The KIDNEY (Outline From Robin's 8th Ed) Eric Jake Lim

THE KIDNEY  Charles E. Alpers Robbin’s Pathologic Basis of Disease 8 th Ed. Outlined by Eric Jake C. Lim (Davao Medical School Foundations, Inc) 12 January 2012 I.

General a. Renal Renal diseases diseases are respon responsibl sible e for great deal deal of morbidity, morbidity, fortunately, are not equally major causes of mortality. b. Morbidity Morbidity is, is, however, however, by by no means means insignifi insignificant cant c. Four basic basic morphologi morphologic c compo component nents s i. Glomeruli1 ii. ii. Tub Tubules les iii. Interstitium2 iv. iv. Blood Blood vess vessel els s

II. II.

d. Some components seem to be more vulnerable to specific forms of renal injury i. Glom Glomer erul ular ar 1. Most Most Glom Glomer erul ular ar are are immu immuno nolo logi gica call lly y mediated ii. ii. Tub Tubular lar 1. Most Most tubular tubular and inters interstiti titial al are caused caused by toxic or infectious agent e.   There There is however however a TENDENCY  for all forms of chronic chronic kidne kidney y disea disease se to ultima ultimatel tely y DESTROY  all all four four (4) (4) componen components ts of kidneys, kidneys, culminatin culminating g in CHRONIC RENAL failure (CRF) and what has been called end-stage kidneys. f. Important Important note on glomer glomerulus ulus (Dr. Visitacion Visitacion)) 1

A tuft formed of capillary loops at the beginning of each nephric tubule in the kidney; this tuft with its capsule (Bowman capsule) constitutes the corpusculum renis (malpighian body). Syn: malpighian glomerulus, malpighian tuft. 2 A small area, space, or gap in the substance of an organ or tissue

i. Lined Lined by fenestra fenestrated ted endot endotheliu helium m ii. Two (2) layers layers of epitheli epithelium um (viscera (viscerall and parietal parietal)) iii. iii. In gener general al patholo pathology gy it is the viscer visceral al layer layer that is situated in the Bowman’s capsule that is of prime importance iv. iv. GBM GBM comp compri rise ses s of  1. Lami Lamina na den densa sa 2. Lami Lamina na rara rara a. Lamin Lamina a rar rara a inte interna rna b. Lamin Lamina a rar rara a exte externa rna Clin Clinic ical al Man Manif ifes esta tati tion ons s of Ren Renal al Dis Disea ease ses s a. Can be grouped grouped into reasona reasonably bly well-defi well-defined ned syndromes syndromes.. i. Azotemia3 1. Refers Refers to elev elevati ation on of the a. blood blood urea urea nitro nitroge gen n (BUN) (BUN) and b. crea creati tini nine ne leve levell 2. Two types types of azotem azotemia ia a. Pre Prerenal nal i. When When hype hyperf rfus usio ion n of the the kidney kidneys s (eg, (eg, hemorr hemorrha hage, ge, shock, shock, volute volute depletion depletion,, and congestive heart failure) that impairs renal function in the absence parenchymal damage. b. Pos Postre trenal nal i. Is seen whenever urine flow is OBSTRUCTIVE beyo beyond nd the the level of the kidney . ii. Uremia4 1. When azotemia becomes becomes associate associated d with constella constellation tion of signs signs and symptoms and biochemical abnormalities. abnormalities. b. Clinical Clinical prese presentati ntation on of the renal renal disea diseases ses i. Neph Nephri riti tic c synd syndro rome me 1. Due to Glomerular disease 2. Domi Domina nate ted d by by a. Acute onset of usually usually gross visible visible Hematuria (RBC in urine)

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An abnormal increase in concentration of urea and other nitrogenous substances in the blood plasma 4 The complex of symptoms due to severe persisting renal failure that can be relieved by dialysis

 The Kidney (Robbins and Cotran, 8 th Ed). Outlined by Eric Jake Lim.

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b. Mild to moderate Proteinuria

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iii.

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c. Hypertension 3. It is the classic manifestation of acute poststreptococcal glomerulonephritis Rapidly progressive glomerulonephritis 1. Characterized by nephritic syndrome with 2. Rapid decline in GFR (hours to days) Nephrotic syndrome 1. Also due to Glomerular disease 2. Characterized by heavy Proteinuria > 3.5 gm/day (unlike nephritic which may either be mild or moderate) 3.  The tetrad  a. Hypoalbuminemia b. Severe edema c. Hyperlipidemia d. Lipiduria 4. Asymptomatic Hematuria or Proteinuria (or a combination of these two) a. Usually a manifestation of subtle or mild Glomerular abnormalities Acute renal failure 1. Dominated by a. Oliguria or anuria b. Recent onset of azotemia c. Can result from i. Glomerular ii. Interstitial or iii. Vascular injury or iv. Acute Glomerular abnormalities Chronic renal failure 1. Characterized by a. Prolonged signs and symptoms of  i. Uremia ii. Is the end result of all CHRONIC renal parenchymal diseases Renal tubular defects 1. Are dominated by a. Polyuria b. Nocturia c. Electrolyte disorders Urinary tract infection

viii.

ix.

c. Acute

i. ii.

1. Characterized by a. Bacteuria b. Pyuria c. May affect either the i. Kidney (pyelonephritis) ii. Bladder (cystitis) Nephrolithiasis 1. Manifested by a. Severe spasms or pain (renal colic) and b. Hematuria c. Often with recurrent stone formation Urinary tract obstruction and renal tumors 1. Have varied clinical manifestations based on specific anatomic location and nature of the lesion renal failure Implies a rapid and frequently reversible deterioration of renal function   The evolution from normal renal function to symptomatic chronic renal failure broadly progress through a series of  four stages that merge into one another 1. Diminished renal reserve a. GFR is about 50% of the normal b. Serum BUN and creatinine values are normal c. Patients are asymptomatic d. However they are more susceptible to developing azotemia 2. Renal insufficiency a. GFR is 20%-50% of the normal b. Azotemia appears, usually associated with anemia and hypertension c. Polyuria and nocturia can occur as a result of decreased concentrating ability d. Sudden stress (eg, nephrotoxins) may precipitate uremia 3. Chronic renal failure a. GFR is less than 20%-25% of the normal b. Kidneys cannot regulate volume and solute composition

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c.

III.

Patients develop edema, metabolic acidosis and hyperkalemia d. Overt uremia may ensue, with neurologic, GI, and cardiovascular complications 4. End-stage renal disease a. GFR is less than 5% of the normal b. Is the terminal stage of uremia Glomerular Diseases a. Constitute some of t he major problems in nephrology b. One of the most common causes of chronic kidney disease in humans c. Systemic immunologic diseases such as i. SLE ii. Vascular disorders (hypertension) iii. Metabolic diseases (DM) iv. Some hereditary conditions such as 1. Fabry 5 disease d. Clinical manifestations i. Nephritic syndrome ii. Rapidly progressive glomerulonephritis iii. Nephrotic syndrome iv. Chronic renal failure v. Isolated urinary abnormalities e.   The Glomerular capillary wall is filtering membrane and consist of the following structures i.  Thin layer of fenestrated endothelial cells ii. Glomerular basement membrane (GBM) 1. With a thick electron-dense central layer the lamina densa and 2. A thin electron-dense layer the a. Lamina rara interna b. Lamina rara externa iii. GBM is primary composed of  1. Collagen (mostly type IV; remember this serves as point of attachments for other  glycoproteins)

IV.

2. Laminin 3. Polyionic proteoglycans (mostly heparan sulfate) iv. Visceral epithelial cells (podocytes) 6 v. Entire Glomerular tuft supported by mesangial cells7 f. Histologic alterations i. Hyperceullarity ii. Basement membrane thickening iii. Hyalinosis8 and iv. Sclerosis Pathogenesis of Glomerular Injury a. Unknown origin yet can be induced experimentally by antigen-antibody reactions b. Two (2) forms of antibody-associated injury i. Injury by antibody reacting in-situ within the glomerulus either binding to insoluble fixed (intrinsic) Glomerular antigens or to molecules planted within the glomerulus and ii. Injury resulting from the deposition of circulating antigen-antibody complexes in the glomerulus c. Immune complex deposition involving intrinsic and in situ renal antigens i. Heyman nephritis d. Antibodies against planted antigens e. Anti-GBM antibody-induced glomerulonephritis f. Circulating immune complex glomerulonephritis g. Antibodies to Glomerular cells h. Cell-mediated immunity in glomerulonephritis i. Activation of alternative complement pathway  j. Epithelial cell injury k. Mediators of Glomerular injury i. Cells 1. Neutrophils and monocyte a. Infiltrate the glomerulus in certain types of glomerulonephritis as a

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due to deficiency of )-galactosidase and characterized by abnormal accumulations of neutral glycolipids (e.g., globotriaosylceramide) in endothelial cells in blood vessel walls; clinical findings include angiokeratomas on the thighs, buttocks, and genitalia, hypohidrosis, paresthesia in extremities, cornea verticillata, and spokelike posterior subcapsular cataracts; death results from renal, cardiac, or cerebrovascular complications; X-linked recessive inheritance caused by mutation the )galactosidase gene (GLA) on Xq

An epithelial cell of the visceral layer of Bowman capsule in the renal corpuscle, attached to the outer surface of the Glomerular capillary basement membrane by cytoplasmic foot processes (pedicels); believed to play a role in the ultrafiltration of  blood. 7 a phagocytic cell in the capillary tuft of the renal glomerulus, interposed between endothelial cells and the basement membrane in the central or stalk region of the tuft. Syn: deep cell, intercapillary cell. 8 Hyaline degeneration, especially that of relatively extensive degree

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result of activation of complement, resulting in generation of   chemotactic agents (mainly C5a), but also by Fc-mediate adherence and activation. b. Macrophages, T-lymphocytes, and natural killer cells c. Platelets d. Resident Glomerular cells ii. Soluble mediators 1. Chemotactic complement components 2. Eicosanoid, nitric oxide, antiotensin, and endothelin 3. Cytokines 4. Chemokines 5. Coagulation system iii. Mechanisms of progression in Glomerular Diseases 1. Two (2) major histologic characteristics of  progressive renal damage a. Focal Segmental Glomerulosclerosis (FSGS)9 b. Tubulointerstitial Fibrosis (TIF) l. Nephritic Syndrome i. Characterized by inflammation in the glomeruli ii. Proteinuria and edema are common iii. Important crescentic component of   glomerulonephritis 1. Acute proliferative (Postreptococcal, Postinfectious) Glomerulonephritis a. Poststreptococcal glomerulonephritis b. Nonstreptococcal acute glomerulonephritis (Postinfectious Glomerulonephritis) m. Rapidly progressive (Crescentic) glomerulonephritis10 i. Classification and pathogenesis 1. Type I 9

segmental collapse of Glomerular capillaries with thickened basement membranes and increased mesangial matrix; seen in some glomeruli of patients with nephrotic syndrome or mesangial proliferative glomerulonephritis. 10 glomerulonephritis usually presenting insidiously, without preceding streptococcal infection, with increasing renal failure leading to uremia within a few months; at autopsy the kidneys are normal in size, numerous Glomerular capsular epithelial crescents are present, and antiglomerular basement membrane antibodies are frequently found. Syn: acute crescentic glomerulonephritis.

a. Anti-GBM antibody-induced disease b. Characterized by i. Linear deposits of IgG and in many cases C3 in the GBM that are visualized by IFmicroscope ii. Clinical picture of   Goodpasture syndrome 2. Type II a. A result of immune complex deposition b. Can be a complication of any of the immune complex nephritides including i. Postinfection glomerulonephritis ii. Lupus nephritis iii. IgA nephropathy11 iv. Henoch-Schonlein purpura12 3. Type III a. Also called pauci-immune type b. Defined by lack of anti-GBM antibodies or immune complexes by the lack of anti-GBM complexes by immunoflourescence and electron microscopy c. Most patients with this type have circulating ANCAs that produce cytoplasmic (c) or perinuclear (p) staining patterns. n. Nephrotic Syndrome i. Certain Glomerular diseases virtually always produce the nephrotic syndrome 11

glomerulonephritis affecting a small proportion of renal glomeruli which commonly presents with hematuria and may be associated with acute upper respiratory infection in young males, not usually due to streptococci; associated with IgA deposits in the Glomerular mesangium and may also be associated with systemic disease, as in Henoch-Schönlein purpura. Syn: Berger disease, Berger focal glomerulonephritis, focal nephritis, IgA nephropathy 12 an eruption of nonthrombocytopenic, palpable purpuric lesions due to dermal leukocytoclastic vasculitis with IgA in vessel walls associated with joint pain and swelling, colic, and passage of bloody stools, and occurring characteristically in young children; glomerulonephritis may occur during an initial episode or develop later. Syn: anaphylactoid purpura(2), Henoch purpura, purpura rheumatica, Schönlein purpura, Henoch-Schönlein syndrome, Schönlein-Henoch syndrome

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ii. Manifestations of the nephrotic syndrome 1. Massive Proteinuria 2. Hypoalbuminemia (3gm/day) 3. Generalized edema 4. Hyperlipidimia and Lipiduria iii. Membranous Nephropathy 1. Is a common cause of nephrotic syndrome in adults 2. Characterized by a. Thickening of the Glomerular capillary wall due to the accumulation of the electron-dense, Ig-containing deposits along the subepithelial side of the basement membrane. 3. Most notable associations are a. Drugs (penicillamine, captopril, gold, NSAID) b. Underlying malignant tumors c. SLE d. Infections (chronic hepatitis B, C , syphilis, schistosomiasis and malaria) e. Other autoimmune disorders iv. Minimal-Change Disease 1. Benign disorder 2. Most frequent cause of neprhotic syndrome in children less common in adults 3. Characterized by effacement of foot  a. Diffuse   process of visceral epithelial  cells (podocytes) in Glomeruli that appears virtually normal by light microscopy. v. Focal Segmental Glomerulosclerosis (FSGS) 1. Characterized by a. Sclero sis of some, but not all, glomeruli (thus it is focal); b. In the affected glomeruli, only portion of the capillary tuft is involved (thus it is segmental) c. Classfication and Types: i. Primary disease (idiopathic focal segmental Glomerulosclerosis) ii. HIV-infection

iii. Secondary event (scarring of  previously active necrotizing lesions, eg, IgA nepropathy) vi. Membranoproliferative Glomerulonephritis13 1. Histologically characterized by a. Alterations in the GBM b. Proliferation of Glomerular cells and c. Leukocytic infiltration d. Synonymously called: mesangiocapillary glomerulonephritis 2. Secondary MPGN a. Invariably Type-! Is more common in adults and arises in the following settings i. Chronic immune complex disorders ii. A1-antitrypsin deficiency iii. Malignant diseases (CLL and lymphoma) iv. Hereditary deficiencies of  complement regulatory proteins o. Isolated Urinary Abnormalities i. IgA Nephropathy (Berger Disease)14 ii. Alport Syndrome15 13

chronic glomerulonephritis characterized by mesangial cell proliferation, increased lobular separation of glomeruli, thickening of glomerular capillary walls and increased mesangial matrix, and low serum levels of complement; occurs mainly in older children, with a variably slow progressive course, episodes of  hematuria or edema, and hypertension. It is classified into three types: type 1, the commonest, in which there are subendothelial electron-dense deposits; type 2, dense-deposit disease, in which the lamina densa is greatly thickened by extremely electron-dense material; type 3, in which there are both subendothelial and subepithelial deposits. Syn: hypocomplementemic glomerulonephritis, lobular glomerulonephritis, mesangiocapillary glomerulonephritis. 14 glomerulonephritis affecting a small proportion of renal glomeruli which commonly presents with hematuria and may be associated with acute upper respiratory infection in young males, not usually due to streptococci; associated with IgA deposits in the glomerular mesangium and may also be associated with systemic disease, as in Henoch-Schönlein purpura. Syn: Berger disease, Berger focal glomerulonephritis, focal nephritis, IgA nephropathy. 15 a genetically heterogeneous disorder characterized by nephritis associated with microscopic hematuria and slow progression of renal failure, sensorineural hearing loss, and ocular abnormalities such as lenticonus and maculopathy; autosomal dominant [MIM*104200, MIM*153640, and MIM*153650], autosomal recessive [MIM*203780], and X-linked recessive [MIM*301050 and MIM*303630] forms exist.  The X-linked form is caused by mutation in the collagen type IV alpha-5 gene

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iii. Thin Basement Membrane Lesion (Benign Familial Hematuria) 1. Fairly common hereditary entity manifested clinically by familial asymptomatic Hematuria 2. Morphologically diffuse thinning of the GBM between 150-250 nm (normal adult should be 300-400 nm) 3. Although mild or moderate Proteinuria, renal function is normal and prognosis is excellent 4. Should be distinguished from IgA, another common cause of hematuria and X-linked Alport) p. Chronic Glomerulonephritis i. glomerulonephritis that presents with persisting proteinuria, chronic renal failure, and hypertension, of insidious onset or as a late sequel of acute glomerulonephritis; the kidneys are symmetrically contracted and granular, with scarring and loss of  glomeruli and the presence of tubular atrophy and interstitial fibrosis. q. Glomerular Lesions Associated with Systemic Disease i. Henoch-Schonlein 1. an eruption of nonthrombocytopenic, palpable purpuric lesions due to dermal leukocytoclastic vasculitis with IgA in vessel walls associated with joint pain and swelling, colic, and passage of bloody stools, and occurring characteristically in young children; glomerulonephritis may occur during an initial episode or develop later. Syn: anaphylactoid purpura(2), Henoch purpura, purpura rheumatica, Schönlein purpura, Henoch-Schönlein syndrome, Schönlein-Henoch syndrome. ii. Diabetic Nephropathy 1. a syndrome occurring in people with diabetes mellitus and characterized by albuminuria, hypertension, and progressive renal insufficiency. 2. Diabetic nephropathy is a major cause of  morbidity and mortality in people with diabetes mellitus (DM). People with diabetes make up the largest number (greater than (COL4A5) on chromosome Xq; the autosomal recessive form is due to mutation in the collagen type IV alpha-3 gene (COL4A3) or alpha-4 gene (COL4A4) on 2q

25%) of those who start renal dialysis for end-stage renal disease (ESRD) each year in the U.S. The incidence of ESRD approaches 40% in people who have had type 1 DM for 20 years. The risk of diabetic nephropathy is higher in males, blacks, Hispanics, and Native Americans. Within 3 years after the diagnosis of DM is made, histologic study shows thickening of glomerular basement membrane and mesangial expansion, changes characteristic of diabetic glomerulosclerosis (Kimmelstiel-Wilson disease). The kidneys increase in size and weight because of both hypertrophy and hyperplasia of parenchymal cells, and renal blood flow and glomerular filtration rate (GFR) are increased; as a result, serum creatinine and urea nitrogen are slightly reduced. After 10–15 years, the first evidence of renal damage may appear as microalbuminuria, a persistent excretion of  albumin in concentrations not detected by routine tests for urinary protein. An albumin excretion rate of 20–200 4g/min (30–300 mg/day) heralds the onset of diabetic nephropathy and strongly predicts eventual ESRD. Further progression of renal damage leads to frank albuminuria and a decline in glomerular filtration rate and nitrogen clearance. The prevalence of hypertension is markedly great er in persons with microalbuminuria, and hypertension accelerates the progression of renal disease. Diabetic nephropathy can lead to hyperkalemia, metabolic acidosis, nephrotic syndrome, papillary necrosis, and increased susceptibility to acute renal failure after exposure to radiographic contrast media. Current practice guidelines for the treatment of DM call for annual assessment of 24-hour albumin excretion, prompt treatment of  urinary tract infections, and avoidance of  nephrotoxic drugs and radiographic dyes. No interventions have been shown to reverse clinical diabetic nephropathy. However,

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prospective randomized studies have established that improved metabolic control, maintaining plasma glucose as near normal as possible at all times, can markedly decrease the development and progression of diabetic nephropathy, as well as of other long-term microvascular complications of  diabetes (retinopathy and neuropathy). In addition, aggressive management of  hypertension with ACE inhibitors or angiotensin II receptor blockers has been shown to delay progression of nephropathy by mechanisms independent of blood pressure control, and limitation of daily protein intake to 0.8 g/kg of body weight (not appropriate in pregnancy) has been shown to delay progression of both diabetic and nondiabetic renal disease. ESRD is treated with kidney transplantation, hemodialysis, or peritoneal dialysis. Because diabetic retinopathy and neuropathy progress more rapidly with the onset of renal failure, dialysis is usually instituted early (when serum creatinine reaches about 6 mg/dL) in diabetic nephropathy. iii. Amyloidosis 1. A disease characterized by extracellular accumulation of amyloid in various organs and tissues of the body; may be local or generalized; may be primary or secondary. iv. Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy Tubular and Interstial Disease a. Acute Kidney Injury (AKI), Acute Tubular Necrosis (ATN) i. Causes 1. Ischemia 2. Direct toxic injury to the tubules 3. Acute tubulointersitial nephritis 4. Urinary obstruction b. Tubulointerstitial Nephritis i. Pyelonephritis16 and Urinary Tract Infection17

Inflammation of the renal parenchyma, calices, and pelvis, particularly due to local bacterial infection

ii. Acute Pyelonephritis18 iii. Chronic Pyelonephritis19 and Reflux Nephropathy 20

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iv. Tubulointerstitial Nephritis induced by Drugs and  Toxins 1. Acute drug-induced interstitial nephritis 2. Analgesic nephropathy 21 3. Nephropathy associated with NSAIDs 4. Aristolochic nephropathy v. Other Tubulointerstitial Diseases 1. Urate Nephropathy 2. Hypercalcemia and Nephrocalcinosis 3. Acute Phosphate Nephropathy 4. Light-chain Cast Nepropathy (Myeloma Kidney) Vascular Diseses a. Benign Nephrosclerosis 22 b. Malignant Hypertension23 and Accelerated Nephrosclerosis c. Renal Artery Stenosis d. Thrombotic Microangiopathies e. Other Vascular Disorders i. Atherosclerotic ischemic renal disorders ii. Atheroembolic Renal Disease iii. Sickle-cell disease Nephropathy

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microbial infection, usually bacterial, of any part of the urinary tract; can involve the parenchyma of the kidney, the renal pelvis, the ureter, the bladder, the urethra or combinations of these organs; often the entire urinary tract is affected; the most common organism causing such infection is Escherichia coli. 18 acute inflammation of the renal parenchyma and pelvis characterized by small cortical abscesses and yellowish streaks in the medulla due to pus in the collecting tubules and interstitial tissue 19 chronic inflammation of the renal parenchyma and pelvis resulting from bacterial infection, characterized by calyceal deformities and overlying large flat renal scars with patchy distribution. 20 damaged renal parenchyma secondary to vesicoureteral reflux of infected urine. 21 chronic interstitial nephritis with renal papillary necrosis, occurring in patients with a long history of excessive consumption of analgesics, especially those containing phenacetin. 22 renal scarring due to arteriolar sclerosis resulting from longstanding hypertension; the kidneys are finely granular and mildly or moderately contracted, with hyaline thickening of the walls of afferent glomerular arterioles and hyaline scarring of  scattered glomeruli; chronic renal failure develops infrequently. Syn: arteriolonephrosclerosis, benign nephrosclerosis. 23 severe hypertension that runs a rapid course, causing necrosis of arteriolar walls in kidney, retina, etc.; hemorrhages occur, and death most frequently is caused by uremia or rupture of a cerebral vessel.

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VII.

VIII.

IX. X.

iv. Renal infarcts Congenital Anomalies a. Agenesis of Kidney b. Hypoplasia c. Ectopic Kidney d. Horshoe kidney 24 e. Multicystic Renal Dysplasia Cystic Disease of the Kidney a. Autosomal-dominant (adult) polycystic kidney disease b. Autosomal-dominant (childhood) polycystic kidney disease c. Cystic diseases of renal medulla i. Medullary sponge kidney ii. Nephrolithiaisis and adult-onset medullary cystic disease D D

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union of the lower or occasionally the upper extremities of the two kidneys by a band of tissue extending across the vertebral column

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