renal pathology: nephrotic and nephritic syndromes john higgins

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Kidney disease Terminology

Renal pathology: Nephrotic and Nephritic SyndromesJohn HigginsLearning 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)Medical renal pathologyoverview GlomeruliGlomerulonephritisDiabetesAmyloidosise.g. Crescentic glomerulonephritis

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

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

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

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, were going to talk about rare glomerular diseases for the rest of this lectureMedical kidney disease New problems (why renal is hard)Clinicopathologic correlationClinical featuresMorphologyDisease namesImmunofluorescence and EMGlomerular immune complex diseasesNew terminology

Practice translating between light, IF, EMKidney DiseaseTerminologyProliferation more cells than normalNecrosisSclerosisDeposits

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

Normal: PASVisceral epithelial cells (podocytes)Endothelial cellsMesangial cellsMesangial proliferationIncrease in the number of cells in the mesangium to four or more per zoneAs in mesangioproliferative glomerulonephritis such as IgA

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

Cellular crescentBowmans capsuleCapillary tuftCrescentNecrosisDeposition of fibrin (fibrinoid necrosis) and/or karyorrhectic fragments

Fibrinoid necrosisBowmans capsuleCrescentResidual capillary tuftFibrinSclerosisAbsolute or relative increase in the amount of extracellular matrixMesangial matrix increasePartial or complete capillary tuft collapse

Mesangial sclerosis

Diabetic glomerulopathyThickenedGBMMesangial cellsMesangial matrix

Segmental sclerosis/hyalinosisResidual normal tuftSclerosed segment

Global glomerulosclerosisDeposits Immune complexLocationMesangialSubendothelialSubepithelialIntramembranousQuality (by immunofluorescence)GranularLinear

Subepithelial depositsGBMEpithelial cell cytoplasmDeposits

Subendothelial depositsGBMEndothelial cell cytoplasmSubendothelial deposit

Intramembranous depositGBM replaced by electron dense deposit

Mesangial depositGBMMesangial cellsDepositLinear depositsIgG and C3 that outline the glomerular basement membraneNot visible by EMSeen in the setting of crescentic glomerulonephritisCharacteristic of Goodpastures disease (anti-glomerular basement membrane disease)

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

Granular IgG by IF

Mesangial deposits of IgA: Dont look as much like a glomerulusDistribution of glomerular lesionsDiffuse involving >50% of the glomeruliGlobal involving and entire glomerulusFocal involving mes, subendothelial)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 children46Bx: in adults, sudeen HTN, edema1 Diffuse, proliferative, exudative glomerulonephritisNeutrophils in capillary lumens (acute exudate)47Neutrophils and monocytes; proli endothelial and mesangial cells; crescents rareRed blood cell castsGranular C3, IgG49Compare IF, EM with MGNGlomerular basement membraneNeutrophilsDepositsSubepithelial humpsEpithelial cellhump-likedepositGBMAcute Post-Streptococcal GNPathogenesis: Immune complex-mediated processthe specific streptoccocal cationic antigenic component responsible is unclear (exogenous antigen)? cationic planted antigen versus circulating immune complexes52*** not due to direct infection by bacteria. Immunological with ab formed against some strep antigenAcute 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

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-Schnlein Purpura-Pauci-Immune GN : No deposits by IF/EM eg. Granulomatosis polyangiitis (Wegeners), microscopic polyangiitis 54Pauci=few

Clinical presentation as RPGN (rapidly progressive GN), characterized by rapid, and progressive loss of renal function , with renal failure within weeks to months Histological diagnosis is crescentic GN Clinical features: ProteinuriaHematuriaOliguria, anuriaRenal failure, progressive and rapidUsually irreversible

Anti-GBM disease (Goodpastures syndrome)Clinical presentation: RPGNIf associated hemoptysis and dyspnea: Goodpastures syndromePathogenesis: circulating auto-antibodies against non-collagenous domain of 3 chain of collagen type IV (cross reacting with glomerular and alveolar basement membranes). 55Trigger: unclear. Exposure to viruse, hydrocarbon solvents (paints, dyes), drugs, cancersHigh prevalence of certain HLA subtypes(? Genetic predisposition to autoimmunity)Glomerular necrosisGlomeruliFibrinoid NecrosisFibrin extravasation, cellular crescentNormal glomerular tuftFibrinCrescent

EM: No depositsLinear IgG; No deposits in EMAlveolar hemorrhageAlveolar septaBloodAnti-GBM disease: Clinical CourseSteroids, cytotoxic agents and plasmapheresis : Resolves pulmonary hemorrhagesRenal function improves if intervened early (sCr 4-5 mg/dl)Irreversible renal failure if therapy is delayedMay recur in renal transplants (anti-GBM antibody titers monitored)60What is plasmapharesisClinical manifestations of glomerular diseaseNephrotic syndromeAcute nephritic syndromeRapidly progressive renal failure (RPGN)Asymptomatic hematuria and/or proteinuriaIgA nephropathy (Bergers disease)Alport syndrome, Thin basement membrane diseaseSystemic DiseaseChronic renal failureIgA NephropathyClinical presentation:Recurrent gross/microscopic hematuriaProteinuria usually non-nephrotic rangeNo systemic disease (vs Henoch-Schnlein Purpura)Acute nephritic syndrome in 5-10% of casesHematuria often preceded by respiratory and gastrointestinal infections62HSP=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 depositsMesangial ProliferationExpanded, hypercellularmesangiumFibrocellular crescentCrescentCellular areasLess cellular, Fibrous areas

Mesangial IgA, C3Mesangial depositsMesangial immune complexGBMHenoch-Schnlein 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)68In notes; it is in systemic disease after SLERash: extensor surfaces of extremities; renal manifestations more in adultsClinical manifestations of glomerular diseaseNephrotic syndromeAcute nephritic syndromeRapidly progressive renal failure (RPGN)Asymptomatic hematuria and/or proteinuriaSystemic Disease: Systemic lupus erythematosus, Henoch-Schnlein Purpura, Goodpastures syndrome, Wegeners granulomatosis, cryoglobulinemic GNChronic renal failureSystemic 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 membranes701997 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)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)72SLE pts have many types of antibodiesGenetic factors; infection: molecular mimicry, exposure of prior concealed epitopes; activation of self reactive lymphocytes; loss of self tolerance

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, RPGNEndocapillary proliferationToo many cells and loss of capillary lumensWire loops (large subendothelial deposits)Intraluminal hyaline thrombi

Cellular crescentDifferent case: Membranous LN (nephrotic syndrome)Diffusely thickened,Lumpy-

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