Glomerulus structure/function, podocytes, renal blood flow, GFR, tubular glomerular feedback, renal disease, renal failure, chronic kidney disease, uremia, glomerular injury, localization of immune complexes, membranous nephropathy, Alport syndrome

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Department
Biomedical Science
Course
BMS 460
Professor
D.Rao Veeramachaneni
Semester
Fall

Description
15 November 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 cells. Intercellular clefts or filtration slits formed by interlocking of foot processes (pedicles) of adjacent podocytes 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 that interact. 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 GFR. 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 are evident 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 disorders. 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 pericarditis) 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 their life 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 normal Renal insufficiency: GFR is 20 – 50% of normal and azotemia appears associated with anemia and hypertension. Polyuria and nocturia develo
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