Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation

Abstract

The development of membranoproliferative glomerulonephritis (MPGN) is associated with uncontrolled activation of the complement alternative pathway. This dysregulation is related either to C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase, or to homozygous loss-of-function mutation of the complement regulatory protein factor H. Heterozygous mutations in the genes coding for factor H, or for the other alternative pathway inhibitory proteins factor I and membrane cofactor protein, have recently been identified in a small number of patients with MPGN with exclusive C3 deposits. We report three hypocomplementemic children with dense deposit disease (n=1) or immune-complex-mediated MPGN type I (n=2), associated with both C3NeF activity and heterozygous mutation of factor H or factor I. These observations highlight the possible combination of genetic and acquired defect in complement control in various subtypes of MPGN, a finding that may influence the treatment strategy in some patients.

Complement factor I in health and disease

“…A peculiar primary glomerulonephritis characterized by isolated mesangial C3 deposits in the absence of mesangial proliferation was reported on the background of heterozygous mutations in the CFI genes (Servais et al, 2007). Recently two heterozygous mutations in the CFI gene were reported in a context of immune-complex-mediated membranoproliferative glomerulonephritis type I, which is an additional illustration of the link between CFI mutations and C3 glomerulopathy (Leroy et al, 2010;Leroy et al, 2011). One of these mutations has been previously reported in a patient with aHUS, and has been associated with a quantitative FI deficiency.…”

Autoantibodies to complement components in C3 glomerulopathy and atypical hemolytic uremic syndrome

“…The few laboratories routinely measuring C3Nef use different methods, predominantly hemolytic assays, and occassionally ELISA and surface plasmon resonance assay that detect various groups of C3Nefs [22,[33][34][35][36][37]. Results of the various measurements can also be influenced by the presence of C4 nephritic factor (C4Nef), anti-C1q autoantibodies or mutations in factor H 8 or factor I [10,[38][39][40]. Recent data suggest that a combination of different assays are likely to identify most C3Nefs, including occult cases [11,22,37].…”

Successful therapy of C3Nef-positive C3 glomerulopathy with plasma therapy and immunosuppression

“…C3 glomerulopathy (C3G) is a rare cause of nephrotic and nephritic syndrome in children and adolescents and responsible for 3-5 % of all pediatric nephrotic syndromes [1]. The dense deposit disease (DDD) subform affects an estimated two to three people per million [2].…”