Lecture notes on Renal

Physiology for MBBS

Dr.Abubakkar Siddique

Version:03

Compiled by Dr.Abubakkar Siddique

Renal Functions and Anatomy

Urinary System
Homeostasis
Body systems
maintain
homeostasis

Homeostasis is
essential for
survival of cells

Cells make up
body systems

Cells

Summary of Kidney Functions

They contribute to homeostasis.
They control electrolyte and water balance of the ECF, plus
urinary output.
If the ECF has an excess of water or electrolytes, the kidneys
eliminate the excess. If there is a deficiency of these substances,
the kidneys can reduce the loss of these from the body.
Other functions of the kidneys include:

maintaining the proper osmolarity of body fluids

maintaining proper plasma volume

helping to maintain proper acid-base balance

excreting wastes of body metabolism

excreting many foreign compounds

producing erythropoietin and renin

converting vitamin D to an active form

Kidney is bean shaped structure

Measures 12 X6 X3 cm
Weight 120 170 gram in adult male and 115 155
gram in adult female
Kidney is contained in fibrous capsule
Kidney lies retroperitoneal, in the paravertebral
gutter, on the posterior abdominal wall
It extends from 12th thoracic vertebra to 3rd lumbar
vertebra

The Rt Kidney is slightly lower

Kidney Parenchyma 1.5 2 cm

Outer cortex 1cm (Contain Glomerular and convoluted
tubules)
Inner medulla
Formed of 8 18 pyramids which are conical shaped
with its base towards cortico-medullary junction
with its apex projects in minor calyces as papillae
On the tip of each papilla are 10 to 25 small openings
that represent the distal ends of the collecting ducts
(of Bellini).
The cortex may extend between pyramids forming
columns of Bertini
Medullary rays are striated elements which radiates
from the pyramids (Strait segments of nephron)

Nephron:
functional
unitofthe
kidney

The Nephron
Nephron is the functional unit of the kidney
Each kidney contains nearly million Nephrons
The first part of the Nephron is the
Glomerulus (renal corpuscle) which lies mainly in the
renal cortex, followed by
proximal convoluted tubule which also lies mainly in
the renal cortex.
This is followed by a loop of Henle which is partly in
the cortex and partly extends deep into the medulla
This is followed by the distal convoluted tubule which
lies in the renal cortex.
Collecting duct which lies partly in the cortex and
partly in the medulla.

Renal Blood Flow

Blood supply of the kidney

Renal arteries arise from the Aorta opposite the
intervertebral disc Lumbar 1 2
The renal artery enters the hillar region and usually
divides to form an anterior and a posterior branch,
then they divide to form interlobar arteries, Then
arcuate arteries, Then interlobular arteries which
penetrate the cortex and form afferent arteriole
Afferent arteriole invaginate the Bowman's capsule
and form Glomerular tuft which is modified
capillaries structure through which GFR is formed

Cortical
and
Juxtamed
ullary
Nephron
Segments

From the glomerulus's efferent arteriole emerges

Efferent arteriole of the outer and middle cortical
glomeruli get down between tubules where they
divide into capillary network called peritubular
capillaries
Efferent arteriole of the inner cortical glomeruli
penetrate deeply into Medullary pyramids forming
vasa recta sharing in the counter current exchange
system
Renal venous system and lymphatic follow same
patterns of arteries
Kidney receive sympathetic and parasympathetic
supply from Celiac plexus

Blood Supply to the Kidneys

Figure 26.5a, b

Blood Supply to the Kidneys

Figure 26.5c, d

Renal blood flow (RBF) is huge relative to

the mass of the kidneysabout 1 L/min,
or 20% of the resting cardiac output.
Considering that the volume of each
kidney is less than 150 cm3, this means
that each kidney is perfused with over
three times its total volume every minute.
All of this blood is delivered to the cortex.
A small fraction of the cortical blood flow is
then directed to the medulla.

The significance of the quantitative differences

between cortical and medullary blood flow is
that the high blood flow in the cortical
peritubular capillaries maintains the interstitial
environment of the cortical renal tubules very
close in composition to that of blood plasma
throughout the body.
In contrast, the low blood flow in the medulla
permits an interstitial environment that is quite
different from blood plasma.

FLOW, RESISTANCE, AND BLOOD

PRESSURE IN THE KIDNEYS
The basic equation for blood flow through any organ
is as follows:
Q = P/ R
where
Q --is organ blood flow,
P--the mean pressure in the artery
supplying the organ minus mean pressure
in the vein draining that organ
R-- the total vascular resistance in that organ

The high RBF is accounted for by low total

renal vascular resistance.
The resistance is low because there are
so many pathways in parallel, that is, so
many glomeruli and their associated
vessels
The resistances of the afferent and
efferent arterioles are about equal in most
circumstances and account for most of the
total renal vascular resistance.
Arteriolar resistances are variable and
are the sites of regulation

Arteriolar resistances are variable and are

the sites of regulation.
A change in the afferent arteriole or
efferent arteriole resistance produces the
same effect on RBF because these
vessels are in series.
When the two resistances both change in
the same direction , their effects on RBF
are additive.
When they change in different directions
one resistance increasing and the other
decreasingthe changes offset each other

The glomerular filtrate contains most inorganic ions

and low-molecular-weight organic solutes in virtually
the same concentrations as in the plasma. It also
contains small plasma peptides and a very limited
amount of albumin .
Filtered fluid must pass through a three-layered
glomerular filtration barrier.
The first layer, the endothelial cells of the capillaries,
is perforated by many large fenestrae (windows),
like a slice of Swiss cheese, which occupy about 10%
of the endothelial surface area. They are freely
permeable to everything in the blood except cells and
platelets.
The middle layer, the capillary basement membrane,
is a gel-like acellular meshwork of glycoproteins and
proteoglycans, with a structure like a kitchen sponge.

The third layer consists of epithelial cells (podocytes) that

surround the capillaries and rest on the basement membrane.
The podocytes have an unusual octopus like structure.
Small fingers, called pedicels (or foot processes), extend from
each arm of the podocyte and are embedded in the basement
membrane .
Pedicels from a given podocyte interdigitate with the pedicels
from adjacent podocytes. Spaces between adjacent pedicels
constitute the path through which the filtrate, once it has passed
through the endothelial cells and basement membrane, travels
to enter Bowmans space.
The foot processes are coated by a thick layer of extracellular
material, which partially occludes the slits. Extremely thin
processes called slit diaphragms bridge the slits between the
pedicels.
Slit diaphragms are widened versions of the tight junctions
and adhering junctions that link all contiguous epithelial cells
together and are like miniature ladders. The pedicels form the
sides of the ladder, and the slit diaphragms are the rungs.

BASIC RENAL PROCESSES

Five Processes of Urinary System

1.
2.
3.
4.
5.

Filtration,
Reabsorption,
Secretion,
Excretion
Micturition

Related by equation:
E=F-R+S
180 L / day filtered, >99% reabsorbed,
1.5 L/day excreted

Three basic processes of the nephrons are glomerular

filtration, tubular reabsorption, and tubular secretion.
Glomerular filtration is the first process. A protein-free plasma is
filtered from the Glomerulus into the Bowmans capsule. Blood
cells are not normally filtered. Normally about 20 % of the plasma
is filtered. Glomerular filtrate is produced at the rate of 125 ml per
minute (180 liters per day).
By tubular reabsorption, filtered substances move from the inside
of the tubular part of the Nephron into the blood of the peritubular
capillaries. The reabsorption rates of most substances are very
high.
Tubular secretion is a selective process by which substances from
the peritubular capillaries enter the lumen of the Nephron tubule.
The 80% of the plasma not filtered passes into the efferent arteriole
and through the peritubular capillaries.
Urine excretion results from these three processes.

Blood
pathway

Filtrate
pathway

Glomerular
capillaries

Glomerular
filtration

Bowmans
capsule

Efferent
arteriole

Venous
blood

Peritubular
capillaries

Tubular
reabsorption

Tubular
secretion

Tubule (from proximal

tubule to collecting duct)

Urine

1) Filtration
= Movement of fluid from blood to lumen of Nephron.
Once in lumen consider it outside body

Composition of filtrate?

Glomerular Filtration
Fluid filtered from the Glomerulus into
Bowmans capsule passes through 3
layers:

the Glomerular capillary wall

the basement membrane
Collagen
Glycoproteins- negative charge

the inner layer of Bowmans capsule

Podocytes
Filtration slits

What Drives Filtration?

How does fluid move from the plasma
across the Glomerular membrane into
Bowmans capsule?
No active transport mechanisms
No local energy expenditure
Simple passive physical forces accomplish
filtration
- Filtration occurs throughout the length of
the capillaries

Forces involved in Filtration

Glomerular capillary blood pressure
(favors filtration)
Plasma-colloid osmotic pressure (opposes
filtration)
Bowmans capsule hydrostatic pressure
(opposes filtration)

Glomerular Capillary Blood

Pressure
Fluid pressure exerted by the blood within the
Glomerular capillaries
Glomerular capillary pressure is significantly
higher than other capillary blood pressures

This is due to the larger diameter of the afferent

arteriole compared with the efferent arteriole

Blood pressure does not fall along the length of

this capillary, which pushes fluid out of the
Glomerulus into Bowmans capsule

(pressure build-up in glom. Cap. ~ 55mmHg)

Pressure opposing filtration

Plasma-colloid oncotic pressure- caused
by the unequal distribution of plasma
proteins across the glomerular membrane

(~30mmHg)

Bowmans capsule hydrostatic pressurethe pressure exerted by the fluid in this

initial part of the tubule- tends to push fluid
out of Bowmans capsule

(~15mmHg)

Net Filtration Pressure

Force favoring filtration (glomerular
capillary blood pressure of 55 mmHg)
minus forces opposing filtration (plasma
colloid osmotic pressure of 30 mmHg &
Bowmans capsule pressure of 15 mmHg)
=55 (30 + 15) = 10 mmHg

GFR = Glomerular Filtration Rate

Describes filtration efficiency: Amount of fluid filtered per
unit of time
Average GFR ~ 180 L/day!
Filtration Coefficient is influenced by
Net filtration pressure
Available surface area of Glomerular capillaries
GFR is closely regulated to remain constant
over range of BP (80 - 180 mm Hg)

Glomerular Filtration Rate

Depends on

The net filtration pressure

How much glomerular surface area is available for
penetration
How permeable the glomerular membrane is

GFR = Kf x net filtration pressure

Where (Kf)= filtration coefficient (a product of
the above two glomerular properties)
- Roughly 125 ml/min in males

Filtration Fraction
The Percentage of Renal Plasma Flow
that is Filtered
FF = GFR/RPF
Roughly 20%

Regulation of GFR
Several mechanisms provide
close control of GFR;

Filtration Pressure (BP)

Hydrostatic, colloid
Resistance in afferent
vs. efferent arterioles

Tubuloglomerular feedback
JG Apparatus
Hormones and ANS
Angiotensin II
(vasoconstrictor)
Prostaglandins
(vasodilator)

Mechanisms to Regulate GFR

Autoregulation (prevent spontaneous
changes in GFR)

Involves Myogenic and Tubuloglomerular

feedback mechanisms

Extrinsic sympathetic control (long-term

regulation of arterial BP)

Mediated by the sympathetic nervous system

Can override autoregulatory mechanisms

Auto regulation
1-Myogenic mechanism
Response to changes in pressure within
the nephrons vascular component
Arterioles contract inherently in response
to the stretch accompanying pressure.
Vessel automatically constricts, which
helps limit blood flow into glomerulus
despite increased systemic pressure
Opposite reaction occurs when smooth
muscles sense a drop in pressure

Importance of Autoregulation of
GFR
Myogenic and Tubuloglomerular feedback
mechanisms work in tandem to auto regulate
GFR within a MAP range of 80-180 mmHg
Autoregulation greatly blunts the direct effect
that changes in arterial pressure might
otherwise have on GFR and preserves water
and solute homeostasis and allows waste
excretion to carry on as usual

Clinical Importance of
GFR and Clearance
GFR is indicator for overall kidney function
Clearance non-invasive way to measure GFR

Inulin (research use)

Neither secreted nor reabsorbed

Creatinine (clinically useful)

If a substance is filtered and reabsorbed but not

secreted clearance rate < GFR
If a substance is filtered and secreted but not
reabsorbed clearance rate > GFR

4) Excretion = Urine Output

Excretion of excess ions, H2O, toxins, foreign
molecules nitrogenous waste (NH4+ , urea)
Depends on Filtration, Reabsorption, Secretion

E=FR+S

Direct measurement of F, R, S impossible

infer from comparison of blood & urinalysis

For any substance: (Renal) Clearance =

plasma volume completely cleared of that
substance per minute

Typically expressed as ml/min

Autoregulation
2-Tubuloglomerular feedback
Juxtaglomerular apparatus

the combination of tubular and vascular cells where

the tubule passes through the angle formed by the
afferent and efferent arterioles as they join the
Glomerulus

Smooth muscle cells within the afferent arteriole

form granular cells
Specialized tubular cells in this region known as
macula-densa sense changes in salt level of
tubular fluid

Tubuloglomerular Feedback
As GFR , flow through DCT

Macula densa cells:

release
paracrines(ATP)
juxtaglomerular
cells(Granular cells)

(smooth muscle fibers from

afferent arteriole): contract
Thus GFR

Extrinsic Sympathetic Control

GFR can be changed purposefully, even when MAP
is within the autoregulatory range
GFR is reduced by the baroreceptor reflex response
to a fall in blood pressure (the SNS causes
vasoconstriction in most arterioles as a
compensatory mechanism to TPR)
Afferent arterioles innervated with sympathetic
vasoconstrictor fibers much more than are the
efferent aa.
GFR causes urine output, conserving some water
and salt, helping to restore plasma volume to normal

Baroreceptor
Reflex
Influence on the
GFR in
Long-term
Regulation of
Arterial Blood
Pressure

2) Tubular Reabsorption (99% of filtrate)

Active
Na+ transport

(Recall Antiports and

Symports)
Passive (think
concentration and
osmotic gradients)

Paracellular eg.urea
Transcytosis
Proteins

ATPase on Basolateral membrane of PCT

GLUCOSE Handling in PCT

Under most circumstances, it would be
deleterious to lose glucose in the urine,
particularly in conditions of prolonged fasting.
Thus, the kidneys normally reabsorb all of the
glucose that is filtered.

This involves taking up glucose from the

tubular lumen along with sodium via a
sodium-dependent glucose symporter
(SGLUT) across the apical membrane of
proximal convoluted tubule epithelial cells
Followed by its exit across the basolateral
membrane into the interstitium via a glucose
transporter (GLUT), a uniporter.

Saturation of Renal Transport

Saturation = Maximum rate of transport (tm)
Same 3 characteristics as
discussed in mediated
transport
Transport maximum
determined by

Saturation Renal
Threshold

Specificity
Competition

PROTEINS & PEPTIDES

in PCT
Although the glomerular filtrate is protein free, it
is not truly free of all protein; it just has a total
protein content much lower than plasma.
Peptides and smaller proteins (e.g., angiotensin,
insulin)
Normally all of these proteins and peptides are
reabsorbed completely, although not in the
conventional way.
They are enzymatically degraded into their
constituent amino acids, which are then returned
to the blood.

For the larger proteins, the initial step in recovery is

endocytosis at the apical membrane. This energyrequiring process is triggered by the binding of filtered
protein molecules to specific receptors on the apical
membrane.
The rate of endocytosis is increased in proportion to
the concentration of protein in the glomerular filtrate
until a maximal rate of vesicle formation, and thus the
Tm for protein uptake, is reached.
The pinched-off intracellular vesicles resulting from
endocytosis merge with lysosomes, whose enzymes
degrade the protein to low-molecular-weight
fragments, mainly individual amino acids.
These end products then exit the cells across the
basolateral membrane into the interstitial fluid, from
which they gain entry to the peritubular capillaries.

Very small peptides, such as angiotensin II,

are catabolized into amino acids or dipeptides and tri-peptides within the proximal
tubular lumen by peptidases located on the
apical surface of the plasma membrane.
These products are then reabsorbed by the
same transporters that normally reabsorb
filtered amino acids.

Medullary concentration gradient

Active transport of Na, K, Cl etc out of ascending
limb (especially thick limb) of loop of Henle to the
medullary interstitium.
Active transport of ions from collecting duct to
medullary interstitium.
Passive diffusion of urea from medullary collecting
ducts into the medullary interstitium.
Diffusion of less amounts of water from medullary
tubules into medullary interstitium

DISTAL CONVOLUTED TUBULE

The distal tubule continues to reabsorb sodium and

chloride,
The major luminal entry step being via the NaCl
symporter
This transporter differs significantly from the NaK
2Cl symporter in the thick ascending limb and is
sensitive to different drugs.
The NaCl symporter is blocked by the thiazide
diuretics.
Sodium channels also permit sodium entry in the
distal convoluted tubule.
Like the ascending limb of the loop of Henle, the
distal tubule is not permeable to water, so that it
further dilutes the already somewhat dilute fluid
entering it from the thick ascending limb.

COLLECTING DUCT SYSTEM

In the collecting ducts, there is a division of

labor among several different cell types.
Reabsorption of sodium and water is
associated with Principal cells
Reabsorption of chloride occurs partially via
paracellular pathways
Active reabsorption is also associated with
another class of collecting duct cells, the
Intercalated cells

The Principal cells

Reabsorb sodium, the luminal entry step being
via Epithelial Sodium Channels(ENaC)
The activity of ENaC in colon and kidney is
modulated by the Aldosterone..
It can be blocked by either Triamterene or
Amiloride which are used medically to serve
as diuretics.
In the kidney it is inhibited by Atrial Natriuretic
peptide is a powerful vasodilator, and a protein
hormone secreted by heart atrial muscle cells.

Principal cells in the collecting ducts are also

the crucial players in reabsorbing water.
The water permeability of the principal cells in
the collecting duct systemboth the cortical
and medullary portionsis subject to
physiological control by circulating
Antidiuretic hormone (ADH, Vasopressin)
The inner medullary collecting duct has a
limited water permeability even in the absence
of ADH, but the outer medullary and cortical
regions have almost no water permeability
without ADH.

Depending on levels of ADH, water permeability for

most of the collecting duct system can vary from very
low to very high.
When water permeability is very low (absence of
ADH), the hypo-osmotic fluid entering the collecting
duct system from the distal convoluted tubule remains
hypo-osmotic as it flows along the ducts. When this
fluid reaches the medullary portion of the collecting
ducts, there is now a huge osmotic gradient favoring
reabsorption, which occurs to some extent. That is,
although there is little cortical water reabsorption
without ADH, there is still a limited medullary
absorption because of the enormous osmotic gradient.
As so much water is not reabsorbed in the cortex,
most of the water entering the medullary collecting
duct flows on to the ureter. The result is the excretion
of a large volume of very hypo-osmotic (dilute) urine,
or water diuresis.

When the collecting duct systems water permeability is

very high (High ADH)
As the hypo-osmotic fluid entering the collecting duct system
from the distal convoluted tubule flows through the cortical
collecting ducts, most of the water is rapidly reabsorbed. This is
because of the large difference in osmolality between the hypoosmotic luminal fluid and the isosmotic (285 mOsm/kg)
interstitial fluid of the cortex.
In essence, the cortical collecting duct is reabsorbing the large
volume of water that did not accompany solute reabsorption in
the ascending limbs of Henles loop and distal convoluted
tubule.
Once the osmolality of the luminal fluid approaches that of the
cortical interstitial fluid, the cortical collecting duct then
reabsorbs approximately equal proportions of solute (mainly
sodium chloride) and water.
The result is that the tubular fluid, which leaves the cortical
collecting duct to enter the medullary collecting duct, is
isosmotic with cortical plasma, but its volume is greatly reduced
compared with the amount entering from the distal tubule.

In the medullary collecting duct, solute

reabsorption continues, but in the presence of
ADH water reabsorption is proportionally even
greater. This is because the ADH has signaled
much of the medullary collecting duct
epithelium to have high water permeability, and
the medullary interstitium is hyper-osmotic
relative to normal plasma.
Therefore, the tubular fluid becomes more and
more hyper-osmotic, and reduced in volume

Formation of a Dilute Urine

Decrease

water reabsorption
Continue electrolyte reabsorption
Mechanism: Decreased ADH release and reduced water
permeability in distal and collecting tubules

Formation of a Concentrated Urine

Increase water reabsorption
Continue electrolyte reabsorption
Mechanism:
Increased ADH release which increases water permeability in
distal and collecting tubules
High osmolarity of renal medulla
Countercurrent flow of tubular fluid

Urea recycling
Thick ascending
limb, DCT &
cortical collecting
duct is
impermeable to
urea.
Urea is permeable
through medullary
collecting duct
(permeability is
enhanced by ADH).
Urea move out from
medullary CT, and
enters into thin limbs of
loop of Henle

J.G Apparatus

J.G
APPARATUS

Granular cells (also called

juxtaglomerular cells)
Act as intrarenal baroreceptors
They act entirely within the kidney. Although granular
cells acting as intrarenal baroreceptors do not send
signals centrally.
These intrarenal baroreceptors sense renal afferent
arteriolar pressure.
If low response by releasing Renin
the activity of the granular cells is affected both by
direct sensing of pressure in the renal arterioles and
by pressures sensed by neural baroreceptors
elsewhere in the body vis sympathetic neves

The Macula Densa cells

The macula densa cells at the end of the thick
ascending limb have NaK2Cl symporters
that rapidly take up Na, Cl, and K when GFR,
and hence, NaCl delivery is high.
Sodium also enters the macula densa cells via
a NaH antiporter. Since the action of this
antiporter causes the cells to lose a hydrogen
ion for every sodium ion entering, this
increases intracellular pH.

A combination of cellular volume change, increased

intra-cellular chloride, and higher intracellular pH
initiates intracellular signaling processes that lead
to the release of ATP from the basolateral surface
of the cells in close proximity to the glomerular
mesangial cells
This ATP stimulates Purinergic P2 receptors on
the mesangial cells and afferent arteriolar smooth
muscle cells.
P2 receptor stimulation increases calcium in these
cells and promotes contraction.
Contraction of mesangial cells decreases the
effective filtration area, which decreases GFR.
Contraction of the afferent arteriolar smooth muscle
cells increases afferent resistance and decreases
RBF and GFR.

In addition, it is the increased calcium in the

afferent arteriolar cells that reduces Renin
secretion.
The ATP may also be metabolized to
Adenosine, which can stimulate Adenosine
receptors that produce the same result as the
P2 receptors

High salt content in the thick ascending limb of

a given nephron generates signals that reduce
glomerular blood flow and reduce filtration in
that nephron, thus blunting (but not eliminating)
the increase in sodium excretion initiated by
other processes in conditions (e.g., volume
expansion) in which the appropriate overall
response is increased sodium excretion.
The same signals that reduce filtration also
reduce the secretion of renin.

Control of Renin secretion.

Three primary mechanisms regulate renin secretion.
First, renal sympathetic nerve activity activates 1-adrenergic
receptors on granular cells of the afferent arteriole to stimulate
renin secretion.
Second, the granular cells also act as intrarenal baroreceptors,
responding to changes in pressure within the afferent arteriole,
which, except in cases of renal artery stenosis, is a reflection of
changes in arterial blood pressure. Deformation of the granular
cells alters renin secretion: when pressure falls, renin
production increases.
Third, macula densa cells in the thick ascending limb sense the
delivery of tubular sodium chloride, leading to the release of
chemical transmitters that alter renin secretion from the
granular cells: when sodium chloride delivery increases, renin
production decreases.

Regulation of Sodium and Water

Excretion

The kidneys work in partnership with the

cardiovascular system. Together they ensure
that
(1) There is enough blood volume to fill the
vascular tree,
(2) Enough pressure to drive blood flow
through peripheral tissues.
(3) The blood, and therefore the cells throughout the body, has the proper osmolality.
All the regulatory mechanisms that control
sodium and water excretion exist for the
purpose of meeting these three goals.

Variations in Renal blood flow (RBF) and

Glomerular filtration rate (GFR) are
major means of regulating sodium
excretion

SODIUM EXCRETION: THE

CARDIOVASCULAR CONNECTION

3) Secretion
2nd route of entry (from ECF) into tubules for
selected molecules
Mostly transepithelial transport (analogous to
reabsorption). Depends mostly on active membrane
transport systems
Provides mechanism for rapid removal of
substances (most important for H+, K+, foreign organic ions
and drugs such as penicillin etc.)

5. Micturition
Spinal cord integration: 2
simultaneous efferent
signals
In infant just simple spinal
reflex
Later: learned reflex under
conscious control from
higher brain centers
Various subconscious factors
affect reflex

Manneken Pis in Brussels