CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 CASE- 1 Col N S Mani Prof & Head Dept of Pathology Armed Forces Medical College, Pune

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Case History 17 yr old female Clinical onset: 5 yr back Persistent nephrotic syndrome x 5 yrs Presently hematuria Clinical impression –Mesangioproliferative nephropathy –IgA Nephropathy Urine: Active sediment with RBCs Raised creatinine/ BUN Serum Complement: C3 Mildly decreased ASO titre normal

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Light Microscopy: H&E Varying patterns of glomerular morphology Lobular accentuation with endocapillary proliferation Mesangial prominence Occasional fibrous crescent Obsolescent glomeruli (40%)

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Light Microscopy: H&E Segmental proliferation Global membrane thickening Endocapillary proliferation with Solidification of glomerular lobules Focal interstitial fibrosis with tubular atrophy Foam cells in interstitium

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 PAS: Intense PAS positivity in glomeruli Positivity along GBM Refractile appearance Absence of inflammatory cells in glomeruli

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 PASM Thin outlining of GBM Splitting of GBM with central lucencies Focal mesangial sclerosis

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Masson Trichrome Intense fuchsinophilia of glomeruli GBM shows refractile thickening Focal interstitial sclerosis highlighted

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Direct Immunofluorescence Strong granular positivity in glomeruli for C3 Positivity along GBM and in mesangial areas Negative for IgG, IgA, IgM

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Transmission Electron Microscopy Intensely osmiophilic deposits along GBM Varying thickness and discontinuous Continuous in some glomeruli Deposits intramembranous No substructure to deposits Mesangium shows only few such deposits No subepithelial humpy deposits Associated foot process effacement of podocytes Segmental mesangial proliferation

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Final Diagnosis Type II Membranoproliferative glomerulonephritis (Dense deposit disease)

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Discussion Defined in Berger and Galle 5-33% of all MPGN M:F:: 1:1 Children and young adults C/F: –Acute nephritis (16-38%)/ renal insufficiency precede CRF –Microscopic & gross hematuria at presentation (11-57%) –Nephrotic syndrome common (12-65%) –Preceding URTI in 50%, ASO raised in 21-45% –Associations: Partial lipodystrophy, narcotics, acquired cutis laxa, SLE, MGUS, after meningococcemia –Persistent activation of alternate complement pathway C3 decreased in 80%, 20% fluctuating C1q & C4 normal

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Discussion LM –Variety of picture seen –Normal glomeruli with capillary thickening (>MPGN I, <MGN) –DPGN Pattern (cellularity, endothelial swelling with narrowing of capillary lumina) –Mesangial matrix increase>> sclerotic nodules like DN –Irregular intramembranous deposits- ribbon like, strongly eosinophilic, refractile –Subepithelial GBM deposits like DPGN, Mesangial deposits –Crescents +/- –PAS: Intense PAS positive –MT: Strong fuchsinophilia –Toluidine blue: dark blue –PASM: splitting with deposits negative

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Discussion Immunofluorescence –Intense C3 along glomerular capillary walls and often mesangium –Patterns: Linear, pseudolinear, smooth, ribbon like, granular, nodular –C3: Double linear appearance- railroad tracks Mesangial rings in mesangial areas –Immunoglobulins absent. Only in FSGS form and usually IgM Electron Microscopy –Deposits in GBM, lamina of Bowman’s capsule, TBM (Prox>Distal), mesangial –Deposits replace width of lamina densa or part of it –Fusiform thickening or irregular masses, often discontinuous –No substructure to deposits

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 Discussion Long term prognosis poor >> ESRD in (1 ½ -10yrs) Prognosis –Clinical Nephrotic syndrome Absence of clinical remissions Initial decrease in renal function Gross hematuria –Bx features Mesangial deposits Degree of mesangial proliferation Glomerular sclerosis Crescents Increased glomerular lobulation/ Increased PMN in glomeruli Pathogenesis –More likely to be transformation of Lamina densa of GBM than immune deposits –Highly osmiophilic- ?? High lipid content –Factor B & Properdin are low- alternate pathway of complement activation –? Primary alteration of GBM > generates substances >> complement activation

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008 References Appel G, Cook TH, Hageman G, et al. Membranoproliferative glomerulonephritis Type II (dense deposit disease). An Update. J Am Soc Nephrol 2005, 16; Zhou XJ, Silva FG. Membranoproliferative glomerulonephritis In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors Heptinstall’s Pathology of the Kidney 6 th ed. Vol 1 Philadelphia Lippincott Williams & Wilkins, 2007;