Glomerular diseases


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Glomerular diseases

  1. 1. Glomerular Diseases Lecture 38 Glomerulopathy
  2. 2. 3 Glomerulonephritis • Nephros – kidney • -itis – inflammation of • Glomus – small round ball or knot • Pathos – suffering or disease • -osis – diseased condition • Glomerulonephritis – inflammation of the glomeruli • Glomerulopathy – disease of the glomeruli
  3. 3. Primary Glomerular Diseases BKMC
  4. 4. Pathogenesis of Glomerular Disease Immune disorder Kidney involvement Injury by inflammation and other mediators Glomerular dysfunction
  5. 5. Pathogenesis of Glomerular Disease Immune disorder Glomerular dysfunction 1. Circulating immune complex 2. Immune complex formation 3. Cell-mediated
  6. 6. Clinical Manifestations BKMC The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes summarized in Table .
  7. 7. HISTOLOGIC ALTERATIONS Various types of glomerulopathies are characterized by one or more of four basic tissue reactions: 1.Hypercellularity 2.Basement membrane thickening 3.Hyalinosis 4.Sclerosis
  8. 8. Minimal Change Disease (Lipoid Nephrosis) • Benign disorder • Most common in 1-7 years (Nephrotic synd) • Pathogenesis: A T-cell derived factor that causes podocyte damage and effacement of foot processes. 1
  9. 9. Morphology • Lipoid Nephrosis • The uniform and diffuse effacement of the foot processes of the podocytes.
  10. 10. Clinical features • Nephrotic syndrome in an otherwise healthy child • Selective proteinuria ( chiefly albumin) • >90% of cases respond to corticosteroid therapy
  11. 11. Focal & Segmental Glomerulosclerosis • FSGS is characterised histologically by sclerosis affecting some glomeruli (focal involvement) & involving only segments of each affected glomerulus. FSGS is associated with the nephrotic syndrome. 2
  12. 12. Pathogenesis(FSGS) • Unknown • Part of a continuum (MCD → FSGS) • Distinct entities • Injury to the podocytes is thought to represent the initiating event of primary FSGS
  13. 13. Morphology (FSGS) • The involvement is focal & segmental. The affected glomeruli exhibit increased mesangial matrix, obliterated capillary lumens, and lipid droplets. • EM shows effacement of foot processes. Global sclerosis may be found occasionally. • Collapsing glomerulopathy- Collapse of the entire glomerular tuft & podocyte hyperplasia.
  14. 14. Clinical course • Response to corticosteroid is poor and • spontaneous remission of idiopathic FSGS is rare. • 50% individuals suffer renal failure after 10 years.
  15. 15. 3.Membranous Glomerulonephritis • Characterized morphologically by the presence of subepithelial immunoglobulin- containing deposits along the GBM. • This is a slowly progressive disease, • most common between 30 & 50 years of age. • Well developed cases show diffuse thickening of the capillary wall.
  16. 16. Membranous Glomerulonephritis (MG) • Idiopathic = 85 % • Secondary =15% • Secondary to other disorders: 1. Infections 2. Malignant tumors 3. Autoimmune conditions 4. Exposure to inorganic salts 5.Drugs
  17. 17. Pathogenesisof MG • Chronic Immune complex nephritis • Most idiopathic forms are induced by antibodies reacting in situ to endogenous antigen. • An autoimmune disease • Activation of MAC→ Activation of mesangial cell & podocytes→ liberate proteases & oxidants→ damage capillary walls→ perturbations in filtration
  18. 18. Morphology • LM: Diffuse thickening of the GBM • EM: Subepithelial deposits (“Spike & dome” pattern) • Effacement of foot processes • Immunofluorescence microscopy: Granular deposits
  19. 19. Clinical Course • Nephrotic syndrome • Nonselective proteinuria • Does not respond to corticosteroids • Variable & Indolent course
  20. 20. 4 Membranoproliferative Glomerulonephritis Mesangiocapillary glomerulonephritis MPGN is characterized histologically by • alterations in the GBM • proliferation of glomerular cells, • leukocyte infiltration.
  21. 21. MPGN • Because the proliferation is predominantly in the mesangium but also may involve the capillary loops, a frequently used synonym is mesangiocapillary glomerulonephritis. • MPGN accounts for 10% to 20% of cases of nephrotic syndrome in children and young adults.
  22. 22. Types of Primary MPGN
  23. 23. Pathogenesis (type I) • In most cases of type I MPGN there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways.
  24. 24. Pathogenesis (type I) • The antigens involved in idiopathic MPGN are unknown. • In many cases they are believed to be proteins derived from infectious agents such as hepatitis C and B viruses.
  25. 25. Pathogenesis (type II) • Most patients with dense-deposit disease (type II MPGN) have abnormalities that suggest activation of the alternative complement pathway.
  26. 26. Pathogenesis (type II) • These patients have a consistently decreased serum C3 but normal C1 and C4.
  27. 27. Pathogenesis (type II) • They also have diminished serum levels of factor B and properdin, components of the alternative complement pathway. In the glomeruli, C3 and properdin are deposited, but IgG is not.
  28. 28. Pathogenesis (type II) • More than 70% of patients with dense- deposit disease have a circulating antibody termed C3 nephritic factor (C3NeF), which is an autoantibody that binds to the alternative pathway C3 convertase. • Binding of the antibody stabilizes the convertase, protecting it from enzymatic degradation and thus favoring persistent C3 activation and hypocomplementemia.
  29. 29. Morphology of MPGN By light microscopy both types of MPGN are similar. The glomeruli are large and hypercellular.
  30. 30. Morphology of MPGN • Crescents are present in many cases. The glomeruli have an accentuated “lobular” appearance due to the proliferating mesangial cells and increased mesangial matrix.
  31. 31. Morphology of MPGN • The GBM is thickened. • The glomerular capillary wall often shows a “double-contour” or “tram-track” appearance.
  32. 32. Morphologyof MPGN Within the duplicated basement membranes there is inclusion or interposition of cellular elements, appearance of “split” basement membranes.
  33. 33. • Types I and II MPGN differ in their ultrastructural and immunofluorescent features. • Type I MPGN is characterized by the presence of discrete subendothelial electron-dense deposits. • By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present, suggesting an immune complex pathogenesis.
  34. 34. Morphology of MPGN • In dense-deposit disease (type II MPGN), a relatively rare entity, the lamina densa of the GBM is transformed into an irregular, ribbon- like, extremely electron-dense structure due to the deposition of dense material of unknown composition in the GBM proper.
  35. 35. Morphology of MPGN • C3 is present in irregular granular or linear foci in the basement membranes on either side but not within the dense deposits. • C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). • IgG is usually absent, as are the early-acting complement components (C1q and C4).
  36. 36. A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions (M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. C, Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope.
  37. 37. Clinical Features. Most patients present in adolescence or as young adults with nephrotic syndrome and a nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. About 50% develop chronic renal failure within 10 years.
  38. 38. Clinical features Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective. There is a high incidence of recurrence in transplant recipients, particularly in dense-deposit disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common.
  39. 39. Secondary MPGN Secondary MPGN (invariably type I) is more common in adults and arises in the following settings: • Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis.
  40. 40. SecondaryMPGN • α1-Antitrypsin deficiency • Malignant diseases (chronic lymphocytic leukemia and lymphoma) • Hereditary deficiencies of complement regulatory proteins
  41. 41. IgA nephropathy • AKA IgA nephritis, IgAN, Berger's disease, Berger's syndrome and synpharyngitic glomerulonephritis) is a form of glomerulonephritis.
  42. 42. 5. IgA Nephropathy (Berger Disease) • Characterized by the presence of prominent IgA deposits in the mesangial regions, detected by immunofluorescence microscopy.
  43. 43. IgA Nephropathy (Berger Disease)
  44. 44. Pathogenesis • In IgA nephropathy, plasma polymeric IgA is increased, and circulating IgA-containing immune complexes are present in some patients. Only IgA1 forms the nephritogenic deposits of IgA nephropathy.
  45. 45. IgA Nephropathy (Berger Disease) Pathogenesis • The prominent mesangial deposition of IgA suggests entrapment of IgA immune complexes in the mesangium, and the presence of C3 combined with the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway and initiate glomerular injury. .
  46. 46. IgA Nephropathy (Berger Disease) • A genetic influence is suggested by the occurrence of this condition in families and in HLA-identical brothers and the increased frequency of certain HLA and complement genotypes in some populations.
  47. 47. Morphology On histologic examination the lesions vary considerably. • The glomeruli may be normal or may show • mesangial widening and endocapillary proliferation (mesangioproliferative glomerulonephritis), • segmental proliferation confined to some glomeruli (focal proliferative glomerulonephritis), • or rarely, overt crescentic glomerulonephritis.
  48. 48. Morphology • The characteristic immunofluorescent picture is of mesangial deposition of IgA, often with C3 and properdin and lesser amounts of IgG or IgM. Early complement components are usually absent.
  49. 49. Clinical Features The disease affects people of any age, but older children and young adults are most commonly affected. Many patients present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract.
  50. 50. Clinical Features • 30% to 40% have only microscopic hematuria, with or without proteinuria; and 5% to 10% develop a typical acute nephritic syndrome.
  51. 51. Clinical Features • The hematuria typically lasts for several days and then subsides, only to return every few months. The subsequent course is highly variable.
  52. 52. Clinical Features • Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years.
  53. 53. Clinical Features • Onset in old age, heavy proteinuria, hypertension, and the extent of glomerulosclerosis on biopsy are clues to an increased risk of progression. • Recurrence of IgA deposits in transplanted kidneys is frequent.
  54. 54. Clinical Features • In approximately 15% of those with recurrent IgA deposits, there is resulting clinical disease, which most frequently runs the same slowly progressive course as that of the primary IgA nephropathy.
  55. 55. 6. Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis Characterized histologically by • diffuse proliferation of glomerular cells, associated with influx of leukocytes. • These lesions are typically caused by immune complexes. • The inciting antigen may be exogenous (Postinfectious glomerulonephritis) or endogenous (SLE).
  56. 56. Acute Proliferative Glomerulonephritis • The most common underlying infections are streptococcal, but the disorder also has been associated with other infections.
  57. 57. Poststreptococcal Glomerulonephritis • It usually appears 1 to 4 weeks after a streptococcal infection of the pharynx or skin. • It occurs most frequently in children 6 to 10 years of age, but adults of any age can also be affected.
  58. 58. Etiology and Pathogenesis. Only certain strains of group A β-hemolytic streptococci are nephritogenic, more than 90% of cases being traced to types 12, 4, and 1, which can be identified by typing of M protein of the cell wall.
  59. 59. Etiology & Pathogenesis of Ac Prolif. G • Poststreptococcal glomerulonephritis is an immunologically mediated disease. • Elevated titers of antibodies against one or more streptococcal antigens are present in a great majority of patients.
  60. 60. Etiology & Pathogenesis of Ac Prolif. G • Serum complement levels are low, • There are granular immune deposits in the glomeruli, supporting an immune complex– mediated mechanism.
  61. 61. Etiology & Pathogenesis • Several cationic antigens, including a nephritis-associated streptococcal plasmin receptor (NAPlr), unique to nephritogenic strains of streptococci, can be found in affected glomeruli.
  62. 62. Etiology & PathogEnEsis • Streptococcal pyogenic exotoxin B (SpeB) and its zymogen precursor (zSpeB), are the principal antigenic determinants in most cases of poststreptococcal glomerulonephritis.
  63. 63. Morphology. • The classic diagnostic picture is enlarged, hypercellular glomeruli.
  64. 64. Morphology of APG • There is also swelling of endothelial cells, and the combination of proliferation, swelling, and leukocyte infiltration obliterates the capillary lumens. • There may be interstitial edema and inflammation, and the tubules often contain red cell casts.
  65. 65. Morphology of APG • By immunofluorescence microscopy, there are granular deposits of IgG, IgM, and C3 in the mesangium and along the GBM.
  66. 66. Morphology of APG • The characteristic electron microscopic findings are discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of “humps”.
  67. 67. Clinical Features Of APG In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria 1 to 2 weeks after recovery from a sore throat.
  68. 68. Clinical features of Acute Proliferative Glomerulonephritis The patients have red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension.
  69. 69. Clinical features of Acute Proliferative Glomerulonephritis In adults the onset is more likely to be atypical, such as the sudden appearance of hypertension or edema, frequently with elevation of BUN.
  70. 70. Clinical features of Acute Proliferative Glomerulonephritis • During epidemics caused by nephritogenic streptococcal infections, glomerulonephritis may be asymptomatic, discovered only on screening for microscopic hematuria.
  71. 71. Laboratory Findings • Elevations of antistreptococcal antibody titers and a decline in the serum concentration of C3 and other components of the complement cascade.
  72. 72. Prognosis • More than 95% of affected children eventually recover totally with conservative therapy aimed at maintaining sodium and water balance. • A small minority of children (perhaps fewer than 1%) do not improve, become severely oliguric, and develop a rapidly progressive form of glomerulonephritis.
  73. 73. Nonstreptococcal Acute Glomerulonephritis (Postinfectious Glomerulonephritis) Glomerulonephritis occurs sporadically in association with other infections, including bacterial viral and parasitic. Granular immunofluorescent deposits and subepithelial humps are present.
  74. 74. 7. RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS RPGN is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis.
  75. 75. RPGN It is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and signs of nephritic syndrome; if untreated, death from renal failure occurs within weeks to months.
  76. 76. RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS • The most common histologic picture is the presence of crescents in most of the glomeruli (crescentic glomerulonephritis).
  77. 77. Crescents are produced by the proliferation of the parietal epithelial cells lining Bowman capsule and by the infiltration of monocytes and macrophages.
  78. 78. Classification and Pathogenesis RPGN may be caused by a number of different diseases, some restricted to the kidney and others systemic. Although no single mechanism can explain all cases, there is little doubt that in most cases the glomerular injury is immunologically mediated.
  79. 79. Classification and Pathogenesis • A practical classification divides RPGN into three groups on the basis of immunological findings. • In each group the disease may be associated with a known disorder, or it may be idiopathic.
  80. 80. RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS 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.
  81. 81. Classification and Pathogenesis • 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).
  82. 82. RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS 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 HenochSchönlein purpura.
  83. 83. Classification & Pathogenesis 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.
  84. 84. • To summarize, all three types of RPGN may be associated with a well-defined renal or extrarenal disease, but in many cases ( 50%), the disorder is idiopathic.∼
  85. 85. Of the patients with this syndrome, about one fifth have anti–GBM antibody–mediated glomerulonephritis without lung involvement; another one fourth have immune complex– mediated crescentic glomerulonephritis; and the remainder are of the pauci-immune type. The common denominator in all types of RPGN is severe glomerular injury.
  86. 86. Morphology RPG The kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. Depending on the underlying cause, the glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation.
  87. 87. Morphology Crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into the urinary space.
  88. 88. Morphology Fibrin strands are frequently prominent between the cellular layers in the crescents.
  89. 89. Morphology By immunofluorescence microscopy, immune complex–mediated cases show granular immune deposits; Goodpasture syndrome cases show linear GBM fluorescence for Ig and complement, and pauci-immune cases have little or no deposition of immune reactants.
  90. 90. Morphology Electron microscopy discloses deposits in those cases due to immune complex deposition (type II). Regardless of type, electron microscopy 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.
  91. 91. Clinical Course Hematuria Red blood cell casts in the urine, Moderate proteinuria Hypertension Edema.
  92. 92. Clinical Course In Goodpasture syndrome the course may be dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage.
  93. 93. 8. CHRONIC GLOMERULONEPHRITIS A pool of end-stage glomerular disease caused specific types of glomerulonephritis: Poststreptococcal glomerulonephritis in adults. • Crescentic glomerulonephritis, • Membranous nephropathy, • MPGN, • IgA nephropathy, • FSGS
  94. 94. Chronic Glomerulonephritis A variable percentage of cases arise mysteriously with no antecedent history of any of the well-recognized forms of acute glomerulonephritis.
  95. 95. Morphology • The kidneys are symmetrically contracted and have diffusely granular cortical surfaces. On section, the cortex is thinned, and there is an increase in peripelvic fat.
  96. 96. Chronic Glomerulonephritis In early cases, the glomeruli may still show evidence of the primary disease. However, there eventually ensues obliteration of glomeruli, transforming them into acellular eosinophilic masses.
  97. 97. Chronic Glomerulonephritis • Arterial and arteriolar sclerosis • Marked atrophy of associated tubules, • Iirregular interstitial fibrosis, • Mononuclear leukocytic infiltration of the interstitium
  98. 98. Dialysis Changes • Arterial intimal thickening • Focal calcification, • Extensive deposition of calcium oxalate crystals in tubules and interstitium; • Acquired cystic disease • Increased numbers of renal adenomas and adenocarcinomas.
  99. 99. Uremic Complications Uremic pericarditis, Uremic gastroenteritis, Secondary hyperparathyroidism Left ventricular hypertrophy Uremic pneumonitis
  100. 100. Clinical Course • Mostly CG develops insidiously and slowly progresses to renal insufficiency or death from uremia. • Frequently, patients have loss of appetite, anemia, vomiting, or weakness.
  101. 101. Clinical course of CG In some, the renal disease is suspected with the discovery of proteinuria, hypertension, or azotemia on routine medical examination. In others, the underlying renal disorder is discovered in the course of investigation of edema.
  102. 102. Clinical course of CG Most patients are hypertensive, and sometimes the dominant clinical manifestations are cerebral or cardiovascular.