Glomerulus Structure and Function
Glomerulus is encased in a thin, double walled capsule (Bowman’s Capsule) which
together form the filtering unit.
Portion of blood which is filtered into the Bowman’s space is known as ultrafiltrate.
Glomerular capillary membrane is composed of three layers: capillary endothelial layer,
the basement membrane and the single celled capsular epithelial layer. The endothelial
layer contains small perforations called fenestrations (fenestrated endothelial cells).
Visceral epithelium or podocytes adhere to basement membrane covering capillary endothelial
Intercellular clefts or filtration slits formed by interlocking of foot processes (pedicles) of
Nephrin, podocin, CD2-associated protein (adhesion molecule) and α-actin 4 are
exclusively located in slit membrane and are required for normal filtration. Podocyte
dysfunction is major cause of many renal diseases.
Fenestrae of endothelial cells are maintained by VEGF produced by visceral epithelium.
Glomerular endothelial cells produce “NO” and ET-1. The middle basement membrane
is a negatively charged selectively permeable network of glycoproteins and
mucopolysaccharides and is secreted by and maintained/renewed by epithelial cells.
Substances with molecular weight of >70 kDa not filtered. Albumin (65.5 kDa) is filtered
to some extent but is reabsorbed.
GFR = Lp x area x NDP where Lp is permeability
Mesangium/mesangial cells: Extension of glomerular basement membrane – cushions
capillaries from high pressure; immune mediated reactions and phagocytic/contractile
Podocytes and their slit diaphragm (filtration slit)
Nephrins and NEPH1 are membrane spanning proteins with large extracellular domains
Podocin organizes nephrin and NEPH1 in specific microdomains in the membrane which
are important for signaling events for the podocytes.
Many of the proteins in the slit diaphragm interact with adaptor proteins inside the cell
(CD2-AP) Renal Blood Flow and GFR
GFR is intimately tied to renal blood flow which is regulated by intrinsic autoregulatory
mechanisms, neural and hormonal regulation
The purpose of myogenic autoregulation over a wide range of blood pressures (80 – 180
mm Hg) is to prevent changes in blood pressure from being transmitted to the
glomerular capillaries which otherwise would cause large fluctuations in GFR and
therefore solute and water excretion is constantly maintained.
RBF = (aortic pressure – renal venous pressure) / renal vascular resistance
RBF and GFR are kept constant if the ratio of ΔP/R is kept constant
An increase in systemic BP would lead to an increase in afferent arteriolar resistance
while a decrease in BP leads to a decrease in afferent arteriolar resistance.
Tubular glomerular feedback
Another intrinsic scheme which regulates renal blood flow and therefore GFR. The
macula densa cells in 1 segment of DCT sense flow rate and NaCl in the lumen of
tubule. Vasoactive signals are transmitted the short distance to the afferent arteriole to
regulate flow and therefore adjust the filtrate volume and concentration of NaCl. A high
NaCl concentration evokes vasoconstriction of afferent arteriole leading to a decrease in
The vasoconstriction occurs in part from the increase in ATP and adenosine from the Na +
transport. The ATP and ADO bind to receptors on the afferent arteriole smooth muscles
which increases Ca entry and contraction. Renin is inhibited in process. Nitric oxide is
also released from macula densa → vasodilation
Clinical Manifestations of Renal Disease
Renal diseases are responsible for a great deal of morbidity but fortunately are not major
causes for mortality.
Renal diseases: 80,000 deaths/year compared with many fold higher for heart disease,
cancer and strokes. 20,000,000 people are affected by non-fatal renal diseases.
Diabetes, hypertension, glomerulonephritis and polycystic kidney disease are leading
causes of end-stage renal diseases (ESRD)
Kidney diseases can be divided into four morphological components: affecting glomeruli,
tubules, interstitium and blood vessels
Some components are particularly prone to specific forms of renal injury. Glomeruli:
immune mediated; tubules and interstitium: toxins or infections
Damage to one component almost always leads to damage to other components
because of interdependence among units. For example, disease of the blood supply affects all areas of kidney dependent on blood supply. Tubular destruction will impair
glomerular function through back pressure transmission.
All forms of chronic renal disease ultimately affect all four compartments and lead to
chronic renal failure (end-stage renal disease). Thus GFR, tubular reabsorption and
endocrine functions deteriorate.
The functional capacity of the kidneys is huge and much damage is done before there is
evidence of functional impairment. Early signs are important clinically. Diminished renal
reserve occurs when the GFR drops to 50% of normal but no symptoms of renal function
Terms associated with renal disease
Azotemia: Elevation of BUN (blood urea nitrogen) and creatinine levels due to decrease
in GFR. Azotemia is a consequence of renal parenchymal damage but also extrarenal
Prerenal azotemia: hypoperfusion of the kidneys (hypotension, shock, volume
depletion and CHF)
Postrenal azotemia: obstruction of urine flow beyond kidney
Uremia: Biochemical abnormalities in the blood; failure of renal excretory function but
also results in metabolic and endocrine alterations which affect GIT (uremia
gastroenteritis); peripheral nerves (peripheral neuropathy) and heart (uremic fibrinous
Clinical Presentation of Renal Disease
Nephritic syndrome: Caused by glomerular disease and dominated by acute onset of red
blood cells in urine and mild to moderate proteinuria with hypertension. Classic
presentation for poststreptococcal glomerulonephritis
Rapidly progressive glomerulonephritis: Nephritic syndrome with rapid decline in GFR
(hours to days)
Nephrotic syndrome: Due to glomerular disease and characterized by heavy proteinuria,
hypoalbuminemia, severe edema, hyperlipidemia and lipiduria
Acute renal failure: Dominated by oliguria or anuria and recent onset of azotemia.
Cause can be glomerular, interstitial or vascular injury as well as acute tubular injury
Chronic renal failure: Characterized by prolonged symptoms and signs of uremia and is
the end result of all chronic renal parenchymal disease
Renal tubular defects: Characterized mainly by polyuria, nocturia and electrolyte
disorders (metabolic acidosis). Causes include medullary cystic disease or diseases
which affect specific tubular functions. The latter may be inherited (familial nephrogenic
diabetes) or acquired (lead nephropathy). Urinary tract infections: Characterized by bacteriuria and pyuria and may affect the
bladder (cystitis) or kidney (pyelonephritis). Occurs in 20% of women at some point in
Nephrolithiasis (renal stones) is manifested by severe spasms of pain (renal colic) and
hematuria. 5% of population develop renal stones
Urinary tract obstruction: Varied clinical manifestations based on anatomical location and
nature of obstruction
Four Stages of Renal Failure
Diminished renal reserve: GFR is 50% of normal but BUN and creatinine levels are
Renal insufficiency: GFR is 20 – 50% of normal and azotemia appears associated with
anemia and hypertension. Polyuria and nocturia develo