Renal pathology: Nephrotic - PowerPoint Presentation

1. Renal pathology: Nephrotic and Nephritic SyndromesJohn Higgins

2. Learning ObjectivesMorphology of renal injuryMechanisms of glomerular injury and clinicopathologic correlations of prototype disease with a typical clinical presentationNephrotic syndrome (minimal change nephrotic syndrome)Nephritic syndrome (Post streptococcal GN)RPGN (anti-GBM disease)Asymptomatic hematuria/Proteinuria (IgA nephropathy)Systemic disease (Lupus nephritis)

3. Medical renal pathologyoverview GlomeruliGlomerulonephritisDiabetesAmyloidosise.g. Crescentic glomerulonephritis

4. Medical renal pathologyoverview TubulesAcute tubular necrosisPyelonephritisMyeloma kidneye.g. Acute tubular necrosis

5. Medical renal pathologyoverview InterstitiumAcute or chronic interstitial nephritise.g. Tubulointerstitial nephritis

6. Medical renal pathologyoverview Blood vesselsClassic polyarteritis nodosaMalignant hypertensionAtheroembolie.g. Necrotizing arteritis

7. Points not to be overlookedTubulointerstitial diseases (such as ATN and pyelonephritis) and vascular diseases (such as arteriolonephrosclerosis due to hypertension) are more common than glomerular diseasesOf the glomerular diseases, diabetes is much more common than glomerulonephritisNevertheless, we’re going to talk about rare glomerular diseases for the rest of this lecture

8. Medical kidney disease – New problems (why renal is hard)Clinicopathologic correlationClinical featuresMorphologyDisease namesImmunofluorescence and EMGlomerular immune complex diseasesNew terminology

9. Practice translating between light, IF, EM

10. Kidney DiseaseTerminologyProliferation – more cells than normalNecrosisSclerosisDeposits

11. Normal: H&EVisceral epithelial cells (podocytes)Endothelial cellsMesangial cells

12. Normal: PASVisceral epithelial cells (podocytes)Endothelial cellsMesangial cells

13. Mesangial proliferationIncrease in the number of cells in the mesangium to four or more per zoneAs in mesangioproliferative glomerulonephritis such as IgA

14. Mesangial proliferation

15. Epithelial proliferation(Crescent formation)Increase in parietal epithelial cells together with infiltrating leukocytesOften associated with fibrinoid necrosis50% or more glomeruli with crescents defines crescentic glomerulonephritis

16. Cellular crescentBowman’s capsuleCapillary tuftCrescent

17. NecrosisDeposition of fibrin (fibrinoid necrosis) and/or karyorrhectic fragments

18. Fibrinoid necrosisBowman’s capsuleCrescentResidual capillary tuftFibrin

19. SclerosisAbsolute or relative increase in the amount of extracellular matrixMesangial matrix increasePartial or complete capillary tuft collapse

20. Mesangial sclerosis

21. Diabetic glomerulopathyThickenedGBMMesangial cellsMesangial matrix

22. Segmental sclerosis/hyalinosisResidual normal tuftSclerosed segment

23. Global glomerulosclerosis

24. Deposits – Immune complexLocationMesangialSubendothelialSubepithelialIntramembranousQuality (by immunofluorescence)GranularLinear

25. Subepithelial depositsGBMEpithelial cell cytoplasmDeposits

26. Subendothelial depositsGBMEndothelial cell cytoplasmSubendothelial deposit

27. Intramembranous depositGBM replaced by electron dense deposit

28. Mesangial depositGBMMesangial cellsDeposit

29. Linear depositsIgG and C3 that outline the glomerular basement membraneNot visible by EMSeen in the setting of crescentic glomerulonephritisCharacteristic of Goodpasture’s disease (anti-glomerular basement membrane disease)

30. Linear IgG by IFSeen with glomerular crescents: anti-GBM nephritis

31. Granular IgG by IF

32. Mesangial deposits of IgA: Don’t look as much like a glomerulus

33. Distribution of glomerular lesionsDiffuse – involving >50% of the glomeruliGlobal – involving and entire glomerulusFocal – involving <50% of the glomeruliSegmental – involving only a portion of a single glomerulus

34. Renal glomerular syndromescorresponding glomerular pathologyNephritic (bleeding)Increased cellularityMesangialCrescentsNecrosisImmune complex deposits in the mesangium and subendothelial spaceLinear glomerular basement membrane depositsNephrotic (heavy proteinuria)Podocyte injuryFoot process fusionSubepithelial immune complex depositsSegmental glomerular basement membrane collapse

35. Nephrotic syndrome causesChildren Primary diseases (95%)Membranous (5%)Minimal change (65%)FSGS (10%)MPGN (10%)Other proliferative GN (10%)Secondary (5%)SLE, drugs, Infections, malignancy, hereditary nephritis, bee-sting allergyAdultsPrimary diseases (60%)Membranous (30%)Minimal change (10%)FSGS (35%)MPGN (10%)Other proliferative GN (15%)Secondary diseases (40%)Diabetes, amyloidosis, SLE, drugs (gold, penicillamine, heroin), Infections (malaria, syphilis, hep. B, HIV), malignancy, bee-sting allergyNotice that:Secondary causes are rare in children but common in adultsSecondary causes may resemble the primary lesions (e.g. malignancy associated membranous) or look nothing like them (e.g. amyloid)In children, the most common primary lesion is minimal change nephrotic syndrome. Because this is steroid responsive, children with NS are treated empirically

36. Minimal change nephrotic syndromeEpithelial cell foot process effacement

37. Focal Segmental Glomerulo Sclerosis (FSGS)Segmental sclerosisNon-specific trapping of plasma proteinsLoss of capillary lumens with foam cells

38. Membranous glomerulopathyDiffuse subepithelial depositsCapillary wall thickening only if deposits are big enoughGranular loop deposits of IgG always present but not specific

39. Conditions associated with membranous nephropathyPrimary/idiopathicmost have antibodies against podocyte antigen Phospholipase A2 receptor (PLA2R)Malignancy: solid tumorsInfection: hepatitis B/C, malaria, syphilisDrugs: penicillamine, goldAutoimmune diseases: SLESarcoidosis

40. Membranoproliferative Glomerulonephritis (MPGN) (type I)Mesangial and endocapillary proliferation with lobular accentuation and double contoured capillary walls

41. Diabetic glomerulosclerosisGBM thickening and mesangial matrix increaseVisible by light microscopy only if advanced enough

42. AmyloidosisHaphazardly arranged 10nm fibrilsAmorphous material by light microscopyCommonly light chain - associated with myeloma but does not have to be

43. Amyloidosis:Congo red stain under polarized light

44. Clinical manifestations of glomerular diseaseNephrotic syndromeAcute nephritic syndrome: Post Streptococcal GNRapidly progressive renal failure (RPGN)Asymptomatic hematuria and/or proteinuriaSystemic DiseaseChronic renal failure

45. Acute Post-Infectious GNGroup A  hemolytic streptococci (types 12,4,1) eg. pharyngitis, impetigoStaphylococcus (eg. subacute bacterial endocarditis, deep seated abscesses, infected ventriculo-atrial shunts); pneumococcus, meningococcusViral infections: Hep B, C, HIV, varicellaParasitic infections: malaria, toxoplasmosis

46. Acute Post-Streptococcal GNRenal symptoms 1-4 weeks after streptococcal throat or skin infection>> ASO titers, low serum complement levelsAtypical clinical presentation and course prompt a renal biopsy in children

47. 1 Diffuse, proliferative, exudative glomerulonephritisNeutrophils in capillary lumens (acute exudate)

48. Red blood cell casts

49. Granular C3, IgG

50. Glomerular basement membraneNeutrophilsDeposits

51. Subepithelial “humps”Epithelial cell“hump”-likedepositGBM

52. Acute Post-Streptococcal GN Pathogenesis: Immune complex-mediated processthe specific streptoccocal cationic antigenic component responsible is unclear (exogenous antigen)? cationic planted antigen versus circulating immune complexes

53. Acute Post-Streptococcal GN: OutcomeSpontaneous resolution in 95% of the children (& 60% of adults)1-2 % have crescents with rapid deterioration of renal function1-3 % develop slow progression to chronic renal failure

54. Crescentic GNsubdivided into 3 categories, based on IF: -anti-GBM disease : linear IgG & C3; no deposits by EM -Immune complex-mediated : abundant deposits eg. SLE, post-infectious GN, Henoch-Schönlein Purpura -Pauci-Immune GN : No deposits by IF/EM eg. Granulomatosis polyangiitis (Wegener’s), microscopic polyangiitis

55. Anti-GBM disease (Goodpasture’s syndrome)Clinical presentation: RPGNIf associated hemoptysis and dyspnea: Goodpasture’s syndromePathogenesis: circulating auto-antibodies against non-collagenous domain of 3 chain of collagen type IV (cross reacting with glomerular and alveolar basement membranes).

56. Glomerular necrosisGlomeruliFibrinoid Necrosis

57. Fibrin extravasation, cellular crescentNormal glomerular tuftFibrinCrescent

58. EM: No depositsLinear IgG; No deposits in EM

59. Alveolar hemorrhageAlveolar septaBlood

60. Anti-GBM disease: Clinical Course Steroids, cytotoxic agents and plasmapheresis : Resolves pulmonary hemorrhages Renal function improves if intervened early (sCr 4-5 mg/dl) Irreversible renal failure if therapy is delayed May recur in renal transplants (anti-GBM antibody titers monitored)

61. Clinical manifestations of glomerular diseaseNephrotic syndromeAcute nephritic syndromeRapidly progressive renal failure (RPGN)Asymptomatic hematuria and/or proteinuriaIgA nephropathy (Berger’s disease)Alport syndrome, Thin basement membrane diseaseSystemic DiseaseChronic renal failure

62. IgA NephropathyClinical presentation:Recurrent gross/microscopic hematuriaProteinuria usually non-nephrotic rangeNo systemic disease (vs Henoch-Schönlein Purpura)Acute nephritic syndrome in 5-10% of casesHematuria often preceded by respiratory and gastrointestinal infections

63. IgA NephropathyLM: mesangioproliferative most commonendocapillary proliferative and/or sclerosing lesions may be seen. Segmental crescents can be present. IF: defining feature Dominant /co-dominant IgA stain (IgA /= IgG); C3, K, L + EM: Mesangial deposits;  segmental subendothelial deposits

64. Mesangial ProliferationExpanded, hypercellularmesangium

65. Fibrocellular crescentCrescentCellular areasLess cellular, “Fibrous” areas

66. Mesangial IgA, C3

67. Mesangial depositsMesangial immune complexGBM

68. Henoch-Schönlein PurpuraMost common in children (3-8 yrs), but also occurs in adultsSyndrome: systemic vasculitisPurpuric skin rash (extensor surfaces of extremeties) Abdominal pain, vomiting, melenaArthralgiasRenal manifestations (IgA nephropathy)

69. Clinical manifestations of glomerular diseaseNephrotic syndromeAcute nephritic syndromeRapidly progressive renal failure (RPGN)Asymptomatic hematuria and/or proteinuriaSystemic Disease: Systemic lupus erythematosus, Henoch-Schönlein Purpura, Goodpasture’s syndrome, Wegener’s granulomatosis, cryoglobulinemic GNChronic renal failure

70. Systemic Lupus ErythematosusMultisystem disease of autoimmune originPredominantly seen in women of childbearing age (F: M=9:1), > severe in AA, HispanicsAcute or insidious in onset; chronic remitting and relapsing coursePrimary target organs: skin, joints, kidney, serosal membranes

71. 1997 Revised Criteria for SLE Classification (4 required for diagnosis)1.Malar rash8.Neurological disorder2.Discoid rash9.Hematological disorder3.Photosensitivity10.Immunological disorder: Anti-dsDNA4.Oral ulcersAnti-Sm Ab5.ArthritisAntiphospholipid Ab6.Serositis 7.Renal disorder11.Antinuclear Ab (ANA)

72. Systemic Lupus ErythematosusRole of antibodies in the diagnosis:ANA is highly sensitive , but not very specificAnti-dsDNA and anti-Sm antibodies are less sensitive but more specificEtiology and pathogenesis:Genetic factorsEnvironmental factors eg. DrugsImmunological factors (dysregulation & loss of self tolerance)

73. SLE and KidneyThe morphological changes in lupus nephritis (LN) are extremely variableThe lesions result from deposition of immune complexes (Ag-AB) The clinical presentation, course and prognosis of various lesions differNephrotic, nephritic-nephrotic, RPGN

74. Endocapillary proliferationToo many cells and loss of capillary lumens

75. “Wire loops” (large subendothelial deposits)

76. Intraluminal hyaline thrombi

77. Cellular crescent

78. Different case: Membranous LN (nephrotic syndrome)Diffusely thickened,Lumpy-bumpy capillary walls

79. IgG, IgM, IgA, C3, C1q, K, L: “full house”

80. Mesangial depositsGBMDeposit

81. Subendothelial depositsGBMDepositDeposit

82. Subepithelial depositsGBMDeposits

83. Tubuloreticular inclusions

84. CLASSIFICATION OF Lupus NephritisClassLMIFEMInormalmesangialmesangial depositsIImesangial hypercellularitymesangialmesangial depositsIIIfocal proliferative GN (< 50% glomeruli)mesangial + capillary wallMes + subendo depIVdiffuse proliferative (> 50% glomeruli)mesangial + capillary wallMes + subendo depVMembranouscapillary wall (+/- mesangial)Subepithelial +/- mesVIAdvanced sclerosis +/-+/-

85. Chronic GlomerulonephritisChronic end-stage damage to glomeruli, tubules and blood vesselsBilateral kidneys symmetrically contractedAssociated with hypertensionClinical features of chronic renal failure and uremia develop

86. 1Atrophic tubulesAtrophic tubulesGlobally sclerosed glomeruli

87. Robbins..