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Glomerular disease

  1. Glomerular diseases DR. SNEHIL AGRAWAL 1
  2. GROSS OF NORMAL KIDNEY In cross section, this normal adult kidney demonstrates the lighter outer cortex and darker medulla with central pelvis. 2
  3. Facts ► Human kidneys are two in number, each weighing about 150 grams ► Filtering more than 170 liters of blood daily to bring out only about 1 liter of concentrated urine. 3
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  6. DEFINITIONS  ACUTE RENAL FAILURE  CHRONIC RENAL FAILURE  AZOTEMIA- ELEVATED SERUM LEVELS OF UREA AND CREATININE WITHOUT ANY CLINICAL SYMPTOMS.  UREMIA- ELEVATED SERUM LEVELS OF UREA AND CREATININE WITH CLINICAL SIGNS AND SYMPTOMS DUE TO METABOLIC AND ENDOCRINE ALTERATIONS. C/F (organ involvement other than kidney):- 1. Uremic Gastroenteritis 2.Peripheral Neuropathy 3.Uremic Fibrinous Pericarditis. 6
  7. Acute Nephritic syndrome ► Acute onset ► Mild to Moderate proteinuria( less than 3.5 g/day) ► Edema ► Azotemia ► Hypertension ► Hematuria ► Etiology (Cause): Acute post streptococcal Glomerulonephritis 7
  8. Nephrotic Syndrome ► Heavy Proteinuria( > 3.5g/day) ► Generalized Edema ► Hypoalbuminemia ► Hyperlipidemia and lipiduria Cause: Minimal change disease( in children) Membranous Nephropathy ( in adult) Nephrotic Syndrome causes a bloated appearance due to fluid retention 8
  9. Proteinuria ► Presence of excess protein in urine ► Example: Nephrotic Syndrome Hematuria Blood in Urine Example: Tumor in Bladder/Kidney, Few glomerular diseases 9
  10. Acute Renal Failure ► Acute loss of renal function ► Oliguria – less urine( < 400ml/day) ► Or, Anuria – No urine flow ► Recent onset azotemia ► Example/ Causes always remember ► 1.Crescentic Glomerulonephritis ► 2.Acute Tubular Necrosis.( ATN) 10
  11. Chronic Renal failure ► Prolonged signs and symptoms of Uremia. ► END RESULT OF ALL CHRONIC RENAL DISEASES. 11
  12. Proteinuria Haematuria SLE IgA nephropathy Minimal change nephropathy Membranous nephropathy Post-infective glomerulonephritis Diabetic nephropathy * Adapted from Davidson’s Principles and Practice of Medicine, 20th Edition Spectrum of glomerular diseases 12
  13. HISTOLOGY 4 COMPONENTS ► GLOMERULUS ► TUBULES ► INTERSTITIUM ► BLOOD VESSELS 13
  14. Histology of Normal Glomerulus Glomerular capillaries Tubules RBC 14
  15. Glomerular filtration occurs mainly through fenestrated epithelium. The normal anionic charge barrier prevents protein molecules such as albumin from passing through the endothelium. 15
  16. ‘Nomenclature’ DISEASES OF GLOMERULUS ► Nephritic & Nephrotic syndrome ► Note: Most Common Causes of Renal Failure. ► Note: Diseases mainly immunologically mediated 16
  17. Diseases of TUBULES & INTERSTITIUM ► 1. Tubulointerstitial Nephritis (PYELONEPHRITIS) ► 2.ACUTE TUBULAR NECROSIS ► 3. Drug induced Interstitial Nephritis 17
  18. Disease of Blood Vessels ► Benign Nephrosclerosis ► Malignant Nephrosclerosis( seen in Malignant Hypertension) ► Thrombotic Microangiopathy ( Associated With Hemolytic Uremic Syndrome of New born) 18
  19. Cystic Diseases of Kidney 1. Simple cysts 2. Adult Polycystic Kidney Disease ( autosomal dominant) 3. Childhood polycystic kidney disease ( autosomal recessive) 4. Others 19
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  22. GBM Glomerular Capillary Lumen Bowman’s Capsule Space + Lamina rara interna Lamina densa Lamina rara externa Foot Processes Podocyte (Visceral epithelium 22
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  25. Light microphotograph of glomerulus 25
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  27. Pathologic Responses of the Glomerulus to Injury Hypercellularity  Characterized by Increase in the number of cells in the glomerular tufts.  This hypercellularity is comprised of one or more combination of mesangial or endothelial cell proliferation, leukocyte infiltration or formation of crescents. Basement Membrane Thickening  On light microscopy appears as thickening of the capillary walls and is best seen by PAS staining.  On electron microscopy it can have one of the two forms:- a) Deposition of amorphous electron dense material on endothelial or epithelial side of GBM or within the GBM itself. b) Thickening of the basement membrane due to increased synthesis of its protein components as occurs in diabetic glomerulosclerosis. 27
  28. Pathologic Responses of the Glomerulus to Injury Hyalinosis  denotes the accumulation of material that is homogenous and eosinophilic by light microscopy.  By electron microscopy the hyaline is extracellular ,amorphous made up of leaked plasma proteins from circulation into glomerular structures.  Hyalinosis is a consequence of endothelial or capillary wall injury. Sclerosis  Characterized by accumulation of extracellular collagenous matrix either confined to mesengeal areas or involving the capillary loops or both. 28
  29. immune mechanisms underlie most forms of primary glomerulopathy and many of the secondary glomerular disorders 29
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  34. HISTOLOGICAL TERMINOLOGIES.  DIFFUSE: INVOLVE. ALL GLOMERULI.  FOCAL: PROPORTION OF GLOMERULI.  GLOBAL: ENTIRE GLOMERULUS.  SEGMENTAL: A PART OF EACH GLOMERULUS.  MESANGIAL: INVOLVING THE MESANGIUM. 34
  35. 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 35
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  38. Nephritic syndrome 38
  39. Nephritic syndrome Glomerular diseases presenting with a nephritic syndrome are often characterized by inflammation in the glomeruli. The nephritic patient usually presents with  Hematuria,  Red cell casts in the urine  Azotemia,  Oliguria, and  Mild to moderate hypertension.  Proteinuria and edema 39
  40. ACUTE PROLIFERATIVE GLOMERULONEPHRITIS.  Acute proliferative glomerulonephritis is a group of glomerular disorders characterized by diffuse proliferation of glomerular cells and infiltration by leucocytes.  These are immune complex mediated disorders and the antigens can be either exogenous or endogenous. Two types: Acute post-streptococcal glomerulonephritis. Acute non- streptococcal glomerulonephritis 40
  41. ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS.  Mainly affecting the children of 6-10 years of age group.  It is an inflammatory but not infective condition that manifests1-4 wks after post streptococcal infection usually throat or skin infection. 41
  42. ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS. ETIOPATHOGENESIS:  Immunologically mediated disorder.  Initiated by throat or skin infection caused by nephritogenic groups. A beta hemolytic streptococci type 12, 4&1.  Antibodies are formed against streptococcal antigen consequently there is formation of immune complex in the circulation.  These circulating immune complex are trapped within glomeruli, deposited on the GBM and initiates the inflammatory response that induce glomerular damage. 42
  43. ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS. MORPHOLOGY: Gross:  Both kidneys are involved and are symmetrically enlarged.  Cortical surface shows pinpoint hemorrhages that are called as” flea bitten kidney”. 43
  44. ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS Light microscopy: Glomeruli:  There is diffuse involvement of all the glomeruli.  Glomeruli are enlarged and hypercellular.  There is proliferation of endothelial, mesangial and epithelial cells.  Infiltration by neutrophils and monocytes are seen in the glomeruli. Tubules: contain RBC cast. Interstitium: shows edema, WBC infiltration. Vessels: Largely unaffected. 44
  45. Diffuse Endocapillary Proliferative GN  Proliferation of endothelial and mesangial cells  Cell Swelling  Inflammatory cells (PMNL)  Obstruction ofcapillary lumina  Enlarged hypercellular glomeruli. 45
  46. APGN- HYPERCELLULARITY 46
  47. ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS Flea bitten kidney:  Multiple pinpoint hemorrhages on the cortical surface of the kidney due to congested glomerulus.  Also seen in malignant nephrosclerosis, HUS and TTP. Electron microscopy:  Electron dense deposits on the epithelial aspect are seen that are called as” humps.” Immunoflourescence.  Immune deposits are seen along GBM that are composed of IgG, IgM and C3. 47
  48. ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS 48
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  50. ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS Lab findings.  Elevated ASO titer.  Decreased serum complement levels: C3.  Elevated blood urea and creatinine levels. 50
  51. ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS Urinary findings. Gross:-  Oliguria.  Red or smoky urine due the presence of RBCs and proteins. Chemicals:  protein: Increased.<3Gm/Day.  Blood is present Microscopy:  Presence of RBCs and RBC casts. 51
  52. ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS Clinical features:  Patient is usually is a young child  Present with sudden onset with features of acute nephritis and fever, malaise and nausea with a history of soar throat or skin infection 1-4 wks earlier to the renal manifestation. 52
  53. ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS Prognosis:  95% cases show complete recovery with treatment.  Less than 1% patients show no recovery and progress to RPGN with clinical features of acute renal failure and rest of them gradually progress to CGN.  Adult carry bad prognosis than children with less than 60% recovery. 53
  54. ACUTE NON STREPTOCOCCAL GLOMERULONEPHRITIS  Type of acute proliferative glomerulonephritis caused by other than group A beta hemolytic streptococci. Agents: Bacterial:  Staphylococci, Pneumococci, Meningococci Viral :  HBV, HCV, EBV, Mumps, HIV Parasites:  Malaria, Toxoplasomosis 54
  55. ACUTE NON STREPTOCOCCAL GLOMERULONEPHRITIS Morphology:  Light microscopy, electron microscopy and immunoflourescence studies are similar to acute post-streptococcal glomerulonephritis.  Prognosis is bad compared to acute post- streptococcal glomerulonephritis 55
  56. RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (CRESCENTIC GLOMERULONEPHRITIS)  In this condition there is severe glomerular injury and patients presenting with rapid and progressive loss of renal function leading to oliguria, ARF and if untreated death.  There is formation of epithelial crescents in the glomeruli so it is called as crescentic glomerulonephritis. 56
  57. Classification and Pathogenesis. TYPE I (ANTI-GBM ANTIBODY)  Renal limited  Goodpasture syndrome TYPE II (IMMUNE COMPLEX)  Idiopathic  Post-infectious glomerulonephritis  Lupus nephritis  Henoch-Schönlein purpura (IgA nephropathy)  Others TYPE III (PAUCI-IMMUNE)  ANCA-associated  Idiopathic  Wegener granulomatosis  Microscopic polyangiitis 57
  58. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.)  The first type of RPGN is anti-GBM antibody–induced disease,  characterized by linear deposits of IgG and, in many cases, C3 in the GBM that are visualized by immunofluorescence.  In some of these patients, the anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure (Goodpasture syndrome).  The Goodpasture antigen is a peptide within the noncollagenous portion of the α3 chain of collagen type IV. 58
  59. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.)  The second type of RPGN is the result of immune complex deposition.  It can be a complication of any of the immune complex nephritides, including postinfectious glomerulonephritis, lupus nephritis, IgA nephropathy, and Henoch Schönlein purpura.  Immunofluorescence studies reveal the granular pattern of staining characteristic of immune complex deposition.  This type of RPGN frequently demonstrates cellular proliferation within the glomerular tuft, in addition to crescent formation. 59
  60. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.)  The third type of RPGN, also called pauci-immune type, is defined by the lack of anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy.  Most patients with this type of RPGN have circulating antineutrophil cytoplasmic antibodies (ANCAs) that produce cytoplasmic (c) or perinuclear (p) staining patterns ,play a role in some vasculitides.  Hence, in some cases this type of RPGN is a component of a systemic vasculitis such as Wegener granulomatosis or microscopic polyangiitis.  In many cases pauci-immune crescentic glomerulonephritis is isolated and hence idiopathic. More than 90% of such idiopathic cases have c-ANCAs or p-ANCAs in the sera 60
  61. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.) Morphology : Gross:  Both kidneys are involved that are enlarged, pale and petechial hemorrhages on the cortical surface. 61
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  63. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.) Light microscopy: Crescents  Crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into the urinary space. Neutrophils and lymphocytes may be present.  The crescents eventually obliterate Bowman space and compress the glomerular tuft.  Fibrin strands are frequently prominent between the cellular layers in the crescents 63
  64. Crescentic glomerulonephritis (PAS stain). Note the collapsed glomerular tufts and the crescent-shaped mass of proliferating parietal epithelial cells and leukocytes internal to Bowman capsule. 64
  65. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.) EM/IF:  Vary according to the cause.  Immune complex–mediated cases show granular immune deposits  Goodpasture syndrome cases show linear GBM fluorescence for Ig and complement,  Pauci-immune cases have little or no deposition of immune reactants. Electron microscopy  Deposits in those cases due to immune complex deposition (type II).  May show distinct ruptures in the GBM, the severe injury that allows leukocytes, proteins, and inflammatory mediators to reach the urinary space, where they trigger the crescent formation  In time, most crescents undergo sclerosis, but restoration of normal glomerular architecture may be achieved with early aggressive therapy. 65
  66. Electron micrograph showing characteristic wrinkling of GBM with focal disruptions in its continuity (arrows). 66
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  70. RAPIDLY PROGRESSIVE G.N. (CRESCENTIC G.N.) Clinical features:  Most cases present as nephritic syndrome  Good pasture syndrome patient present With hemoptysis and life threatening pulmonary hemorrhages.  This condition progresses to ARF and death if untreated. 70
  71. NEPHROTIC SYNDROME 71
  72. NEPHROTIC SYNDROME  Clinical condition characterised by massive proteinuria of more 3.5 gm/day, hypoalbuminemia (serum albumin <3 gm%), generalized edema, hyperlipidemia and lipiduria. 72
  73. Pathogenesis of proteinuria:  Derangement in glomerular capillary walls resulting in increased permeability to plasma proteins.  The glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the plasma filtrate passes.  Increased permeability resulting from either structural or physicochemical alterations allows protein to escape from the plasma into the urinary space. 73
  74. Types of proteins lost in the urine  Largest proportion of protein lost - Albumin.  Highly selective proteinuria: Low molecular weight proteins like albumin and transferrin are lost.  Poorly selective proteinuria: Higher molecular weight globulins are lost along with albumin. 74
  75. Grading of Proteinuria. Normal proteinuria: Microalbuminuria: Macroalbuminuria or gross proteinuria: Massive proteinuria: < 30 gm/day. 30 gm/day but < 300 gm/day. > 300 gm/day. > 3.5 grams/day. 75
  76. Pathogenesis of Hyperlipedemia & Lipiduria. Increased lipoprotein synthesis Decreased lipid catabolism Abnormal lipid transport HYPERLIPEDEMIA INCREASED EXCRETION OF LIPOPROTEIN Lipiduria 76
  77. Pathogenesis of edema Increased protein loss Increased renal catabolism of filtered protein HYPOALBUMINEMIA DECREASED PLASMA ONCOTIC PRESSURE GENERALISED EDEMA 77
  78. Pathophysiology of Nephrotic Syndrome. INCREASED GLOMERULAR PERMIABILITY PROTEINURIA LOSS OF COAGULATION FACTORS THROMBOSISMALNUTRITION INFECTIONS LOSS OF I G HYPOALBUMINEMIA EDEMA INCREASED LIPOPROTEIN SYNTHESIS HYPERLIPEDEMIA LIPIDURIA INCREASED PLATELET AGGREGATION 78
  79. Molecular basis of nephrotic syndrome. NEPHRIN IS AN IMPORTANT PROTEIN AND MUTATION OF NEPHRIN GENE IS SEEN IN- 1. MINIMAL CHANGE DISEASE 2. FOCAL SEGMENTAL GLOMERULAR SCLEROSIS. 3. CONGENITAL NEPHROTIC SYNDROME OF FINNISH TYPE. 79
  80. ETIOLOGY:  Primary or secondary.  Primary is more common in children  Secondary is more common in adults. 80
  81. PRIMARY LESIONS:  Membranous glomerulopathy.  Minimal change disease (MCD).  Focal segmental glomerulosclerosis (FSGS).  Membranoproliferative glomerulonephritis.  IgA nephropathy. 81
  82. Secondary causes  Diabetes mellitus. Drugs-gold, Pencillamine.  Amyloidosis.  Neoplastic condition-carcinoma and lymphoma  Infections- Malaria, syphilis, HBV, AIDS.  S L E  Henoch-Scholein purpura. 82
  83. MEMBRANOUS GLOMERULOPATHY  Immune complex mediated disease in which deposits of mainly IgG and complement collect in the epithelial side of basement membrane with diffuse thickening of glomerular capillary wall.  Most common cause of nephrotic syndrome in adults (40%) 83
  84. Causes: 1. Idiopathic in 85% cases. 2. Secondary in 15% cases. Drugs: pencillamine, NSAID, gold,captopril. SLE. Infections: HBV, HCV, Syphilis, malaria. Malignancy: Melanoma, carcinoma lung and colon. 84
  85. PATHOGENESIS  Membranous glomerulopathy is a form of chronic immune complex–mediated disease.  In secondary membranous glomerulopathy, the inciting antigens can sometimes be identified in the immune complexes.  For example, membranous glomerulopathy in SLE is associated with deposition of autoantigen-antibody complexes. 85
  86. PATHOGENESIS  Susceptibility to Heymann nephritis in rats and membranous glomerulopathy in humans is linked to the major histocompatibility complex locus, which can influence the ability to produce antibodies to the nephritogenic antigen.  Thus, idiopathic membranous glomerulopathy, like Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused most likely by antibodies to a renal autoantigen. 86
  87. PATHOGENESIS Glomerular capillary wall become leaky in membranous glomerulopathy  There is a paucity of neutrophils, monocytes, or platelets in glomeruli.  Presence of complement and corroborating experimental work suggest a direct action of C5b-C9, the pathway leading to the formation of the membrane attack complex.  C5b-C9 activates glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage. 87
  88. MORPHOLOGY. Light microscopy:  Almost all the glomeruli are involved  Uniform, diffuse thickening of glomerular capillary wall. As the disease advances,  sclerosis may occur in glomeruli  The epithelial cells of the proximal tubules contain protein reabsorption droplets  Interstitial mononuclear cell inflammation 88
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  90. ELECTRON MICROSCOPY:  Thickening is seen to be caused by irregular dense deposits of immune complexes between the basement membrane and the overlying epithelial cells, the latter having effaced foot processes.  Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains, 90
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  92. IMMUNOFLOURESCENCE:  Granular deposits of immune complex containing IgG and C3 are demonstrated. 92
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  94. CLINICAL COURSE  Manifest as nephrotic syndrome.  Heamaturia and mild hypertension in 15-35% cases  10 % patients gradually progressive to RF. 94
  95. MINIMAL CHANGE DISEASE. (LIPOID NEPHROSIS)  Diffuse loss of foot process of visceral epithelial cells (podocytes) in glomeruli.  Appear normal on light microscopy.  Common in children 2—6 yrs.  Dramatic response to steroid treatment. 95
  96. Etiopathogenesis of MCD. IMMUNE DYSFUNCTION ELABORATION OF CYTOKINE LIKE SUBSTANCE THAT AFFECTS VISCERAL EPITHILIAL CELLS. DEFECT IN CHARGE BARRIER DUE TO LOSS OF FOOT PROCESSES DETACHMENT OF EPITHELIAL CELLS PROTEINURIA 96
  97. Etiopathogenesis.  Association with respiratory infection and immunisation.  Dramatic response to steroid.  Associated with other atopic disorders.  Increased incidence in patients with defective T-CELL Mediated immunity as in Hodgkin’s disease. 97
  98. MORPHOLOGY GROSS:  Kidneys appear normal. Light Microscopy:  Glomeruli appear normal.  Lipid vacuolation is seen in the proximal convoluted Tubular cells. 98
  99.  MINIMAL CHANGE DISEASE. 99
  100. Morphology of M.C.D. (PAS STAIN) NORMAL BASEMENT MEMBRANE AND ABSENCE OF PROLIFERATION 100
  101. Electron microscopy  Diffuse loss of foot Processes in visceral epithelial cells. Immunoflourescence  No Ig or complement deposits. 101
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  103. Clinical course  Commonest in children .  Present as Nephrotic Syndrome.  Highly selective proteinuria.  Renal function is good.  Prognosis is good. 103
  104. FOCAL SEGMENTAL GLOMERULOSCLEROSIS  Focal segmental glomerulosclerosis (FSGS) defines a characteristic pathologic pattern of glomerular injury and is not necessarily a distinct disease.  The hallmark of kidney biopsy is an increased degree of scarring seen on light microscopy of some but not all of the glomeruli present (focal) that involves some but not all portions of the affected glomeruli (segmental).  Characterized by proteinuria commonly in nephrotic range.  Predominant cause of idiopathic nephrotic syndrome in adults. 104
  105. CLASSIFICATION  As a primary disease (idiopathic focal segmental glomerulosclerosis)  In association with other conditions - HIV infection, heroin addiction, sickle-cell disease,massive obesity  As a secondary event- scarring of previously active necrotizing lesions, in cases of focal glomerulonephritis (e.g., IgA nephropathy)  Adaptive response to loss of renal tissue (renal ablation), whether from congenital anomalies (e.g., unilateral renal agenesis or renal dysplasia) or acquired causes (e.g., reflux nephropathy), or in advanced stages of other renal disorders, such as hypertensive nephropathy.  In uncommon inherited forms of nephrotic syndrome where the disease may be caused by mutations in genes that encode proteins localized to the slit diaphragm, e.g., podocin, α-actinin 4, and TRPC6 (transient receptor potential calcium channel-6) 105
  106. Pathogenesis.  Epithelial damage is the hallmark of FSGS.  Mechanisms of epithelial damage: circulating factors and genetically determined defects affecting components of the slit diaphragm complex. The hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyperpermeable foci and increased ECM deposition. 106
  107. LIGHT MICROSCOPY  May involve only a minority of the glomeruli and may be missed.  In the sclerotic segments there is collapse of capillary loops, increase in matrix and segmental deposition of plasma proteins along the capillary wall (hyalinosis).  The hyalinosis may become so pronounced as to occlude the capillary lumen.  Lipid and foam cells are often present.  Glomeruli that do not show segmental lesion usually appear normal. 107
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  109. COLLAPSING GLOMERULOPATHY  It is clinically and pathologically distinct variant of FSGS  Characterized by widespread collapse of glomerular capillary loops.  Poor prognosis  It can occur as an idiopathic disease or as secondary process associated with i/v drug abuse or HIV infection. 109
  110. On electron microscopy both sclerotic and nonsclerotic areas show diffuse effacement of foot processes. There may also be focal detachment of the epithelial cells and denudation of the underlying GBM 110
  111. IgM and C3 may be present in the sclerotic areas and in the mesangium 111
  112. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS  MPGN is best considered a pattern of immune-mediated injury rather than a specific disease.  Accounts for 10% to 20% of cases of nephrotic syndrome.  Characterized by alteration of glomerular cells and leukocyte infiltration.  Proliferation is predominantly in the mesengium and involves capillary loops also , hence a synonym mesengiocapillary glomerulonephritis is used.  Persistent and slowly progressive. 112
  113.  Primary MPGN :- when the cause is idiopathic.  On the basis of distinct ultra structural, immunofluorescence and pathological findings it is divided into:- A) Type I MPGN B) Type II MPGN (dense deposit disease) C) Type III MPGN (very rare, it is characterized by a mixture of subepithelial deposits and the typical pathological findings of Type I disease)  Secondary MPGN :- when associated with other systemic disorders. 113
  114.  Activation of both classical and alternative complement pathways.  Antigens involved are unknown, sometimes believed to be protein derived from infectious agents like hepatitis C and B viruses.(planted antigens) Type II MPGN tends to present with nephritis while MPGN type I presents more often with nephrotic features.  There is activation of alternative complement pathway.  Serum levels of C3 remains low for a longer period than type I disease.  More than 70% of patients have a circulating antibody termed C3 nephiritic factor ( C3NeF ). 114
  115. LIGHT MICROSCOPY  Glomeruli are large and hypercellular.  Hypercellularity - proliferation of cells in the mesengium and endocapillary also.  Lobular appearance due to proliferating mesengial cells and increased mesengeal matrix.  The GBM is thickened, often segementally.  The glomerular capillary wall - double contour or tram-track appearance- caused by “duplication” of the basement membrane (also commonly referred to as splitting) 115
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  118. Secondary MPGN  Common in adults and arises in the following settings:  Chronic immune complex disorders- SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis, α1-Antitrypsin deficiency  Malignant diseases, particularly lymphoid tumors such as chronic lymphocytic leukemia, which are commonly complicated by development of autoantibodies 118
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  123. IgA NEPHROPATHY  Characterized by the presence of prominent IgA deposits in the mesengeal region.  Diagnosis is made only by immunochemical method. 123
  124. PATHOGENESIS Abnormalities of immune regulation increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents IgA1-containing immune complexes are then trapped in the Mesengium activate the alternative complement pathway and initiate glomerular injury 124
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  128. 128DIABETIC NEPHROPATHY  The single most common causes of end-stage renal disease.  All diabetics get hyperfiltration, thickened glomerular basement membranes and increased mesangial matrix (diffuse glomerulosclerosis).  Both the hyperfiltration and the GBM thickening appear to be secondary to prolonged hyperglycemia.  In many advanced cases, there is also nodular glomerulosclerosis ("Kimmelstiel-Wilson lesion"), with round masses of GBM-mesangial matrix material in the glomerular tufts.
  129. 129 PATHOLOGY  Diffuse global thickening of BM  Nodular sclerosis  Arteriolosclerosis  Trapping of serum proteins RESULTS  Glomerulosclerosis  Arteriolosclerosis  Hypertension  Pyelonephritis  Papillary necrosis
  130. 130Nodular glomerulosclerosis (Kimmelstiel- Wilson)
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  132. 132Minimal Change Disease Loss of Foot processes
  133. 133Focal Segmental Glomerulosclerosis Hyaline arteriolosclerosis
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  137. Normal Proliferative 137
  138. 138 Diffuse Endocapillary Proliferative GN Immunofluorescence shows coarse granular deposits containing immunoglobulin and complement.
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  141. 141Crescentic GN
  142. 142Crescent - (Trichrome Stain)
  143. 143Goodpasture Syndrome
  144. 144 MPGN : lobular pattern (Lobular GN)
  145. 145  glomerular capillary loops show two basements membranes giving the loops a tram track appearance (arrow).
  146. 146 Direct immunofluorescence shows mesangial and capillary loop granular fluorescence. Cases of idiopathic membranoproliferative glomerulonephritis usually show positivity for IgG andC3. Membranoproliferative glomerulonephritis, type I is a morphologic diagnosis, not an etiologic diagnosis. Cases of lupus glomerulonephritis and cryoglobulinemic glomerulonephritis frequently show a membranoproliferative, type I pattern of injury
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  149. 149 membranoproliferative glomerulonephritis, type II (also known as dense deposit disease) the dense deposits are also found in the basement membranes of tubules
  150. 150Membranous GN
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  156. 156 Lupus nephritis
  157. 157Nodular glomerulosclerosis (Kimmelstiel- Wilson)
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