CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology

CME on Renal Pathology, 17th December 08, PuneIndian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology (ISN) -ISNCON 2008

CASE- 1

Col N S ManiProf & Head

Dept of PathologyArmed Forces Medical College, Pune


Case History17 yr old femaleClinical onset: 5 yr backPersistent nephrotic syndrome x 5 yrsPresently hematuria Clinical impression– Mesangioproliferative nephropathy– IgA Nephropathy

Urine: Active sediment with RBCs Raised creatinine/ BUNSerum Complement: C3 Mildly decreasedASO titre normal


Light Microscopy: H&E

Varying patterns of glomerular morphologyLobular accentuation with endocapillary proliferationMesangial prominenceOccasional fibrous crescentObsolescent glomeruli (40%)


Light Microscopy: H&E

Segmental proliferationGlobal membrane thickeningEndocapillary proliferation withSolidification of glomerular lobules

Focal interstitial fibrosis with tubular atrophyFoam cells in interstitium


PAS: Intense PAS positivity in glomeruli Positivity along GBM Refractile appearance Absence of inflammatory cells in glomeruli


PASM Thin outlining of GBM Splitting of GBM with central lucencies Focal mesangial sclerosis


Masson Trichrome

Intense fuchsinophilia of glomeruliGBM shows refractile thickening

Focal interstitial sclerosis highlighted


Direct Immunofluorescence

Strong granular positivity in glomeruli for C3 Positivity along GBM and in mesangial areas Negative for IgG, IgA, IgM


Transmission Electron MicroscopyIntensely osmiophilic deposits along GBMVarying thickness and discontinuousContinuous in some glomeruliDeposits intramembranousNo substructure to depositsMesangium shows only few such depositsNo subepithelial humpy depositsAssociated foot process effacement of podocytesSegmental mesangial proliferation


Final Diagnosis

Type II Membranoproliferative glomerulonephritis

(Dense deposit disease)


DiscussionDefined in 1963- Berger and Galle5-33% of all MPGNM:F:: 1:1Children and young adultsC/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% fluctuatingC1q & C4 normal


DiscussionLM– 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


DiscussionImmunofluorescence– Intense C3 along glomerular capillary walls and often mesangium– Patterns: Linear, pseudolinear, smooth, ribbon like, granular, nodular– C3:

Double linear appearance- railroad tracksMesangial 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


DiscussionLong term prognosis poor >> ESRD in (1 ½ -10yrs)

Prognosis– Clinical

Nephrotic syndromeAbsence of clinical remissionsInitial decrease in renal functionGross hematuria

– Bx featuresMesangial depositsDegree of mesangial proliferationGlomerular sclerosisCrescentsIncreased 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


ReferencesAppel G, Cook TH, Hageman G, et al. Membranoproliferative glomerulonephritis Type II (dense deposit disease). An Update. J Am Soc Nephrol 2005, 16; 1392.

Zhou XJ, Silva FG. Membranoproliferative glomerulonephritis In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors Heptinstall’s Pathology of the Kidney 6th ed. Vol 1 Philadelphia Lippincott Williams & Wilkins, 2007; 254-319.

Documents

CME on Renal Pathology, 17th December 08, Pune Indian Society of Renal and Transplantation Pathology in collaboration with Indian Society of Nephrology