Primary Membranoproliferative Glomerulonephritis (PMG)

Background

People Panel D_2x5_Rare DiseasesPMG includes the C3 glomerulopathies dense deposit disease (DDD) and C3 glomerulonephritis and is diagnosed by the characteristic histological pattern of damage to the glomerulus in the absence of identifiable infection or autoimmune disease. The disease usually presents in childhood or early adulthood with blood and/or protein in the urine, with or without the nephrotic syndrome. Approximately half of patients have a detectable C3 nephritic factor, an autoantibody that stabilises the C3 convertase, activating complement in the circulation. There is progressive renal impairment with ~50% requiring renal replacement therapy within 10 years of diagnosis. There is no treatment of proven benefit and the disease frequently recurs in transplants.

MPGN has historically responded poorly to treatment and frequently recurs following transplantation, leaving patients dependent on dialysis treatment lifelong. The appreciation that MPGN frequently results from disorders of regulation of the complement system of innate immunity, coupled with the recent development of a licensed drug (eculizumab) that blocks complement, has made this an attractive disease for therapeutic trials, with interest expressed by both Alexion and GSK in conducting trials of both eculizumab and novel therapeutic agents in this UK cohort. However, the rarity, heterogeneity and slow pace of MPGN can mask therapeutic effects. Exome sequencing in this UK cohort will provide a way to identify and categorise the subgroup(s) of patients most likely to respond to such treatments, increasing the power of these studies. In addition, identifying new genes and pathways will provide the starting point for the development of novel treatments for the disease, which are in great demand clinically.

Recruitment Criteria:

Children and young adults presenting with mixed nephrotic and nephritic syndromes and hypocomplementemia (usually 7-30 years old)

IgG and usually very strong C3 reactivity

Subendothelial and mesangial electron-dense deposits (if electron microscopy results available)

Centres at which PMG is currently recruiting:

University College London Hospital

Leads
Dr Daniel Gale, University College London