzyme of the proximal tubule brush borders, as well as
600 by an increase in microproteinuria: Clara cell protein (CC16),
*P < 0.05
200 retinol-binding protein (RBP) and 2-microglobulin (2-m). The data
*
were obtained from 106 healthy persons working in cadmium smelt-
* ing plants. These markers could be used for the screening of cadmi-
um workers. (Adapted from Nortier and coworkers [6].)
0
I II III IV

I II III IV
Creatinine
103 103 90* 79*
clearance, mL/min

Urinary Cd,
0.55 1.34 3.28* 8.45*
µg/g/creatinine
 Toxic Nephropathies 10.5

Lithium nephropathy

LITHIUM NEPHROTOXICITY

Reversible polyuria and polydipsia

Persistent nephrogenic diabetes insipidus
Incomplete distal tubular acidosis
Chronic renal failure (chronic interstitial fibrosis)

FIGURE 10-9
Lithium acts both distally and proximally to antidiuretic hor-
mone–induced generation of cyclic adenosine monophosphatase.
Polyuria and polydipsia can occur in up to 40% of patients on
lithium therapy and are considered harmless and reversible.
However, nephrogenic diabetes insipidus may persist months after FIGURE 10-10 (see Color Plate)
lithium has been discontinued [7]. Lithium also induces an impair- Lithium nephropathy. A 22-year-old female patient was on mainte-
ment of distal urinary acidification. Chronic renal failure secondary nance lithium therapy (lithium carbonate 750 mg/d) for 5 years.
to chronic interstitial fibrosis may appear in up to 21% of patients She presented with polyuria (6500 mL/d) and moderate renal fail-
on maintenance lithium therapy for more than 15 years [8]. ure (creatinine clearance, 60 mL/min). Proteinuria was not present,
However, these observations are still a matter of debate [7]. and the urinary sediment was unremarkable. A renal biopsy
showed focal interstitial fibrosis with scarce inflammatory cell infil-
trate, tubular atrophy, and characteristic dilated tubule (microcyst
formation). Half of the glomeruli (not shown) were sclerotic.
(Magnification  125, periodic acid–Schiff reaction.)

Germanium nephropathy
FIGURE 10-11
CIRCUMSTANCES OF CHRONIC RENAL FAILURE Germanium (atomic number, 32; atomic weight, 72.59) is con-
SECONDARY TO GERMANIUM SUPPLEMENTS tained in soil, plants, and animals as a trace metal. It is widely
used in the industrial fields because of its semiconductive capacity.
The increased use of natural remedies and trace elements to pro-
Ge-dioxyde elixir, food additives, or capsules (used to improve health tect, improve, or restore the health has lead regular supplementa-
in normal persons [Japan]) tion with germanium salts either through food addition or by the
Ge-lactate-citrate (used to rebuild the immune system) in patients means of elixirs and capsules. The chronic supplementation by
with HIV infection (Switzerland) germanium salts was at the origin of the development of chronic
Ge-lactate-citrate (used to improve health) in patients with cancer renal failure secondary to a tubulointerstitial nephritis [9–12].
(the Netherlands)
Ge-dioxyde elixir (used to restore health) in patients with chronic
hepatitis (Japan)
10.6 Tubulointerstitial Disease

A B
FIGURE 10-12
Light microscopy of renal tissue in a patient with chronic renal Renal tubular epithelial cells show numerous dark small inclu-
failure secondary to the chronic intake of germanium, showing sions. B, Periodic acid–Schiff reaction. (Magnification,  350).
focal tubular atrophy and focal interstitial lymphocyte infiltra- (From Hess and coworkers [12]; with permission).
tion. A, Hematoxylin and eosin stain. (Magnification  162.)

Exposure to Analgesics

Normal papilla
Swollen
Forniceal erosion

Detachment

Calcification

FIGURE 10-13
Analgesic nephropathy and papillary necrosis. The characteristic
feature of analgesic nephropathy is the papillary necrosis process
that begins with swollen papillae and continues with forniceal ero-
sion, detachment, and calcification of necrotic papillae.

FIGURE 10-14
Pathology of analgesic nephropathy. Nephrectomy showing a kid-
ney reduced in size with necrosed and calcified papillae.
 Toxic Nephropathies 10.7

CLINICAL FEATURES OF ANALGESIC NEPHROPATHY

Daily consumption of analgesic mixtures 100%

Women 80%
Headache 80%
Gastrointestinal disturbances 35–40%
Urinary tract infection 30–48%
Papillary necrosis (clinical) 20%
Papillary calcifications (computed tomography scan) 65%

FIGURE 10-16
Classic analgesic nephropathy is a slowly progressive disease
resulting from the daily consumption over several years of mix-
tures containing analgesics usually combined with caffeine,
codeine, or both. Caffeine and codeine create psychological depen-
dence. Most cases of analgesic nephropathy occur in women. In
80% of the cases, analgesics were taken for persistent headache.
FIGURE 10-15 Gastrointestinal complaints are also frequent, as are urinary tract
Radiologic appearance of papillary necrosis in analgesic nephropa- infections. Evidence of clinical papillary necrosis (fever and pain)
thy. The pyelogram was obtained by pyelostomy. It shows a swollen is present in 20% of cases. Calcifications of papillae (detected by
papilla (upper calyx), forniceal erosions (middle calyx), and detach- computed tomography scan) are present in 65% of persons who
ment of papilla, or filling defect (lower calyx). abuse analgesics [13].

FIGURE 10-17
EPIDEMIOLOGY OF ANALGESIC NEPHROPATHY Worldwide epidemiology of analgesic nephropathy. The frequency
AMONG ESRD PATIENTS of analgesic nephropathy in patients with end-stage renal diseases
(ESRD) varies greatly within and among countries [14–16]. The
highest prevalence rates of end-stage renal disease from analgesic
Australia 20% nephropathy occur in South Africa (22%), Switzerland and Australia
Belgium 18% (20%), Belgium (18%), and Germany (15%). In Belgium, the preva-
Canada 6%
lence is 36% in the north and 10% in the south. In Great Britain,
the rate is 1% nationwide; in Scotland it is 26%. In United States,
Germany 15%
the rate is 5% nationwide, 13% in North Carolina, and 3% in
South Africa 22%
Washington, DC. In Canada, the rate is 6% nationwide.
Switzerland 20%
United Kingdom 1%
United States 5%

FIGURE 10-18
25 Prevalence of analgesic nephropathy versus
Prevalence (EDTA, 1989)
Analgesic nephropathy nephropathy with unknown cause. Cross-
20
Unknown cause national comparisons in Europe indicate
15 that the proportion of cases of end-stage
renal disease attributed to analgesics varies
%

10 considerably; however, it is inversely pro-

portional to unknown causes. These find-
5 ings suggest an underestimation of the
prevalence of analgesic nephropathy in sev-
0
eral countries, probably owing to the lack
any

in
a
m

nce
ds

y
d

al

of well-defined criteria for diagnosis

stri

Ital
rlan

Spa
tug
giu

rlan
rm

Fra
Au
Bel

[13,15]. EDTA—European Dialysis and

Por
itze

the
Ge
Sw

Ne
.

Transplant Association. (From Elseviers and

F.R

coworkers [13]; with permission).

10.8 Tubulointerstitial Disease

has been replaced with acetaminophen

3000 in analgesia mixtures without signifi-
Belgium

1983 sales of mixtures containing two

Pills taken in lifetime cant changes in the cause of analgesic
< 5000 Rs = 0.86
P< 0.001 nephropathy in some countries [15].
≥ 5000

analgesic components
A, The risk factor for end-stage renal
2000
disease of unknown cause is increased in
relationship to the cumulative intake of
10.0
95% confidence intervals

acetaminophen as well as nonsteroidal

1000 anti-inflammatory drugs but not to
Odds ratio,

5.0 aspirin. Moreover, mixtures containing

several analgesic compounds were
shown to be more nephrotoxic than are
0 simple drugs. B, In Belgium, the preva-
1.0 0 10 20 30 40 50
0 Acetaminiophen Aspirin 1991 prevalence of analgesic lence of analgesic nephropathy in 1991
A B nephropathy, % was strongly correlated with sales of
analgesic mixtures in 1983. Rs—coeffi-
cient of correlation. (A, Adapted from
FIGURE 10-19 Perneger and coworkers [17]; B, adapt-
Risk of analgesic nephropathy associated with specific types of analgesics. The initial ed from Elseviers and De Broe [18];
reports of analgesic nephropathy chiefly concerned phenacetin mixtures. Phenacetin with permission).

Renal volume Indentations Papillary calcifications

RA RV RA
Right kidney Left kidney

A SP A

B B 0 1–2 3–5 >5

Decreased: A + B < 103 mm (males)
A < 96 mm (females) B Bumpy contours C

FIGURE 10-20
D. PERCENTAGES OF SENSITIVITY AND SPECIFICITY High performance of computed tomography (CT) scan for diagnos-
ing analgesic nephropathy. Three criteria may be used to diagnose
analgesic nephropathy by CT scan: decrease in renal size, measured
Criteria Sensitivity, % Specificity, % by the sum of both sides of the rectangle enclosing the kidney at
the level of the renal vessels (A); indentations counted at the level
Decrease in renal size 95 10 at which most indentations are present (more than three are quali-
Bumpy contours 50 90 fied of bumpy contours) (B); and papillary calcifications (C).
Papillary calcifications 87 97 Percentages of sensitivity and specificity are given for the three cri-
teria (D). Example of papillary calcifications on CT scan (E). RA—
renal artery; RV—renal vein; SP—spine. (Adapted from Elseviers
and De Broe [19]; with permission).

E
 Toxic Nephropathies 10.9

FIGURE 10-21
HONCOCH3 NCOCH3 O OH
Malignancies of the urinary tract and their association with anal-
gesic nephropathy. Malignancies of the renal pelvis and ureters were
reported in up to 9% of patients with analgesic nephropathy. This
high prevalence can be explained by the appearance of carcinogenic
OC2H5 O O OH substances in the major pathways of the metabolism of phenacetin.
N-hydroxy- Probable carcinogenic substances are indicated by a plus sign.
p-ocetophenetidine

HNCOCH3 HNCOCH3 NH2 HNOH NO

OH
[OH]

OC2H5 OC2H5 OC2H5 OC2H5 OC2H5

Phenacetin N-hydroxy- p-nitroso-
(p-ocetophenetidine) p-phenetidine phenetidine

HNCOCH3 NH2 H 2N O OH
OH
H NH2

OH OC2H5 OC2H5 OC2H5

N-acetyl-p-amino- 2-hydroxy- Arene oxide NIH shift
phenol (NAPA) phenetidine

FIGURE 10-22
Malignant uroepithelial tumors of the
upper urinary tract in patients with anal-
gesic nephropathy. A, Pyelogram showing
a filling defect, indicating a tumor of the
renal pelvis. B, Retrograde pyelography
showing a long malignant stricture of
the ureter, causing ureteral dilation and
hydronephrosis. (Courtesy of W Lornoy,
MD, OL Vrouwziekenhuis, MD.)

B
10.10 Tubulointerstitial Disease

Exposure to Cyclosporine

Cyclosporine toxicity Cyclosporine induced hypertension

Cyclosporine
Cyclosporine
Intestinal
absorption
25–30% Acute effects Chronic effects

Inactive
metabolites Sympathetic Endothelium Cytosol
Liver
cytochrome nervous Thromboxane calcium
P450 system Endothelin

Chronic
Renal vasoconstruction renal failure
Inhibition
Ketoconazole
Verapamil Sodium chloride
Diltiazem retention
Erythromycin
Hypertension

FIGURE 10-23
Toxicity of cyclosporine. Cyclosporine is a neutral fungal FIGURE 10-24
hydrophobic 11-amino acid cyclic polypeptide. Cyclosporine is
Cyclosporine and hypertension. Hypertension can develop in 10%
metabolized by hepatic cytochrome P450 to multiple less active
to 80% of patients treated with cyclosporine, depending on dosage
and less toxic metabolites. Drugs that inhibit cytochrome P450
and length of the exposure. Cyclosporine increases cytosol calcium
enzymes such as ketoconazole, verapamil, diltiazem, and ery-
and, thus, enhances arteriolar smooth muscle responsiveness to
thromycin increase the concentration of cyclosporine and may
vasoconstrictive stimuli. Vasoconstrictive effects of cyclosporine
thus precipitate renal side effects [20,21].
also are mediated by enhanced thromboxane action, sympathetic
nerve stimulation, and release of endothelin. Renal vasoconstric-
tion results in salt retention and hypertension. In chronic exposure
to cyclosporine, hypertension also is a part of cyclosporine-induced
chronic renal failure [22].

FIGURE 10-25
Mechanisms of cyclosporine renal injury Pathogenesis of cyclosporine nephropathy. Chronic administration of cyclosporine may
induce sustained renal vasoconstriction. Impairment of renal blood flow leads to tubuloin-
Cyclosporine terstitial fibrosis. Cyclosporine increases the recruitment of renin-containing cells along the
afferent arteriole. Hyperplasia of the juxtaglomerular apparatus increases angiotensin II
levels that, in turn, stimulate tumor growth factor- (TGF-) secretion, resulting in inter-
Sustained Renin stitial fibrosis [20].
vasoconstriction

Angiotensin II

Renal ischemia TGF-ß

Interstitial
fibrosis
 Toxic Nephropathies 10.11

100 CyA, 7.5 mg/kg 100 CyA, 9.3 mg/kg 100 CyA, 10 to 6 mg/kg
Glomerular filtration rate,

Glomerular filtration rate,

Glomerular filtration rate,

80 80 80
% of normal values

% of normal values

% of normal values
60 60 60

40 40 40

20 20 20

0 0 0
0 8 Weeks 0 13 Months 0 36 Months
A Psoriasis B Autoimmune diseases C Cardiac transplantations

FIGURE 10-26
100 CyA, 5 mg/kg Cyclosporine (CyA) nephrotoxicity in nonrenal diseases. A, Patients treated with
cyclosporine (7.5 mg/kg) for psoriasis experienced a median decrease to 84% of the initial
Glomerular filtration rate,

80 values in the glomerular filtration rate after 8 weeks of therapy. B, Of patients treated with
% of normal values

60
cyclosporine (9.3 mg/kg) for autoimmune diseases, 21% showed cyclosporine nephropathy
on biopsy, with a decrease to 60% of the initial values in renal function. C, Patients with
40 cardiac transplantation treated with high doses of cyclosporine (10 to 6 mg/kg) developed
a reduction to 57% of the initial values in renal function 36 months after transplantation.
20 Patients treated with azathioprine did not show any reduction in renal function. D,
0
Patients receiving cyclosporine (5 mg/kg) for uveitis for 2 years showed a decrease in
0 24 Months glomerular filtration rate to 65% of the initial values. (Panel A adapted from Ellis and
D Uveitis coworkers [23]; panel B adapted from Feutren and Mihatsch [24]; panel C adapted from
Myers and Newton [25]; and panel D adapted from Deray and coworkers [26].)

A B
FIGURE 10-27
Morphology of cyclosporine nephropathy on renal biopsy of a periodic acid–Schiff reaction). B, A striped form of interstitial
patient with cardiac transplantation. Two different types of lesions fibrosis characterized by irregularly distributed areas of stripes of
are seen in cyclosporine nephropathy. A, Arteriolopathy: Hyalin, interstitial fibrosis and tubular atrophy in the renal cortex. Tubules
paucicellular thickening of the intima with focal wall necrosis in other areas were normal (magnification x 100 periodic
results in narrowing of the vascular lumen (magnification  300 acid–Schiff reaction).
10.12 Tubulointerstitial Disease

Exposure to Aminosalicylic Acid

10.6
10
C.P. man born
Seerum creatinine, mg/dL

8 January 19, 1971

6
4.9
4.2 4.0 3.9
4 IBD diagnosis
32 mg/d
2 1.1 Renal biopsy Renal biopsy
Methyl- 16 mg/d
Oral Pentasa® 500 mg/d, 3 x per day Hemodialysis prednisolone
0

De , 1994

1, 4
Jan 1994
1

96
994
4

995

96
De , 1994
De 2, 199
199

199

199

, 19

, 19
2, 1

6, 1
t 3,

rch

23,

y1

c1
c2
v2

c2
c3
rch
Oc
Ma

Ma
Feb

De
No
Ma

B C
FIGURE 10-28
Aminosalicylic acid and chronic tubulointerstitial nephritis. A, A of the interstitium tubular atrophy, and fibrosis. Several atrophic
36-year-old man suffering from Crohn’s disease exhibited severe tubules are surrounded by one or more layers of -smooth mus-
renal failure after 23 months of treatment with 5-aminosalicylic cle actin positive cells. The patient had normal renal function on
acid (5-ASA, or Pentasa, Hoechst Marion Roussel, Kansas City, beginning treatment with 5-ASA. After 5 years of 5-ASA therapy,
MO). B, The first renal biopsy showing widening and massive the patient demonstrated severe impaired renal function. The
cellular infiltration of the interstitium, tubular atrophy, and rela- association between the use of 5-ASA and development of chron-
tive spacing of glomeruli. C, The second renal biopsy 8 months, ic tubulointerstitial nephritis in patients with inflammatory bowel
after discontinuation of the drug and moderate improvement of disease (IBD) has gained recognition in recent years [27,28].
the renal function, again showing important cellular infiltration (Courtesy of ME De Broe, MD.)
 Toxic Nephropathies 10.13

Exposure to Ochratoxins
FIGURE 10-29
Ochratoxin A
Ochratoxin nephropathy. Ochratoxin A is a mycotoxin produced by various species of
COOH OH O Aspergillus and Penicillium. Ochratoxins contaminate foods (mainly cereals) for humans as
well as for cattle. Ochratoxins are mutagenic, oncogenic, and nephrotoxic. Ochratoxins are
– CH2- CH-NH-CO- responsible for chronic nephropathy in pigs and also may be the cause of endemic Balkan
CH3 nephropathy and some chronic interstitial nephropathies seen in North Africa and France [29].
CI

Contamination of cereals
Chronic nephropathy in pigs
Endemic Balkan nephropathy
Chronic interstitial nephritis in Tunisia
Chronic interstitial nephritis in France (?)
R. Danube

Austria
Hungary CLINICAL FEATURES OF BALKAN NEPHROPATHY
Slovenia
R. Sava
Croatia
R. S Romania Residence in an endemic area
ava Slavonski
Brod Occupational history of farming
Bneljina Oravita Progressive renal failure
Belgrade Turn Severin
Bosnia and Microproteinuria of tubular type
Herezgovina Lazarevac be
Paracin anu Unremarkable urinary sediment
R. D
Sarajevo Mikhaylovgrad Small and shrunken kidneys
Nis
Yugoslavia Vratsa Associated urothelial tumors
Italy Sofia Bulgaria

Macedonia
FIGURE 10-31
Albania Clinical features in Balkan nephropathy. Balkan nephropathy is
characterized by progressive renal failure in residents (generally
Greece farmers) living in endemic areas for over 10 years. The urinary
sediment is unremarkable and no proteinuria is seen, except for
a microproteinuria of tubular type. The kidneys are small and
shrunken. Urothelial cancers are frequently associated with Balkan
nephropathy [29,30].
FIGURE 10-30
Endemic Balkan nephropathy. Endemic nephropathy is encoun-
tered in some well-defined areas of the Balkans. Distribution (dark
areas) is along the affluents of the Danube, in a few areas on the
plains and low hills owing to high humidity and rainfall. (From
Stefanovic and Polenakovic [30]; with permission.)
10.14 Tubulointerstitial Disease

A B
FIGURE 10-32
Pathology of Balkan nephropathy. Balkan nephropathy is characterized hyperplasia of the myocythial cells with narrowing of the lumen of the
by pure interstitial fibrosis with marked tubular atrophy (A) and by vessel (B) (From Stefanovic and M. Polenakovic [30]; with permission).

FIGURE 10-33
Pathology of ochratoxin nephropathy. In addition to interstitial
fibrosis, large hyperchromatic nuclei in tubular epithelial cells are
shown by the arrow (interstitial caryomegalic nephropathy).
(Masson trichrome stain, magnification x 160.) The renal biopsy
was obtained from a woman from France who had renal failure
(creatinine clearance 40 mL/min) without significant proteinuria
and urinary sediment abnormalities. Ochratoxin levels were 367
and 1810 ng/mL, respectively, in the patient’s blood and urine.
(From Godin and coworkers [29].)

80 74.2
12.8
Cereal samples contaminated

Number of urothelial cancers

70
per million inhabitants

60
by ochratoxin, %

10
50
40
30
20
1.6
10 3.2
0 0
Endemic Nonendemic Endemic Nonendemic
Areas of Balkan nephropathy Areas of Balkan nephropathy

FIGURE 10-34 FIGURE 10-35

Balkan nephropathy and ochratoxin A in food. A survey of home- Balkan nephropathy and urothelial cancers. Urothelial cancers
produced foodstuffs in the Balkans has revealed that contamination appear as a frequent complication of Balkan nephropathy. An
with ochratoxin A is more frequent in areas in which endemic increased prevalence of upper tract urothelial tumors is described
nephropathy is prevalent (endemic areas) than in areas in which in inhabitants of areas in which Balkan nephropathy is endemic.
nephropathy is absent. (Adapted from Krogh and coworkers [31].) (Adapted from Godin and coworkers [29].)
 Toxic Nephropathies 10.15

Exposure to Chinese Herbs

FIGURE 10-36
Release of Chinese herb Epidemiology of Chinese herbs nephropathy. Chinese herbs
(so-called Stephania tetrandra)
on Belgian market nephropathy was described for the first time in Belgium in 1993
40 [32]. A peak incidence of new cases of women with rapidly pro-
Chinese herb nephropathy

90 92 gressive interstitial nephritis in Brussels during 1992 lead to suspi-

(number of new cases)

31 32
30 cion of a new cause of renal disease. The relationship between this
24 new renal disease and the recent introduction of Chinese herbs
(namely, Stephania tetrandra) in a slimming regimen was estab-
20
15 lished [32]. The withdrawal from the market of this herb has
decreased the incidence of interstitial nephritis in Brussels, Belgium.
10 7
5
1 1
0
1989 1990 1991 1992 1993 1994 1995 1996
Year

FIGURE 10-37
A. CHINESE HERBAL MEDICINE Role of Aristolochia in Chinese herbs nephropathy. Stephania tetran-
dra was the Chinese herb chronologically associated with the develop-
ment of Chinese herbs nephropathy. However, tetrandrine, the alka-
Chinese Name Western name Chemical Marker loid characterizing Stephania tetrandra was not found in the capsules
taken by the patients. In fact, confusion between Stephania tetrandra
Han fang-ji Stephania tetrandra Tetrandrine and Aristolochia fang chi was done in the delivery of Chinese herbs in
Guang fang-ji Aristolochia fang chi Aristolochic acid Belgium [33]. Chinese characters and the pingin name of Stephania
tetrandra (Han fang-ji) are identical to that of Aristolochia fang chi
(Guang fang-ji). Investigations conducted on batches of Stephania
tetrandra powders distributed in Belgium have shown that most of
them contained aristolochic acids (characteristic of Aristolochia) and
30
30 not tetrandrine (From Vanhaelen and coworkers [33] and P Daenens,
Katholiek Universiteit Leuven, Belgium, report of expertise 1996.)
(Number of batches)
Chinese herbs

20

10
7
5
4

0
+A, +T +A, –T –A, +T –A, –T
+A, aristolochic acid present
–A, aristolochic acid absent
+T, tetrandrine present
B –T, tetrandine absent
10.16 Tubulointerstitial Disease

FIGURE 10-38
DNA ADDUCTS FORMED BY DNA aristolochic acid adducts in kidney tissues of patients with
ARISTOLOCHIC ACID IN RENAL TISSUE Chinese herbs nephropathy. The role of Aristolochia in the pathogen-
esis of Chinese herbs nephropathy was confirmed by the demonstra-
tion of DNA aristolochic acid adducts (a biomarker of aristolochic
Chinese Herb Nephropathy (n = 5) Controls (n = 6) acids exposure) in renal tissue of patients with Chinese herbs
nephropathy, whereas these adducts were absent in the renal tissue
0.7–5.3 per 107 nucleotides 0 of control cases. (Adapted from Schmeiser and coworkers [34].)

CLINICAL FEATURES OF CHINESE HERB NEPHROPATHY

Rapidly progressive renal failure

Microproteinuria of tubular type
Unremarkable urinary sediment
Small and shrunken kidneys
Valvular hear diseases (dexfenfluramine-associated therapy), 30%
Associated urothelial cancers

FIGURE 10-39 FIGURE 10-40

The clinical features of Chinese herbs nephropathy are character- Photographic image of the pathology of Chinese herbs nephropa-
ized by rapidly progressive renal failure without both urinary sedi- thy. Chinese herbs nephropathy is characterized by a large reduc-
ment abnormalities and proteinuria except for a microproteinuria tion in kidney volume. Moreover, an associated tumor of the lower
of tubular type. The kidneys are small and shrunken. Vascular ureter is shown.
heart diseases are associated in 30% of cases (probably owing to
dexfenfluramine administered with the Chinese herbs for slimming
purposes) [35]. Some cases of associated urothelial cancers also are
described [36,37].

A B
FIGURE 10-41 (see Color Plate)
Pathology of Chinese herb nephropathy. The major pathologic extensive interstitial fibrosis with relative sparing of glomeruli.
lesion consists of extensive interstitial fibrosis with atrophy (Masson trichrome stain, magnification  50.) B, A normal
and loss of the tubules, predominantly located in superficial glomerulus surrounded by a paucicellular interstitial fibrosis
cortex [38,39]. A, A low-power view of transition between and atrophic tubules. (Masson’s trichrome stain, magnification
superficial cortex (left) and deep cortex (right) shows an  300.)
 Toxic Nephropathies 10.17

50 NEP CC16 B2–m

40 5
40 4
30

log ug/24 h
log ug/24 h
ug/24 h

30 3
20
20 2
10 10 1
0 0 0
Controls Normal Renal End-stage Controls Normal Renal End-stage Controls Normal Renal End-stage
renal function failure renal disease renal function failure renal disease renal function failure renal disease
A After exposure to Chinese herbs B After exposure to Chinese herbs C After exposure to Chinese herbs

FIGURE 10-42
5
RBP A–D, Microproteinuria and neutral endopeptidase enzymuria in Chinese herbs nephropathy.
Proximal tubular injury in Chinese herbs nephropathy is demonstrated by a significant
4 increase in urinary excretion of microproteins (Clara cell protein, CC16; 2-microglobulin
log ug/24 h

3 [2-m] and retinol binding protein [RBP]) as well as a decrease in urinary excretion of neu-
tral endopeptidase (NEP) a marker of the brush border tubular mass. (Adapted from Nortier
2
and coworkers [40].)
1
0
Controls Normal Renal End-stage
renal function failure renal disease
D After exposure to Chinese herbs

FIGURE 10-43
Chinese herbs nephropathy and renal pelvic carcinoma. Urothelial cancers are associated
with Chinese herbs nephropathy [36,37]. Shown is a filling defect (arrow) in the renal
pelvis in an antegrade pyelogram obtained from a patient with Chinese herbs nephropathy
and hematuria. (From Vanherweghem and coworkers [37]; with permission).
10.18 Tubulointerstitial Disease

A B
FIGURE 10-44
Pathology of urothelial tumors associated with Chinese herbs is shown in Fig. 10-40). A, Part of the urothelial proliferation.
nephropathy. Microscopic pattern is shown of a lower urothe- Plurifocal thickening of the urothelium is present. (Hematoxylin
lial tumor obtained by ureteronephrectomy of a native kidney and eosin stain x 50.) B, In situ transitional cell carcinoma
in a patients with transplantation who has Chinese herbs with high mitotic rate. (Magnification x 400 periodic acid–
nephropathy (the macroscopic appearance of the nephrectomy Schiff reaction.)

0.7
Controls, n = 23 TOXIC CHRONIC INTERSTITIAL NEPHROPATHIES
0.6 Steroids, n = 12 WITH UROTHELIAL CANCERS
1/P creatinine ratio

0.5
0.4
Analgesic nephropathy (phenetidin compounds)
0.3 Balkan nephropathy (ochratoxins)
0.2 Chinese herbs nephropathy (aristolochic acids)

0.1
–6 –3 0 3 6 9 12
Months
FIGURE 10-46
Of interest is the association between chronic renal interstitial
FIGURE 10-45
fibrosis and urothelial cancers. This association appears, at least,
Effects of steroids on the evolution of renal failure in Chinese herbs in three chronic toxic nephropathies: analgesic nephropathy,
nephropathy. Steroid therapy was shown to decrease the evolution Balkan nephropathy, and Chinese herbs nephropathy. This associ-
of renal failure in a subgroup of patients with Chinese herbs ation indicates that nephrotoxins promoting interstitial fibrosis
nephropathy [41]. The evolution is shown of the 1/P creatinine (analgesics, ochratoxins, and aristolochic acids) also may be
ratio of patients with Chinese herbs nephropathy, 12 of whom oncogenic substances.
were treated with steroids as compared with 23 not treated with
steroids (control group). In the control group the 1/P creatinine
curve was limited to 6 months of follow-up because at 12 months,
17 of the 23 patients were on renal replacement therapy. (From
Vanherweghem and coworkers [41]; with permission.)
 Toxic Nephropathies 10.19

References
1. Nuyts GD, Van Vlem E, Thys J, et al.: New occupational risk factors 22. Luke RG: Mechanism of cyclosporine-induced hypertension. Am J
for chronic renal failure. Lancet 1995, 346:7–11. Hypertens 1991, 4:468-471.
2. Nuyts GD, Daelemans RA, Jorens PG, et al.: Does lead play a role in 23. Ellis CN, Fradin MS, Messana JM, et al.: Cyclosporine for plaque-
the development of chronic renal disease? Nephrol Dial Transplant type psoriasis. N Engl J Med 1991, 324:277–284.
1991, 6:307–315. 24. Feutren G, Mihatsch MJ: Risk factors for cyclosporine-induced
3. Batuman V, Maesaka JK, Haddad B, et al.: The role of lead in gout nephropathy in patients with autoimmune diseases. N Engl J Med
nephropathy. N Engl J Med 1981, 304:520–523. 1992, 326: 1654–1660.
4. Sanchez-Fructuoso AI, Torralbo A, Arroyo M, et al.: Occult lead 25. Myers BD, Newton L: Cyclosporin induced chronic nephropathy: an
intoxication as a cause of hypertension and renal failure. Nephrol obliterative renal injury. J Am Soc Nephrol 1991, 2:S45–S52.
Dial Transplant 1996, 11:1775–1780. 26. Deray G, Benhmida M, Le Hoang P, et al. Renal function and blood
5. Roels HA, Lauwerys RR, Buchet JP, et al.: Health significance of cad- pressure in patients receiving long-term, low-dose cyclosporine therapy
mium induced renal dysfunction: a five year follow up. Br J Ind Med for idiopathic autoimmune uveitis. Ann Intern Med 1992, 117:578–583.
1989, 46:755–764. 27. World MJ, Stevens PE, Ashton MA, Rainford DJ: Mesalazine-associ-
6. Nortier J, Bernard A, Roels H, et al.: Urinary neutral endopeptidase ated interstitial nephritis. Nephrol Dial Transplant 1996, 11:614–621.
in workers exposed to cadmium: interaction with cigarette smoking. 28. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM: 5-Aminosalicylic
Occup Environ Med 1997, 54:432–436. acid (5-ASA) and chronic tubulointerstitial nephritis in patients with
7. Walker RG: Lithium nephrotoxicity. Kidney Int 1993, 44(suppl chronic inflammatory bowel disease: Is there a link? Nephrol Dial
42):S93–S98. Transplant 1997; 12:1839–1841.
8. Bendz H, Aurell M, Balldin J, et al.: Kidney damage in long-term lithi- 29. Godin M, Fillastre JP, Simon P, et al.: L’ochratoxine est-elle néphro-
um patients: a cross-sectional study of patients with 15 years or more toxique chez l’homme ? In Actualités Néphrologiques. Edited by
on lithium. Nephrol Dial Transplant 1994, 9:1250–1254. Brentano JL, Bach JF, Kreis H, Grunfeld JP. Paris:
9. Sanai T, Okuda S, Onoyama K, et al.: Germanium dioxide-induced Flammarion–Medecine Sciences; 1996:225–250.
nephropathy: a new type of renal disease. Nephron 1990, 54:53–60. 30. Stefanovic V, Polenakovic MH: Balkan nephropathy: kidney disease
10. Van Der Spoel JI, Stricker BH, Esseveld MR, Schipper MEI: Dangers beyond the Balkans? Am J Nephrol 1991, 11:1–11.
of dietary germanium supplements. Lancet 1990, 336:117. 31. Krogh P, Hald B, Plestina R, Ceovic S: Balkan (endemic) nephropathy
11. Takeuchi A, Yoshizawa N, Oshima S, et al.: Nephrotoxicity of germa- and foodborn ochratoxin A: preliminary results of a survey of food-
nium compounds: report of a case and review of the literature. stuffs. Acta Path Microbiol Scand Sect B 1977, 85:238–240.
Nephron 1992, 60:436–442. 32. Vanherweghem JL, Depierreux M, Tielemans C, et al.: Rapidly pro-
12. Hess B, Raisin J, Zimmermann A, et al.: Tubulointerstitial nephropa- gressive interstitial renal fibrosis in young women: association with
thy persisting 20 months after discontinuation of chronic intake of slimming regimen including Chinese herbs. Lancet 1993,
germanium lactate citrate. Am J Kidney Dis 1993, 21:548–552. 341:387–391.
13. Elseviers MM, Bosteels V, Cambier P, et al.: Diagnostic criteria of 33. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL:
analgesic nephropathy in patients with end-stage renal failure: Identification of aristolochic acid in Chinese herbs. Lancet 1994,
results of the Belgian study. Nephrol Dial Transplant 1992, 343:174.
7:479–486. 34. Schmeiser HH, Bieler CA, Wiessler M, et al.: Detection of DNA-
14. Drukker W, Schwarz A, Vanherweghem JL: Analgesic nephropathy: adducts formed by aristolochic acid in renal tissue from patients with
an underestimated cause of end-stage renal disease. Int J Artif Organs Chinese herbs nephropathy. Cancer Res 1996, 56:2025–2028.
1986, 9:216–243. 35. Vanherweghem JL: Association of valvular heart disease with Chinese
15. Klag MJ, Whelton PK, Perneger TV: Analgesics and chronic renal dis- herbs nephropathy. Lancet 1997, 350:1858.
ease. Curr Opinion Nephrol Hypertens 1996, 5:236–241. 36. Cosijns JP, Jadoul M, Squifflet JP: Urothelial malignancy in nephropa-
16. Vanherweghem JL, Even-Adin D: Epidemiology of analgesic thy due to Chinese herbs. Lancet 1994, 344:118.
nephropathy in Belgium. Clin Nephrol 1982, 17:129–133. 37. Vanherweghem JL, Tielemans C, Simon J, Depierreux M: Chinese
17. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated herbs nephropathy and renal pelvic carcinoma. Nephrol Dial
with the use of acetaminophen, aspirin, and nonsteroidal anti-inflam- Transplant 1995, 10:270–273.
matory drugs. N Engl J Med 1994, 331:1675–1679. 38. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL:
18. Elseviers MM, De Broe ME: Analgesic nephropathy in Belgium is Pathologic aspects of a newly described nephropathy related to the
related to the sales of particular analgesic mixtures. Nephrol Dial prolonged use of Chinese herbs. Am J Kidney Dis 1994, 24:172–180.
Transplant 1994, 9:41–46. 39. Cosijns JP, Jadoul M, Squifflet JP et al.: Chinese herbs nephropathy: a
19. Elseviers MM, De Schepper A, Corthouts R, et al.: High diagnostic clue to Balkan endemic nephropathy? Kidney Int 1994,
performance of CT scan for analgesic nephropathy in patients with 45:1680–1688.
incipient to severe renal failure. Kidney Int 1995, 48:1316–1323. 40. Nortier JL, Deschodt-Lankman MM, Simon S, et al. Proximal tubular
20. Shihab FS: Cyclosporine nephropathy: pathophysiology and clinical injury in Chinese herbs nephropathy: monitoring by neutral endopep-
impact. Sem Nephrol 1996, 16:536–547. tidase enzymuria. Kidney Int 1997, 51:288–293.
21. Bennett WM, De Mattos A, Meyer MM, et al.: Chronic cyclosporine 41. Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M:
nephropathy: The Achilles’ heel of immunosuppressive therapy. Effects of steroids on the progression of renal failure in chronic inter-
Kidney Int 1996, 50:1089–1100. stitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J
Kidney Dis 1996, 27:209–215.
Metabolic Causes of
Tubulointerstitial Disease
Steven J. Scheinman

A
variety of metabolic conditions produce disease of the renal
interstitium and tubular epithelium. In many cases, disease
reflects the unique functional features of the nephron, in
which the ionic composition, pH, and concentration of both the
tubular and interstitial fluid range widely beyond the narrow con-
fines seen in other tissues. Recent genetic discoveries have offered
new insights into the molecular basis of some of these conditions, and
have raised new questions. This chapter discusses nephrocalcinosis,
the relatively nonspecific result of a variety of hypercalcemic and
hypercalciuric states, as well as the renal consequences of hyperox-
aluria, hypokalemia, and hyperuricemia.

CHAPTER

11
11.2 Tubulointerstitial Disease

FIGURE 11-1
The recent discovery of the calcium-sensing
receptor and increased understanding of its
expression along the nephron have provided
explanations for many of the known effects
of hypercalcemia to cause clinical distur-
bances in renal tubular function [1]. In the
parathyroid gland the calcium-sensing recep-
tor allows the cell to sense extracellular levels
of calcium and transduce that signal to regu-
late parathyroid hormone production and
release. In the nephron, expression of the
calcium receptor can be detected on the api-
cal surface of cells of the papillary collecting
Hypercalcemia duct, where calcium inhibits antidiuretic
inhibits reabsorption hormone action. Thus, hypercalcemia impairs
of NaCl, Ca, and Mg urinary concentration and leads to isotonic
polyuria. The most intense expression of the
calcium receptor is in the thick ascending
limb of the loop of Henle, particularly the
cortical portion, where the calcium receptor
protein is located on the basolateral side of
the cells; this explains the known effects of
hypercalcemia in inhibiting reabsorption of
calcium, magnesium, and sodium chloride
in the thick ascending limb [2]. In addition,
Hypercalcemia
inhibits hypercalcemia causes hypercalciuria through
reabsorption an increased filtered calcium load and
of water suppression of parathyroid hormone release
with a consequent reduction in calcium
reabsorption. Ca—calcium; Mg—magne-
sium; NaCl—sodium chloride.

FIGURE 11-2
RENAL EFFECTS OF CALCIUM Hypercalcemia leads to renal vasoconstriction and a reduction in
the glomerular filtration rate. However, no expression of the calci-
um-sensing receptor has been reported so far in renal vascular or
Hypercalcemia glomerular tissue. Calcium receptor expression is present in the
Collecting duct proximal convoluted tubule, on the basolateral side of cells of the
Resistance to vasopressin, leading to isotonic polyuria
distal convoluted tubule, and on the basolateral side of macula
densa cells. Functional correlates of calcium receptor expression
Thick ascending limb of the loop of Henle
at these sites are not yet clear [3].
Impaired sodium chloride reabsorption, leading to modest salt wasting
Hypercalciuria leads to microscopic hematuria and, in fact, is
Inhibition of calcium transport, leading to hypercalciuria
the most common cause of microscopic hematuria in children. The
Inhibition of magnesium transport, leading to hypomagnesemia
mechanism is presumed to involve microcrystallization of calcium
Renal vasculature
salts in the tubular lumen. Conflicting effects of calcium on urinary
Arteriolar vasoconstriction acidification have been reported in clinical settings in which other
Reduction in ultrafiltration coefficient factors, such as parathyroid hormone levels, may explain the obser-
Hypercalciuria vations. whether or not it is the result of renal tubular acidosis,
Microscopic hematuria Nephrocalcinosis often is associated with impaired urinary acidifica-
Nephrocalcinosis tion, whether or not it is the result of renal tubular acidosis.
Impaired urinary acidification
 Metabolic Causes of Tubulointerstitial Disease 11.3

FIGURE 11-3
CAUSES OF NEPHROCALCINOSIS Nephrocalcinosis represents calcification of the renal parenchyma. It
is primarily medullary in most cases except in dystrophic calcification
associated with inflammatory, toxic, or ischemic disease. Nephro-
Medullary (total) 97.6 calcinosis can be seen in association with chronic or severe hypercal-
Primary hyperparathyroidism 32.4 cemia or in a variety of hypercalciuric states. The spectrum of causes
Distal renal tubular acidosis 19.5
of nephrocalcinosis is described by Wrong [3]. The numbers represent
the percentage of the total of 375 patients. It is likely that the case mix
Medullary sponge kidney 11.3
is affected to some extent by Wrong’s interests in, eg, renal tubular
Idiopathic hypercalciuria 5.9
acidosis (RTA) and Dent’s disease, but this is by far the largest pub-
Dent’s disease 4.3
lished series. As in other studies, the most important causes of
Milk-alkali syndrome 3.2
nephrocalcinosis are primary hyperparathyroidism, distal RTA, and
Oxalosis 3.2
medullary sponge kidney. The primary factor predisposing patients
Hypomagnesemia-hypercalciuria 1.6 to renal calcification in many of these conditions is hypercalciuria,
Sarcoidosis 1.6 as occurs in idiopathic hypercalciuria, Dent’s disease, milk-alkali
Renal papillary necrosis 1.6 syndrome, sarcoidosis, hypervitaminosis D, and often in distal RTA.
Hypervitaminosis D 1.6 In distal RTA and milk-alkali syndrome, relative or absolute urinary
Other* 4.0 alkalinity promote precipitation of calcium phosphate crystals in the
Undiscovered causes 6.7 tubular lumena, and hypocitraturia is an important contributing
Cortical (total) 2.4 factor in distal RTA. Causes of cortical nephrocalcinosis in this study
included acute cortical necrosis, chronic glomerulonephritis, and
chronic pyelonephritis.
Adapted from Wrong [3]; with permission.
* Other causes include Bartter syndrome, idiopathic Fanconi syndrome, hypothy-
roidism, and severe acute tubular necrosis.

both systemic acidosis and hypokalemia.

Impaired urinary acidification Alkaline urine The high urine pH favors precipitation of
calcium phosphate (CaPO4). Thus, RTA-1
should be suspected in any patient with
Systemic acidosis
Hypercalciuria pure calcium phosphate stones [4].
Systemic acidosis also promotes hypercal-
ciuria, although not all patients with
RTA-1 have excessive urinary calcium
Hypokalemia Decreased urinary Resorption of excretion [5]. Hypercalciuria results from
citrate excretion bone mineral resorption of bone mineral and the conse-
quent increased filtered load of calcium as
Reduced renal
tubular calcium Hypercalciuria
acidosis leads to consumption of bone
reabsorption buffers. Acidosis also has a direct effect of
inhibiting renal tubular calcium reabsorp-
CaPO4 precipitation tion. Conversely, nephrocalcinosis from
other causes can impair urinary acidifica-
tion and lead to RTA in some patients.
FIGURE 11-4 The mainstay of therapy for RTA-1 is
Nephrocalcinosis in type I (distal) renal tubular acidosis. Nephrocalcinosis and potassium citrate, which corrects acidosis,
nephrolithiasis are common complications in distal renal tubular acidosis (RTA-1). replaces potassium, restores urinary cit-
Several factors contribute to the pathogenesis. The most important of these factors rate excretion, and reduces urinary loss of
are a reduction in urinary excretion of citrate and a persistently alkaline urine. Citrate calcium [5]. (From Buckalew [5]; with
inhibits the growth of calcium stones; its excretion is reduced in RTA-1 as a result of permission.)
11.4 Tubulointerstitial Disease

involved in the coordinated transport of salt in the thick ascending

Epithelial cell of the thick ascending limb of the loop of Henle. In this nephron segment, sodium chloride
limb of the loop of Henle is transported into the cell together with potassium by the bumet-
Lumen Blood
amide-inhibitible sodium-potassium-2 chloride cotransporter
(NKCC2). Recycling of potassium back to the lumen through an
Na+ ClC-Kb
apical potassium channel (ROMK) allows an adequate supply of
NKCC2 2Cl– potassium for optimal activity of the NKCC2. Chloride exits the
K+ basolateral side of the cell through a voltage-gated chloride channel
(ClC-Kb), and sodium is expelled separately by the sodium-potassi-
Na+ um adenosine triphosphatase cotransporter. Inactivating mutations
ROMK K+
ATP in NKCC2, ROMK, and ClC-Kb have been identified in patients
K+ with Bartter syndrome [6–8].
Approximately 20% of filtered calcium is reabsorbed in the
thick ascending limb, and inactivation of any of these three trans-
port proteins can lead to hypercalciuria. Nephrocalcinosis occurs
in almost all patients with mutations in NKCC2 or ROMK, but it
FIGURE 11-5 is less common in patients with a mutation in the basolateral chlo-
Bartter syndrome. Bartter syndrome is a hereditary renal functional ride channel ClC-Kb, even though patients with chloride-channel
disorder characterized by hypokalemic metabolic alkalosis, renal mutations currently make up the largest reported group [8]. This
salt wasting with normal or low blood pressure, polyuria, and interesting observation is unexplained at present. In addition, a sig-
hypercalciuria. Other features include juxtaglomerular hyperplasia, nificant number of patients with Bartter syndrome have been found
secondary hyperreninemia and hyperaldosteronism, and excessive to have normal coding sequences for all three of these genes, indi-
urinary excretion of prostaglandin E. It often has been noted that cating that mutations in other gene(s) may explain Bartter
patients with Bartter syndrome appear as if they were chronically syndrome in some patients.
exposed to loop diuretics; in fact, the major differential diagnosis is In contrast, the Gitelman variant of Bartter syndrome is associated
with diuretic abuse. Bartter syndrome often presents with growth with hypocalciuria. In this respect these patients resemble people
retardation in children, and nephrocalcinosis is common. Bartter treated with thiazide diuretics. In fact, mutations have been found
syndrome is inherited as an autosomal recessive trait. in the thiazide-sensitive sodium chloride cotransporter of the distal
The speculation that this syndrome could be explained by tubule [9]. Hypomagnesemia is common and often severe, and
impaired reabsorption in the loop of Henle has now been confirmed patients with Gitelman syndrome do not develop nephrocalcinosis.
by molecular studies. R.P. Lifton’s group [6–8] identified loss-of- ATP—adenosine triphosphate. (From Simon and coworkers [8];
function mutations in three genes encoding different proteins, each with permission.)

FIGURE 11-7
Noncontrast
abdominal
radiograph in a
24-year-old man
with X-linked
nephrolithiasis
(Dent’s disease).
The patient had
recurrent calcium
nephrolithiasis
beginning in child-
hood and developed
end-stage renal
disease requiring
dialysis at 40 years
of age. Extensive
medullary calcinosis
is evident.

FIGURE 11-6
Nephrocalcinosis. Ultrasound image of right kidney in a patient
with primary hyperparathyroidism. Echogenicity of the renal
cortex is comparable to that of the adjacent liver. The dense
nephrocalcinosis is entirely medullary. (Courtesy of Robert
Botash, MD.)
 Metabolic Causes of Tubulointerstitial Disease 11.5

X-LINKED NEPHROLITHIASIS (DENT’S DISEASE)

Males who are affected Females who are carriers

Low molecular weight proteinuria Extreme Absent, mild, or moderate
Other defects in proximal tubular function Variable Uncommon
Hypercalciuria Occurs early in most Present in half
Nephrocalcinosis Nearly all have it Rare
Calcium stones Common but not universal Uncommon
Renal failure Common but not universal Rare
Rickets Present in some Not reported

FIGURE 11-8
Syndromes of X-linked nephrolithiasis have been Rickets occurs early in childhood in some patients but
reported under various names, including Dent’s disease is absent in most patients with X-linked nephrolithiasis
in the United Kingdom, X-linked recessive hypophos- (Dent’s disease). In a few families, all affected males have
phatemic rickets in Italy and France, and a syndrome of had rickets. In other families, rickets is present in only
low molecular weight (LMW) proteinuria with hyper- one of several males sharing the same mutation. At pre-
calciuria and nephrocalcinosis in Japanese schoolchild- sent, the variability of this feature and other features of
ren. Mutations in a gene encoding a voltage-gated chlo- the disease is unexplained and may reflect dietary or envi-
ride channel (ClC-5) are present in all of these syn- ronmental factors or the participation of other genes in
dromes, establishing that they represent variants of one the expression of the phenotype.
disease [10]. The disease occurs most often in boys, Females who are carriers often have mild to moder-
with microscopic hematuria, proteinuria, and hypercal- ate LMW proteinuria. This abnormality can be used
ciuria. Many but not all have recurrent nephrolithiasis clinically as a screening test, but LMW protein excre-
from an early age. Affected males excrete extremely tion will not be abnormal in all heterozygous females.
large quantities of LMW proteins, particularly 2- Approximately half of women who are carriers have
microglobulin and retinol-binding protein. Other defects hypercalciuria, but other biochemical abnormalities are
of proximal tubular function, including hypophos- rare. Although symptomatic nephrolithiasis and even
phatemia, aminoaciduria, glycosuria, or hypokalemia, renal insufficiency have been reported in female carri-
occur variably and often intermittently. Many affected ers, they are very uncommon.
males have mild to moderate polyuria and nocturia, and The gene for ClC-5 that is mutated in X-linked nephro-
they often exhibit this symptom on presentation. lithiasis (Dent’s disease) is expressed in the endosomal
Urinary acidification is usually normal, and patients do vacuoles of the proximal tubule; it appears to be impor-
not have acidosis in the absence of advanced renal tant in acidification of the endosome. Thus, defective
insufficiency. Nephrocalcinosis is common by the endosomal function would explain the LMW proteinuria.
teenage years, and often earlier. Renal failure is common The mechanism of hypercalcinuria remains unexplained
and often progresses to end-stage renal disease by the at present. This gene belongs to the family of voltage-
fourth or fifth decade, although some patients escape it. gated chloride channels that includes ClC-Kb, one of the
Renal biopsy documents a nonspecific pattern of inter- gene mutations in some patients with Bartter syndrome.
stitial fibrosis and tubular atrophy, with glomerular scle- To date, 32 mutations have been reported in 40 families,
rosis that is probably secondary [11]. and nearly all are unique [11].
11.6 Tubulointerstitial Disease

HYPEROXALURIA

Type Mechanism Clinical consequences

Primary (genetic):
PH1 Functional deficiency of AGT Nephrolithiasis
Nephrocalcinosis and progressive renal failure
Systemic oxalosis (kidneys, bones, cartilage, teeth, eyes, peripheral
nerves, central nervous system, heart, vessels, bone marrow)
PH2 Functional deficiency of DGDH Nephrolithiasis
Secondary:
Dietary Sources include for example spinach, rhubarb, beets, peanuts, Increased risk of nephrolithiasis
chocolate, and tea
Enteric Enhanced oxalate absorption because of increased oxalate solu- Nephrolithiasis
bility, bile salt malabsorption, and altered gut flora (eg, inflam- Nephrocalcinosis
matory bowel disease and bowel resection) Systemic oxalosis (rarely)
Metabolism from excess of precursors Ascorbate Nephrolithiasis
Ethylene glycol, glycine, glycerol, xylitol, methoxyflurane Tubular obstruction by crystals leading to acute renal failure
Pyridoxine deficiency Cofactor for AGT Nephrolithiasis

FIGURE 11-9
Oxalate is a metabolic end-product of limited solubility in physiologic from either exposure to metabolic precursors of oxalate or pyri-
solution. Thus, the organism is highly dependent on urinary excretion, doxine deficiency. Normally, dietary sources of oxalate account for
which involves net secretion. Normal urine is supersaturated with only approximately 10% of urinary oxalate. Restriction of dietary
respect to calcium oxalate. Crystallization is prevented by a number of oxalate can be effective in some patients with kidney stones who
endogenous inhibitors, including citrate. A mild excess of oxalate load, are hyperoxaluric, but even conscientious adherence to dietary
as occurs with excessive dietary intake, contributes to nephrolithiasis. restriction is disappointing in many patients who may have mild
A more severe oxalate overload, as in type 1 primary hyperoxaluria, metabolic hyperoxaluria, an entity that probably exists but is poorly
can lead to organ damage through tissue deposition of calcium oxalate understood. Intestinal absorption of oxalate can be enhanced
and possibly through the toxic effects of glyoxalate [12]. markedly in patients with bowel disease, particularly inflammatory
Two types of primary hyperoxaluria (PH) have been identified bowel disease or after extensive bowel resection or jejunoileal bypass.
(Fig. 11-10), of which type 1 (PH1) is much more common. PH1 In this setting, several mechanisms have been described including a)
results from absolute or functional deficiency of the liver-specific enhanced oxalate solubility as a consequence of binding of calcium
enzyme alanine:glyoxalate aminotransferase (AGT). This deficiency to fatty acids in patients with fat malabsorption; b) a direct effect
leads to calcium oxalate nephrolithiasis in childhood, with nephro- of malabsorbed bile salts to enhance absorption of oxalate by
calcinosis and progressive renal failure. Because the kidney is the intestinal mucosa, and c) altered gut flora with reduction in the
main excretory route for oxalate, in the face of excessive oxalate population of oxalate-metabolizing bacteria [4,12]. Because of
production even mild degrees of renal insufficiency can lead to the important role of the colon in absorbing oxalate, ileostomy
systemic deposition of oxalate in a wide variety of tissues. It is inter- abolishes enteric hyperoxaluria [4].
esting that the liver itself is spared from calcium oxalate deposition. Excessive endogenous production of oxalate occurs in patients
Clinical consequences include heart block and cardiomyopathy, ingesting large quantities of ascorbic acid, which may increase the
severe peripheral vascular insufficiency and calcinosis cutis, and bone risk of nephrolithiasis. In the setting of acute exposure to large
pain and fractures. Many of these conditions are exacerbated by the quantities of metabolic precursors, such as ingestion of ethylene
effects of end-stage renal disease. In contrast, PH2 is much more rare glycol or administration of glycine or methoxyflurane, tubular
than is PH1. Patients with PH2 have recurrent nephrolithiasis. obstruction by calcium oxalate crystals can lead to acute renal
Nephrocalcinosis, renal failure, and systemic oxalosis have not been failure. Pyridoxine deficiency is associated with increased oxalate
reported in PH2. The metabolic defect in PH2 appears to be a func- excretion clinically in humans and experimentally in animals; it
tional deficiency of D-glycerate dehydrogenase (DGDH) [12]. can contribute to mild hyperoxaluria. In all patients with primary
Secondary causes of hyperoxaluria include dietary excess, enteric hyperoxaluria, a trial of pyridoxine therapy should be given,
hyperabsorption, and enhanced endogenous production resulting because some patients will have a beneficial response.
 Metabolic Causes of Tubulointerstitial Disease 11.7

consequences of these defects. Both diseases are inherited as autoso-

mal recessive traits.
Primary hyproxaluria metabolism
In PH1, much clinical, biochemical, and molecular heterogeneity
exists. Liver AGT catalytic activity is absent in approximately two
Peroxisome Cytosol
thirds of patients with PH1. It is detectable in the remaining third,
Glycolate Glycolate however, in whom the enzyme is targeted to the mitochondria
rather than peroxisomes. Absence of peroxisomal AGT activity
DGDH leads to impaired transamination of glyoxalate to glycine, with
Block in PH2
excessive production of oxalate and, usually, glycolate. In PH2,
Glycine Glyoxylate Glycine deficiency of cytosolic DGDH results in overproduction of oxalate
AGT
and glycine. Mild cases of PH1, without nephrocalcinosis or systemic
oxalosis, resemble PH2 clinically, but the two usually can be distin-
Block in PH1 guished by measurement of urinary glycolate and glycine. Assay of
Oxalate Oxalate AGT activity in liver biopsy specimens can be diagnostic in PH1
even when renal failure prevents analysis of urinary excretion.
The gene encoding AGT has been localized to chromosome
2q37.3 and has been cloned and sequenced. Mutations in this gene
FIGURE 11-10 have been identified in patients with absent enzymatic activity,
Metabolic events in the primary hyperoxalurias. Primary hyper- abnormal enzyme targeting to mitochondria, aggregation of AGT
oxaluria type 1 (PH1) results from functional deficiency of the within peroxisomes, and absence of both enzymatic activity and
peroxisomal enzyme alanine:glyoxalate aminotransferase (AGT). immunoreactivity. However, mutations have not been identified in
PH2 results from a deficiency of the cytosolic enzyme d-glycerate all patients with PH1 who have been studied, and molecular
dehydrogenase (DGDH), which also functions as glyoxalate reduc- diagnosis is not yet routinely available [12]. (Adapted from
tase. This figure presents a simplified illustration of the metabolic Danpure and Purdue [12].)

A B
FIGURE 11-11
Sequential biopsies of a transplanted kidney documenting progressive and eosin. Panels A–C show specimens viewed by polarization
recurrence of renal oxalosis. This patient with primary hyperoxaluria microscopy, all at the same low-power magnification, from biop-
type I received renal transplantation, without liver transplantation, at sies taken after transplantation within the first year (A), third
24 years of age. Panels A–D show tissue stained with hematoxylin year (B),
(Continued on next page)
11.8 Tubulointerstitial Disease

C D
radial array of oxalate crystals and phagocytosis of small crystals by
multinucleated giant cells (E).
Conservative treatment of PH1 is of limited efficacy. Dietary
Multinucleated restriction has little effect on the course of the disease. High-dose
giant cells pyridoxine should be tried in all patients, but many patients do not
Ox Oxalate crystals respond. Strategies to prevent calcium oxalate stone formation
Ox include a high fluid intake (recommended in all patients), magnesium
oxide (because magnesium increases the solubility of calcium oxalate
Ox Ox salts), and inorganic phosphate. Lithotripsy or surgery may be neces-
Ox sary but do not alter the progression of nephrocalcinosis [12,13].
Ox Hemodialysis is superior to peritoneal dialysis in its ability to
remove oxalate, but neither one is able to maintain a rate of
oxalate removal sufficient to keep up with the production rate in
Ox
patients with PH1. Once end-stage renal disease develops, hemo-
dialysis does not prevent the progression of systemic oxalosis. In
some patients, renal transplantation accompanied by an aggressive
E program of management has been followed by a good outcome for
years [14]. However, oxalosis often recurs in the transplanted kid-
ney, particularly if any degree of renal insufficiency develops for
FIGURE 11-11 (Continued) any reason. In recent years, liver transplantation has been used
and fifth year (C), following renal transplantation. Deposition of with success, with or without renal transplantation, and offers the
oxalate crystals became progressively more severe with time, and the prospect of definitive cure. Results of liver transplantation are best
kidney failed after 5 years. Panel D illustrates a higher-power magni- in patients who have not yet developed significant renal insufficien-
fication, without polarization, of the biopsy at 5 years, showing a cy [12]. (Courtesy of Paul Shanley, MD.)
 Metabolic Causes of Tubulointerstitial Disease 11.9

URIC ACID AND RENAL DISEASE

Disease Clinical setting Features Therapeutic issues

Uric acid nephrolithiasis Hyperuricosuria Uric acid nephrolithiasis Allopurinol; alkalinize urine
Calcium nephrolithiasis Allopurinol
Acute uric acid nephropathy Cytotoxic chemotherapy for leukemia or Intratubular obstruction by uric acid crystals Prevention with allopurinol, fluids,
lymphoma; occasionally spontaneous in acidic urine and alkalinization
Acute dialysis as indicated
Chronic gouty nephropathy Gout or hyperuricemia in the setting of Intrarenal tophi; sodium urate crystals in Hemodialysis for renal failure
hypertension, preexisting renal disease, interstitium with accompanying destructive
advanced age, vascular disease, inflam- inflammatory reaction
matory reaction, and chronic exposure
to lead
Familial hyperuricemic nephropathy Autosomal dominant inheritance Interstitial fibrosis, chronic inflammation; No consensus regarding allopurinol
crystals are rare

FIGURE 11-12
Uric acid contributes to the risk of kidney stones in several ways. Pure dialysis because of the higher clearance rates for uric acid. Frequent
uric acid stones occur in patients with hyperuricosuria, particularly hemodialysis, even multiple times per day, may be necessary to pre-
when the urine is acidic. Thus, therapy involves both allopurinol and vent extreme hyperuricemia and facilitate recovery of renal func-
alkalinization with potassium alkali salts. Hyperuricosuria also pro- tion. A modification of continuous arteriovenous hemodialysis has
motes calcium oxalate stone formation. In these patients, calcium recently been reported to be effective in management of these
nephrolithiasis can be prevented by therapy with allopurinol. The patients [16].
mechanism may involve heterogenous nucleation of calcium oxalate Chronic gouty nephropathy is a term referring to deposition of
by uric acid microcrystals, binding of endogenous inhibitors of calci- sodium urate crystals in the renal interstitium, with an accompanying
um crystallization, or “salting out” of calcium oxalate by urate [4]. destructive inflammatory reaction. As a specific entity with intrarenal
Acute uric acid nephropathy occurs most often in the setting of tophi, gouty nephropathy appears to have become uncommon. It
brisk cell lysis from cytotoxic therapy or radiation for myeloprolif- appears clear that long-standing hyperuricemia alone is not sufficient
erative or lymphoproliferative disorders or other tumors highly to cause this condition in most patients, and that renal failure in
responsive to therapy. Uric acid nephropathy can uncommonly patients with hyperuricemia or gout is almost always accompanied
occur spontaneously in malignancies or other states of high uric by other predisposing conditions, particularly hypertension or expo-
acid production. Examples are infants with the Lesch-Nyhan syn- sure to lead [17].
drome who have excessive uric acid production resulting from defi- Familial hyperuricemic nephropathy is an entity that now has been
ciency of hypoxanthine-guanine phosphoribosyltransferase deficiency reported in over 40 kindreds. It is characterized by recurrent gout,
and, rarely, adults with gout who become volume-contracted and often occurring in youth and even childhood; hyperuricemia; and
whose urine is concentrated and acidic. The mechanism involves renal failure. Histopathology reveals interstitial inflammation and
intratubular obstruction by crystals of uric acid in the setting of an fibrosis, almost always without evidence of urate crystal deposition,
acute overwhelming load of uric acid, particularly in acidic urine. In although this has been found in two patients. In contrast to gouty
recent years, the widespread use of an effective prophylactic regimen nephropathy, hypertension usually is absent until renal failure is
for chemotherapy has made acute uric acid nephropathy much less advanced. The hyperuricemia appears to reflect decreased renal
common [15]. This regimen includes preparation of the patient with excretion of urate rather than overproduction of urate. Although
high-dose allopurinol, volume-expanding the patient to maintain a hyperuricemia precedes and is disproportionate to any degree of
dilute urine, and alkaline diuresis. In patients whose tumor lysis renal failure, the role, if any, that uric acid plays in the pathogenesis
leads to hyperphosphatemia, however, it is important to discontinue of the renal failure remains unclear. These is no consensus among
urinary alkalinization or else calcium phosphate precipitation may authors regarding the potential value of allopurinol in this disease.
occur. Occasionally, patients will develop renal failure despite these The inheritance follows an autosomal dominant pattern, but, beyond
measures. In such patients, hemodialysis is preferable to peritoneal this, the genetics of the disease are not understood [18,19].
11.10 Tubulointerstitial Disease

References
1. Hebert SC: Extracellular calcium-sensing receptor: implications for 11. Scheinman SJ: X-linked hypercalciuric nephrolithiasis: clinical syn-
calcium and magnesium handling in the kidney. Kidney Int 1996, dromes and chloride channel mutations. Kidney Int 1998, 53:3–17.
50:2129–2139. 12. Danpure CJ, Purdue PE: Primay hyperoxaluria. In The Metabolic and
2. Riccardi D, Hall A, Xu J, et al.: Localization of the extracellular Ca2+ Molecular Bases of Inherited Disease, edn 6. Edited by Scriver CR, et
(polyvalent) cation-sensing receptor in kidney. Am J Physiol (Renal al. New York: McGraw-Hill; 1995:2385–2424.
Fluid Electrolyte Physiol), 1998, in press. 13. Scheinman JI: Primary hyperoxaluria. Miner Electrolyte Metab 1994,
3. Wrong OM: Nephrocalcinosis. In The Oxford Textbook of Clinical 20:340–351.
Nephrology. Edited by Davison AM, et al. London: Oxford 14. Katz A, Freese D, Danpure CJ, et al.: Success of kidney transplanta-
University Press; 1997:1378–1396. tion in oxalosis is unrelated to residual hepatic enzyme activity.
4. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of Kidney Int 1992, 42:1408–1411.
kidney stones. N Engl J Med 1992, 327:1141–1152. 15. Razis E, Arlin ZA, Ahmed T, et al.: Incidence and treatment of tumor
5. Buckalew VM: Nephrolithiasis in renal tubular acidosis. J Urol 1989, lysis syndrome in patients with acute leukemia. Acta Haematol 1994,
141:731–737. 91:171–174.
6. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome, 16. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow
hypokalaemic alkalosis with hypercalciuria, is caused by mutations in rate continuous arteriovenous hemodialysis: a new approach for the
the Na-K-2Cl cotransporter NKCC2. Nature Genet 1996, 13:183–188. treatment of acute renal failure and tumor lysis syndrome. Am J
7. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene- Kidney Dis 1994, 23:591–596.
ity of Bartter’s syndrome revealed by mutations in the K+ channel, 17. Beck LH: Requiem for gouty nephropathy. Kidney Int 1986,
ROMK. Nature Genet 1996, 14:152–156. 30:280–287.
8. Simon DB, Bindra RS, Mansfield TA, et al.: Mutations in the chloride 18. Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy
channel gene, CLCNKB, cause Bartter’s syndrome type III. Nature associated with hyperuricemia and gout. Arch Intern Med 1993,
Genet 1997, 17:171–178. 153:357–365.
9. Simon DB, Nelson-Williams C, Bia MJ, et al.: Gitelman’s variant of 19. Reiter L, Brown MA, Edmonds J: Familial hyperuricemic nephropathy.
Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by Am J Kidney Dis 1995, 25:235–241.
mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet
1996, 12:24–30.
10. Lloyd SE, Pearce SHS, Fisher SE, et al.: A common molecular basis
for three inherited kidney stone diseases. Nature 1996, 379:445–449.
Renal Tubular Disorders
Lisa M. Guay-Woodford

I
nherited renal tubular disorders involve a variety of defects in renal
tubular transport processes and their regulation. These disorders
generally are transmitted as single gene defects (Mendelian traits),
and they provide a unique resource to dissect the complex molecular
mechanisms involved in tubular solute transport. An integrated
approach using the tools of molecular genetics, molecular biology,
and physiology has been applied in the 1990s to identify defects in
transporters, channels, receptors, and enzymes involved in epithelial
transport. These investigations have added substantial insight into the
molecular mechanisms involved in renal solute transport and the
molecular pathogenesis of inherited renal tubular disorders. This
chapter focuses on the inherited renal tubular disorders, highlights
their molecular defects, and discusses models to explain their under-
lying pathogenesis.

CHAPTER

12
12.2 Tubulointerstitial Disease

Overview of Renal Tubular Disorders

FIGURE 12-1
OVERVIEW OF RENAL TUBULAR DISORDERS Inherited renal tubular disorders generally
INHERITED AS MENDELIAN TRAITS are transmitted as autosomal dominant,
autosomal recessive, X-linked dominant,
or X-linked recessive traits. For many of
Inherited disorder Transmission mode Defective protein these disorders, the identification of the
disease-susceptibility gene and its associated
Renal glucosuria ?AR, AD Sodium-glucose transporter 2 defective protein product has begun to pro-
Glucose-galactose malabsorption syndrome AR Sodium-glucose transporter 1 vide insight into the molecular pathogenesis
Acidic aminoaciduria AR Sodium-potassium–dependent of the disorder.
glutamate transporter
Cystinuria AR Apical cystine-dibasic amino acid
transporter
Lysinuric protein intolerance AR Basolateral dibasic amino acid
transporter
Hartnup disease ? ?
Blue diaper syndrome AR Kidney-specific tryptophan transporter
Neutral aminoacidurias: AR ?
Methioninuria
Iminoglycinuria
Glycinuria
Hereditary hypophosphatemic rickets AR ? Sodium-phosphate cotransporter
with hypercalciuria
X-linked hypophosphatemic rickets X-linked dominant Phosphate-regulating with endopepti-
dase features on the X chromosome
Inherited Fanconi’s syndrome isolated disorder AR and AD ?
Inherited Fanconi’s syndrome associated with AR –
inborn errors of metabolism
Carbonic anhydrase II deficiency AR Carbonic anhydrase type II
Distal renal tubular acidosis AR ?
AD Basolateral anion exchanger (AE1)
Bartter-like syndromes:
Antenatal Bartter variant AR NKCC2, ROMK, ClC-K2
Classic Bartter variant AR ClC-K2b
Gitelman’s syndrome AR NCCT
Pseudohypoparathyroidism:
Type Ia AD Guanine nucleotide–binding protein
Type Ib ?
Low-renin hypertension:
Glucocorticoid-remedial aldosteronism AD Chimeric gene (11-hydroxylase and
aldosterone synthase)
Liddle’s syndrome AD  and  subunits of the sodium channel
Apparent mineralocorticoid excess AR 11--hydroxysteroid dehydrogenase
Pseudohypoaldosteronism:
Type 1 AR and AD  and  subunits of the sodium channel
Type 2 (Gordon’s syndrome) AD ?
Nephrogenic diabetes insipidus:
X-linked X-linked recessive Arginine vasopressin 2 receptor
Autosomal AR and AD Aquaporin 2 water channel
Urolithiases:
Cystinuria AR Apical cystine–dibasic amino
acid transporter
Dent’s disease X-linked Renal chloride channel (ClC-5)
X-linked recessive nephrolithiasis X-linked Renal chloride channel (ClC-5)
X-linked recessive hypophosphatemic rickets X-linked Renal chloride channel (ClC-5)
Hereditary renal hypouricemia AR ? Urate transporter

AD—autosomal dominant; AR—autosomal recessive; ClC-K2—renal chloride channel; NCCT—thiazide-sensitive

cotransporter; NKCC2—bumetanide-sensitive cotransporter; ROMK—inwardly rectified.
 Renal Tubular Disorders 12.3

Renal Glucosuria
FIGURE 12-2
400 Physiology and pathophysiology of glucose titration curves. Under
Tmax
normal physiologic conditions, filtered glucose is almost entirely
Observed curve reabsorbed in the proximal tubule by way of two distinct sodium-
coupled glucose transport systems. In the S1 and S2 segments, bulk
Threshold
reabsorption of glucose load occurs by way of a kidney-specific
200 high-capacity transporter, the sodium-glucose transporter-2 (SGLT2)
[1]. The residual glucose is removed from the filtrate in the S3 seg-
ment by way of the high-affinity sodium-glucose transporter-1
Glucose reabsorption, mg/min 1.73m2

(SGLT1) [2]. This transporter also is present in the small intestine.

As are all membrane transport systems, glucose transporters are
saturable. The top panel shows that increasing the glucose concen-
0 tration in the tubular fluid accelerates the transport rate of the
0 200 400 600 glucose transporters until a maximal rate is achieved. The term
400 threshold applies to the point that glucose first appears in the
urine. The maximal overall rate of glucose transport by the proxi-
Normal mal tubule SGLT1 and SGLT2 is termed the Tmax. Glucose is
detected in urine either when the filtered load is increased (as in
Type B renal glucosuria diabetes mellitus) or, as shown in the bottom panel, when a defect
occurs in tubular reabsorption (as in renal glucosuria). Kinetic
200
studies have demonstrated two types of glucosuria caused by either
reduced maximal transport velocity (type A) or reduced affinity of
Type A renal glucosuria the transporter for glucose (type B) [3]. Mutations in the gene
encoding SGLT1 cause glucose-galactose malabsorption syndrome,
a severe autosomal recessive intestinal disorder associated with
0 mild renal glucosuria (type B). Defects in SGLT2 result in a com-
0 200 400 600 paratively more severe renal glucosuria (type A). However, this dis-
Filtered glucose load, mg/min 1.73m2 order is clinically benign. Among members of the basolateral glu-
cose transporter (GLUT) family, only GLUT1 and GLUT2 are rele-
vant to renal physiology [4]. Clinical disorders associated with
mutations in the genes encoding these transporters have yet to be
described. (From Morris and Ives [5]; with permission.)
12.4 Tubulointerstitial Disease

Aminoacidurias

CLASSIFICATION OF INHERITED AMINOACIDURIAS

Major categories Forms OMIM number* Amino acids involved

Acidic amino acids Acidic aminoaciduria 222730 Glutamate, aspartate
Basic amino acids and cystine Cystinuria 220100, 600918, 104614 Cystine, lysine, arginine, ornithine
Lysinuric protein intolerance 222690, 222700, 601872 Lysine, arginine, ornithine
Isolated cystinuria 238200 Cystine
Lysinuria – Lysine
Neutral amino acids Hartnup disease 234500, 260650 Alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine,
serine, threonine, tryptophan, tyrosine, valine
Blue diaper syndrome 211000 Tryptophan
Iminoglycinuria 242600 Glycine, proline, hydroxyproline
Glycinuria 138500 Glycine
Methioninuria – Methionine

*OMIM—Online Mendelian Inheritance in Man (accessible at http://www3.ncbi.nlm.nih.gov/omin/).

FIGURE 12-3
Over 95% of the filtered amino acid load is normally reabsorbed in Cystine actually is a neutral amino acid that shares a common
the proximal tubule. The term aminoaciduria is applied when more carrier with the dibasic amino acids lysine, arginine, and ornithine.
than 5% of the filtered load is detected in the urine. Aminoaciduria The transport of all four amino acids is disrupted in cystinuria. The
can occur in the context of metabolic defects, which elevate plasma rarer disorder, lysinuric protein intolerance, results from defects in
amino acid concentrations and thus increase the glomerular filtered the basolateral transport of dibasic amino acids but not cystine.
load. Aminoaciduria can be a feature of generalized proximal tubu- Increased intracelluar concentrations of lysine, arginine, and
lar dysfunction caused by toxic nephropathies or Fanconi’s syn- ornithine are associated with disturbances in the urea cycle and
drome. In addition, aminoaciduria can arise from genetic defects in consequent hyperammonemia [7].
one of the several amino acid transport systems in the proximal Disorders involving the transport of neutral amino acids include
tubule. Three distinct groups of inherited aminoacidurias are distin- Hartnup disease, blue diaper syndrome, methioninuria, iminogly-
guished based on the net charge of the target amino acids at neutral cinuria, and glycinuria. Several neutral amino acid transporters
pH: acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. Clinical data suggest that
(no charge) [5]. Hartnup disease involves a neutral amino acid transport system
Acidic aminoaciduria involves the transport of glutamate and in both the kidney and intestine, whereas blue diaper syndrome
aspartate and results from a defect in the high-affinity sodium- involves a kidney-specific tryptophan transporter [5]. Methioninuria
potassium–dependent glutamate transporter [6]. It is a clinically appears to involve a separate methionine transport system in the
benign disorder. proximal tubule. Case reports describe seizures, mental retardation,
Four syndromes caused by defects in the transport of basic and episodic hyperventilation in affected patients [8]. The patho-
amino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Iminoglycinuria
protein intolerance, isolated cystinuria, and isolated lysinuria. and glycinuria are clinically benign disorders.
 Renal Tubular Disorders 12.5

FIGURE 12-4
ROSENBERG CLASSIFICATION OF CYSTINURIAS In this autosomal recessive disorder the apical
transport of cystine and the dibasic amino
acids is defective. Differences in the urinary
Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes
and intestinal amino acid transport studies in
I homozygotes have provided the basis for
Heterozygote No abnormality defining three distinct phenotypes of cystin-
Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids
uria [9]. Genetic studies have identified
II
mutations in the gene (SCL3A1) encoding a
Heterozygote Excess excretion of cystine and basic amino acids
Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the
III dibasic amino acids in patients with type I
Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III
Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the
disease-causing gene [12]. A second cystin-
uria-susceptibility gene recently has been
From Morris and Ives [5]; with permission.
mapped to chromosome 19 [13].

FIGURE 12-5
Urinary cystine crystals. Excessive urinary excretion of cystine (250 to
1000 mg/d of cystine/g of creatinine) coupled with its poor solubility
in urine causes cystine precipitation with the formation of characteris-
tic urinary crystals and urinary tract calculi. Stone formation often
causes urinary tract obstruction and the associated problems of renal
colic, infection, and even renal failure. The treatment objective is to
reduce urinary cystine concentration or to increase its solubility.
High fluid intake (to keep the urinary cystine concentration below
the solubility threshold of 250 mg/L) and urinary alkalization are the
mainstays of therapy. For those patients refractory to conservative
management, treatment with sulfhydryl-containing drugs, such as
D-penicillamine, mercaptopropionylglycine, and even captopril can
be efficacious [14,15].
12.6 Tubulointerstitial Disease

Renal Hypophosphatemic Rickets

INHERITED FORMS OF HYPOPHOSPHATEMIC RICKETS

Disorder Vitamin D Parathyroid hormone Serum calcium Urinary calcium Treatment

X-linked hypophosphatemic rickets Low, low normal Normal, high normal Low, normal Elevated Calciferol, phosphate supplementation
Hereditary hypophosphatemic rickets Elevated Low, low normal Normal Elevated Phosphate supplementation
with hypercalciuria

Vitamin D—1,25-dihydroxy-vitamin D3

FIGURE 12-6
Several inherited disorders have been described that result in isolated Pi); and associated metabolic bone disease, eg, rickets in children or
renal phosphate wasting. These disorders include X-linked hypo- osteomalacia in adults [5]. These disorders can be distinguished on
phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the
with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the
autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical
recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are
hypophosphatemic rickets (XLRH). These inherited disorders share contrasted here. Whereas both disorders have defects in renal Pi
two common features: persistent hypophosphatemia caused by reabsorption, the renal hormonal response to hypophosphatemia is
decreased renal tubular phosphate (Pi) reabsorption (expressed as impaired in HYP but not in HHRH. Indeed, in children with
decreased ratio of plasma concentration at which maximal phosphate HHRH, phosphate supplementation alone can improve growth rates,
reabsorption occurs [TmP] to glomerular filtration rate [GFR], resolve the radiologic evidence of rickets, and correct all biochemical
[TmP/GFR], a normogram derivative of the fractional excretion of abnormalities except the reduced TmP GFR [5].

ized by growth impairment in children, metabolic bone disease, phos-

PEX (endopeptidase)
phaturia, and abnormal bioactivation of vitamin D [16]. Cell culture,
parabiosis, and transplantation experiments have demonstrated that
Phosphatonin Degradation the defect in HYP is not intrinsic to the kidney but involves a circulat-
ing humoral factor other than parathyroid hormone [16,17].
Phosphate is transported across the luminal membrane of the
proximal tubule by a sodium-phosphate cotransporter (NaPi). This
ATP transporter is regulated by multiple hormones. Among these is a puta-
Na + 3Na+ tive phosphaturic factor that has been designated phosphatonin [18].
It is postulated that phosphatonin inhibits Pi reabsorption by way of
Pi 2K+ the sodium-coupled phosphate cotransporter, and it depresses serum
1α-hydroxylase ADP 1,25-dihydroxy-vitamin D3 production by inhibiting 1--hydroxlase
activity and stimulating 24-hydroxylase activity. Positional cloning
studies in families with HYP have identified a gene, designated PEX
25-Vitamin D 1,25-Vitamin D (phosphate-regulating gene with homologies to endopeptidases on the
X chromosome), that is mutated in patients with X-linked hypophos-
phatemia [19]. PEX, a neutral endopeptidase, presumably inactivates
Lumen Interstitium phosphatonin. Defective PEX activity would lead to decreased
phosphatonin degradation, with excessive phosphaturia and deranged
vitamin D metabolism. A similar scenario associated with increased
FIGURE 12-7 phosphatonin production has been proposed as the basis for
Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP). oncogenic hypophosphatemic osteomalacia, an acquired disorder
HYP, the most common defect in renal phosphate (Pi) transport, is manifested in patients with tumors of mesenchymal origin [17].
transmitted as an X-linked dominant trait. The disorder is character- Na+—sodium ion; K+—potassium ion.
 Renal Tubular Disorders 12.7

Fanconi’s Syndrome
FIGURE 12-8
INHERITED FANCONI’S SYNDROME Fanconi’s syndrome is characterized by two components: general-
ized dysfunction of the proximal tubule, leading to impaired net
reabsorption of bicarbonate, phosphate, urate, glucose, and amino
Disorder OMIM number* acids; and vitamin D–resistant metabolic bone disease [20]. The
clinical manifestations in patients with either the hereditary or
Idiopathic 227700, 227800 acquired form of Fanconi’s syndrome include polyuria, dehydra-
Cystinosis 219800, 219900, 219750 tion, hypokalemia, acidosis, and osteomalacia (in adults) or
Hepatorenal tyrosinemia (tyrosinemia type I) 276700 impaired growth and rickets (in children). Inherited Fanconi’s syn-
Hereditary fructose intolerance 229600 drome occurs either as an idiopathic disorder or in association with
Galactosemia 230400 various inborn errors of metabolism.
Glycogen storage disease type I 232200
Wilson’s disease 277900
Oculocerebrorenal (Lowe’s) syndrome 309000
Vitamin-D–dependent rickets 264700

*OMIM—Online Mendelian Inheritance in Man (accessible at

http://www3.ncbi.nlm.nih.gov/omin/).
From Morris and Ives [5]; with permission.

with Fanconi’s syndrome cause a global disruption in sodium-

coupled transport systems rather than a disturbance in specific
Na Na+ transporters. Bergeron and coworkers [20] have proposed a patho-
ATP (2) physiologic model that involves the intracellular gradients of sodium,
(1)
3Na+
adenosine triphosphate (ATP), and adenosine diphosphate (ADP).
Na+
(4) A transepithelial sodium gradient is established in the proximal
S 2K+ tubule cell by sodium (Na) entry through Na-solute cotransport
ADP systems (Na-S) (1) and Na exit through the sodium-potassium
adenosine triphosphatase (Na-K ATPase) (2). This Na gradient
(3) ADP drives the net uptake of cotransported solutes. A small decrease in
ATP
H+ the activity of the Na-K ATPase cotransporter may translate into
a proportionally larger increment in the Na concentration close
ATP to the luminal membrane, thus decreasing the driving force that
energizes all Na-solute cotransport systems. Concomitantly,
reciprocal ATP and ADP gradients are established in the cell by
the activity of membrane bound ATPases (Na-K ATPase (2) and
hydrogen-ATPase (3)) and mitochondrial (4) ATP synthesis. A small
Lumen Interstitium reduction in mitochondrial rephosphorylation of ADP may result
in a juxtamembranous accumulation of ADP and a reciprocal
decrease in ATP, altering the ADP-ATP ratio and downregulating
FIGURE 12-9 pump activities. Therefore, a relatively small mitochondrial defect
Proposed pathogenic model for Fanconi’s syndrome. The underly- may be amplified by the effects on the intracellular sodium gradi-
ing pathogenesis of Fanconi’s syndrome has yet to be determined. ents and ADP-ATP gradients and may lead to a global inhibition
It is likely, however, that the various Mendelian diseases associated of Na-coupled transport. H+—hydrogen ion.
12.8 Tubulointerstitial Disease

Renal Tubular Acidoses

FIGURE 12-10
INHERITED RENAL TUBULAR ACIDOSES Renal tubular acidosis (RTA) is characterized by hyperchloremic
metabolic acidosis caused by abnormalities in renal acidification,
eg, decreased tubular reabsorption of bicarbonate or reduced urinary
Disorder Transmission mode excretion of ammonium (NH4+). RTA can result from a number of
disease processes involving either inherited or acquired defects. In
Isolated proximal RTA Autosomal recessive addition, RTA may develop from an isolated defect in tubular trans-
Carbonic anhydrase II deficiency Autosomal recessive port; may involve multiple tubular transport abnormalities, eg,
Isolated distal RTA Autosomal dominant Fanconi’s syndrome; or may be associated with a systemic disease
Distal RTA with sensorineural deafness Autosomal recessive process. Isolated proximal RTA (type II) is rare, and most cases of
proximal RTA occur in the context of Fanconi’s syndrome. Inherited
forms of classic distal RTA (type I) are transmitted as both autoso-
RTA—renal tubular acidosis. mal dominant and autosomal recessive traits. Inherited disorders in
which RTA is the major clinical manifestation are summarized.

and water to hydrogen ions (H+) and bicar-

bonate (HCO-3) [21]. A least two isoenzymes
Proximal tubule Distal tubule: α intercalated cell of carbonic anhydrase are expressed in the
Cl– kidney and play critical roles in urinary
Interstitium acidification. In the proximal tubule, bicar-
bonate reabsorption is accomplished by the
combined action of both luminal carbonic
Na+ HCO3– K+ Cl– HCO3
– anhydrase type IV (CA4) and cytosolic car-
bonic anhydrase type II (CA2), the luminal
sodium-hydrogen exchanger, and the baso-
–
HCO3

CO2 + H2O

CA2 lateral sodium-bicarbonate exchanger.

–

CA2
H2CO3

OH– Impaired bicarbonate reabsorption in the

CO2
proximal tubule is the underlying defect in
H+

type II or proximal RTA. In the distal

nephron, carbonic anhydrase type II is
H+ K+ expressed in the intercalated cells of the
cortical collecting duct. There carbonic
anhydrase type II plays a critical role in
CA4 catalyzing the condensation of hydroxy ions,
Na+ Lumen
Na+ + H2CO3
–
CO2 H+ K+ H+ generated by the proton-translocating H+-
H adenosine triphosphatase (H+ ATPase), with
HCO3
–
– carbon dioxide to form bicarbonate. In
HCO3
carbonic anhydrase type II deficiency, the
increase in intracellular pH impairs the
activity of the proton-translocating H-ATPase.
FIGURE 12-11 Carbonic anhydrase inhibitors (eg, acetazo-
Carbonic anhydrase II deficiency. Carbonic anhydrase II deficiency is an autosomal recessive lamide) act as weak diuretics by blocking
disorder characterized by renal tubular acidosis (RTA), with both proximal and distal compo- bicarbonate reabsorption. Cl-—chloride ion;
nents, osteopetrosis, and cerebral calcification. Carbonic anhydrase catalyzes the reversible H2CO3—carbonic acid; K+—potassium ion;
hydration of carbon dioxide (CO2), and thereby accelerates the conversion of carbon dioxide Na+—sodium ion.
 Renal Tubular Disorders 12.9

and the hydrogen ions (H+) generated from

Cl– dietary protein catabolism are secreted. The
distal nephron is composed of several distinct
segments, eg, the connecting tubule, cortical
Cortical collecting duct, and medullary collecting duct.
K+ Cl– HCO3
–
α intercalated The tubular epithelia within these segments
collecting Principal cell
duct cell are composed of two cell types: principal cells
that transport sodium, potassium, and water;
CA2
and intercalated cells that secrete hydrogen
CO2 OH– ions and bicarbonate (HCO-3) [22].
Urinary acidification in the distal nephron
K+
depends on several factors: an impermeant
luminal membrane capable of sustaining
large pH gradients; a lumen-negative poten-
Lumen – Na+ K+ tial difference in the cortical collecting duct
H+ K+ H+
that supports both hydrogen and potassium
Cl–
ion (K+) secretion; and secretion of hydrogen
ions by the intercalated cells of the cortical
and medullary collecting ducts at a rate suffi-
Outer K+
cient to regenerate the bicarbonate consumed
Cl– HCO3
–
α intercalated
medullary Principal cell by metabolic protons [22]. Abnormalities in
collecting cell
any of these processes could result in a distal
duct acidification defect.
Recent studies in families with isolated
autosomal dominant distal RTA have
K+ identified defects in the basolateral chloride-
bicarbonate exchanger, AE1 [23,24]. Defects
in various components of the H+-adenosine
triphosphatase (H+ ATPase) and subunits of
Lumen + H 2O H+ K+ H+ the H+-K+ ATPase (H+\K+ ATPase) also have
been proposed as the basis for other heredi-
tary forms of distal RTA. CA2—cytosolic
FIGURE 12-12 carbonic anhydrase type II; Cl-—chloride
Distal renal tubular acidosis (RTA). The collecting duct is the principal site of distal tubule ion; CO2—carbon dioxide; Na+—sodium
acidification, where the final 5% to 10% of the filtered bicarbonate load is reabsorbed ion; OH-—hydroxy ions.

Bartter-like Syndromes
FIGURE 12-13
CLINICAL FEATURES DISTINGUISHING BARTTER-LIKE SYNDROMES Familial hypokalemic, hypochloremic meta-
bolic alkalosis, or Bartter’s syndrome, is not
a single disorder but rather a set of closely
Classic Bartter’s Gitelman’s Antenatal Bartter’s related disorders. These Bartter-like syn-
Feature syndrome syndrome syndrome dromes share many of the same physiologic
derangements but differ with regard to the
Age at presentation Infancy, early childhood Childhood, adolescence In utero, infancy age of onset, presenting symptoms, magni-
Prematurity, polyhydramnios +/- - ++ tude of urinary potassium and prostaglandin
Delayed growth ++ - +++
excretion, and extent of urinary calcium
Delayed cognitive development +/- - +
excretion. At least three clinical phenotypes
Polyuria, polydipsia ++ + +++
have been distinguished: classic Bartter’s
Tetany Rare ++ -
syndrome, the antenatal hypercalciuric
Serum magnesium Low in 20% Low in about 100% Low-normal to normal
Urinary calcium excretion Normal to high Low Very high
variant (also called hyperprostaglandin E
Nephrocalcinosis +/- - ++ syndrome), and hypocalciuric-hypomagne-
Urine prostaglandin excretion High Normal Very high semic Gitelman’s syndrome [25].
Clinical response to +/- - Often life-saving
indomethacin

From Guay-Woodford [25]; with permission.

12.10 Tubulointerstitial Disease

FIGURE 12-14
Lumen Interstitium Transport systems involved in transepithelial sodium-chloride trans-
port in the thick ascending limb (TAL). Clinical data suggest that
Ca2+ the primary defect in the antenatal and classic Bartter syndrome
AA sensing
receptor variants involves impaired sodium chloride transport in the TAL.
Na+ 3Na+ Under normal physiologic conditions, sodium chloride is transported
K+ across the apical membrane by way of the bumetanide-sensitive
2Cl– 2K+
sodium-potassium-2chloride (Na-K-2Cl) cotransporter (NKCC2).
K+
This electroneutral transporter is driven by the low intracellular sodi-
20 HETE
Cl– um and chloride concentrations generated by the sodium-potassium
K+
Ca2+ pump and the basolateral chloride channels and potassium-chloride
Cl– cotransporter. In addition, apical potassium recycling by way of the
ATP
low-conductance potassium channel (ROMK) ensures the efficient
functioning of the Na-K-2Cl cotransporter. The activity of the ROMK
ATP cAMP V2R
Stimulatory channel, in turn, is regulated by a number of cell messengers, eg,
EP3 calcium (Ca2+) and adenosine triphosphate (ATP), as well as by the
Inhibitory
PGE2 calcium-sensing receptor (CaR), prostaglandin EP3 receptor, and vaso-
pressin receptor (V2R) by way of cAMP-dependent pathways and
arachidonic acid (AA) metabolites, eg, 20-hydroxy-eicosatetraenoic
Vte + Ca2+
Mg2+ acid (20-HETE). The positive transluminal voltage (Vte) drives the
paracellular reabsorption of calcium ions and magnesium ions
(Mg2+) [25]. cAMP—cyclic adenosine monophosphate; PGE2—
prostaglandin E2; PKA—protein kinase A.

FIGURE 12-15
Defective Defective Defective Proposed pathogenic model for the antenatal
NKCC2 ROMK CIC-Kb and classic variants of Bartter’s syndrome.
Gene defect
Genetic studies have identified mutations in
Pathophysiology
the genes encoding the bumetanide-sensitive
Defective NaCl ↓ Voltage-driven sodium-potassium-2chloride cotransporter
transport in TAL paracellular (NKCC2), luminal ATP–regulated potas-
reabsorption of
Ca2+ and Mg2+
sium channel (ROMK), and kidney-specific
Volume ↑ NaCl delivery to chloride channel (ClC-K2). These findings
contraction the distal nephron support the theory of a primary defect in
thick ascending limb (TAL) sodium-chloride
(Na-Cl) reabsorption in, at least, subsets of
↑ Renin
patients with the antenatal or classic variants
of Bartter’s syndrome. In the proposed model
↑ Angiotensin II (AII) the potential interrelationships of the com-
plex set of pathophysiologic phenomena are
Hypercalciuria illustrated. The resulting clinical manifesta-
↑ Kallikrein ↑ Aldosterone ↑ H+ and K+ Hypermagnesuria tions are highlighted in boxes [25]. Ca2+—
secretion calcium ion; H+—hydrogen ion; K+—potas-
sium ion; Mg2+—magnesium ion; PGE2—
Normotension prostaglandin E2.
Blunted vascular
response to AII and Metabolic alkalosis Impaired
norepinephrine Hypokalemia vasopressin-
stimulated
urinary
↑ PGE2 concentration

Hyposthenuria
Fever
↑ Urinary ↑ Bone
prostaglandins reabsorption
 Renal Tubular Disorders 12.11

FIGURE 12-16
Defective NCCT Proposed pathogenic model for Gitelman’s
Gene defect
syndrome. The electrolyte disturbances
Pathophysiologic model
evident in Gitelman’s syndrome also are
DefectiveHypercalciuria
NaCl transport in DCT observed with administration of thiazide
? diuretics, which inhibit the sodium-chloride
(Na-Cl) cotransporter in the distal convoluted
tubule (DCT). In families with Gitelman’s
Volume ↑ NaCl delivery to Cl– efflux mediates ↓ Na+-dependent
contraction Mg2+ reabsorption syndrome, genetic studies have identified
the distal nephron cell hyperpolarization defects in the gene encoding the thiazide-
in DCT
sensitive cotransporter (NCCT) protein.
↑ Renin
The proposed pathogenic model is predicated
on loss of function of the NCCT protein
↑ Angiotensin II (AII) and, thus, most closely applies to those
patients who inherit Gitelman’s syndrome
↑ Aldosterone ↑ H+ and K+ secretion ↑ Ca2+ reabsorption as an autosomal recessive trait. Given that
the physiologic features of this syndrome
Metabolic alkalosis are virtually indistinguishable in familial
Hypocalciuria Hypermagnesuria and sporadic cases, it may be reasonable
hypokalemia
to propose the same pathogenesis for all
patients with Gitelman’s syndrome. How-
ever, it is important to caution that evidence
for NCCT mutations in sporadic cases has
not yet been established [25]. Ca2+—calci-
um ion; Cl-—chloride ion; H+—hydrogen ion;
K+—potassium ion; Mg2+—magnesium ion;
Na+—sodium ion.

Pseudohypoparathyroidism

CLINICAL SUBTYPES OF PSEUDOHYPOPARATHYROIDISM

Disorder Pathophysiology Skeletal anomalies Associated endocrinopathies

Pseudohypoparathyroidism type Ia Defect in guanine nucleotide—binding protein Yes Yes
Pseudohypoparathyroidism type Ib Resistance to parathyroid hormone, normal guanine No No
nucleotide—binding protein activity
? Defect in parathyroid hormone receptor

FIGURE 12-17
Pseudohypoparathyroidism applies to a heterogeneous group of hered- Pseudohypoparathyroidism type Ia (Albright’s hereditary osteo-
itary disorders whose common feature is resistance to parathyroid dystrophy) is associated with a myriad of physical abnormalities
hormone (PTH). Affected patients are hypocalcemic and hyperphos- and resistance to multiple adenylate cyclase–coupled hormones,
phatemic, despite elevated plasma PTH levels. Hypocalcemia and most notably thyrotropin and gonadotropin [27]. The molecular
hyperphophatemia result from the combined effects of defective PTH- defect in a guanine nucleotide–binding protein (Gs) blocks the
mediated calcium reabsorption in the distal convoluted tubule and coupling of PTH and other hormone receptors to adenylate cyclase.
reduced formation of 1,25-dihydroxy-vitamin D3. The latter leads to The molecular defect has not been identified in type Ib, although
defects in renal phosphate excretion, calcium mobilization from bone, specific resistance to PTH suggests a defect in the PTH receptor.
and gastrointestinal calcium reabsorption. Differences in clinical fea- Oral supplementation with 1,25 dihydroxy-vitamin D3 and, if
tures and urinary cyclic adenosine monophosphate response to infused necessary, oral calcium, is used to correct the hypocalcemia and
PTH provide the basis for distinguishing three distinct subtypes of minimize PTH-induced bone disease [26]. Pseudohypoparathroid-
pseudohypoparathyroidism (type Ia, type Ib, and type II) [26]. ism type II may be an acquired disease.
12.12 Tubulointerstitial Disease

Disorders of Aldosterone-Regulated Transport

and the basolateral sodium-potassium adenosine triphosphatase
(A) GRA chimeric gene (Na-K ATPase). Sodium moves from the lumen into the cell and
down its electrochemical gradient, thus generating a lumen-negative
Aldosterone synthetase 11-OHase transepithelial voltage that drives potassium secretion from the
principal cells and hydrogen secretion from the intercalated cells.
Unequal crossover The type I mineralocorticoid receptor (MR) is nonspecific and can
bind both aldosterone and cortisol, but not cortisone. The selective
receptor specificity for aldosterone is mediated by the kidney isoform
of the enzyme, 11--hydroxysteroid dehydrogenase, which oxidizes
Aldosterone synthetase Chimeric gene 11-OHase intracellular cortisol to its metabolite cortisone.
Three hypertensive syndromes, glucocorticoid-remedial aldostero-
(B) nism (GRA), Liddle’s syndrome, and apparent mineralocorticoid
Amiloride-sensitive excess (AME), share a common clinical phenotype that is charac-
Na+ channel terized by normal physical examinations, hypokalemia, and very
Na+ Na+ low plasma renin activity. The molecular defect in GRA derives
from an unequal crossover event between two adjacent genes
K+
encoding 11--hydroxylase and aldosterone synthase (A). The
resulting chimeric gene duplication fuses the regulatory elements
Aldosterone MR of 11--hydroxylase and the coding sequence of aldosterone synthase.
(A) Consequently, aldosterone is ectopically synthesized in the adrenal
zona fasciculata and its synthesis regulated by adrenocorticotropic
hormone rather than its physiologically normal secretagogue, angio-
K+ channel Cortisol Degradation tensin II [28]. Activating mutations in the  and  regulatory sub-
(A) GRA (C) units of the epithelial sodium channel (B) are responsible for
(B) Liddle's Liddle’s syndrome [29]. Deficiency of the kidney type 2 isozyme
(C) AME of 11--hydroxysteroid dehydrogenase (C) can render type I MR
responsive to cortisol and produce the syndrome of apparent mineral-
ocorticoid excess [30]. Inhibitors of this enzyme (eg, licorice) also can
FIGURE 12-18 produce an acquired form of apparent mineralocorticoid excess.
Aldosterone-regulated transport in the cortical collecting duct and Medical management of these disorders focuses on dietary sodium
defects causing low-renin hypertension. The mineralocorticoid aldos- restriction, blocking the sodium channel with the potassium-sparing
terone regulates electrolyte excretion and intravascular volume by diuretics triamterene and amiloride, downregulating the ectopic
way of its action in the principal cells of the cortical collecting duct. aldosterone synthesis with glucocorticoids (GRA), or blocking
The binding of aldosterone to its nuclear receptor (MR) leads directly the MR using the competitive antagonist spironolactone (GRA
or indirectly to increased activity of the apical sodium (Na) channel and AME).
 Renal Tubular Disorders 12.13

FIGURE 12-19
Low-renin hypertension Algorithm for evaluating patients with low-
renin hypertension. Glucocorticoid-remedial
aldosteronism (GRA), Liddle’s syndrome,
and apparent mineralocorticoid excess (AME)
+ Family history – Family history can be distinguished from one another by
characteristic urinary steroid profiles [31].
K+—potassium ion; PE—physical examina-
tion; TH18oxoF/THAD—ratio of urinary
Abnormal PE Normal PE 18-oxotetrahydrocortisol (TH18oxoF) to
Serum K+ urinary tetrahydroaldosterone (normal:
0–0.4; GRA patients: >1); THF + allo-
THF/THE—ratio of the combined urinary
Virilization Hypogonadism
tetrahydrocortisol and allotetrahydrocortisol
Low
High-normal Low-normal to urinary tetrahydrocortisone (normal:
serum K+
11β-hydroxylase 17α-hydroxylase <1.3; AME patients: 5–10-fold higher).
Gordon's deficiency deficiency
syndrome
TH180x0F Negligible urinary THF + alloTHF
Urinary THAD aldosterone THE
steroid profile:

Diagnosis: GRA Liddle's syndrome AME

and metabolic acidosis. The diagnosis is sup-

CLINICAL SUBTYPES OF PSEUDOHYPOALDOSTERONISM ported by elevated plasma renin and plasma
aldosterone concentrations. Life-saving inter-
ventions include aggressive sodium chloride
supplementation and treatment with ion-bind-
Disorder Clinical features Treatment
ing resins or dialysis to reduce the hyper-
Pseudohypoaldosteronism type I kalemia. This autosomal recessive form of
Autosomal recessive Dehydration, severe neonatal salt wasting, Sodium chloride PHA1 results from inactivating mutations in
hyperkalemia, metabolic acidosis supplementation the  or  subunits of the epithelial sodium
Elevated plasma renin activity Ion-binding resin; dialysis channel [32]. A milder form of PHA1 with
Severity of electrolyte abnormalities may autosomal dominant inheritance also has
diminish after infancy been described; however, the molecular defect
Autosomal dominant Mild salt wasting remains unexplained [33]. Adolescents or
Pseudohypoaldosteronism type II Hypertension, hyperkalemia, mild hyper- Thiazide diuretics adults with hyperkalemic, hyperchloremic
(Gordon’s syndrome) chloremic metabolic acidosis metabolic acidosis, low-normal renin and
Undetectable plasma renin activity aldosterone levels, and hypertension have
been recently described and classified as
having pseudohypoaldosteronism type II
(PHA2) or Gordon’s syndrome [34]. Pheno-
FIGURE 12-20 typically, this disorder is the mirror image of
Mineralocorticoid resistance with hyperkalemia (pseudohypoaldosteronism) includes at Gitelman’s syndrome; however, the thiazide-
least three clinical subtypes, two of which are hereditary disorders. Pseudohypoaldo- sensitive cotransporter (NCCT) has been
steronism type I (PHA1) is characterized by severe neonatal salt wasting, hyperkalemia, excluded as a candidate gene [35].
12.14 Tubulointerstitial Disease

Nephrogenic Diabetes Insipidus

FIGURE 12-21
The relationship between urine osmolality and plasma arginine
Primary polydipsia vasopressin (AVP). Nephrogenic diabetes insipidus (NDI) is charac-
1200 Pituitary diabetes insipidus
terized by renal tubular unresponsiveness to the antidiuretic hor-
mone AVP or its antidiuretic analogue 1-desamino-8-D-arginine
1000 vasopressin (DDAVP). In both the congenital and acquired forms
of this disorder the clinical picture is dominated by polyuria, poly-
Urine osmolality, mOsm/kg

800 dipsia, and hyposthenuria despite often elevated AVP levels [17].
(From Robertson et al. [36]; with permission.)
600

400

200 NDI

0 1 2 3 4 5 10 15
Plasma AVP, pg/mL

volume occurs. As shown, the binding of

Physiologic Pathophysiologic
arginine vasopressin (AVP) to the vaso-
pressin V2 receptor (V2R) stimulates a
AQP3 AQP2 X-linked AQP3 AQP2 series of cyclic adenosine monophosphate–
–ADH
H 2O NDI H 2O (cAMP) mediated events that results in the
fusion of cytoplasmic vesicles carrying
V2R V2R water channel proteins (aquaporin-2
[AQP2]), with the apical membrane,
thereby increasing the water permeability
AQP4 AQP4
of this membrane. Water exits the cell
through the basolateral water channels
AQP3 and AQP4. In the absence of AVP,
water channels are retrieved into cytoplasmic
AQP2 Autosomal AQP2 vesicles and the water permeability of the
recessive apical membrane returns to its baseline
+ADH AQP3 AQP3
NDI
H 2O low rate [37].
ATP ATP
Genetic studies have identified mutations
V2R H 2O V2R
in two proteins involved in this water trans-
cAMP cAMP port process, the V2 receptor and AQP2
water channels. Most patients (>90%)
AQP4 AQP4
inherit NDI as an X-linked recessive trait.
In these patients, defects in the V2 receptor
Interstitium Lumen Interstitium Lumen have been identified. In the remaining
patients, the disease is transmitted as either
an autosomal recessive or autosomal domi-
FIGURE 12-22 nant trait involving mutations in the AQP2
Pathogenic model for nephrogenic diabetes insipidus (NDI). The principle cell of the inner gene [38,39]. ADH— antidiuretic hormone;
medullary collecting duct is the site where fine tuning of the final urinary composition and ATP—adenosine triphosphate.
 Renal Tubular Disorders 12.15

Urolithiases
amino acid transport in the proximal tubule.
Cystinuria is the leading single gene cause of
INHERITED CAUSES OF UROLITHIASES
inheritable urolithiasis in both children and
adults [41,42]. Three Mendelian disorders,
Dent’s disease, X-linked recessive nephrolithi-
Disorder Stone characteristics Treatment asis, and X-linked recessive hypophospha-
Cystinuria Cystine High fluid intake, urinary alkalization temic rickets cause hypercalciuric urolithiasis.
Sulfhydryl-containing drugs These disorders involve a functional loss of
Dent’s disease Calcium-containing High fluid intake, urinary alkalization the renal chloride channel ClC-5 [43]. The
X-linked recessive nephrolithiasis Calcium-containing High fluid intake, urinary alkalization common molecular basis for these three
X-linked recessive hypophos- Calcium-containing High fluid intake, urinary alkalization inherited kidney stone diseases has led to
phatemic rickets speculation that ClC-5 also may be involved
Hereditary renal hypouricemia Uric acid, calcium oxalate High fluid intake, urinary alkalization in other renal tubular disorders associated
Allopurinol with kidney stones. Hereditary renal hypour-
Hypoxanthine-guanine phospho- Uric acid High fluid intake, urinary alkalization icemia is an inborn error of renal tubular
ribosyltransferase deficiency Allopurinol transport that appears to involve urate reab-
Xanthinuria Xanthine High fluid intake, dietary purine restriction sorption in the proximal tubule [16].
Primary hyperoxaluria Calcium oxalate High fluid intake, dietary oxalate restriction In addition to renal transport deficiencies,
Magnesium oxide, inorganic phosphates defects in metabolic enzymes also can cause
urolithiases. Inherited defects in the purine
salvage enzymes hypoxanthine-guanine phos-
phoribosyltransferase (HPRT) and adenine
FIGURE 12-23 phosphoribosyltransferase (APRT) or in the
Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women catabolic enzyme xanthine dehydrogenase
in North America and Europe [40]. Renal stone formation is most commonly associated with (XDH) all can lead to stone formation [44].
hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial Finally, defective enzymes in the oxalate
predisposition. In comparison, a group of relatively rare disorders exists, each of which is metabolic pathway result in hyperoxaluria,
transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The oxalate stone formation, and consequent
most common of these disorders is cystinuria, which involves defective cystine and dibasic loss of renal function [45].

Acknowledgment
The author thanks Dr. David G. Warnock for critically reviewing this manuscript.

References
1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with 7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperam-
similarity to the sodium/glucose cotransporter. Am J Physiol 1992, monemia in congenital lysinuria. J Pediatr 1979, 94:255.
263:F459–F465. 8. Smith A, Strang L: An inborn error of metabolism with the urinary
2. Hediger M, Coady M, Ikeda T, Wright E: Expression cloning and excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis
cDNA sequencing of the Na/glucose co-transporter. Nature 1987, Child 1958, 33:109.
330:379–381. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemi-
3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption cal evidence for three genetically distinct diseases. J Clin Invest 1966,
and the genetics of renal glycosuria. J Theor Biol 1966, 11:10–21. 45:365–371.
4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 10. Pras E, Arber N, Aksentijevich I, et al.: Localization of a gene causing
219:713–725. cystinuria to chromosome 2p. Nature Genet 1994, 6:415–419.
5. Morris JR, Ives HE: Inherited disorders of the renal tubule. In The 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by
Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saunders, mutations in rBAT, a gene involved in the transport of cystine. Nature
1996:1764–1827. Genet 1994, 6:420–425.
6. Kanai Y, Hediger M: Primary structure and functional characteriza- 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in
tion of a high affinity glutamate transporter. Nature 1992, cystinuria: the SLC3A1 gene is linked to type I but not to type III
360:467–471. cystinuria. Proc Am Acad Sci USA 1995, 92:9667–9671.
12.16 Tubulointerstitial Disease

13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of 30. White P, Mune T, Rogerson F, et al.: 11--hydroxysteroid dehydroge-
cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping nase and its role in the syndrome of apparent mineralocorticoid
a new locus on 19q. Am J Med Genet 1997, 60:617–624. excess. Pediatr Res 1997, 41:25–29.
14. Stephens AD: Cystinuria and its treatment: 25 years’ experience at St. 31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma
Bartholomew’s Hospital. J Inherited Metab Dis 1989, 12:197–209. renin activity as a critical marker in pediatric hypertension. Pediatr
15. Perazella M, Buller G: Successful treatment of cystinuria with captopril. Nephrol 1997, 11:343–346.
Am J Kidney Dis 1993, 21:504–507. 32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits of
16. Grieff M: New insights into X-linked hypophosphatemia. Curr Opin the epithelial sodium channel cause salt wasting with hyperkalemic
Nephrol Hypertens 1997, 6:15–19. acidosis, pseudohypoaldosteronism type 1. Nature Genet 1996,
17. Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev 12:248–253.
Med 1974, 25:315. 33. Kuhle U: Pseudohypoaldosteronism: mutation found, problem solved?
18. Econs M, Drezner M: Tumor-induced osteomalacia: unveiling a new Mol Cell Endocrinol 1997, 133:77–80.
hormone. N Engl J Med 1994, 330:1679–1681. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal
19. The HYP Consortium: A gene (PEX) with homologies to endopepti- glomerular filtration rate. Hypertension 1986, 8:93–102.
dases is mutated in patients with X-linked hypophosphatemic rickets. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial
Nature Genet 1995, 11:130–136. hyperkalaemia and hypertension, pseudohypoaldosteronism type II,
20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. In to chromosomes 1q31-42 and 17p11-q2. Nature Genet 1997,
The Metabolic and Molecular Bases of Inherited Diseases. Edited by 16:202–205.
Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 36. Robertson GL, et al: Development and clinical application of a new
1995:3691–3704. method for the radioimmunoassay of arginine vasopressin in human
21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteo- plasma. J Clin Invest 1973, 52:2340–2352.
petrosis with renal tubular acidosis and cerebral calcification. In The 37. Bichet D, Osche A, Rosenthal W: Congenital nephrogenic diabetes
Metabolic and Molecular Bases of Inherited Diseases. Edited by insipidus. JASN 1997, 12:1951–1958.
Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 38. van Lieburg A, Verdijk M, Knoers N, et al.: Patients with autosomal
1965:3581–3602. recessive nephrogenic diabetes insipidus homozygous for mutations
22. Bastani B, Gluck S: New insights into the pathogenesis of distal renal in the aquaporin 2 water channel gene. Am J Hum Genet 1994,
tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409. 55:648–652.
23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis 39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal dominant and
is associated with mutations in the red cell anion exchanger (band 3, autosomal recessive nephrogenic diabetes insipidus: novel mutations
AE1) gene. J Clin Invest 1997, 100:1693–1707. in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A.
24. Jarolim P, Shayakul C, Prabakaran D, et al.: Autosomal dominant dis- 40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney
tal renal tubular acidosis is associated in three families with heterozy- stones. N Engl J Med 1992, 327:1141–1152.
gosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3
41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of
exchanger. J Biol Chem, 1998, 273:6380–6388.
Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle
25. Guay-Woodford L: Bartter syndrome: unraveling the pathophysiologic D. York: McGraw-Hill; 1995:3581–3602.
enigma. Am J Med, 1998, 105:151–161.
42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhood.
26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic Pediatr Clin North Am 1987, 34:683–710.
and Molecular Bases of Inherited Diseases. Edited by Scriver CH,
Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 43. Lloyd S, Pearce S, Fisher S, et al.: A common molecular basis for three
1995:3073–3085. inherited kidney stone diseases. Nature 1996, 379:445–449.
27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular 44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine metab-
aspects. Semin Nephrol 1989, 9:168–178. olism in paediatric nephrology. Pediatr Nephrol 1993, 7:105–118.
28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11--hydroxy- 45. Danpure C, Purdue P: Primary Hyperoxaluria. In The Metabolic and
lase aldosterone synthase gene causes glucocorticoid-remediable aldos- Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet
teronism and human hypertension. Nature 1992, 355:262–265. AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:2385–2424.
29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’s syndrome:
heritable human hypertension caused by mutations in the  subunit
of the epithelial sodium channel. Cell 1994, 79:407–414.