This document summarizes renal pathology and glomerular diseases. It discusses how diseases can affect the glomeruli, tubules, interstitium and vasculature. The glomeruli are described as a network of capillaries lined by endothelial cells, the glomerular basement membrane, and podocytes. Immunological and toxic mechanisms can cause glomerular injury. Membranous glomerulopathy is described as the most common cause of nephrotic syndrome in adults, characterized by thickening of the glomerular capillary wall.

1. RENAL PATHOLOGY Diseases affect a) glomeruli (often immunological) b) tubules (toxic, infectious) c) interstitium (toxic, infectious) d) vascular Disease in one area usually results in damage or disease on neighboring areas Large functional reserve a) > 75% destruction before impairment www.freelivedoctor.com

2. Congenital Anomalies Review page 961 , “Robbins and Cotran” PATHOLOGIC BASIS OF DISEASE . 7 TH ed. Understand and describe the following congenital anomalies of the kidney a) agenesis b) hypoplasia c) ectopic kidney d) horseshoe kidney www.freelivedoctor.com

3. GLOMERULI Network of capillaries a) lined by fenestrated endothelium b) basement membrane c) podocytes (“foot processes”) Glomeruli capillary wall a) lined with fenestrated endothelium ( 70- 100 nm) b) glomerular basement membrane (GBM) i) consist of collagen (type IV), heparan sulfate, laminin, glycoproteins www.freelivedoctor.com

4. - Type IV collagen forms network to which glycoprotein's attach c) visceral epithelial cells (podocytes; “foot processes”) i) composed of interdigitating processes embedded to basement membrane ii) adjacent foot processes are separated by 20-30 nm filtration slits bridged by thin diaphragm (nephrin) d) entire glomerulus is supported by mesangial cells i) lying between capillaries www.freelivedoctor.com

5. ii) phagocytic, contractile, proliferate, secretion of biologically active mediators - modified smooth muscle cells iii) involved in many types of GN Glomeruli a) very permeable to H 2 O and small solutes b) impermeable to proteins (~ 70 kDa or larger; i.e., albumin) c) “glomerular barrier function” i) selective permeability based on: - size - charge: cationic more permeable www.freelivedoctor.com

6. ii) podocytes important in maintaining this “function” - slit diaphragm maintain size- selectivity by specific proteins 1.- NEPHRIN : extend towards each other from neighboring podocytes comprising the slit diaphragm !! 2.- PODOCIN : intracellular (podocyte) protein where nephrin attaches - mutations in genes encoding these proteins give rise to nephrotic syndrome (i.e., glomerular disease) www.freelivedoctor.com

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11. Clinical Manifestations Termimology a) Azotemia :  BUN and  creatinine i) related to  GFR - prerenal azotemia:  RBF, hypoperfusion w/out parenchymal damage - postrenal azotemia: obstruction of urine flow below level of kidney www.freelivedoctor.com

12. b) when azotemia becomes associated with a variety of clinical S & S and biochemical abnormalities  UREMIA Major Renal Syndromes a) Nephritic syndrome : glomerular disease, hematuria, mild  moderate proteinuria, azotemia, edema,  BP i) classic presentation of post streptococcal GN b) Nephrotic syndrome : heavy proteinuria (> 3.5 g/day), hypoalbuminemia, severe edema, hyperlipidemia and lipiduria www.freelivedoctor.com

13. c) Acute renal failure : oliguria/anuria, recent onset of azotemia, can result from GN, tubular or interstitial disease d) Nephroliathiasis : renal stones, renal colic, hematuria, recurrent stone formation e) Chronic renal failure : 4 stages i)  renal reserve: GFR ~ 50% normal BUN & creatinine normal, pt. asymptomatic, more susceptible to develop azotemia ii) renal insufficiency: GFR 20-50% of normal, azotemia, anemia,  BP, polyuria/nocturia (via  concentrating ability) www.freelivedoctor.com

14. iii) renal failure : GFR less than 20-25% kidneys cannot regulate volume, ions: edema, hypocalcemia, metabolic acidosis, uremia with neurological, CV and GI complications iv) end stage renal disease : GFR < 5% of normal, terminal stage of uremia www.freelivedoctor.com

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16. Glomerular Disease Chronic GN one of most common causes of chronic renal failure Glomerular disease often associated with systemic disorders such as: a) diabetes mellitus b) SLE c) amyloidosis d) vasculitis - pts. with manifestations of glomerular disease should be considered for these systemic syndromes, etc. www.freelivedoctor.com

17. GN characterized by one or more of the following (inflammatory diseases of glomerulus) a) hypercellularity : i) cell proliferation of mesangial cells or endothelial cells ii) leukocyte infiltration (neutrophils, monocytes and sometimes lymphocytes) iii) formation of crescents - epithelial cell proliferation (from immune/inflammatory injury) - fibrin thought to elicit this injury (TNF, IL-1, IFN-  are others) www.freelivedoctor.com

18. b) basement membrane thickening i) deposition of immune complexes on either the endothelial or epithelial side of GBM or w/in GBM itself ii) thickening of GBM proper as with diabetes mellitus (diabetic glomerulosclerosis) c) hyalinization (hyalinosis) and sclerosis i) accumulation of material that is eosinophilic and homogeneous - obliterates capillary lumen of glomerulus (sclerotic feature) www.freelivedoctor.com

19. - result of capillary or endothelial injury. Usually end result of various forms of glomerular damage (intraglomerular thromboses, accumulation of other metabolic materials) Since etiology of primary GN is unknown, classification is based on histology. Subdivided: a) diffuse (all glomeruli) b) global (entire glomerulus) c) focal (portion of glomeruli) d) segmental (part of each glomerulus) e) mesangial (affecting mesangial region) www.freelivedoctor.com

20. Pathogenesis of Glomerular Disease/Injury Little is known regarding etiology or triggering Immune mechanisms underlie most cases of primary GN and many of the secondary cases a) 2 forms of Ab-associated injury i) injury resulting from soluble Ag-Ab deposits in glomerulus ii) injury from Ab reacting in-situ with glomerulus - insoluble fixed glomerular Ag - molecules planted w/in glomerulus www.freelivedoctor.com

21. Examples In Situ Immune Complex Deposition a) Ab act directly with intrinsic tissue Ag “ planted” in the glomerulus from the circulation b) 2 forms of Ab-mediated glomerular injury i) anti-GBM Ab-induced nephritis - Ab directed against fixed Ag in GBM - in humans spontaneous AGBM nephritis is autoimmune disease www.freelivedoctor.com

22. - Ab bind along GBM forming a “linear pattern” - sometimes AGBM Ab cross react with BM of lung  GOODPASTURE SYNDROME - < 1% of GN cases - some cases show severe glomerular damage and rapidly progressive crescentic GN ii) Heymann nephritis - a form of membranous GN - Ab bind along GBM in “granular pattern” www.freelivedoctor.com

23. c) Trigger for induction of autoimmune Ab is unclear i) ETX ii) mercuric chloride iii) graft-vs.-host reaction Ab can react with “planted” Ag in GBM a) cationic Ag binding to anionic GBM sites b) bacterial byproducts c) IgG deposition in mesangium www.freelivedoctor.com

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25. re: Ab-mediated injury  Ag-Ab deposition in GBM is major pathway of glomerular injury !! a) largest proportion of cases of GN are granular immune pattern along the GBM or mesangium Cell mediated immune GN a) sensitized T cells can cause glomerular injury, in absence of immune deposits i) may occur in some forms of rapidly progressive GN www.freelivedoctor.com

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27. Mediators of immune injury seen as loss of glomerular barrier function a) proteinuria b)  GFR in some instances Complement-leukocyte mechanism a) well established i) activated complement (C5a)  neutrophils and monocytes - release proteases  degrade GBM ii) ROS iii) some are neutrophil-independent - C5-C9 (lytic component; membrane attack complex) www.freelivedoctor.com

28. - Membrane attack complex stimulate growth factors (TGF)  GBM thickening iv) direct cytotoxicity Other mechanisms of glomerular injury a) epithelial cell injury i) can be induced by Ab to visceral epithelial cell Ag ii) toxins iii) cytokines iv) loss of foot processes - caused by alterations in nephrin www.freelivedoctor.com

29. b) renal ablation GN i) any renal disease   GFR (30-50% of normal) - lead to end stage renal failure ii) patients develop proteinuria and diffuse glomerulosclerosis - initiated by unaffected glomeruli  hypertrophy to maintain function  single nephron hypertension  damage www.freelivedoctor.com

30. Glomerular Syndromes and Disorders Nephrotic Syndrome a) massive proteinuria (> 3.5 g/day) b) hypoalbuminemia c) generalized edema d) hyperlipidemia and lipiduria Initial event is derangement of GBM  increasing permeability and progressive loss of plasma proteins  hypoalbuminemia  decrease in plasma colloid osmotic pressure  edema   plasma volume   aldosterone www.freelivedoctor.com

31.  ANP, GFR   water and solute retention by kidney  exacerbation of edema (anasarca; massive amounts of edematous fluid); hypoalbuminemia   lipoprotein production by the liver In children < 15 yrs, nephrotic syndrome almost always caused by primary renal disease (~ 98 %) In adults nephrotic syndrome may often be associated with secondary renal disease www.freelivedoctor.com

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33. GLOMERULAR DISEASES ( NONINFLAMMATORY ) Membranous Glomerulopathy (epithelial cell and BM disease) a) most common cause of nephrotic syndrome in adults (C5-C9 cytotoxic) b) diffuse thickening of glomerular capillary wall !! c) most cases are idiopathic i) most believed to be autoimmune d) most cells are normocellular or only mildly hypercellular www.freelivedoctor.com

34. e) believed to be caused by i) deposition of immune complexes w/in capillary wall - IgG and C3 ii) formation of in situ immune complexes iii) refer to Heymans nephritis and Goodpasture syndrome iv) classified as non inflammatory since there is NO cellular proliferation f) In adults, a frequent association is with carcinoma !! (i.e., melanoma, lung and colon) www.freelivedoctor.com

35. g) associated with systemic infections i) HBV ii) SLE h) associated with certain drug treatments i) gold, penicillamine, NSAID Clinical a) variable i) spontaneous remission or renal failure w/in 10-15 yrs b) persistent proteinuria w/ normal function c) better response to corticosteroids in children vs. adults www.freelivedoctor.com

36. d) Progression of disease i) stage I : small granular subepithelial deposits ii) stage II : “spikes” of BM protrude between deposits of electron dense material (e.g., IgG, C3) iii) stage III : deposits of electron dense material are incorporated into GBM iv) stage iv : GBM very distorted and damaged www.freelivedoctor.com

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38. Minimal change disease (Lipoid nephrosis; (Epithelial cell disease)) a) major cause of nephrotic syndrome in b)  children < 15 yrs; peak 2-6 yrs i) also in adults with nephrotic syndrome (~ 20 %) c) effacement of “foot” processes d) glomeruli show only “minimal” changes e) most patients are boys who usually present prior to 6 yrs of age i) selective proteinuria (albumin) ii) history of recent Ag exposure ?? f) idiopathic (sometimes follows respiratory infection or routine immunizations) www.freelivedoctor.com

39. Minimal Change Disease www.freelivedoctor.com

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41. g) T cell involvement suggested i) HL patients present w/ similar S & S ii) epithelial cell diseases have altered T ell function h) loss of lipoproteins through the glomeruli  accumulates lipids in proximal tubule cells  foamy cytoplasm. Together with lipids in the urine  LIPOID NEPHROSIS i) remission w/in 8 weeks with use of corticosteroid use (very dramatic response is one hallmark of this disease) j) relapses do not tend to progress to chronic renal failure www.freelivedoctor.com

42. k) development of azotemia should suggest incorrect diagnosis of minimal change disease l) in absence of complications, outcome of patients with epithelial cell disease is same as general population Focal segmental glomerulosclerosis (epithelial cell and BM disease) a) some glomeruli exhibit segmental areas of sclerosis whereas others are normal b) nephrotic syndrome www.freelivedoctor.com

43. c) occurs in the following setting: i) associated with other conditions - HIV - heroin addiction - sickle cell disease - morbid obesity ii) secondary event - IgA nephropathy iii) adaptive process to loss of kidney - renal ablation - advanced stages of other renal diseases (e.g., hypertension) iv) primary disease (e.g., idiopathic focal segmental glomerulosclerosis) www.freelivedoctor.com

44. d) most common cause of nephrotic syndrome in USA i) Hispanics and African Americans e) differs from minimal change disease i) higher incidence of hematuria, reduced GFR, and hypertension ii) poor response to corticosteroids iii) proteinuria is non selective iv) progression to chronic glomerulosclerosis v) IgM and C3 trapping on sclerotic segments www.freelivedoctor.com

45. vi) whether this is a specific disease or is an evolution of minimal change disease is unresolved !! - degeneration of visceral epithelial cells hallmark of FSGN - similar cell damage as seen in minimal change disease vii) genetic basis - NPHS1 gene  encodes nephrin - several mutations of this gene give rise to congenital nephrotic syndrome of the Finnish type (CNF) www.freelivedoctor.com

46. Focal segmental glomerulosclerosis www.freelivedoctor.com

47. - NPHS2 gene - encodes to podocin - mutations give rise to steroid resistant nephrotic syndrome in children Paraproteinemic nephropathies a) abnormally elevated immunoglobulin or immunoglobulin fragments (i.e., paraproteins) may cause renal disease i) present in blood and/or urine ii) renal diseases include - multiple myeloma - Waldenstrom macroglobulinemia - cryoglobulinemia www.freelivedoctor.com

48. Multiple myeloma a) neoplasm of Ig producing plasma cells b) occurs in 5 th decade c) more than 50% of all patients with multiple myeloma have renal involvement i) hypercalcemia ii) hyperuricemia iii) renal infections iv) renal lesions are of three types - tubular and interstitial lesions - amyloidosis - light chain deposition disease www.freelivedoctor.com

49. 2. Waldenstrom macroglobulinemia a)  serum IgM b)  blood viscosity c) renal involvement results in partial or total occlusion of glomerular capillaries 3. Cryoglobulinemia a) IgM or IgG b) defined by their capacity to precipitate at 4  C c) renal disease is often immune complex mediated d) microthrombi in glomeruli e) mesangial & endothelial cell proliferation www.freelivedoctor.com

50. Hereditary nephritis (Alport syndrome) a) most often present as recurrent hematuria b) structural defects in GBM i) specific molecular defect affecting type IV collagen c) usually does not present with nephrotic syndrome and proteinuria d) more severe in men i) die by age 40 e) progressive hearing loss (high frequencies) f) ocular defects most often  the lens www.freelivedoctor.com

51. Benign familial hematuria (thin GBM disease) a) presents as recurrent hematuria in childhood or young adults (similar to Alport syndrome) b) no progression to renal failure (unlike Alport syndrome) c) reduced thickness of GBM (capillary site) d) one of most important causes of asymptomatic hematuria e) IgA nephropathy and this disease are two most major diagnostic considerations of asymptomatic hematuria www.freelivedoctor.com

52. GLOMERULAR LESIONS ASSOCIATED WITH SYSTEMIS DISEASES Diabetic glomerulosclerosis (Kimmelstiel- Wilson Disease) a) diabetic microangiopathy i) small arteries, arterioles and capillaries) - hyaline arteriosclerosis in diabetics involves both afferent and efferent arterioles www.freelivedoctor.com

53. ii) occur by progressive accumulation of GBM material - severity and duration of hyperglycemia !! ?? b) etiology of proteinuria not known i) non-nephrotic proteinuria ii) nephrotic c) earliest lesion is thickening of GBM d) followed by glomerular enlargement e) “diffuse glomerulosclerosis” refers to enlarged glomeruli w/expanded mesangium and diffusely thickened GBM www.freelivedoctor.com

54. f) nodular glomerulosclerosis (i.e., Kimmelstiel-Wilson Disease) – highly specific for diabetes g) one of leading causes of chronic renal failure in USA h) 2 processes play role in diabetic glomerular lesions i) metabolic defect (i.e., glycosylation end products that: -  GBM thickening -  mesangial matrix ii) hemodynamic effects: - glomerular hypertrophy (  GFR) - develop of glomerulosclerosis www.freelivedoctor.com

55. Diabetic glomerulosclerosis www.freelivedoctor.com

56. i) Clinical i) proteinuria usually mild ii) nephrotic syndrome present  renal failure w/in 6 yrs. - severe proteinuria usually associated with other signs of advanced diabetes (i.e., retinopathy) Amyloidosis a) deposits of amyloid w/in glomeruli i) mostly light chain AA or AL type ii) Congo red amyloid positive deposits mainly in mesangium and capillaries www.freelivedoctor.com

57. Amyloid nephropathy www.freelivedoctor.com

58. b) clinical i) nephrotic syndrome ii) progressive glomerular destruction leads to death from uremia Henoch-Schönlein Purpura a) purpuric skin lesions on legs, arms and buttock b) abdominal pain, vomiting, intestinal bleeding, arthralgias and renal abnormalities (hematuria, proteinuria, nephrotic syndrome) c) not all these S & S need to be present www.freelivedoctor.com

59. d) disease most common in children i) 3-8 yrs e) does occur in adults where disease is more severe i) may develop rapidly progressive form of glomerulornephritis with many crescents f) onset often follows upper respiratory infection i) IgA deposits in mesangium which has led to concept that IgA nephropathy (purely a renal disease) and Henoch-Schönlein Purpura are spectra of same disease www.freelivedoctor.com

60. Glomerular Diseases (INFLAMMATORY) (“GLOMERULONEPHRITIS”) Inflammatory lesions of glomerulus characterized by hypercellularity which may be diffuse or focal + proliferation a) Diffuse types of glomerulornephritis i) post infectious ii) membranoproliferative iii) some lupus forms b) Focal types of glomerulornephritis i) IgA ii) other lupus forms www.freelivedoctor.com

61. c) glomerular injury may be either global (entire glomerulus) or segmental d) glomerulornephritis clinically characterized by the NEPHRITIC SYNDROME i) may present with only portions of these S & S (i.e., hematuria) ii) on occasion, proteinuria may predominate e) different forms of GN are differentiated via microscopy www.freelivedoctor.com

62. f) neutrophils contribute to  cellularity, particularly in children i) many neutrophils in glomeruli referred to as “exudative” g) proliferation of podocytes and Bowman’s capsule (visceral and parietal epithelium, respectively) i) leads to formation of “crescents” - highly cellular lesions - extend from Bowman’s capsule into glomerulus having shape of crescents. These are severe lesions (associated with necrosis, early and fibrosis, late) www.freelivedoctor.com

63. Pathogenesis of inflammatory GN Immunologic injury a) trapping of circulating immune complexes b) in situ immune complex formation c) activation of alternative complement d) cell mediated processes Circulating immune complex nephritis a) glomerular trapping of circulating Ag-Ab v complexes. i) glomerulus as “innocent bystander” - penetrate GBM than are  - trapped in GBM www.freelivedoctor.com

64. b) confirmed by EM i) presence of subepithelial “humps” ii) peripheral granular staining directed - IgG - C3 c) alternatively, circulating immune complex do not penetrate GBM but localize to i) mesangium or subendothelium d) trapping is affected by: i) size and charge of aggregates ii) glomerular hemodynamics iii) presence of vasoactive substances www.freelivedoctor.com

65. e) Ag may be exogenous or endogenous i) exogenous - bacterial Ag induced by 1. Strep infections 2. bacterial endocarditis 3. viruses (HBV) ii) endogenous - DNA in pathogenesis of lupus 2. In Situ immune complex formation a) Goodpasture Syndrome b) Ag (endogenous) already embedded in GBM i) Ab binds !! ii) linear localization of IgG along GBM www.freelivedoctor.com

66. c) Ag-Ab interaction activates complement ! i) rapidly progressive GN occurs 3. Alternative complement activation a) focal glomerulornephritis i) caused by IgA b) form of membranoproliferative GN 4. Cell-mediated Immunity a) no direct evidence for any specific GN caused by cell mediated processes\ i) indirect evidence for a delayed (type iv) cell type GN - lymphocytes from some patients with GN react in vitro with a glomerular Ag www.freelivedoctor.com

67. once immune complexes localized w/in GBM other secondary affects cause immune mediated injury  mediators: a) complement (C5b-C9; cytotoxic) b) neutrophils (chemotaxis via C5a) c) monocytes & macrophages d) coagulation system NEPHRITIC SYNDROME hematuria oliguria  BUN and creatinine hypertension proteinuria (< 3.5 g/day); ± edema www.freelivedoctor.com

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69. Glomerulornephritis - - INFLAMMATORY Acute GN (post infectious GN) a) sudden onset of nephritic syndrome b) diffuse hypercellularity og glomeruli c) most often associated with i) group A β -hemolytic streptococci - S. pyogenes ii) others less frequently - staph - spirochetes - viruses d) most often affect children i) one of most common renal diseases www.freelivedoctor.com

70. e) latent period of ~ 10-14 days f) diffuse enlargement and hypercellularity of glomeruli, hypercellularity due to: i) proliferation of endothelial and mesangial cells and infiltration of neutrophils and monocytes g) characteristics: i) subepithelial “humps” of GBM ii) granular IgG and C3 along GBM in association with “humps” h) Clinical: i) most resolve but in rare occasions can progress to develop many crescents and renal failure www.freelivedoctor.com

71. Acute GN (post infectious GN) www.freelivedoctor.com

72. ii) primary infection in pharynx or skin iii) nephritic syndrome (abrupt) - hematuria - oliguria - facial edema - hypertension iv)  serum C3 Membranoproliferative GN a) characterized by GBM thickening (i.e., “membrano”) + mesangial cell proliferation (“proliferative ”) www.freelivedoctor.com

73. b) two major groups: Types I and II (+ III) i) Type I: majority of cases are idiopathic. Associations with - HBV - HCV - bacterial endocarditis - strep infections - granular deposition of Ig (IgG, IgM) and complement (C3) and C1q and C4 ii) type II (and III) - circulating C3 Ab (C3 nephritic factor)   C3 (hypocomplementemia) www.freelivedoctor.com

74. - characteristic “ribbon-like” zone of  cellularity on thickened GBM (“dense deposit disease”) c) Clinical: i) occurs primarily in older children and young adults ii) nephritic or nephrotic syndrome iii) low levels of C3 iv) do not have postinfectious GN v) no systemic inflammatory condition vi) most progress to end-stage renal failure, regardless of treatment !! www.freelivedoctor.com

75. Membranoproliferative GN Type I www.freelivedoctor.com

76. SLE (immune complex disease); “Lupus Nephritis” a) chronic autoimmune disorder b) affects 1  young women c) > 70% will develop renal disease d) circulating anti DNA Ab and  C3, etc. i) T cell function is decreased ii) trapping of immune complexes cause of the renal damage ( in situ ) e) nephritic or nephrotic syndrome f) dysfunction of renal tubules (usually accompanies GN) g) cellular proliferation is mesangial, subepithelial and subendothelial cells www.freelivedoctor.com

77. i) involves the glomeruli w/more severe inflammation h) hematoxylin bodies  only light microscopic feature of tissue damage i) episodic inflammation – usually present with old lesions j) IgG most common. IgA and IgM also present. Complement present i) IgG, IgA, IgM, C3, C4 and C1q present in same glomerulus “FULL HOUSE” www.freelivedoctor.com

78. k) 5 classes based on WHO classification i) Class I – histologically normal ii) Class II – pure mesangial lesion iii) Class III – focal and segmental GN iv) Class IV – diffuse proliferative GN v) Class V – diffuse membranous - Class II and V have more benign course relative to Class III and IV l) renal disease  major consequence of SLE i) renal failure  cause of death in ~ 33 % of patients with SLE www.freelivedoctor.com

79. Focal GN a) only some of the glomeruli are involved i) or to segments of the glomerulus b) different from focal & segmental glomerulosclerosis which is a noninflammatory disease i) glomeruli essentially normocellular c) many conditions produce this defect i) primary renal disease or systemic diseases such as IgA nephropathy and Henoch-Schönlein GN (see table) www.freelivedoctor.com

80. d) IgA nephropathy (Berger Disease) i) association with chronic liver disease - impaired capacity to remove circulating immune complexes ii) IgA and fibronectin found in > 70 % of IgA nephropathy patients. iii) Ag involve bacterial, viral and dietary - infectious agents is suggested from data showing hematuria following upper respiratory or GI infection !! - dietary agents  milk proteins I in mesangium; gluten-sensitivity www.freelivedoctor.com

81. iv) C3 and properdin (via activation of alternate pathway) usually present together with IgA in mesangium - C1q and C4 (classic pathway activation) are typically absent v) IgA nephropathy is a mesangial proliferative lesion (granular deposits) vi) clinical - common in young men (15-30) - presents with hematuria - nephrotic type proteinuria is uncommon (may indicate more severe glomerular damage) www.freelivedoctor.com

82. - ~ 20 % of IgA nephropathy patients progress to end-stage renal failure !! - most common type of 1  GN in several parts of the world (France, Italy, Japan, Singapore and Austria) -- ~ 20 %. In USA is responsible for ~ 3-10 % of 1  GN www.freelivedoctor.com

83. IgA nephropathy (Berger Disease) www.freelivedoctor.com

84. e) Henoch-Schönlein (HS) Purpura i) close relationship with IgA nephropathy - differentiate: IgA purely renal; HS is a systemic disease, etc. Crescentic GN a) ominous morphological pattern i) majority of glomeruli are surrounded by accumulation of cells in Bowman’s capsule (parietal epithelial cells) ii) indicative of fulminant glomerular damage and always leaves scarring www.freelivedoctor.com

85. iii) does not denote a specific etiologic form of GN b) most patients with substantial (~ 80%) crescents progress to renal failure c) Fibrin in Bowman’s capsule is important for the formation of glomerular crescents i) Tx with anticoagulants d) associated with areas of segmental necrosis within glomeruli e) Types: i) Type I – anti-GBM antibody disease (GOODPASTURE SYNDROME) or idiopathic www.freelivedoctor.com

86. - plasmapheresis to remove circulating Ab is helpful in this type of RPGN (i.e., crescentic) - etiology unknown ii) Type II – immune-complex mediated disease - can be complication of any of the immune complex nephritides  SLE, IgA nephropathy,  HS Purpura  all these show granular pattern (characteristic of immune complex) - not helped with plasmapheresis www.freelivedoctor.com

87. iii) Type III – pauci-immune type - lack of anti-GBM Ab or immune complexes - patients do have ANCA (~90%)  either c or p patterns } in some cases, is a component of vasculitides (i.e., Wegener Granulomatosis) f) clinical: i) hematuria with red cell cast in urine ii) transplant or chronic dialysis in most patients www.freelivedoctor.com

88. Crescentic GN www.freelivedoctor.com

89. TUBULOINTERSTITIAL DISEASE Most tubular diseases involve the interstitium 2 distinct types of diseases a) ischemic or toxic tubular injury  i) ATN ii) acute renal failure b) inflammatory diseases i) “tubulointerstitial nephritis” ATN (Clinical entity) Destruction of tubular epithelial cells Acute suppression of renal function www.freelivedoctor.com

90. Most common cause of acute renal failure: a) oliguria (, 400 ml/day) b) severe glomerular disease (RPGN c) acute thrombotic angioplasties d) diffuse renal vascular disease (Polyarteritis nodosa) e) diffuse cortical necrosis f) interstitial nephritis (acute drug- induced) g) acute papillary necrosis www.freelivedoctor.com

91. Is reversible and arise from: a) severe trauma b) septicemia (shock and hypotension) c) ATN associated with shock – “ischemic” - d) mismatched blood transfusion and other hemodynamic problems as well as myoglobinuria  all reversible ischemic ATN e) nephrotoxic ATN – variety of poisons i) - heavy metals (Hg) ii) - CCl4 iii) - etc. www.freelivedoctor.com

92. Occurs frequently a) since it is reversible, proper management means difference between recovery and death 2 major problems are: a) - tubular injuries b) - blood flow disturbances Major disturbances: a) Change charge in tubules (mainly -) i) Na+ - K+ - ATPase cause less Na+ reabsorption and traps Na+, within tubule with more distal tube delivery of Na+ which causes vasoconstriction (feedback) www.freelivedoctor.com

93. Treatment protocol 1) - initiating phase 2) - maintenance phase 3) - recovery phase Initiating phase Last about 36 hours. Incited by: a) medical, surgical, obstetric event i) slight oliguria (transient decrease in blood flow) ii) rise in BUN www.freelivedoctor.com

94. Maintenance phase Anywhere from 2-6 days a) sharp decline in urine output (50-400 ml/day) i) may last few days to 3 weeks b) fluid overload, uremia c) may die from poor management Recovery phase Steady increase in urine output (up to 3L/day) Electrolyte imbalances may continue Increased vulnerability to infection Because of these, about 25% patients die in this phase www.freelivedoctor.com

95. Tubulointerstitial Nephritis (TIN) Inflammatory disease of Interstitium/tubules Glomerulus not involved at all or only late in disease Infections induced TIN – “pyelonephritis” Non infection – interstitial nephritis a) Caused by: i) drugs ii) metabolic disorders (hypokalemia) iii radiation injury iv) immune reactions www.freelivedoctor.com

96. TIN divided into 2 categories, regardless of etiology a) - acute b) - chronic Acute Pyelonephritis Kidney/renal pelvis (distal to collecting ducts) Caused by bacterial infections (lower UTI) – cystitis, urethritis and prostatitis or upper UTI – (pyelonephritis) or both tracts Principle causative bacteria are gram - rods a) E. coli (most common), Proteus, enterobacter, Klebsiella www.freelivedoctor.com

97. 2 routes bacteria can reach kidney a) blood stream (not very common) b) lower urinary tract (ascending infections) i) - catheterization ii) - cystoscopy Most commonly affect females (in absence of instrumentation) a) close proximity to rectum b) shorter urethra Urine sterile, flushing keeps bladder sterile a) Obstruction increased incidence of UTI i) prostate hypertrophy ii) uterine prolapse iii) UT obstructions www.freelivedoctor.com

98. Incompetent vesicoureteral orifice a) one way valve (at level of bladder) b) incompetence – reflux of urine into ureters – vesicoureteral reflux (VUR) – usually congenital defect – 30-50% of young children with UTI c) - usually congenital defect d) spinal cord injury can produce a flaccid bladder (residual volume remain in urinary tract) – favors bacterial growth www.freelivedoctor.com

99. e) Diabetes increases risk of serious complications i) septicemia ii) recurrence of infection iii) diabetic neuropathy – dysfunction of bladder f) pregnancy i) 6% develop pyelonephritis; 40- 60% develop UTI if not treated Chronic pyelonephritis and reflux nephropathy Interstitial inflammation with scarring of renal parenchyma Important cause of chronic renal failure www.freelivedoctor.com

100. Two forms: a) - Chronic obstructive pyelonephritis b) - Chronic reflux-associated pyelonephritis Chronic obstructive pyelonephritis Can be bilateral (congenital disease) Obstruction predisposes kidney to infection recurrent infections on obstructive foci causes scarring – chronic pyelonephritis! www.freelivedoctor.com

101. chronic reflux-associated pyelonephritis (reflux nephropathy) More common form of chronic pyelonephritis scarring Occurs from superimposed of a UTI on vesiculouretheral and intrarenal reflux a) reflux may be bi- or unilateral i) unilateral causes atrophy ii) bilateral can cause chronic renal insufficiency iii) diffuse or patchy - Unclear if sterile vesiculouretheral disease causes renal damage www.freelivedoctor.com

102. Hallmark is scarring involving pelvis/calyces, leading to papillary blunting and deformities Renal papilla – area of kidney where opening from collecting ducts enters renal pelvis Kidneys are asymmetrically contracted Signs and Symptoms: a) hypertension b) seen following normal physical exam c) slowly progressive  late in disease d) can cause loss of concentrating mechanisms (if bilateral and progressive) i) - polyuria ii) - nocturia www.freelivedoctor.com

103. Drug-induced interstitial nephritis Acute TIN – seen with synthetic penicillins, diuretics (thiazides), NSAI a) disease begins ~15 days (2-40 range) i) fever ii) rash (25% cases) iii) renal findings: hematuria, leukouria iv) increased serum creatinine or acute renal failure with oliguria (50% of cases) Immune mechanism is indicated (suggested) a) IgE increased (hypersensitivity – Type I) Injury produced by IgE and cell-mediated immune reactions www.freelivedoctor.com

104. Analgesic Nephropathy Patients who consume large quantities of analgesics may develop chronic interstitial nephritis , often associated with renal papillary necrosis Usually result from consumption of a mixture for long periods of time: a) - aspirin b) - caffeine c) - acetaminophen d) - codeine e) - phenacetin www.freelivedoctor.com

105. Primary pathogenesis is a) papillary necrosis followed by b) interstitial nephritis is secondary c) acetaminophen – oxidative damage d) aspirin inhibits prostaglandins – vasoconstriction e) all the above leads to papillary ischemia Chronic renal failure, hypertension and anemia Complications may be incidence of “transitional cell carcinoma” of renal pelvis or bladder. www.freelivedoctor.com

106. Diseases of Blood Vessels Nearly all diseases of kidney involve blood vessels. Kidneys involved in pathogenesis of essential and secondary hypertension Systemic vascular disease (i.e. arteritis) also involve kidney www.freelivedoctor.com

107. Benign nephrosclerosis Renal changes associated with benign hypertension a) always associated with hyaline arteriosclerosis Kidneys are atrophic Many renal diseases cause hypertension which in turn may lead to benign nephrosclerosis. Therefore this disease seen simultaneously with other diseases of kidney www.freelivedoctor.com

108. This disease by itself usually does not cause severe damage a) mild oliguria b) loss (slight) of concentrating mechanism c) decreases GFR d) mild degree of proteinuria is a constant finding These patients usually die from hypertensive heart disease or cerebrovascular disease rather than from renal disease www.freelivedoctor.com

109. Malignant hypertension Less common than benign May arise de novo (without preexisting hypertension) or may arise suddenly in patient with mild hypertension Factors: a) initial event – some form of vascular damage to kidney b) result is increased permeability of small blood vessels to fibrinogen and other plasma proteins, endothelial injury and platelet deposits www.freelivedoctor.com

110. c) This leads to appearance of fibroid necrosis in small arteries and arterioles and intravascular thrombosis d) platelets (platelet derived growth factors) and plasma cause intimal hyperplasia of vessels resulting in hyperplastic arteriosclerosis, which is typical of malignant hypertension e) narrowing of renal afferent arteriole stimulates angiotensin II production (ischemic-induced) with aldosterone secretion increases www.freelivedoctor.com

111. Diastolic pressure > 120 mmHg, papilledema, encephalopathy, CV disorders, renal failure 90% deaths due to uremia 10% deaths due to CV or cerebral disorders (hemorrhage) www.freelivedoctor.com

112. Thrombotic Microangiopathies Clinical syndromes Widespread thrombosis in microcirculation (a/C) Damage to endothelial cells !! Diseases: a) childhood hemolytic-uremia syndrome (HUS) b) Thrombotic thrombocytopenic purpura Most follow intestinal infection (E. Coli) Disease is one of main causes of acute renal failure in children Vasoconstriction (decreased NO, increased endothelium, decreased PGI 2 ) www.freelivedoctor.com

113. Although the various diseases have diverse etiologies, 2 predominant factors  a) endothelial injury and activation, leading to vascular thrombosis and, b) platelet aggregation c) both of these causing vascular obstruction and vasoconstriction 1.- Endothelial injury activation can be initiated by a variety of agents, while some remain elusive a) denuding the endothelial cells, exposes vascular to thrombogenic subendothelium i)  NO, PGI 2 , enhance platelet aggregation and vasoconstriction www.freelivedoctor.com

114. ii) vasoconstriction also initiated via endothelial derived endothelin-1 iii) activation of endothelial cells increases adhesiveness to platelets, etc iv) endothelial cells elaborate large multimers of vW factor  platelet aggregation 2.- Platelet Aggregation serum factors causing platelet aggregation a) large multimers of vW factor (secreted by endothelial cells) i) usually cleaved by ADAMTS-13 (vW factor-cleaving metalloprotease www.freelivedoctor.com

115. HUS/TTP 1.- Classic childhood HUS (> 75%) bloody diarrhea  intestinal infection a) verocytotoxin-releasing bacteria i) Verocytotoxin-producing strains of E. coli (eg 0157:H7 or 0103); ii) Similar to Shigella toxin. iii) undercooked hamburger iv) “petting” zoos www.freelivedoctor.com

116. characterized: a) sudden onset (post GI or influenza infection) b) hematemesis c) melena d) severe oliguria e) hematuria f) hemolytic anemia (microangiopathic) g) hypertension in > 50% of cases www.freelivedoctor.com

117. Pathogenesis a) related to Shigella toxin i) affects endothelium -  adhesion of leukocytes -  endothelin and  NO - endothelial lysis (inpresence of cytokines such as TNF ii) these changes favor thrombosis and vasoconstriction iii) verocytotoxin can directly bind to platelets and cause activation most patients recover in few weeks, with proper care (i.e., dialysis, etc); < 5% lethality www.freelivedoctor.com

118. 2.- Adult HUS associated with: a) infection i) typhoid fever ii) E. coli septicemia iii) etx or shiga toxin iv) viral infections b) antiphospholipid syndrome i) SLE ii) similar to membranoproliferative GN but w/out immune complex deposits c) complication of pregnancy (“postpartum renal failure” www.freelivedoctor.com

119. d) vascular renal disease i) systemic sclerosis ii) malignant hypertension e) chemotherapeutic and immunosuppressive drugs i) mitomycin ii) cyclosporine iii) bleomycin iv) cisplatin v) radiation Tx 3.- Familial HUS recurrent thromboses (~ 50 lethality) deficit of complement regulatory protein a) Factor H www.freelivedoctor.com

120. 4.- Idiopathic Thrombotic Thrombocytopenic Purpura Manifested by: a) thrombi in glomeruli b) fever c) hemolytic anemia d) neurologic symptoms e) thrombocytopenic purpura defect in ADAMTS-13 (acquired or inherited) a) normally cleaves large vW multimers i) large vW factors promote platelet aggregation more common in women most patients < 40 years www.freelivedoctor.com

121. neurologic involvement is dominant feature renal involvement in ~ 50% of patients a) eosinophilic thrombi in glomerular capillaries, interlobular artery and afferent arterioles b) similar changes as with HUS exchange transfusion and steroid Tx  mortality rate to < 50% www.freelivedoctor.com

122. Cystic Diseases Common and difficult to diagnose In adult polycystic disease – major cause of chronic renal failure Confused with malignant tumors Simple cyst a) Innocuous lesion b) Occur as single or multiple cysts c) Usually 1-5 cm diameter d) Clear fluid, smooth membrane, gray glistening www.freelivedoctor.com

123. e) Single layer of cuboidal cells f) Usually confined to cortex g) No clinical significance Importance to differentiate from tumors a) are fluid filled rather than solid b) have smooth contours c) almost always avascular Occur in patients with end-stage renal disease who have undergone long term dialysis Occasionally, renal adenomas or adenosarcoma arise from these cysts www.freelivedoctor.com

124. Adult polycystic kidney disease (autosomal dominant) Multiple expanding cysts of both kidneys that eventually destroy parenchyma of kidney Accounts for 10% of chronic renal failure In 90% of families, PKD1 (defective gene) is located on chromosome #16 a) encodes for protein (polycystin-1), extracellular and is a cell membrane associated protein b) how mutations in this gene cause cysts formation is unclear www.freelivedoctor.com

125. Polycystin 2 (PKD2 gene) mutations also cause cyst formation No symptoms until 4th decade a) by then, kidneys are very large b) common complaint is “flank pain” c) hematuria d) most important complications i) hypertension (~75% patients) ii) UTI iii) aneurysms in circle of Willis (10- 30%) and risk for subarachnoid hemorrhage www.freelivedoctor.com

126. iv) Asymptomatic liver cysts in ~30- 40% v) fatal disease (uremia or hypertension) vi) progresses very slowly viii) Treatment with renal transplantation Childhood polycystic kidney disease (autosomal recessive) Rare Serious manifestations at birth and young infants may die quickly a) pulmonary failure b) renal failure www.freelivedoctor.com

127. Numerous small cysts in cortex and medulla Bilateral disease Many epithelial cysts in liver Patients who survive infancy develop liver cirrhosis (congenital hepatic cirrhosis) Unidentified gene location on chromosome 6p Urinary Outflow-Obstruction Renal Stones Urolithiasis: Calculus formation at any level in urine collecting system, most often arise in kidney www.freelivedoctor.com

128. Occur frequently (!1% of all autopsies) More common in males Familial tendency ~75% of renal stone a) calcium oxalate b) calcium phosphate 15% composed of magnesium ammonium phosphate 10% uric acid or cystine stones All stones composed of mucoprotein www.freelivedoctor.com

129. Cause of stones is obscure a) Supersaturation in urine of stones constituents (exceeds solubility) b) 50% of patients forming “calcium stones” do not have increased plasma Ca ++ but do have high urine Ca ++ i) most Ca ++ absorbed from gut in large amounts (absorptive hypercalciuria) ii) only 5-10% has associated hypercalcemia www.freelivedoctor.com

130. - hyperparathyroidism - Vit D intoxication - Sarcoidosis (autoimmune disease, bacterial - productions of Vit D (toxic) c) Magnesium ammonium Phosphate stones i) almost always occur in patients with alkaline urine due to UTI ii) proteus vulgaris and staph split urea in kidney and therefore predispose patient to urolithiasis www.freelivedoctor.com

131. Gout and diseases involved with rapid cell turnover (e.g. leukemia) lead to high uric acid levels in urine and possibility of uric acid stones Unlike magnesium ammonium phosphate stone, both uric acid and cystine stones are more likely to form when urine is acidic (pH < 5.5) Stone formation 80% unilateral Hematuria and predispose to infection www.freelivedoctor.com

132. Hydronephrosis Dilation of renal pelvis and calyces with atrophy of parenchyma caused by obstruction of outflow of urine Most common causes: a) congenital i) atresia of the urethra (absence of a normal body passage or opening from an organ to other parts of the body) www.freelivedoctor.com

133. b) acquired i) stones ii) tumors iii) inflammation iv) spinal cord damage with paralysis of bladder v) normal pregnancy Bilateral nephrons only if blockage is below level or ureters Major problems are tubular with impaired concentration mechanisms Obstruction leads to inflammatory response a) interstitial fibrosis Complicating pyelonephritis is common www.freelivedoctor.com

134. Tumors Most common malignant tumor is: a) renal cell carcinoma (80-85% of all 1° Ca in kidney) b) nephroblastoma (Wilms tumor) c) calyces and pelvis Tumor of lower urinary tract are 2x as common as renal cell Cancer 1.- Renal cell Ca Derived from renal tubular epithelial cells a) located primarily in cortex 2-3% of all cell Ca in adults (~30,000 cases/yr) 6th to 7th decades in life www.freelivedoctor.com

135. Higher risk in smokers and occupational exposure to cadmium 30 fold increase in susceptibility in patients with polycystic disease Classification: a) clear cell Cancer i) most common (70-80% renal ca) b) most are sporadic c) familial links (von Hippel-Lindau [VHL]) i) autosomal dominant disease ii) predispose to a variety of CA – hemangioblastoma of cerebellum and retina www.freelivedoctor.com

136. iii) genetic abnormality chromosome 3 (loss of tumor suppressor gene) – clear cell CA 2.- Papillary renal cell Ca 10-15% of all renal CA Multifocal and bilateral Both sporadic and familial forms No genetic abnormalities in chromosome 3 a) Protooncogene on chromosome 7 www.freelivedoctor.com

137. 3- Chromophobe Renal Carcinoma Least common (~5% of all renal cell CA) Cortical collecting ducts or their collated cells Stain more darkly than clear cell CA Lack of a lot of chromosomes (1,2,6,10,17,&21) Have good prognosis Renal cell CA are difficult to diagnose! a) Present with hematuria in ~50% of cases 4. Wilms tumor Occurs infrequently in adults 1/3 most common organ cancer in children <10 years, therefore, one of major cancers in children Sporadic or familial in nature a) autosomal dominant www.freelivedoctor.com

138. Urinary bladder and collecting system tumors (Renal pelvis to urethra) Tumors in collecting system above bladder are uncommon Bladder Cancer more frequent cause of death than are kidney tumors a) Bladder tumors i) small benign papillomas (rare) ii) large invasive CA iii) most recur after removal and kill by infiltrative obstruction of ureters rather than by metastasizing iv) Shallow lesion have good prognosis www.freelivedoctor.com

139. v) deep invasive Cancer, survival (5yr) is <20% with overall 5 yr survival at 50-60% b) - Cancer of ureters is very rare i) 5 yr survival <10% www.freelivedoctor.com

140. RENAL PATHOLOGY Dr. Richard M Raymond Diseases affect a) glomeruli (often immunological) b) tubules (toxic, infectious) c) interstitium (toxic, infectious) d) vascular Disease in one area usually results in damage or disease on neighboring areas Large functional reserve a) > 75% destruction before impairment www.freelivedoctor.com

141. Congenital Anomalies Review page 961 , “Robbins and Cotran” PATHOLOGIC BASIS OF DISEASE . 7 TH ed. Understand and describe the following congenital anomalies of the kidney a) agenesis b) hypoplasia c) ectopic kidney d) horseshoe kidney www.freelivedoctor.com

142. GLOMERULI Network of capillaries a) lined by fenestrated endothelium b) basement membrane c) podocytes (“foot processes”) Glomeruli capillary wall a) lined with fenestrated endothelium ( 70- 100 nm) b) glomerular basement membrane (GBM) i) consist of collagen (type IV), heparan sulfate, laminin, glycoproteins www.freelivedoctor.com

143. - Type IV collagen forms network to which glycoprotein's attach c) visceral epithelial cells (podocytes; “foot processes”) i) composed of interdigitating processes embedded to basement membrane ii) adjacent foot processes are separated by 20-30 nm filtration slits bridged by thin diaphragm (nephrin) d) entire glomerulus is supported by mesangial cells i) lying between capillaries www.freelivedoctor.com

144. ii) phagocytic, contractile, proliferate, secretion of biologically active mediators - modified smooth muscle cells iii) involved in many types of GN Glomeruli a) very permeable to H 2 O and small solutes b) impermeable to proteins (~ 70 kDa or larger; i.e., albumin) c) “glomerular barrier function” i) selective permeability based on: - size - charge: cationic more permeable www.freelivedoctor.com

145. ii) podocytes important in maintaining this “function” - slit diaphragm maintain size- selectivity by specific proteins 1.- NEPHRIN : extend towards each other from neighboring podocytes comprising the slit diaphragm !! 2.- PODOCIN : intracellular (podocyte) protein where nephrin attaches - mutations in genes encoding these proteins give rise to nephrotic syndrome (i.e., glomerular disease) www.freelivedoctor.com

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150. Clinical Manifestations Termimology a) Azotemia :  BUN and  creatinine i) related to  GFR - prerenal azotemia:  RBF, hypoperfusion w/out parenchymal damage - postrenal azotemia: obstruction of urine flow below level of kidney www.freelivedoctor.com

151. b) when azotemia becomes associated with a variety of clinical S & S and biochemical abnormalities  UREMIA Major Renal Syndromes a) Nephritic syndrome : glomerular disease, hematuria, mild  moderate proteinuria, azotemia, edema,  BP i) classic presentation of post streptococcal GN b) Nephrotic syndrome : heavy proteinuria (> 3.5 g/day), hypoalbuminemia, severe edema, hyperlipidemia and lipiduria www.freelivedoctor.com

152. c) Acute renal failure : oliguria/anuria, recent onset of azotemia, can result from GN, tubular or interstitial disease d) Nephroliathiasis : renal stones, renal colic, hematuria, recurrent stone formation e) Chronic renal failure : 4 stages i)  renal reserve: GFR ~ 50% normal BUN & creatinine normal, pt. asymptomatic, more susceptible to develop azotemia ii) renal insufficiency: GFR 20-50% of normal, azotemia, anemia,  BP, polyuria/nocturia (via  concentrating ability) www.freelivedoctor.com

153. iii) renal failure : GFR less than 20-25% kidneys cannot regulate volume, ions: edema, hypocalcemia, metabolic acidosis, uremia with neurological, CV and GI complications iv) end stage renal disease : GFR < 5% of normal, terminal stage of uremia www.freelivedoctor.com

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155. Glomerular Disease Chronic GN one of most common causes of chronic renal failure Glomerular disease often associated with systemic disorders such as: a) diabetes mellitus b) SLE c) amyloidosis d) vasculitis - pts. with manifestations of glomerular disease should be considered for these systemic syndromes, etc. www.freelivedoctor.com

156. GN characterized by one or more of the following (inflammatory diseases of glomerulus) a) hypercellularity : i) cell proliferation of mesangial cells or endothelial cells ii) leukocyte infiltration (neutrophils, monocytes and sometimes lymphocytes) iii) formation of crescents - epithelial cell proliferation (from immune/inflammatory injury) - fibrin thought to elicit this injury (TNF, IL-1, IFN-  are others) www.freelivedoctor.com

157. b) basement membrane thickening i) deposition of immune complexes on either the endothelial or epithelial side of GBM or w/in GBM itself ii) thickening of GBM proper as with diabetes mellitus (diabetic glomerulosclerosis) c) hyalinization (hyalinosis) and sclerosis i) accumulation of material that is eosinophilic and homogeneous - obliterates capillary lumen of glomerulus (sclerotic feature) www.freelivedoctor.com

158. - result of capillary or endothelial injury. Usually end result of various forms of glomerular damage (intraglomerular thromboses, accumulation of other metabolic materials) Since etiology of primary GN is unknown, classification is based on histology. Subdivided: a) diffuse (all glomeruli) b) global (entire glomerulus) c) focal (portion of glomeruli) d) segmental (part of each glomerulus) e) mesangial (affecting mesangial region) www.freelivedoctor.com

159. Pathogenesis of Glomerular Disease/Injury Little is known regarding etiology or triggering Immune mechanisms underlie most cases of primary GN and many of the secondary cases a) 2 forms of Ab-associated injury i) injury resulting from soluble Ag-Ab deposits in glomerulus ii) injury from Ab reacting in-situ with glomerulus - insoluble fixed glomerular Ag - molecules planted w/in glomerulus www.freelivedoctor.com

160. Examples In Situ Immune Complex Deposition a) Ab act directly with intrinsic tissue Ag “ planted” in the glomerulus from the circulation b) 2 forms of Ab-mediated glomerular injury i) anti-GBM Ab-induced nephritis - Ab directed against fixed Ag in GBM - in humans spontaneous AGBM nephritis is autoimmune disease www.freelivedoctor.com

161. - Ab bind along GBM forming a “linear pattern” - sometimes AGBM Ab cross react with BM of lung  GOODPASTURE SYNDROME - < 1% of GN cases - some cases show severe glomerular damage and rapidly progressive crescentic GN ii) Heymann nephritis - a form of membranous GN - Ab bind along GBM in “granular pattern” www.freelivedoctor.com

162. c) Trigger for induction of autoimmune Ab is unclear i) ETX ii) mercuric chloride iii) graft-vs.-host reaction Ab can react with “planted” Ag in GBM a) cationic Ag binding to anionic GBM sites b) bacterial byproducts c) IgG deposition in mesangium www.freelivedoctor.com

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164. re: Ab-mediated injury  Ag-Ab deposition in GBM is major pathway of glomerular injury !! a) largest proportion of cases of GN are granular immune pattern along the GBM or mesangium Cell mediated immune GN a) sensitized T cells can cause glomerular injury, in absence of immune deposits i) may occur in some forms of rapidly progressive GN www.freelivedoctor.com

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166. Mediators of immune injury seen as loss of glomerular barrier function a) proteinuria b)  GFR in some instances Complement-leukocyte mechanism a) well established i) activated complement (C5a)  neutrophils and monocytes - release proteases  degrade GBM ii) ROS iii) some are neutrophil-independent - C5-C9 (lytic component; membrane attack complex) www.freelivedoctor.com

167. - Membrane attack complex stimulate growth factors (TGF)  GBM thickening iv) direct cytotoxicity Other mechanisms of glomerular injury a) epithelial cell injury i) can be induced by Ab to visceral epithelial cell Ag ii) toxins iii) cytokines iv) loss of foot processes - caused by alterations in nephrin www.freelivedoctor.com

168. b) renal ablation GN i) any renal disease   GFR (30-50% of normal) - lead to end stage renal failure ii) patients develop proteinuria and diffuse glomerulosclerosis - initiated by unaffected glomeruli  hypertrophy to maintain function  single nephron hypertension  damage www.freelivedoctor.com

169. Glomerular Syndromes and Disorders Nephrotic Syndrome a) massive proteinuria (> 3.5 g/day) b) hypoalbuminemia c) generalized edema d) hyperlipidemia and lipiduria Initial event is derangement of GBM  increasing permeability and progressive loss of plasma proteins  hypoalbuminemia  decrease in plasma colloid osmotic pressure  edema   plasma volume   aldosterone www.freelivedoctor.com

170.  ANP, GFR   water and solute retention by kidney  exacerbation of edema (anasarca; massive amounts of edematous fluid); hypoalbuminemia   lipoprotein production by the liver In children < 15 yrs, nephrotic syndrome almost always caused by primary renal disease (~ 98 %) In adults nephrotic syndrome may often be associated with secondary renal disease www.freelivedoctor.com

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172. GLOMERULAR DISEASES ( NONINFLAMMATORY ) Membranous Glomerulopathy (epithelial cell and BM disease) a) most common cause of nephrotic syndrome in adults (C5-C9 cytotoxic) b) diffuse thickening of glomerular capillary wall !! c) most cases are idiopathic i) most believed to be autoimmune d) most cells are normocellular or only mildly hypercellular www.freelivedoctor.com

173. e) believed to be caused by i) deposition of immune complexes w/in capillary wall - IgG and C3 ii) formation of in situ immune complexes iii) refer to Heymans nephritis and Goodpasture syndrome iv) classified as non inflammatory since there is NO cellular proliferation f) In adults, a frequent association is with carcinoma !! (i.e., melanoma, lung and colon) www.freelivedoctor.com

174. g) associated with systemic infections i) HBV ii) SLE h) associated with certain drug treatments i) gold, penicillamine, NSAID Clinical a) variable i) spontaneous remission or renal failure w/in 10-15 yrs b) persistent proteinuria w/ normal function c) better response to corticosteroids in children vs. adults www.freelivedoctor.com

175. d) Progression of disease i) stage I : small granular subepithelial deposits ii) stage II : “spikes” of BM protrude between deposits of electron dense material (e.g., IgG, C3) iii) stage III : deposits of electron dense material are incorporated into GBM iv) stage iv : GBM very distorted and damaged www.freelivedoctor.com

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177. Minimal change disease (Lipoid nephrosis; (Epithelial cell disease)) a) major cause of nephrotic syndrome in b)  children < 15 yrs; peak 2-6 yrs i) also in adults with nephrotic syndrome (~ 20 %) c) effacement of “foot” processes d) glomeruli show only “minimal” changes e) most patients are boys who usually present prior to 6 yrs of age i) selective proteinuria (albumin) ii) history of recent Ag exposure ?? f) idiopathic (sometimes follows respiratory infection or routine immunizations) www.freelivedoctor.com

178. Minimal Change Disease www.freelivedoctor.com

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180. g) T cell involvement suggested i) HL patients present w/ similar S & S ii) epithelial cell diseases have altered T ell function h) loss of lipoproteins through the glomeruli  accumulates lipids in proximal tubule cells  foamy cytoplasm. Together with lipids in the urine  LIPOID NEPHROSIS i) remission w/in 8 weeks with use of corticosteroid use (very dramatic response is one hallmark of this disease) j) relapses do not tend to progress to chronic renal failure www.freelivedoctor.com

181. k) development of azotemia should suggest incorrect diagnosis of minimal change disease l) in absence of complications, outcome of patients with epithelial cell disease is same as general population Focal segmental glomerulosclerosis (epithelial cell and BM disease) a) some glomeruli exhibit segmental areas of sclerosis whereas others are normal b) nephrotic syndrome www.freelivedoctor.com

182. c) occurs in the following setting: i) associated with other conditions - HIV - heroin addiction - sickle cell disease - morbid obesity ii) secondary event - IgA nephropathy iii) adaptive process to loss of kidney - renal ablation - advanced stages of other renal diseases (e.g., hypertension) iv) primary disease (e.g., idiopathic focal segmental glomerulosclerosis) www.freelivedoctor.com

183. d) most common cause of nephrotic syndrome in USA i) Hispanics and African Americans e) differs from minimal change disease i) higher incidence of hematuria, reduced GFR, and hypertension ii) poor response to corticosteroids iii) proteinuria is non selective iv) progression to chronic glomerulosclerosis v) IgM and C3 trapping on sclerotic segments www.freelivedoctor.com

184. vi) whether this is a specific disease or is an evolution of minimal change disease is unresolved !! - degeneration of visceral epithelial cells hallmark of FSGS - similar cell damage as seen in minimal change disease vii) genetic basis - NPHS1 gene  encodes nephrin - several mutations of this gene give rise to congenital nephrotic syndrome of the Finnish type (CNF) www.freelivedoctor.com

185. Focal segmental glomerulosclerosis www.freelivedoctor.com

186. - NPHS2 gene - encodes to podocin - mutations give rise to steroid resistant nephrotic syndrome in children Paraproteinemic nephropathies a) abnormally elevated immunoglobulin or immunoglobulin fragments (i.e., paraproteins) may cause renal disease i) present in blood and/or urine ii) renal diseases include - multiple myeloma - Waldenstrom macroglobulinemia - cryoglobulinemia www.freelivedoctor.com

187. Multiple myeloma a) neoplasm of Ig producing plasma cells b) occurs in 5 th decade c) more than 50% of all patients with multiple myeloma have renal involvement i) hypercalcemia ii) hyperuricemia iii) renal infections iv) renal lesions are of three types - tubular and interstitial lesions - amyloidosis - light chain deposition disease www.freelivedoctor.com

188. 2. Waldenstrom macroglobulinemia a)  serum IgM b)  blood viscosity c) renal involvement results in partial or total occlusion of glomerular capillaries 3. Cryoglobulinemia a) IgM or IgG b) defined by their capacity to precipitate at 4  C c) renal disease is often immune complex mediated d) microthrombi in glomeruli e) mesangial & endothelial cell proliferation www.freelivedoctor.com

189. Hereditary nephritis (Alport syndrome) a) most often present as recurrent hematuria b) structural defects in GBM i) specific molecular defect affecting type IV collagen c) usually does not present with nephrotic syndrome and proteinuria d) more severe in men i) die by age 40 e) progressive hearing loss (high frequencies) f) ocular defects most often  the lens www.freelivedoctor.com

190. Benign familial hematuria (thin GBM disease) a) presents as recurrent hematuria in childhood or young adults (similar to Alport syndrome) b) no progression to renal failure (unlike Alport syndrome) c) reduced thickness of GBM (capillary site) d) one of most important causes of asymptomatic hematuria e) IgA nephropathy and this disease are two most major diagnostic considerations of asymptomatic hematuria www.freelivedoctor.com

191. GLOMERULAR LESIONS ASSOCIATED WITH SYSTEMIS DISEASES Diabetic glomerulosclerosis (Kimmelstiel- Wilson Disease) a) diabetic microangiopathy i) small arteries, arterioles and capillaries) - hyaline arteriosclerosis in diabetics involves both afferent and efferent arterioles www.freelivedoctor.com

192. ii) occur by progressive accumulation of GBM material - severity and duration of hyperglycemia !! ?? b) etiology of proteinuria not known i) non-nephrotic proteinuria ii) nephrotic c) earliest lesion is thickening of GBM d) followed by glomerular enlargement e) “diffuse glomerulosclerosis” refers to enlarged glomeruli w/expanded mesangium and diffusely thickened GBM www.freelivedoctor.com

193. f) nodular glomerulosclerosis (i.e., Kimmelstiel-Wilson Disease) – highly specific for diabetes g) one of leading causes of chronic renal failure in USA h) 2 processes play role in diabetic glomerular lesions i) metabolic defect (i.e., glycosylation end products that: -  GBM thickening -  mesangial matrix ii) hemodynamic effects: - glomerular hypertrophy (  GFR) - develop of glomerulosclerosis www.freelivedoctor.com

194. Diabetic glomerulosclerosis www.freelivedoctor.com

195. I) Clinical i) proteinuria usually mild ii) nephrotic syndrome present  renal failure w/in 6 yrs. - severe proteinuria usually associated with other signs of advanced diabetes (i.e., retinopathy) Amyloidosis a) deposits of amyloid w/in glomeruli i) mostly light chain AA or AL type ii) Congo red amyloid positive deposits mainly in mesangium and capillaries www.freelivedoctor.com

196. Amyloid nephropathy www.freelivedoctor.com

197. b) clinical i) nephrotic syndrome ii) progressive glomerular destruction leads to death from uremia Henoch-Schönlein Purpura a) purpuric skin lesions on legs, arms and buttock b) abdominal pain, vomiting, intestinal bleeding, arthralgias and renal abnormalities (hematuria, proteinuria, nephrotic syndrome) c) not all these S & S need to be present www.freelivedoctor.com

198. d) disease most common in children i) 3-8 yrs e) does occur in adults where disease is more severe i) may develop rapidly progressive form of glomerulornephritis with many crescents f) onset often follows upper respiratory infection i) IgA deposits in mesangium which has led to concept that IgA nephropathy (purely a renal disease) and Henoch-Schönlein Purpura are spectra of same disease www.freelivedoctor.com

199. Glomerular Diseases (INFLAMMATORY) (“GLOMERULONEPHRITIS”) Inflammatory lesions of glomerulus characterized by hypercellularity which may be diffuse or focal + proliferation a) Diffuse types of glomerulornephritis i) post infectious ii) membranoproliferative iii) some lupus forms b) Focal types of glomerulornephritis i) IgA ii) other lupus forms www.freelivedoctor.com

200. c) glomerular injury may be either global (entire glomerulus) or segmental d) glomerulornephritis clinically characterized by the NEPHRITIC SYNDROME i) may present with only portions of these S & S (i.e., hematuria) ii) on occasion, proteinuria may predominate e) different forms of GN are differentiated via microscopy www.freelivedoctor.com

201. f) neutrophils contribute to  cellularity, particularly in children i) many neutrophils in glomeruli referred to as “exudative” g) proliferation of podocytes and Bowman’s capsule (visceral and parietal epithelium, respectively) i) leads to formation of “crescents” - highly cellular lesions - extend from Bowman’s capsule into glomerulus having shape of crescents. These are severe lesions (associated with necrosis, early and late fibrosis) www.freelivedoctor.com

202. Pathogenesis of inflammatory GN Immunologic injury a) trapping of circulating immune complexes b) in situ immune complex formation c) activation of alternative complement d) cell mediated processes Circulating immune complex nephritis a) glomerular trapping of circulating Ag-Ab v complexes. i) glomerulus as “innocent bystander” - penetrate GBM than are  - trapped in GBM www.freelivedoctor.com

203. b) confirmed by EM i) presence of subepithelial “humps” ii) peripheral granular staining directed - IgG - C3 c) alternatively, circulating immune complex do not penetrate GBM but localize to i) mesangium or subendothelium d) trapping is affected by: i) size and charge of aggregates ii) glomerular hemodynamics iii) presence of vasoactive substances www.freelivedoctor.com

204. e) Ag may be exogenous or endogenous i) exogenous - bacterial Ag induced by 1. Strep infections 2. bacterial endocarditis 3. viruses (HBV) ii) endogenous - DNA in pathogenesis of lupus 2. In Situ immune complex formation a) Goodpasture Syndrome b) Ag (endogenous) already embedded in GBM i) Ab binds !! ii) linear localization of IgG along GBM www.freelivedoctor.com

205. c) Ag-Ab interaction activates complement ! i) rapidly progressive GN occurs 3. Alternative complement activation a) focal glomerulornephritis i) caused by IgA b) form of membranoproliferative GN 4. Cell-mediated Immunity a) no direct evidence for any specific GN caused by cell mediated processes\ i) indirect evidence for a delayed (type iv) cell type GN - lymphocytes from some patients with GN react in vitro with a glomerular Ag www.freelivedoctor.com

206. once immune complexes localized w/in GBM other secondary affects cause immune mediated injury  mediators: a) complement (C5b-C9; cytotoxic) b) neutrophils (chemotaxis via C5a) c) monocytes & macrophages d) coagulation system NEPHRITIC SYNDROME hematuria oliguria  BUN and creatinine hypertension proteinuria (< 3.5 g/day); ± edema www.freelivedoctor.com

207. www.freelivedoctor.com

208. Glomerulornephritis - - INFLAMMATORY Acute GN (post infectious GN) a) sudden onset of nephritic syndrome b) diffuse hypercellularity of glomeruli c) most often associated with i) group A β -hemolytic streptococci - S. pyogenes ii) others less frequently - staph - spirochetes - viruses d) most often affect children i) one of most common renal diseases www.freelivedoctor.com

209. e) latent period of ~ 10-14 days f) diffuse enlargement and hypercellularity of glomeruli, hypercellularity due to: i) proliferation of endothelial and mesangial cells and infiltration of neutrophils and monocytes g) characteristics: i) subepithelial “humps” of GBM ii) granular IgG and C3 along GBM in association with “humps” h) Clinical: i) most resolve but in rare occasions can progress to develop many crescents and renal failure www.freelivedoctor.com

210. Acute GN (post infectious GN) www.freelivedoctor.com

211. ii) primary infection in pharynx or skin iii) nephritic syndrome (abrupt) - hematuria - oliguria - facial edema - hypertension iv)  serum C3 Membranoproliferative GN a) characterized by GBM thickening (i.e., “membrano”) + mesangial cell proliferation (“proliferative ”) www.freelivedoctor.com

212. b) two major groups: Types I and II (+ III) i) Type I: majority of cases are idiopathic. Associations with - HBV - HCV - bacterial endocarditis - strep infections - granular deposition of Ig (IgG, IgM) and complement (C3) and C1q and C4 ii) type II (and III) - circulating C3 Ab (C3 nephritic factor)   C3 (hypocomplementemia) www.freelivedoctor.com

213. - characteristic “ribbon-like” zone of  cellularity on thickened GBM (“dense deposit disease”) c) Clinical: i) occurs primarily in older children and young adults ii) nephritic or nephrotic syndrome iii) low levels of C3 iv) do not have postinfectious GN v) no systemic inflammatory condition vi) most progress to end-stage renal failure, regardless of treatment !! www.freelivedoctor.com

214. Membranoproliferative GN Type I www.freelivedoctor.com

215. SLE (immune complex disease); “Lupus Nephritis” a) chronic autoimmune disorder b) affects 1  young women c) > 70% will develop renal disease d) circulating anti DNA Ab and  C3, etc. i) T cell function is decreased ii) trapping of immune complexes cause of the renal damage ( in situ ) e) nephritic or nephrotic syndrome f) dysfunction of renal tubules (usually accompanies GN) g) cellular proliferation is mesangial, subepithelial and subendothelial cells www.freelivedoctor.com

216. i) involves the glomeruli w/more severe inflammation h) hematoxylin bodies  only light microscopic feature of tissue damage i) episodic inflammation – usually present with old lesions j) IgG most common. IgA and IgM also present. Complement present i) IgG, IgA, IgM, C3, C4 and C1q present in same glomerulus “FULL HOUSE” www.freelivedoctor.com

217. k) 5 classes based on WHO classification i) Class I – histologically normal ii) Class II – pure mesangial lesion iii) Class III – focal and segmental GN iv) Class IV – diffuse proliferative GN v) Class V – diffuse membranous - Class II and V have more benign course relative to Class III and IV l) renal disease  major consequence of SLE i) renal failure  cause of death in ~ 33 % of patients with SLE www.freelivedoctor.com

218. Focal GN a) only some of the glomeruli are involved i) or to segments of the glomerulus b) different from focal & segmental glomerulosclerosis which is a noninflammatory disease i) glomeruli essentially normocellular c) many conditions produce this defect i) primary renal disease or systemic diseases such as IgA nephropathy and Henoch-Schönlein GN (see table) www.freelivedoctor.com

219. d) IgA nephropathy (Berger Disease) i) association with chronic liver disease - impaired capacity to remove circulating immune complexes ii) IgA and fibronectin found in > 70 % of IgA nephropathy patients. iii) Ag involve bacterial, viral and dietary - infectious agents is suggested from data showing hematuria following upper respiratory or GI infection !! - dietary agents  milk proteins I in mesangium; gluten-sensitivity www.freelivedoctor.com

220. iv) C3 and properdin (via activation of alternate pathway) usually present together with IgA in mesangium - C1q and C4 (classic pathway activation) are typically absent v) IgA nephropathy is a mesangial proliferative lesion (granular deposits) vi) clinical - common in young men (15-30) - presents with hematuria - nephrotic type proteinuria is uncommon (may indicate more severe glomerular damage) www.freelivedoctor.com

221. - ~ 20 % of IgA nephropathy patients progress to end-stage renal failure !! - most common type of 1  GN in several parts of the world (France, Italy, Japan, Singapore and Austria) -- ~ 20 %. In USA is responsible for ~ 3-10 % of 1  GN www.freelivedoctor.com

222. IgA nephropathy (Berger Disease) www.freelivedoctor.com

223. e) Henoch-Schönlein (HS) Purpura i) close relationship with IgA nephropathy - differentiate: IgA purely renal; HS is a systemic disease, etc. Crescentic GN a) ominous morphological pattern i) majority of glomeruli are surrounded by accumulation of cells in Bowman’s capsule (parietal epithelial cells) ii) indicative of fulminant glomerular damage and always leaves scarring www.freelivedoctor.com

224. iii) does not denote a specific etiologic form of GN b) most patients with substantial (~ 80%) crescents progress to renal failure c) Fibrin in Bowman’s capsule is important for the formation of glomerular crescents i) Tx with anticoagulants d) associated with areas of segmental necrosis within glomeruli e) Types: i) Type I – anti-GBM antibody disease (GOODPASTURE SYNDROME) or idiopathic www.freelivedoctor.com

225. - plasmapheresis to remove circulating Ab is helpful in this type of RPGN (i.e., crescentic) - etiology unknown ii) Type II – immune-complex mediated disease - can be complication of any of the immune complex nephritides  SLE, IgA nephropathy,  HS Purpura  all these show granular pattern (characteristic of immune complex) - not helped with plasmapheresis www.freelivedoctor.com

226. iii) Type III – pauci-immune type - lack of anti-GBM Ab or immune complexes - patients do have ANCA (~90%)  either c or p patterns } in some cases, is a component of vasculitides (i.e., Wegener Granulomatosis) f) clinical: i) hematuria with red cell cast in urine ii) transplant or chronic dialysis in most patients www.freelivedoctor.com

227. Crescentic GN www.freelivedoctor.com

228. TUBULOINTERSTITIAL DISEASE Most tubular diseases involve the interstitium 2 distinct types of diseases a) ischemic or toxic tubular injury  i) ATN ii) acute renal failure b) inflammatory diseases i) “tubulointerstitial nephritis” ATN (Clinical entity) Destruction of tubular epithelial cells Acute suppression of renal function www.freelivedoctor.com

229. Most common cause of acute renal failure: a) oliguria (< 400 ml/day) b) severe glomerular disease (RPGN) c) acute thrombotic angioplasties d) diffuse renal vascular disease (Polyarteritis nodosa) e) diffuse cortical necrosis f) interstitial nephritis (acute drug- induced) g) acute papillary necrosis www.freelivedoctor.com

230. Is reversible and arise from: a) severe trauma b) septicemia (shock and hypotension) c) ATN associated with shock – “ischemic” - d) mismatched blood transfusion and other hemodynamic problems as well as myoglobinuria  all reversible ischemic ATN e) nephrotoxic ATN – variety of poisons i) heavy metals (Hg) ii) CCl4 iii) etc. www.freelivedoctor.com

231. Occurs frequently a) since it is reversible, proper management means difference between recovery and death 2 major problems are: a) tubular injuries b) blood flow disturbances Major disturbances: a) Change charge in tubules (mainly -) i) Na+ - K+ - ATPase cause less Na+ reabsorption and traps Na+, within tubule with more distal tube delivery of Na+ which causes vasoconstriction (feedback) www.freelivedoctor.com

232. Treatment protocol 1) - initiating phase 2) - maintenance phase 3) - recovery phase Initiating phase Last about 36 hours. Incited by: a) medical, surgical, obstetric event i) slight oliguria (transient decrease in blood flow) ii) rise in BUN www.freelivedoctor.com

233. Maintenance phase Anywhere from 2-6 days a) sharp decline in urine output (50-400 ml/day) i) may last few days to 3 weeks b) fluid overload, uremia c) may die from poor management Recovery phase Steady increase in urine output (up to 3L/day) Electrolyte imbalances may continue Increased vulnerability to infection Because of these, about 25% patients die in this phase www.freelivedoctor.com

234. Tubulointerstitial Nephritis (TIN) Inflammatory disease of Interstitium/tubules Glomerulus not involved at all or only late in disease Infections induced TIN – “pyelonephritis” Non infection – interstitial nephritis a) Caused by: i) drugs ii) metabolic disorders (hypokalemia) iii) radiation injury iv) immune reactions www.freelivedoctor.com

235. TIN divided into 2 categories, regardless of etiology a) acute b) chronic Acute Pyelonephritis Kidney/renal pelvis (distal to collecting ducts) Caused by bacterial infections (lower UTI) – cystitis, urethritis and prostatitis or upper UTI – (pyelonephritis) or both tracts Principle causative bacteria are gram - rods a) E. coli (most common), Proteus, enterobacter, Klebsiella www.freelivedoctor.com

236. 2 routes bacteria can reach kidney a) blood stream (not very common) b) lower urinary tract (ascending infections) i) catheterization ii) cystoscopy Most commonly affect females (in absence of instrumentation) a) close proximity to rectum b) shorter urethra Urine sterile, flushing keeps bladder sterile a) Obstruction increased incidence of UTI i) prostate hypertrophy ii) uterine prolapse iii) UT obstructions www.freelivedoctor.com

237. Incompetent vesicoureteral orifice a) one way valve (at level of bladder) b) incompetence – reflux of urine into ureters – vesicoureteral reflux (VUR) – usually congenital defect – 30-50% of young children with UTI c) usually congenital defect d) spinal cord injury can produce a flaccid bladder (residual volume remain in urinary tract) – favors bacterial growth www.freelivedoctor.com

238. e) Diabetes increases risk of serious complications i) septicemia ii) recurrence of infection iii) diabetic neuropathy – dysfunction of bladder f) pregnancy i) 6% develop pyelonephritis; 40- 60% develop UTI if not treated Chronic pyelonephritis and reflux nephropathy Interstitial inflammation with scarring of renal parenchyma Important cause of chronic renal failure www.freelivedoctor.com

239. Two forms: a) Chronic obstructive pyelonephritis b) Chronic reflux-associated pyelonephritis Chronic obstructive pyelonephritis Can be bilateral (congenital disease) Obstruction predisposes kidney to infection recurrent infections on obstructive foci causes scarring – chronic pyelonephritis! www.freelivedoctor.com

240. chronic reflux-associated pyelonephritis (reflux nephropathy) More common form of chronic pyelonephritis scarring Occurs from superimposed of a UTI on vesicoureteral and intrarenal reflux a) reflux may be bi- or unilateral i) unilateral causes atrophy ii) bilateral can cause chronic renal insufficiency iii) diffuse or patchy Unclear if sterile vesicoureteral disease causes renal damage www.freelivedoctor.com

241. Hallmark is scarring involving pelvis/calyces, leading to papillary blunting and deformities Renal papilla – area of kidney where opening from collecting ducts enters renal pelvis Kidneys are asymmetrically contracted Signs and Symptoms: a) hypertension b) seen following normal physical exam c) slowly progressive  late in disease d) can cause loss of concentrating mechanisms (if bilateral and progressive) i) polyuria ii) nocturia www.freelivedoctor.com

242. Drug-induced interstitial nephritis Acute TIN – seen with synthetic penicillins, diuretics (thiazides), NSAI a) disease begins ~15 days (2-40 range) i) fever ii) rash (25% cases) iii) renal findings: hematuria, leukouria iv) increased serum creatinine or acute renal failure with oliguria (50% of cases) Immune mechanism is indicated (suggested) a) IgE increased (hypersensitivity – Type I) Injury produced by IgE and cell-mediated immune reactions www.freelivedoctor.com

243. Analgesic Nephropathy Patients who consume large quantities of analgesics may develop chronic interstitial nephritis , often associated with renal papillary necrosis Usually result from consumption of a mixture for long periods of time: a) aspirin b) caffeine c) acetaminophen d) codeine e) phenacetin www.freelivedoctor.com

244. Primary pathogenesis is a) papillary necrosis followed by b) interstitial nephritis is secondary c) acetaminophen – oxidative damage d) aspirin inhibits prostaglandins – vasoconstriction e) all the above leads to papillary ischemia Chronic renal failure, hypertension and anemia Complications may be incidence of “transitional cell carcinoma” of renal pelvis or bladder. www.freelivedoctor.com

245. Diseases of Blood Vessels Nearly all diseases of kidney involve blood vessels. Kidneys involved in pathogenesis of essential and secondary hypertension Systemic vascular disease (i.e. arteritis) also involve kidney www.freelivedoctor.com

246. Benign Nephrosclerosis Sclerosis of renal arterioles and small arteries a) some degree of ischemia i) hypertension Renal changes associated with benign hypertension a) always associated with hyaline arteriosclerosis i) deposits in arterioles - extravasation of plasma proteins through injured endothelial cells; also in BM www.freelivedoctor.com

247. ii) results in narrowing of lumen no renal insufficiency nor uremia in uncomplicated cases a) diabetes, blacks, more severe blood pressure elevations  risk of renal insufficiency Kidneys are atrophic Many renal diseases cause hypertension which in turn may lead to benign nephrosclerosis. Therefore this disease seen simultaneously with other diseases of kidney www.freelivedoctor.com

248. This disease by itself usually does not cause severe damage a) mild oliguria b) loss (slight) of concentrating mechanism c) decreases GFR d) mild degree of proteinuria is a constant finding These patients usually die from hypertensive heart disease or cerebrovascular disease rather than from renal disease Pathogenesis a) medial and intimal thickening. Due to: i) age, hemodynamic changes, genetic factors, etc. www.freelivedoctor.com

249. Malignant hypertension (malignant nephrosclerosis) malignant nephrosclerosis is the f orm of renal disease associated with malignant hypertension Less common than benign May arise de novo (without preexisting hypertension) or may arise suddenly in patient with mild hypertension (i.e., essential benign hypertension) Frequent cause of death from uremia www.freelivedoctor.com

250. Factors: a) initial event – some form of vascular damage to kidney b) result is increased permeability of small blood vessels to fibrinogen and other plasma proteins, endothelial injury and platelet deposits c) This leads to appearance of fibrinoid necrosis in small arteries and arterioles and intravascular thrombosis www.freelivedoctor.com

251. d) platelets (platelet derived growth factors) and plasma cause intimal hyperplasia of vessels resulting in hyperplastic arteriosclerosis, which is typical of malignant hypertension e) narrowing of renal afferent arteriole (i.e., progressive ischemia) stimulates angiotensin II production (ischemic- induced) with renin secretion increased. Aldosterone also increased. i) self perpetuating cycle - constriction (Angio II)  vasoconstriction  ischemia  renin  etc. www.freelivedoctor.com

252. Diastolic pressure > 130 mmHg, papilledema, encephalopathy, CV disorders, renal failure a) often, early symptoms due to  intracranial pressure i) headache, nausea, vomiting, visual impairments b) hypertensive crisis i) loss of consciousness, convulsions ii) proteinuria and hematuria (micro- or macro-) 90% deaths due to uremia 10% deaths due to CV or cerebral disorders (hemorrhage) www.freelivedoctor.com

253. This is a different kind of arteriosclerosis. This is hyperplastic arteriolosclerosis, which most often appears in the kidney in patients with malignant hypertension. The arteriolar wall is markedly thickened and the lumen is narrowed. Arteriosclerosis, or &quot;hardening of the arteries&quot; is a generic term that includes atherosclerosis, arteriolosclerosis, and medial calcific sclerosis. www.freelivedoctor.com

254. Renal Artery Stenosis Unilateral is uncommon cause of hypertension a) ~ 70 % due to atheromatous plaque at origin of renal artery i) second leading cause is fibromuscular dysplasia of renal artery (hyperplasia of all layers) - More common in women - Tend to occur in younger groups (20-30 yrs) www.freelivedoctor.com

255. b) potentially curable form of hypertension i) related to degree of stenosis - caused primarily by renin secretion - ACE inhibitors show marked  in arterial blood pressure - revascularization Ischemic kidney shows signs of diffuse ischemic atrophy Patients present usually resembling essential hypertension arteriography required to localize stenotic lesion 70-80 % cure rate www.freelivedoctor.com

256. Thrombotic Microangiopathies Clinical syndromes Widespread thrombosis in microcirculation (a/c) Damage to endothelial cells !! Diseases: a) childhood hemolytic-uremia syndrome (HUS) b) Thrombotic thrombocytopenic purpura Most follow intestinal infection ( E. coli ) Disease is one of main causes of acute renal failure in children Vasoconstriction (decreased NO, increased endothelin-1, decreased PGI 2 ) www.freelivedoctor.com

257. Although the various diseases have diverse etiologies, 2 predominant factors  a) endothelial injury and activation, leading to vascular thrombosis and, b) platelet aggregation c) both of these causing vascular obstruction and vasoconstriction 1.- Endothelial injury activation can be initiated by a variety of agents, while some remain elusive a) denuding the endothelial cells, exposes vascular to thrombogenic subendothelium i)  NO, PGI 2 , enhance platelet aggregation and vasoconstriction www.freelivedoctor.com

258. ii) vasoconstriction also initiated via endothelial derived endothelin-1 iii) activation of endothelial cells increases adhesiveness to platelets, etc. iv) endothelial cells elaborate large multimers of vW factor  platelet aggregation 2.- Platelet Aggregation serum factors causing platelet aggregation a) large multimers of vW factor (secreted by endothelial cells) i) usually cleaved by ADAMTS-13 (vW factor-cleaving metalloprotease) www.freelivedoctor.com

259. HUS/TTP 1.- Classic childhood HUS (> 75% following infection) bloody diarrhea  intestinal infection a) verocytotoxin-releasing bacteria i) Verocytotoxin-producing strains of E. coli (eg 0157:H7 or 0103); ii) Similar to Shigella toxin. iii) undercooked hamburger iv) “petting” zoos www.freelivedoctor.com

260. characterized: a) sudden onset (post GI or influenza infection) b) hematemesis c) melena d) severe oliguria e) hematuria f) hemolytic anemia (microangiopathic) g) hypertension in > 50% of cases www.freelivedoctor.com

261. Pathogenesis a) related to Shigella toxin i) affects endothelium -  adhesion of leukocytes -  endothelin and  NO - endothelial lysis (in presence of cytokines such as TNF) ii) these changes favor thrombosis and vasoconstriction iii) verocytotoxin can directly bind to platelets and cause activation most patients recover in few weeks, with proper care (i.e., dialysis, etc); < 5% lethality www.freelivedoctor.com

262. 2.- Adult HUS associated with: a) infection i) typhoid fever ii) E. coli septicemia iii) etx or shiga toxin iv) viral infections b) antiphospholipid syndrome i) SLE ii) similar to membranoproliferative GN but w/out immune complex deposits c) complication of pregnancy (“postpartum renal failure” www.freelivedoctor.com

263. d) vascular renal disease i) systemic sclerosis ii) malignant hypertension e) chemotherapeutic and immunosuppressive drugs i) mitomycin ii) cyclosporine iii) bleomycin iv) cisplatin v) radiation Tx 3.- Familial HUS recurrent thromboses (~ 50 lethality) deficit of complement regulatory protein a) Factor H www.freelivedoctor.com

264. 4.- Idiopathic Thrombotic Thrombocytopenic Purpura Manifested by: a) thrombi in glomeruli b) fever c) hemolytic anemia d) neurologic symptoms e) thrombocytopenic purpura defect in ADAMTS-13 (acquired or inherited) a) normally cleaves large vW multimers i) large vW factors promote platelet aggregation more common in women most patients < 40 years www.freelivedoctor.com

265. neurologic involvement is dominant feature renal involvement in ~ 50% of patients a) eosinophilic thrombi in glomerular capillaries, interlobular artery and afferent arterioles b) similar changes as with HUS exchange transfusion and steroid Tx  mortality rate to < 50% www.freelivedoctor.com

266. Other vascular disorders Atherosclerotic renal disease a) bilateral stenosis i) fairly common in older adults ii) cause of chronic ischemia Atheroembolic renal disease a) via atheroma in older patients with severe atherosclerosis Sickle cell disease a) vasa recta plugging by sickled cells i) hematuria ii)  renal concentrating mechanism iii) patchy papillary necrosis iv) proteinuria www.freelivedoctor.com

267. Diffuse cortical necrosis a) uncommon i) obstetric emergency ii) septic shock iii) following extensive surgery b) glomerular and arteriolar microthrombi c) unilateral or patchy involvement are compatible with survival Renal infarcts a) favored sites for infarcts i) “end organ” nature of vasculature b) most infarcts due to emboli i) via left ventricle/atria as result of MI - mural thrombosis www.freelivedoctor.com

268. Cystic Diseases Common and difficult to diagnose In adult polycystic disease – major cause of chronic renal failure Confused with malignant tumors Simple cyst a) Innocuous lesion b) Occur as single or multiple cysts c) Usually 1-5 cm diameter d) Clear fluid, smooth membrane, gray glistening www.freelivedoctor.com

269. e) Single layer of cuboidal cells f) Usually confined to cortex g) No clinical significance Importance to differentiate from tumors a) are fluid filled rather than solid b) have smooth contours c) almost always avascular Occur in patients with end-stage renal disease who have undergone long term dialysis Occasionally, renal adenomas or adenosarcoma arise from these cysts www.freelivedoctor.com

270. Adult polycystic kidney disease (autosomal dominant) Multiple expanding cysts of both kidneys that eventually destroy parenchyma of kidney Accounts for 10% of chronic renal failure In 90% of families, PKD1 (defective gene) is located on chromosome #16 a) encodes for protein (polycystin-1), extracellular and is a cell membrane associated protein b) how mutations in this gene cause cysts formation is unclear www.freelivedoctor.com

271. Polycystin 2 (PKD2 gene) mutations also cause cyst formation No symptoms until 4th decade a) by then, kidneys are very large b) common complaint is “flank pain” c) hematuria d) most important complications i) hypertension (~75% patients) ii) UTI iii) aneurysms in circle of Willis (10- 30%) and risk for subarachnoid hemorrhage www.freelivedoctor.com

272. iv) Asymptomatic liver cysts in ~30- 40% v) fatal disease (uremia or hypertension) vi) progresses very slowly viii) Treatment with renal transplantation Childhood polycystic kidney disease (autosomal recessive) Rare Serious manifestations at birth and young infants may die quickly a) pulmonary failure b) renal failure www.freelivedoctor.com

273. Numerous small cysts in cortex and medulla Bilateral disease Many epithelial cysts in liver Patients who survive infancy develop liver cirrhosis (congenital hepatic cirrhosis) Unidentified gene location on chromosome 6p Urinary Outflow-Obstruction Renal Stones Urolithiasis: Calculus formation at any level in urine collecting system, most often arise in kidney www.freelivedoctor.com

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276. Occur frequently (!1% of all autopsies) More common in males Familial tendency ~75% of renal stone a) calcium oxalate b) calcium phosphate 15% composed of magnesium ammonium phosphate 10% uric acid or cystine stones All stones composed of mucoprotein www.freelivedoctor.com

277. Cause of stones is obscure a) Supersaturation in urine of stones constituents (exceeds solubility) b) 50% of patients forming “calcium stones” do not have increased plasma Ca ++ but do have high urine Ca ++ i) most Ca ++ absorbed from gut in large amounts (absorptive hypercalciuria) ii) only 5-10% has associated hypercalcemia www.freelivedoctor.com

278. - hyperparathyroidism - Vit D intoxication - Sarcoidosis (autoimmune disease, bacterial) - productions of Vit D (toxic) c) Magnesium ammonium Phosphate stones i) almost always occur in patients with alkaline urine due to UTI ii) Proteus vulgaris and Staph split urea in kidney and therefore predispose patient to urolithiasis www.freelivedoctor.com

279. Gout and diseases involved with rapid cell turnover (e.g. leukemia) lead to high uric acid levels in urine and possibility of uric acid stones Unlike magnesium ammonium phosphate stone, both uric acid and cystine stones are more likely to form when urine is acidic (pH < 5.5) Stone formation 80% unilateral Hematuria and predispose to infection www.freelivedoctor.com

280. Hydronephrosis Dilation of renal pelvis and calyces with atrophy of parenchyma caused by obstruction of outflow of urine Most common causes: a) congenital i) atresia of the urethra (absence of a normal body passage or opening from an organ to other parts of the body) www.freelivedoctor.com

281. b) acquired i) stones ii) tumors iii) inflammation iv) spinal cord damage with paralysis of bladder v) normal pregnancy Bilateral only if blocked below level of ureters Major problems are tubular with impaired concentration mechanisms Obstruction leads to inflammatory response a) interstitial fibrosis Complicating pyelonephritis is common Pain from distension of collecting system www.freelivedoctor.com

282. Tumors Most common malignant tumor is: a) renal cell carcinoma (80-85% of all 1° Ca in kidney) b) nephroblastoma (Wilms tumor) c) urothelial tumors of calyces and pelvis Tumor of lower urinary tract are 2x as common as renal cell Cancer www.freelivedoctor.com

283. Benign tumors Renal papillary adenoma a) arising tubular epithelium b) common (7-22 % found on autopsy) Renal fibroma or harmartoma (renomedullary interstitial cell tumor) a) firm white-gray, < 1cm, found in pyramids (fibroblast-like cells) Oncocytoma (large nucleoli); eosinophilic cells www.freelivedoctor.com

284. Malignant Tumors Renal cell Ca (adenocarcinoma of kidney) Derived from renal tubular epithelial cells a) located primarily in cortex 2-3% of all cell Ca in adults (~30,000 cases/yr) 6th to 7th decades in life Male preponderance (~ 3:1) www.freelivedoctor.com

285. Higher risk in smokers (2:1) and occupational exposure to cadmium, hypertension and acute renal failure and acquired cystic disease. 30 fold increase in susceptibility in patients with polycystic disease Classification: 1. clear cell Cancer i) most common (~ 85 % renal ca) a) most are sporadic (~ 95%), nonpapillary b) familial links (von Hippel-Lindau [VHL]) i) autosomal dominant disease ii) predispose to a variety of CA – hemangioblastoma of cerebellum and retina www.freelivedoctor.com

286. iii) genetic abnormality chromosome 3, which houses the VHL gene (VHL gene acts as a tumor suppressor gene) – clear cell CA Clinical a) palpable mass, hematuria (most reliable), costovertebral pain b) great mimicker (paraneoplastic syndromes) i) polycythemia ii) hypercalcemia iii) hypertension iv) Cushing syndrome v) eosinophilis www.freelivedoctor.com

287. common characteristic is to metastasize prior to giving rise to symptoms a) common site are the lungs (~ 50%) and bones (~ 30%) b) renal vein involvement (increases morbidity and mortality) Renal cell CA are difficult to diagnose! a) Present with hematuria in ~50% of cases www.freelivedoctor.com

288. 2.- Papillary renal cell Ca 10-15% of all renal CA papillary growth pattern Multifocal and bilateral Both sporadic and familial forms No genetic abnormalities in chromosome 3 a) Protooncogene on chromosome 7 www.freelivedoctor.com

289. 3- Chromophobe Renal Carcinoma Least common (~5% of all renal cell CA) Cortical collecting ducts or their collated cells Stain more darkly than clear cell CA Lack of a lot of chromosomes (1,2,6,10,17,&21) Have good prognosis vs clear cell and papillary 4.- Collecting duct (Bellini duct) carcinoma ~ 1% of renal epithelial cell carcinoma arise from collecting duct in medulla www.freelivedoctor.com

290. 4. Wilms tumor (nephroblastoma) Occurs infrequently in adults 1/3 most common organ cancer in children <15 years, (major cause in children) a) most common 1  renal tumor of childhood b) usually diagnosed between ages 2-5 yrs. Sporadic or familial in nature a) autosomal dominant b) 3 groups at risk for developing i) WAGR syngrome ii) Denys-Drash syndrome (WT 1 gene) iii) Beckwith-Wiedemann syndrome (WT 2 gene) www.freelivedoctor.com

291. Clinical Good outcome with early diagnosis. Tumor has tendency to easily metastasize major complaint is associated with large size of the tumor a) readily palpable mass less common complaints include a) fever b) abdominal pain c) hematuria d) intestinal obstruction (uncommon) www.freelivedoctor.com

292. Urothelial CA of renal pelvis ~ 5-10% of 1  renal tumors originate from urothelium of renal pelvis a) benign renal papillomas b) invasive urothelial (transition cell) CA become apparent quickly (hematuria) a) usually never palpable (small) In 50% there may be associated bladder urothelial tumor a) increased incidence in patients with analgesic nephropathy b) infiltration of pelvis and calyces is common i) prognosis not good www.freelivedoctor.com

293. Urinary bladder and collecting system tumors (Renal pelvis to urethra) Tumors in collecting system above bladder are uncommon Bladder Cancer more frequent cause of death than are kidney tumors a) Bladder tumors i) small benign papillomas (rare) ii) large invasive CA iii) most recur after removal and kill by infiltrative obstruction of ureters rather than by metastasizing iv) Shallow lesion have good prognosis www.freelivedoctor.com

294. v) deep invasive Cancer, survival (5yr) is <20% with overall 5 yr survival at 50-60% b) Cancer of ureters is very rare i) 5 yr survival <10% www.freelivedoctor.com