Membranoproliferative Glomerulonephritis Secondary to Dysfunction of the Alternative Pathway of Complement.
Sanjeev Sethi, Fernando Fervenza, Yuzhou Zhang, Samih Nasr, Julie Vrana, Richard JH Smith. Mayo Clinic, Rochester, MN; Carver College of Medicine, Iowa City, IA; Mayo Clinic, Rochester
Background: Dense Deposit Disease (DDD) is the prototypical membranoproliferative glomerulonpehritis (MPGN) in which dysregulation of the alternative pathway (AP) of complement results in accumulation of complement debris in glomeruli. MPGN with C3 deposition (GN-C3) is a recently recognized entity that bears many similarities to DDD. The aim of this study was to evaluate AP in cases of MPGN with C3 deposition.
Design: Five cases of MPGN with extensive C3 deposition were studied. IF was negative for immunoglobulins, C1q, kappa and lambda light chains, but showed extensive C3 deposition in the mesangium and along the GBM. EM showed electron dense deposits in the mesangium and along GBM (Case 1-3) but lacked the classic sausage shaped dense deposits of DDD, and were diagnosed as GN-C3. EM in case 5 exhibited the classic findings of DDD. Case 4 showed features of both DDD and GN-C3, with some loops showing electron dense deposits, and other loops showing sausage shaped deposits of DDD.
Results: Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (sMAC, all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a missence factor H mutation (one case).
|Case 1||Case 2||Case 3||Case 4||Case 5|
|CFH||1 copy H402||1 copy H402||2 copies of H402||2 copies of H402; c.2867 C>T p. Thr956Met||1 copy H402|
|CFI||No mutation||No mutation||No mutation||No mutation||No mutation|
|MCP||No mutation||No mutation||No mutation||No mutation||No mutation|
|CFB||ND||No mutation||No mutation||ND||No mutation|
|CFHR5||ND||No mutation||No mutation||ND||No mutation|
|AP functional assay||6.6% very low||109.0% normal||1.0% very low||5.5% very low||1.0% very low|
|sMAC (Normal <0.30 mg/dL||0.46||0.41||1.23||0.93||0.31|