Membranoproliferative glomerulonephritis and C3 glomerulopathy in children: change in treatment modality? A report of a case series

Abstract

BackgroundMembranoproliferative glomerulonephritis (MPGN) with immune complexes and C3 glomerulopathy (C3G) in children are rare and have a variable outcome, with some patients progressing to end-stage renal disease (ESRD). Mutations in genes encoding regulatory proteins of the alternative complement pathway and of complement C3 (C3) have been identified as concausative factors.MethodsThree children with MPGN type I, four with C3G, i.e. three with C3 glomerulonephritis (C3GN) and one with dense deposit disease (DDD), were followed. Clinical, autoimmune data, histological characteristics, estimated glomerular filtration rate (eGFR), proteinuria, serum C3, genetic and biochemical analysis were assessed.ResultsThe median age at onset was 7.3 years and the median eGFR was 72 mL/min/1.73 m2. Six children had marked proteinuria. All were treated with renin–angiotensin–aldosterone system (RAAS) blockers. Three were given one or more immunosuppressive drugs and two eculizumab. At the last median follow-up of 9 years after diagnosis, three children had normal eGFR and no or mild proteinuria on RAAS blockers only. Among four patients without remission of proteinuria, genetic analysis revealed mutations in complement regulator proteins of the alternative pathway. None of the three patients with immunosuppressive treatment achieved partial or complete remission of proteinuria and two progressed to ESRD and renal transplantation. Two patients treated with eculizumab revealed relevant decreases in proteinuria.ConclusionsIn children with MPGN type I and C3G, the outcomes of renal function and response to treatment modality show great variability independent from histological diagnosis at disease onset. In case of severe clinical presentation at disease onset, early genetic and biochemical analysis of the alternative pathway dysregulation is recommended. Treatment with eculizumab appears to be an option to slow disease progression in single cases.

Recurrent and de novo Glomerulonephritis After Kidney Transplantation

“…The initiation of eculizumab in these 3 patients resulted in stabilization of kidney function and proteinuria in 2 patients, with no response in 1 patient and treatment with eculizumab was subsequently discontinued (139). Other reports comprising of 6 pediatric patients with MPGN I, C3GN, or DDD ( n = 5 native kidneys and n = 1 with recurrence of C3 glomerulopathy post-kidney transplant) showed a modest benefit of eculizumab in reducing proteinuria and stabilization of kidney function suggesting a potential therapeutic role of eculizumab in a subgroup of patients (145, 146). Nevertheless, given the heterogeneity in the use and varying treatment responses to eculizumab in these cases (and small number of cases of post-transplant recurrence), larger studies are required to ascertain the true benefits of eculizumab in the treatment of disease recurrence post-transplant.…”

Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

“…The genetic defects include either mutations in the C3 convertase components-complement component C3 and complement factor B (CFB)-or regulatory proteins-such as complement factor H (CFH), CFH-related 1, 2, 3, and 5, complement factor I (CFI), and CD46. [1][2][3][4] Histologically, kidneys of patients with C3G show abundant glomerular C3 deposition in the absence of Igs, and a range of pathologic features, such as mesangial matrix expansion, membrane and endocapillary proliferation with crescent formation. 1,5 Histologic evidence of membrane attack complex (MAC) deposition suggests terminal activation of complement component C5.…”

Characteristics and outcomes of glomerulonephritis with membranoproliferative pattern in children

“…Several studies were done to evaluate the causes, clinical presentations, effects of various treatments and prognosis of adult MPGN (10)(11)(12)(13)(14), yet studies of children MPGN remain to be small-scale with narrow cases (15)(16)(17). The rareness of the disease as well the terminology shift with the revolution of diagnostic classification conceal the authentic characteristics and outcomes from being concluded.…”