THE URINARY SYSTEM AND METABOLIC DISORDERS

I. PHYSIOLOGY

1. Body Fluid Compartments

2. Urine Formation
3. Regulation of ECF Fluid Osmolarity and Na Concentration
4. Acid Base Balance

1. BODY FLUID COMPARTMENTS

Constant volume and stable composition of body fluids is essential for homeostasis. The kidneys are
central in maintaining this relative constancy.

Intake and Output of water

• Daily intake of water
o Ingested in the form of liquids or water in food- 2100ml/day
▪ Highly variable
o Synthesized from oxidation of carbohydrates- 200ml/day
• Daily loss of body water
o Insensible water loss occurs continually without our conscious awareness- 700ml/day
▪ Skin (independent of sweating)- 300-400ml/day
• Minimized by lipids (Cholesterol, Fatty Acids and Ceramides) in the
stratum corneum- Skin barrier/ Moisture Barrier

Burn injuries- destroys the cornified layer of the skin causing the rate of evaporation to increase by as
much as 10-fold or 3-5 L/day

▪ Respiratory tract – 300-400ml/day

• Water loss through the lungs from respiration
• As air enters the warm respiratory tract it becomes saturated with
moisture to a vapor pressure of 47mmhg before it is expelled. (Inspired
air is less than 47mmhg).
Cold weather- vapor pressure is nearly 0mmHg, causing an even greater loss as temperature decreases.
Gives a dry feeling in the respiratory passages
o Fluid loss from sweat- highly variable depending on activity and environmental
temperature
▪ 1ooml/day but may get as high as 1-2L/hour
▪ Thirst mechanism is essential
o Water loss in Feces- 100ml/day

Diarrhea- increase water loss to several liters per day when severe
Cholera- can cause severe dehydration in a matter of hours which can lead to kidney failure
o Water loss by the kidneys- the most important means by which the body maintains
balance between water intake and water output
▪ Regulates water and electrolyte balance
▪ Urine volume can be as low as 0.5L/day in a dehydrated person or as high as
20L/day in a person drinking large amounts of water
▪ Electrolyte intake is variable such as Na, Cl and K
 ▪ The kidneys precisely match intake with excretion rates of water and
electrolytes

Body Fluid Compartments

• Total body water- 60% of body weight
o Varies with age, gender and degree of obesity
• Extracellular Fluid
▪ 20% of body weight
o Interstitial fluid
▪ 3/4th of ECF
o Blood plasma
▪ Non cellular part of blood
▪ Exchanges substances continuously with interstitial fluid through pores of the
capillary membranes
▪ Pores are permeable to almost all solutes in ECF except proteins
▪ 1/4th of ECF- 3L
o Transcellular fluid- synovial, pericardial, peritoneal, intraocular spaces and CSF
▪ Specialized type of ECF
▪ 1-2L
• Intracellular Fluid
o 40% of total body weight
o Fluid collectively found within the 75 trillion cells of the body
o Composition of cell fluids are remarkably similar

Blood Volume:
o Considered a separate fluid compartment because it is contained in a chamber of its
own- the circulatory system
o Average volume- 7% of body weight or about 5L
o Blood plasma- 60%
o Red Blood cells- 40%
• Hematocrit- fraction of blood composed of rbc’s
o 3-4% of plasma remains entrapped among cells- true hct is 96% of measured hct

Ionic composition of Plasma and Interstitial fluid

o Made possible by highly permeable capillary membranes
o Most important difference is the higher protein concentration in plasma because
capillaries have low permeability for plasma proteins
o Donnan effect- due to negatively charged plasma proteins the plasma has a net negative
charge that binds extra amounts of cations Na and K compared to the interstitial fluid.
The interstitial fluid has a slightly higher concentration of anions that are repelled by
plasma proteins.

ECF vs ICF
• ECF contains large amounts of Na and Cl ions and bicarbonate ions but only small quantities of K,
Ca, Mg, PO4 and organic anions
• ICF is sepratated from ECF by cell membrane that is highly permeable to water but not to most
electrolytes in the body
• ICF contains small amounts of Na and almost no Ca ions. Instead in contains large amounts of
nPO4 ions and moderate quantities of Mg and sulfate ions all of which has low concentrations in
ECF and contains large amounts of proteins almost four times as in the plasma
 The kidneys especially regulate composition of ECF that allows the cells to bathe in proper
concentration of electrolytes and nutrients for optimal cell function.

Regulation of Fluid exchange and Osmotic equilibrium between ICF and ECF
• Between ECF and Interstitial Fluid
o Balance of Hydrostatic pressure and Colloid osmotic pressure
• Between ECF and ICF
o Osmotic effects of smaller solutes especially Ma, Cl and other electrolytes
o Cell membrane of cells are highly permeable to water but relatively impermeable to
small ions so that the intracellular fluid remains isotonic

Clinical Abnormalities of Fluid Volume Regulation

HYPONATREMIA AND HYPERNATREMIA

In analyzing abnormalities of plasma Na concentration- first determine whether the abnormality is

caused by primary loss or gain of Na or primary loss or gain of water.

• Primary measurement: Plasma Na Concentration

o Fluid status evaluation
o Reasonable indicator of plasma osmolarity
o Normal: 142mEq/L
• Hyponatremia: Excess water or Loss of Na
o Loss of Na:
▪ Hypo-osmotic dehydration
• Decreased ECF volume
• Causes:
o Diarrhea, vomiting,
o overuse of diuretics that inhibit ability of Kidney to conserve Na,
o Na wasting kidney diseases
o Addison’s disease – decrease secretion of Aldosterone
o Excess water retention:
▪ Hypo-osmotic overhydration
• Diluted Na in ECF
• Causes:
o Excessive secretion of antidiuretic hormone- kidney tubules
reabsorb more water
• Hypernatremia: Water loss or Excess Na
o Increase Na
▪ Hyper-osmotic dehydration
• Loss of water from ECF concentrates Na
• Causes:
o Dehydration due to water intake that is less than water loss-
sweating during prolonged, heavy exercise
o Inability to secrete ADH (DIABETES INSIPIDUS)- kidneys excrete
huge amounts of dilute urine (Kidneys could not conserve
water)
▪ Nephrogenic DI- kidneys cannot respond to ADH
o Excess Na added in ECF
▪ Hyperosmotic overhydration
 • Excessive secretion of Aldosterone- excess Na causes water retention

EDEMA: Excess Fluid in Tissues

• In most instances, edema occurs mainly in the ECF compartment but may involve the ICF as well

• Intracellular Edema:
o 2 Conditions are especially prone to cause intracellular swelling
▪ Depression of metabolic systems of the tissue
▪ Lack of adequate nutrition to the cells
• Decreased blood flow to the tissues, too low to maintain normal tissue
metabolism ( a prelude to death of the tissue)
• Inflamed tissues- inflammation has a direct effect on the cell
membranes to increase their permeability- allowing Na and other ions
to diffuse into the cells with subsequent osmosis of water into the cells.
• Extracellular Edema:
o 2 General causes:
▪ Abnormal leakage of fluid from plasma to the interstitial spaces across the
capillaries
• Increased capillary hydrostatic pressure
o Heart failure
▪ Increased venous pressure and capillary pressure
causing increased capillary filtration
▪ Fall in arterial pressure leads to decreased excretion of
salt and water by the kidneys which increases blood
volume and further raises capillary hydrostatic pressure
to cause more edema
• Kidney stimulated to secrete renin and
increased formation of of Angiotensin II and
increased secretion of Aldosterone both of
which cause additional salt and water retention
by the kidneys
o Decreased Kidney excretion of salt and water
▪ Ex. Glomerulonephritis
▪ Large amounts of salt and water are added to the ECF
▪ Most of the salt and water leak into the interstitial
spaces
• Widespread increase in interstitial fluid volume
• Increase in blood volume results in hypertension
• Decreased plasma colloid osmotic pressure
o 2 general causes
▪ Failure to produce normal amounts of proteins
▪ Leakage of proteins from plasma causes plasma colloid
osmotic pressure to fall
• Nephrotic syndrome- loss of proteins in the
urine.
o Multiple types of renal diseases cand
amage the membranes of the renal
glomeruli causing the membranes to
become leaky for plasma proteins and
allow large quantities to be excreted
 o Edema occurs when loss cannot be
restored by synthesis. Generalized
edema occurs when plasma proteins fall
below 205g/100ml
• Cirrhosis of the liver- large amounts of fibrous
tissue among the liver parenchymal cells
o Failure of hepatocytes to synthesize
sufficient plasma proteins leading to a
decrease in plasma colloid osmotic
pressure
o Liver fibrosis compresses on portal
venous drainage to raise capillary
hydrostatic pressure throughout the GIT
area and filtration of fluid out of the
plasma and into the intrabdominal
areas (plus decrease in plasma protein
concentration)- ascites
▪ Failure of the lymphatics to return fluid from the interstitium back into the
blood
• Plasma proteins that leak in the interstitium have no other way to be
removed
• The rise on protein concentration raises the colloid osmotic pressure of
the interstitial fluid which draws more fluid out of the capillaries
• Blockage of lymph flow with infections of the lymph nodes.
o Filariasis
o Certain types of Cancer
o After surgery that cause lymph vessels to be removed or
obstructed (Radical Mastectomy)

• Safety factors that normally prevent edema

o Low compliance of interstitium when interstitial fluid is in the negative pressure range
o Ability of lymph flow to increase 10 to 50 fold
o Washdown of interstitial fluid protein concentration which reduces interstitial colloid
osmotic pressure as capillary filtration increases.

2. URINE FORMATION
• Multiple functions of the kidneys in homeostasis
o Excretion of metabolic waste products, foreign chemicals, drugs and hormone
metabolites
▪ Kidneys are the primary means of eliminating waste products of metabolism
• Urea (from metabolism of amino acids)
• Creatinine (from metabolism of muscle creatinine)
• Uric Acid (From nucleic acids)
• End products of hemoglobin breakdown like Bilirubin
• Metabolites of various hormones
o Regulation of Water and Electrolyte Balances
o Regulation of arterial pressure
▪ Long term regulation by excreting variable amounts of Na and water
▪ Short term regulation by secreting vasoactive factors such as renin
o Regulation of Acid-Base balance
 ▪ Kidneys contribute to acid base regulation along with the lungs and body fluid
buffers by:
• excreting acids
• regulating the body fluid buffer stores
▪ The kidney is the only means of eliminating certain acids as sulfuric acid and
phosphoric acid generated from protein metabolism
o Regulation of erythrocyte production
▪ Erythropoietin stimulates the production of rbc’s
▪ Hypoxia is an important stimulus for erythropoietin release
o Regulation of 1,25- Dihydroxyvitamin D3 (Calcitriol) production
▪ Active Vit D or Calcitriol is essential for normal calcium deposition in bone and
calcium reabsorption by the GIT
o Glucose synthesis
▪ Kidneys synthesize glucose from amino acids and other precursors during
prolonged fasting- gluconeogenesis
Urine formation
• Glomerular filtration
• Reabsorption of substances from the renal tubules into the blood
• Secretion of substances from blood into the renal tubules
o Important in determining the amount of K and H ions and a few other substances that
are excreted in urine

• Glomerular Filtration:
o Glomerular capillary membrane:
▪ 3 major layers
• Endothelium of the capillary (fenestrated)
o Negative charge hinders protein passage
• Basement membrane
o Meshwork of proteoglycan fibrillae and collagen with large
spaces
o Water and small solutes can filter thru
o Strong negative charge associated with proteoglycans also
prevents protein passage
• Layer of epithelial cells (podocytes)
o Podocytes are separated by gaps called slit pores
o Also negatively charged
▪ Glomerular capillaries are relatively impermeable to proteins hence glomerular
filtrate is protein free and devoid of cellular elements including rbc’s
▪ Poorly reabsorbed substances and excreted in large amounts in urine/ High
excretion rate
• Most substances that must be cleared from the blood
• End product of metabolism especially:
o Urea
o Creatinine
o Uric acid
o Urates
• Certain foreign substances and drugs (also secreted)
▪ Highly reabsorbed substances
• Electrolytes such as Na, Cl, Bicarbonate ions
▪ Substances that are completely reabsorbed and do not appear in urine
 • Amino acids
• Glucose

o Forces favoring filtration

▪ Glomerular hydrostatic pressure- 60mmhg
▪ Bowman’s capsule colloid osmotic pressure- 0mmhg
o Forces opposing filtration
▪ Bowman’s capsule hydrostatic pressure- 18mmhg
▪ Glomerular capillary colloid osmotic pressure- 32mmhg

Values change markedly under different physiologic conditions whereas others are
altered mainly in disease sates

o Increased Glomerular Capillary Filtration Coefficient- Increases GFR

▪ 4.2ml/min/mm
▪ A value 400 as high as most capillary systems of the body
▪ Rapid rate of fluid filtration
▪ Diseases that lower Glomerular Capillary Filtration Coefficient – decreased GFR
• Reduced surface area for filtration by reducing the number of functional
glomerular capillaries
• Increased thickness of glomerular capillary membrane
o DM and Chronic uncontrolled hypertension
▪ Increased thickness of glomerular capillary basement
membrane
▪ Eventually by damaging capillaries- loss in capillary
function
o Increased Bowman’s Capsule Hydrostatic Pressure- Reduction of GFR
▪ Pathological states
• Obstruction of urinary tract
o Precipitation of Ca or uric acid may lead to stones that lodge in
the urinary tract to raise Bowman’s capsule pressure- reduces
GFR and eventually damage or even destroy the kidney unless
the obstruction is relieved
o Increased Glomerular Capillary Colloid Osmotic Pressure- Decreases GFR
▪ Factors that affect glomerular capillary colloid osmotic pressure
• Arterial plasma colloid osmotic pressure
• Fraction of plasma filtered by the glomerular capillaries
o Increased Glomerular Capillary Hydrostatic Pressure- Increases GFR
▪ Determinants of Glomerular hydrostatic pressure
• Arterial pressure
• Afferent arteriolar resistance
• Efferent arteriolar resistance
o Autoregulation of GFR and renal blood flow
▪ Normal GFR 180L/day; tubular reabsorption 178.5Lday; Urine output 1.5L/day
▪ Tubuloglomerular feedback
• Juxtaglomerular complex
o Macula densa cells in the initial portion of DCT
o Juxtaglomerular cells in the walls of the afferent and efferent
arterioles
• 2 components
o Afferent arteriolar feedback mechanism
 o Efferent arteriolar feedback mechanism
Feedback Mechanism
• Decrease GFR slows the flow rate in loop of Henle
• Increase reabsorption of Na and Cl ions in the ascending loop of Henle
• Decrease Na and Cl ions stimulates Macula Densa leading to 2 effects:
o Decreases resistance in afferent arteriole which raises
glomerular hydrostatic pressure and helps return GFR back to
normal
o Increase renin release from Juxtaglomerular cells of afferent and
efferent arteriole
▪ Angiotensinogen converted to Angiotensin I
▪ Angiotensin I to Angiotensin II
▪ Angiotensin II constricts efferent arteriole to increase
glomerular hydrostatic pressure and increase GFR back
to normal
▪ Myogenic autoregulation
• Ability of individual blood vessels to resist stretching during increased
arterial pressure
• Increased wall tension or wall tension allows increased movements Ca
ions from ECF into the cells.
• Contraction prevents overdistention and raises vascular resistance that
helps prevent excessive increases in renal blood flow and GFR when
arterial pressure increases.
▪ Other factors that increase renal blood flow and GFR
• High protein intake
• Increased blood glucose

Nephrologic syndromes
• Elements that reflect underlying pathologic processes
o Reduction in GFR (Azotemia)
o Abnormalities in urine sediment (RBC’s, WBC’s, Casts and Crystals)
o Abnormal excretion of serum proteins (Proteinuria)
o Disturbances in urine volume (Oliguria, Anuria, Polyuria)
o Presence of Hypertension and/or expanded total body fluid volume (edema)
o Electrolyte abnormalities
o Fever/Pain
• Assessment of GFR
o Gold standard: Direct measurement involves administration of radioactive isotope
(inulin or iothalamate)
o Serum creatinine is used as a surrogate to estimate GFR
o Amount in the blood stream is relatively stable
o Creatinine clearance: approximation of GFR is measured from serum creatinine and
urinary creatinine excretion rates for a defined period (usually 24 hours)
▪ Useful for estimation because it is a small, freely filtered solute that is not
reabsorbed by the tubules
o Clinical application:
▪ Primary metric to determine sufficiency of kidney ‘function’
▪ To determine the severity of kidney damage
 ▪ To monitor progression of kidney disease
• Azotemia:
o A biochemical abnormality, defined as elevation, or buildup of, nitrogenous products
(BUN-usually ranging 7 to 21 mg/dL), creatinine in the blood, and other secondary waste
products within the body.
o Raising the level of nitrogenous waste is attributed to the inability of the renal system to
filter (decreased glomerular filtration rate-GFR) such as waste products adequately.
o Typical feature of both acute and chronic kidney injury
o Azotemia is important when answering the question- What condition has led to the
development of the Acute Kidney Injury?

▪ Prerenal Azotemia:
• Decreased renal perfusion accounts for 40-80% of cases of acute renal
failure
• Readily reversible with appropriate treatment
• Causes:
o Decreased circulating blood volume
▪ GIT hemorrhage
▪ Burns
▪ Diarrhea
▪ Diuretics
o Volume sequestration
▪ Pancreatitis
▪ Peritonitis
▪ Rhabdomyolysis
o Decreased effective arterial volume
▪ Cardiogenic shock
▪ Sepsis
*Once mean arterial pressure drops below 80mmHg- GFR declines rapidly
• Prolonged renal hypoperfusion may lead to Acute Tubular Necrosis
(ATN) which is an intrinsic renal disease.
▪ Postrenal Azotemia:
• Urinary tract obstruction accounts for 5%
• Usually, reversible
• Causes:
o Obstruction at the:
▪ Urethra or bladder outlet
▪ Bilateral ureteral obstruction
▪ Intrinsic Renal disease:
• Caused by processes in:
o Large renal vessels
o Intrarenal microvasculature and glomeruli
o Tubulointerstitium- Ischemic and toxic ATN account for 90% of
cases
▪ Seen in patients who have undergone major surgery,
trauma, severe hypovolemia, overwhelming sepsis or
extensive burns
• Picture of Urinalysis in processes involving tubules and interstitium (AKI)
o Mild to moderate proteinuria, hematuria and pyuria (75% of
cases)
o Occasionally WBC casts
 o RBC point more to glomerular diseases
o Eosinophiluria- allergic interstitial nephritis or atheroembolic
renal disease
▪ Emboli are cholesterol rich and lodge in medium and
small renal arteries
• May have normal urinalysis except of
eosinophils and casts
• Diagnosis is confirmed by renal biopsy
▪ Mild proteinuria and hematuria- Renal artery
thrombosis
▪ Renal vein thrombosis- heavy proteinuria and hematuria
• Require angiography for confirmation
• Oliguria and Anuria
o Oliguria: <400ml, 24-hour urine output
▪ Acute renal failure of any etiology (carries a more serious prognosis for renal
recovery except for prerenal azotemia)
o Anuria: complete absence of urine formation (<100ml)
▪ Total urinary tract obstruction
▪ Total renal vein or artery obstruction
▪ Shock (severe hypotension and intense renal vasoconstriction)
▪ Cortical necrosis
▪ ATN
▪ RPGN
• Proteinuria
o Nephrotic syndrome- One of the most important causes of edema
▪ proteinuria
▪ hypoalbuminemia
▪ edema
▪ hyperlipidemia
▪ Loss of Antithrombin III (makes hypercoagulable blood and prone to DVT/
Pulmonary Embolism)
▪ Increased permeability of the glomerulus
▪ Glomerular capillaries leak large amounts of into the filtrate and urine
▪ 3.5 gms of protein can be lost in urine/day
▪ Destruction of Epithelial cells and basement membrane that make the
glomerular barrier permeable to proteins
▪ Plasma colloid osmotic pressure falls- capillaries all over the body filter large
amounts of fluid into the various tissues- edema and decreased plasma volume
▪ Kidneys retain Na and water until plasma volume is restored to nearly normal
• Further dilution of protein concentration- more fluid leakage into the
tissue with massive extracellular edema.
▪ Caused by any disease that increase permeability of the glomerular membrane
• Focal segmental glomerulosclerosis/ Chronic glomerulonephritis This
disease affects the kidney’s glomeruli, causing some of these filters to
become scarred. FSGS is the most common cause of nephrotic
syndrome in Black adults.
• Membranous nephropathy/ Amyloidosis- deposition of an abnormal
proteinoid substance in the wall of the blood vessels and seriously
damages the glomerular basement membrane. Most common cause of
nephrotic syndrome in white adults
 • Minimal change nephrotic syndrome- no major abnormality in the
glomerular capillary membrane can be detected by light microscopy
o Loss of the negative charges that are normally present in the
glomerular capillary basement membrane
o May be autoimmune
o Proteins pass with ease especially albumin
o Can occur in adults but more common in children 2-6 years old
▪ Plasma protein concentration can fall below 2g/dl and
colloid osmotic pressure to less than 10mmhg (normal
of 28mmhg)
▪ Severe edema
• Hematuria, Pyuria and Casts:
o Hematuria: 2-5 RBC’s/hpf
o Isolated hematuria without proteinuria, other cells or casts- bleeding from urinary tract
▪ Stones
▪ Neoplasms
▪ Tuberculosis
▪ Trauma
▪ Prostatitis
o Single urinalysis with hematuria
▪ Menstruation
▪ Viral illness
▪ Allergy
▪ Exercise
▪ Mild trauma
o Persistent or significant hematuria (>3rbc’s/hpf on 3 urinalyses or a single urinalysis with
>100rbc’s or gross hematuria)- significant renal or urologic lesions
o Hematuria, pyuria and bacteriuria- infection
o Isolated hematuria with dysmorphic RBC’s
▪ Glomerular disease
• IgA nephropathy
• Hereditary nephritis
• Thin basement membrane disease
▪ Dysmorphic RBC’s may also result form pH and osmolarity changes along the
distal nephron
o Hematuria with dysmorphic RBC’s, RBC casts, protein excretion >500mg/day- is
diagnostic of Glomerulonephritis
▪ RBC cast form as RBC get trapped in the tubules forming a cylindrical mold of
gelled Tamm-Horsfall protein
o Isolated pyuria is unusual since inflammatory reaction are associated with hematuria
o WBC casts with bacteria- pyelonephritis
o Casts- chronic renal disease

o Nephritic Syndrome
▪ clinical syndrome that presents as hematuria, elevated blood pressure,
decreased urine output, and edema.
▪ The major underlying pathology is inflammation of the glomerulus (immune
complex deposition)
▪ It causes a sudden onset of the appearance of red blood cell (RBC) casts and
blood cells, a variable amount of proteinuria, and white blood cells in the urine.
 The primary pathology can be in the kidney, or it can be a consequence of
systemic disorders.
▪ Causes:
• In children, the most common cause of acute glomerulonephritis is post-
streptococcal glomerulonephritis.[1] Sudden onset of the nephritic
syndrome occurs seven to ten days after a streptococcal throat or 2-3
weeks after a skin infection (impetigo).[2] The most common pathogen
involved is group A-beta hemolytic streptococci.

• A similar form of glomerulonephritis (infection associated) may occur in

association with certain infections, e.g., bacterial infections
(meningococcemia, staphylococcal endocarditis, and pneumococcal
pneumonia, etc.), viral infections (mainly hepatitis B, hepatitis C,
mumps, HIV infection, varicella, and EBV causing infectious
mononucleosis), and parasitic infections (malaria and toxoplasmosis).

• Crescentic or rapidly progressive glomerulonephritis (RPGN) is

characterized by the nephritic syndrome presenting with the clinical
picture of sudden and severe acute renal failure. However, RPGN does
not have a specific etiology. It may occur due to:
• Anti-GBM antibody-mediated disease (e.g., Goodpasture syndrome)
• Diseases caused by immune complex deposition, with granular
deposits of antibodies and complement by immunofluorescence:
This results from the complication of any of the immune complex
nephritides and includes postinfectious glomerulonephritis, lupus
nephritis, IgA nephropathy, and Henoch-Schönlein purpura.
• Pauci-immune crescentic GN may be associated with systemic or
renal vasculitis.
• In systemic lupus erythematosus (SLE), patients with focal or
generalized proliferative glomerular inflammation can present with
nephritic syndrome
• Tubular Processing of the Glomerular Filtrate
o Glomerular Filtration is non-selective- all solutes in plasma are filtered except plasma
proteins of substances bound to them
o Tubular reabsorption is highly selective
▪ Substances that are almost completely reabsorbed
• Glucose
• Amino acids
▪ Substances that are highly reabsorbed but rates are variable depending on the
needs of the body
• Na
• CL
• HCO3
▪ Substances that are poorly reabsorbed
• Urea
• Creatinine
o Transport Mechanisms
▪ Across tubular epithelial membranes
• Active transport
o Pinocytosis
▪ Proximal tubule reabsorb large molecules by pinocytosis
▪ Proteins attach to brush border
▪ Inside the cell, the protein is digested into amino acids
which are reabsorbed in the basolateral membrane
o Primary active transport
▪ Na-K ATPase – located in basolateral surface of tubular
epithelial cells in most parts of the tubule
• Creates low Na concentration in the cells that
favors passive Na diffusion into the apical
surface of tubular epithelium due to the Na
gradient that the active transport creates.
• Creates a high K concentration intracellularly
 • Low Na and High K intacellularly creates a net
negative charge of -70mv
o Negative charge attracts Na in the
tubular lumen to cross passively into the
tubular epithelial membrane
▪ Hydrogen ATPase
▪ K ATPase
▪ Ca ATPase
o Secondary active transport
▪ Involves a specific membrane protein/ carrier protein
▪ Carrier proteins found in brush border in the proximal
tubule with its large surface area
▪ Na-Glucose cotransport
▪ Na- Amino acid cotransport
▪ Na-H countertransport
• Secondary active secretion- mediated by
specific enzymes in the brush border of the
proximal tubule
• Passive transport
o Transcellular
▪ Water and solutes
▪ Majority of Na transport
o Paracellular
▪ Tight junctions in the proximal tubules are more
permeable and becoming less permeable distally
▪ Water and solutes
▪ Water mostly reabsorbed in this manner in the proximal
tubule
▪ Water dissolved K, Mg, Cl ions are carried in reabsorbed
fluid
▪ Na transport
• Across peritubular capillary walls
o Ultrafiltration/ Bulk flow
▪ Hydrostatic forces
▪ Colloid Osmotic forces
o Transport maximum- limit to the rate at which a solute can be transported
▪ Due to saturation of specific transport mechanisms when the amount of solute
delivered (tubular load) exceeds the capacity of the carrier proteins and specific
enzymes involved in the transport process
▪ Ex. Glucose transport maximum is 375mg/ml
• Filtered at a rate of 125mg/min
• With large increases n GFR and or plasma glucose concentration, the
tubular load of glucose may exceed 375mg/min (all the nephrons have
reached their maximal capacity to reabsorb glucose)
o Excess glucose is not reabsorbed and passes into the urine
• Glucose threshold (250mg/min)
o At plasma glucose concentration of 200mg/ml- tubular load may
reach 250mg/min
▪ Of A small amount of glucose begins to appear in the
urine
 ▪ Not all nephrons have the same transport maximum for
glucose, some nephrons excrete glucose before others
have reached their transport maximum
• Reabsorption and Secretion Along Different Parts of the Nephron

Proximal tubule:
o Proximal tubular reabsorption
▪ Proximal tubules epithelial cells
• Highly metabolic
• Large numbers of mitochondria to support potent active transport
processes
• Extensive brush border on the apical side provides a large surface area
that is loaded with protein carrier molecules.
o Transport large fraction of Na ions across apical membrane and
its cotransport mechanisms with amino acids and glucose
o Counter-transport which transport Na in the apical membrane
while secreting Hydrogen ions into the tubular lumen
• Extensive intercellular and basal channels
▪ 65% of filtered load of Na and Water
▪ Slightly lower percentage of Cl, HCO3, and K
▪ Reabsorption of all filtered glucose and amino acids
▪ Apical transport
• First half of proximal tubule- Na is reabsorbed b co-transport with
organic solutes, glucose and amino acids and other solutes like HCO3
and leaving behind Cl
• Second half of proximal tubule- High Cl ion concentration, little glucose
and amino acids remain
o Cl ion is transported into the interstitial fluid by paracellular
diffusion
o Secretion by the proximal tubule
▪ Waste products of metabolism: Organic acids-Bile salts, oxalate, urate and
catecholamines
• Also filtered from glomerular capillaries
• Almost a total lack in reabsorption results in rapid excretion in urine
▪ Potentially harmful drugs or toxins are rapidly cleared from the blood and
secreted into the tubules
▪ para-aminohippuric acid (PAH) is secreted so rapidly that the average person can
clear about 90% from the plasma and excrete it in urine
Loop of Henle
• Thin descending limb
o Highly permeable to water
o Moderately permeable to most solutes including urea and Na
o 20% filtered water is reabsorbed
o Important in concentrating tubular fluid
• Thick ascending limb
o Impermeable to water- very dilute tubular fluid
o Thick epithelial cells with high metabolic activity
o 25% of filtered loads of Na, CL and K are reabsorbed
o Paracellular reabsorption Na, Ca, HCO3, and Mg
o Na-K ATPase in the epithelial basolateral membranes
 ▪ Provides a favorable gradient for movement of Na from tubular fluid into the
cell
• Mediated by Na,2Cl,K co-transporter (site of loop diuretics)
o Na-H ion counter-transport mechanism
• Distal tubule
o Early distal tubule
▪ Juxtaglomerular complex- provides feedback control of GFR and blood flow
▪ Distal tubule- highly convoluted with the same re-absorptive characteristics of
the ascending limb of the loop of Henle
• Reabsorption of Na, K and Cl
• Impermeable to water and urea
• Diluting segment
▪ Na, Cl co-transporter moves Na Cl from tubular lumen to the cell (inhibited by
Thiazide diuretics)
▪ Na-K ATPase pump transports Na into the interstitial fluid
▪ Cl diffuses out of the cell via Cl channels in the basolateral membrane
o Late distal tubule and Cortical collecting tubule
▪ Completely impermeable to urea
▪ Reabsorb Na and secrete K under the influence of Aldosterone
▪ Permeability to water is controlled by ADH/ Vasopressin
• Important in the control of dilution or concentration of urine
▪ 2 Cell types
• Principal cells
o Reabsorb Na via Na channels on the apical membrane and
secrete K
o Cl diffuses into into the interstitial fluid
o Stimulated by Aldosterone
o Site of action of Aldosterone antagonists and Na Channel
blockers- K sparing diuretics
• Intercalated cells
o Reabsorb K and secrete Hydrogen ions
o Hydrogen ion secretion is mediated by Hydrogen ATPase
transport mechanism
▪ Important in acid base regulation
o Within the cell, carbonic anhydrase catalyzes the reaction
▪ H20+CO2 H2CO3 H20+ H
o Medullary collecting duct
▪ Reabsorb less than 10% of filtered water
▪ Final site for processing of urine
▪ Epithelium is simple cuboidal with smooth surfaces with few mitochondria
▪ Special characteristics
• Permeability to water is controlled by ADH which reduces urine volume
and concentrates solutes
▪ Permeable to urea unlike the cortical collecting duct
• Reabsorption into the medullary interstitium raises the osmolarity of the
region and contributes to the overall ability to form concentrated urine
▪ Also has Hydrogen ion ATPase that can secrete H against a large concentration
gradient similar to cortical collecting duct and thus important in acid base
regulation
• Abnormalities in urine volume
• Polyuria:
o >3L/day
o Quantification of volume by 24 hour urine collection may be needed
o 2 Potential mechanisms of Polyuria
▪ Excretion of non absorbable solutes (such as glucose)
▪ Excretion of water (usually from a defect of ADH production or renal
responsiveness)
o Need to distinguish solute diuresis from water diuresis
▪ Assess clinical presentation
▪ Measurement of urine osmolality

▪ Water diuresis
• UO: >3L/day
• Urine is dilute (<250mosmol/L)
• Causes:
o Polydipsia- urine osmolality is maximally dilute at
50mosmol/L
▪ Psychiatric
▪ Neurologic lesions
▪ Medications
o Central Diabetes Insipidus (DI)
▪ Hyphysectomy
▪ Neoplastic
▪ Inflammatory
▪ Trauma
▪ Vascular
▪ Infectious
▪ Genetic
o Peripheral DI
▪ Acquired tubular diseases
▪ Drugs or toxins
▪ Congenital
▪ Solute Diuresis
• UO: >3L/day
• Urine osmolality >300mosomol/L
• Causes
o Poorly controlled DM with glucosuria is the most common
cause leading to volume depletion and serum hypertonicity
o Iatrogenic- mannitol administration, radiocontrast media
and high protein feedings (enteral or parenteral) leading to
increased urea production and excretion
o Cystic renal diseases or Bartter’s syndrome may develop
during a tubulointerstitial process (such as resolving ATN)
▪ Salt wasting disorders- tubule damage results in
direct impairment of Na reabsorption and indirectly
reduces the responsiveness of the tubule to
aldosterone
▪ Diagnostics:
• Plasma vasopressin- central vs nephrogenic
 • Water deprivation test plus exogenous vasopressin- primary
polydipsia vs central and nephrogenic DI
3. Regulation of ECF Osmolarity and Na concentration
• Determinants of Body Water
o Fluid intake
o Renal excretion of water
• Excess water excretion by forming dilute urine
o ADH
▪ Stimuli: abnormal decrease in the osmolarity of body fluids (excess water int eh
body)
▪ Feedback: Decrease in ADH release by posterior pituitary
• Reduced permeability of distal tubules and collecting ducts to water
• Large amounts of dilute urine excreted by as much as 20L/day with a
concentration of up to 50mOsm/L

o Renal mechanisms
▪ Tubular fluid is isosmotic in the Proximal renal tubule
• Water and solutes are reabsorbed in equal proprotions
• Little change is osmolarity (300mOsm/kg)
▪ Descending Loop of Henle
• Water is reabsorbed by osmosis and equilibrates with surrounding
interstitial fluid (600mOsm/L)
▪ Ascending Loop of Henle to early distal tubule
• Impermeable to water even with large amounts of ADH
• Avid reabsorption of Na, K and Cl
• Dilution of tubular fluid (progressive dilution to about 100mOsm/L)
▪ Late distal tubule, Cortical collecting duct and collecting duct
• Additional reabsorption of Na, Cl
• In the absence of ADH this portion is impermeable to water
o Tubular fluid becomes more dilute
o Excretion of large volumes of urine
• In the presence of high ADH concentrations
o The cortical collecting tubule becomes highly permeable to
water so that large amounts of water are reabsorbed from the
tubule to the cortex interstitium where it is swept away by
rapidly flowing peritubular capillaries (helps to preserve high
medullary interstitial fluid osmolarity because water
reabsorption happens at the cortex)
o With high levels of ADH, collecting ducts become permeable to
water so that at the end of the collecting duct, the fluid
equilibrates with the hyperosmolar medullary interstitium to
produce a concentrated urine about 1200mOsm/L
• Requirements for excreting concentrated urine
o High ADH levels
o Hyperosmolar renal medullary interstitial fluid surrounding the collecting ducts which
provides the osmotic gradient necessary for water reabsorption to occur in the presence
of high levels of ADH

▪ Stimuli: abnormal increase in the osmolarity of body fluids

▪ Feedback: Release of ADH by posterior pituitary
 • ADH increases the permeability of distal tubules and collecting ducts to
water
• Large amounts of water get reabsorbed
• Urine volume is decreased but does not alter the rate of renal excretion
of solutes
o Concentrated urine
o Kidneys can excrete concentrated urine with a concentration of
1200-1400 mOsm/L

o Hyperosmolar renal medulla

▪ Juxtamedulalry nephrons- 25% of nephrons
• Loops of Henle and vasa recta the go deeply into the medulla before
returning to the cortex
▪ Collecting ducts which carry urine through the hyperosmotic renal medulla
before excretion
▪ 300mOsm/L- osmolarity of interstitial fluid in almost all parts of the body
(similar to plasma)
▪ Interstitial fluid in the medulla of the kidney is much higher, increasing
progressively to about 1200-1400mOsm/L in the pelvic tip of the medulla
▪ Factors that contribute to the hyperosmotic renal medullar interstitium
• Active transport of Na and co-transport of K, Cl and other ions in the
ascending limb of loop of Henle of juxtamedullary nephrons
o Most important determinant
o Solutes reabsorbed in the ascending limb is not followed by
osmotic flow of water because it is impermeable to water
• Active transport of ions from collecting ducts into the medullary
interstitium
• Facilitated diffusion of large amounts of urea from inner medullary
collecting ducts into the medullary interstitium
• Diffusion of only small amounts of water from medullary tubules into
the medullary interstitium
▪ Urea
• Contributes to about 40-50% of osmolarity to the renal medullary
interstitium when the kidney is forming a maximally concentrated urine
• Urea reabsorption
o Distal and cortical collecting tubules are impermeable to urea
o High levels of ADH cause rapid water reabsorption from the
cortical collecting tubule- urea concentration increases rapidly
o Inner medullary collecting ducts- still more water reabsorption
takes place – even higher urea concentration
▪ The inner medullary collecting ducts are permeable to
urea
▪ The high concentration of urea creates a diffusion
gradient that brings it into the renal interstitium
• Facilitated by specific urea transporters, UT-A1,
activated by ADH
• Urea recirculation
o 20-50% of filtered load of urea is excreted
o Proximal tubule- 40-50% is reabsorbed
o Thin segments of Loop of Henle- urea concentration rises due
to:
 ▪ Water reabsorption especially with high ADH
▪ Urea secretion from medullary interstitium
o Thick limb of the Loop of Henle, distal tubule and cortical
collecting tubule
▪ Relatively impermeable to urea
▪ At high ADH levels
• Activation of Urea transporters UT-A1
• Urea diffuses into the medullary interstitium
o A moderate share of urea in the
medullary interstitium eventually
diffuses into the thin loop of Henle
o Several recirculation’s occur before it it
excreted
o Each circuit contributes to a higher
concentration of urea- provides an
additional mechanism for a
hyperosmotic renal medulla
• Countercurrent exchange in the vasa recta
o 2 features of renal medullary blood flow that preserve high
solute concentrations
▪ Medullary blood flow is slow. The sluggish blood flow is
sufficient to:
• Supply metabolic needs of the tissues
• Minimize solute loss from medullary
interstitium
▪ Vasa recta serve as countercurrent exchangers
minimizing wash out of solutes from the medullary
interstitium
o The vasa recta does not created the medullary hyperosmolarity,
but they prevent it from being dissipated.
• Renal Failure
• Acute renal failure
o Kidneys abruptly stop working entirely or almost entirely but may eventually recover
nearly normal function
o Causes:
▪ Prerenal
• heart failure with reduced cardiac output
• low blood pressure
• diminished blood volume- hemorrhage
▪ Intrarenal
• Abnormalities within the kidney itself
• Those that affect blood vessels, glomeruli, tubule
▪ Postrenal
• Obstruction of urinary collecting system (calyces to the bladder)
• Kidney stones (calcium, urate, cystine)
• Chronic renal failure
o There is progressive loss of function of more and more nephrons that gradually decrease
overall kidney function
o Normal blood concentrations of most electrolytes and normal body fluid volumes can
still be maintained until the number functioning nephrons decrease below 20-25% or
normal
o Vicious cycle of Chronic Renal failure leading to end stage renal disease
▪ Loss of nephrons causes adaptive changes in the remaining nephrons that lead
to increased blood flow, increased GFR and increased urine output in the
surviving nephrons.
▪ Adaptive changes include hypertrophy as well as functional changes like:
• Decrease vascular resistance
• Tubular reabsorption in surviving nephrons
▪ Increase pressure and stretch on the remaining glomeruli occurs due to the
functional changes- causes sclerosis (replacement of normal tissue with
connective tissue) which leads to further reduction in kidney function, further
adaptive changes ensue creating a vicious cycle.
o Chronic Glomerulonephritis
▪ Inflammation and damage to the capillary loops in the glomeruli
▪ Slowly progressive disease that leads to irreversible renal failure
▪ It may be a primary disease following acute GN
▪ Secondary disease to systemic diseases like SLE
▪ In the final stages of the disease the glomeruli are replaced by fibrous tissue and
lose function
o Injury to Renal Interstitium
▪ Interstitial nephritis: Primary or secondary disease of renal interstitium
• Result from vascular, glomerular or tubular damage that destroys
individual nephrons
• Primary damage to the interstitium by poisons, drugs, and bacterial
infections
▪ Pyelonephritis
• Renal interstitial injury caused by bacterial infection
• Most commonly E.coli coming from fecal contamination of urinary tract
o Hematogenous spread
o Ascending infection
• Conditions that interfere with normal flushing of bacteria from the
bladder
o Incomplete emptying, residual urine
o Obstruction to urine outflow
• Cystitis- inflammation of the bladder
o Vesicoureteral reflux
• Begins with renal medulla- affects medulla more than the cortex
o Manifests with markedly impaired ability to concentrate urine
o Excretion of Protein in Urine due to Increased Glomerular Permeability
▪ Nephrotic Syndrome
• Loss of large quantities of plasma proteins into the urine
• Causes:
o Chronic glomerulonephritis
o Amyloidosis
o Minimal change nephrotic syndrome
o Isosthenuria: inability of kidney to concentrate or dilute urine
▪ Effect of rapid rate of tubular flow
• Rapid flow through collecting ducts prevents adequate water
reabsorption
• Rapid flow through loop of Henle and collecting ducts prevents the
countercurrent mechanism
 • As more nephrons are progressively destroyed- the maximum
concentrating ability of the kidney declines and urine osmolarity and
specific gravity approach those of the glomerular filtrate
o Effects of renal failure on the body fluids
▪ Uremia
• Generalized edema due to water and salt retention
• Acidosis due to failure of kidneys to excrete normal acidic products
• High concentration of non protein nitorgens (urea, creatinine, uric acid)
• High concentration of other substances excreted by the kidney like,
phenols, sulfates, phosphates, potassium and guanidine bases
• Urea and creatinine measurements provide an important means of
assessing the degree of renal failure
▪ Water retention- Edema
• Need to restrict water intake
• Hypoalbuminemia, decrease in plasma colloid osmotic pressure
• Compensating nephrons attempt to retain salt recognizing
hypoalbuminemia as blood volume depletion.
• Fluid moves into interstitial spaces- edema
▪ Acidosis
• Failure to excrete metabolic acid causes the body to lean on the body
buffers for regulation
• When buffering power is used up- blood pH falls drastically.
• Patient becomes comatose and die at pH below 6.7
▪ Anemia
• Due to decreased eryhtropietin
▪ Osteomalacia
• Decreased production of active Vit D and by phosphate retention in the
kidneys
• Bones are partially absorbed become greatly weakened
• Active Vit D is needed for Ca absorption form the GIT
• Chronic renal failure cause phosphate to rise in serum due to decreased
GFR
o Phosphate binds Ca in plasma which stimulates parathyroid
hormone secretion- demineralization of bones
o Secondary hyperparathyroidism
▪ Hypertension
• Exacerbates injury to glomeruli and blood vessels of the kidney
• Major cause of end stage renal disease- vicious cycle

Renal Control of Acid Base Balance

•Kidneys control acid base balance by excreting either acid or basic urine
•HCO3 excretion removes base from the blood
•Hydrogen ion excretion removes acid form the blood
•Excretes non volatile acids

•Conserves HCO3 all of this is reabsorbed in the tubules

•Must react with H ion to become H2CO3 before it can be reabsorbed
•HCO3 is a primary buffer system in the blood
•Alkalosis:
•There is a reduction on H ion concentration in the ECF
•The kidneys fail to reabsorb all the filtered HCO3
•Acidosis:
•Kidneys do not excrete HCO3 into the urine
•Large number of H ion are secreted into the tubular lumen
•For each HCO3 reabsorbed a H ion must be secreted

•H ion secretion and HCO3 reabsorption happens in all segment of the tubules except descending
and ascending thin limbs of the loop of Henle
•80-90% occurs in the proximal tubule
•10% in the thick ascending loop of Henle
•Remainder in the distal tubule and collecting duct
•H ion reabsorption by secondary active transport
•Na-H countertransport
•Proximal tubule
•Thick ascending segment of the Loop of Henle
•Early distal tubule

•HCO3 reabsorption
•Na-HCO3 cotransort
•Cl-HCO3 counter transport

•Net filtration of H ion is 4400mEq?day; HCO# is 4320mEq/Day

•Sligh excess of H ion (80mEq/day) is excreted in urine in combination with other urinary
buffers especially phosphate and ammonia
•Basic mechanism: Incomplete titration of H against HCO3 leaving one or the other to pass into the
urine
•Primary active transport of H ion
•Late distal tubules and through the rest
•Luminal membrane- H ionATPase
•Important in forming maximally acidic urine (4.5)
•Intercalated cells in late distal tubules and collecting tubules

•Excess H ions with Phosphate and Ammonia buffers

•Small part H ion (80mEq) secreted in excess of HCO3 filtered into the tubular fluid is
excreted in ionic form (.03mEq/L) .
•Remaining H ion is combined with buffers in the tubular fluid
•Phosphate buffer system
•HPO4 and H2PO4
•Tubular buffer that is poorly reabsorbed
•Ammonia Buffer system
•More quanitatively important buffer system
 •NH3/NH4 buffer system
•NH4 is synthesized in from glutamine (metabolism of amino acids in the liver)
•Glutamine is delivered to the epithelial cell of the tubules
•Proximal tubules, thick ascending limb, distal tubules
•Glutamine is metabolized into 2HCO3 and 2NH4
•NH4 secreted into lumen by Na-NH4 counter transport
•HCO3 transported across basolateral membrane along with reabsorbed Na
•Collecting tubules
•H ion is secreted by H ion ATPase which combines with NH3 to form NH4
for excretion
•Collecting ducts are permeable to NH3 which diffuses into the lumen
•Impermeable to NH4
•