Genetic and Acquired Complement Abnormalities in Idiopathic Membranoproliferative Glomerulonephritis

Idiopathic Membranoproliferative Glomerulonephritis (MPGN) is a kidney disease that predominantly affects children and young adults. It accounts for around 5% of End Stage Renal Disease (ESRD) in children.

Presently, there are no specific treatments for idiopathic MPGN and consequently there is progression to ESRD requiring long term dialysis treatment. Although renal transplantation is undertaken, MPGN usually recurs in the transplant leading to graft failure.

The pivotal role of the complement system in MPGN has been recognised for some time. Complement is an ancient defence system which coats both foreign cells (such as bacteria and viruses) and our own cells (including those of the kidney) with a substance called C3. This substance will eventually lead to the destruction of bacteria and viruses by damaging the cell wall. If our own cells are not protected against C3 they can suffer a similar fate. This is why we have a series of regulators which inactivate C3. We have, in pilot studies, found that patients with MPGN have mutations in and antibodies against a regulator called factor H.

In this study I wish to examine whether MPGN patients have mutations in other complement genes and antibodies against other complement proteins.

I will undertake this work in the Newcastle Renal Genetics Group (RGG). This research environment provides World leading expertise in the genetics of complement mediated renal disease and has access to a large database of patients with MPGN.

There are now specific agents to treat both complement and antibody associated diseases. Fully characterising the underlying complement defect will allow progress towards the treatment of MPGN.

The RGG has used such a strategy to yield a successful treatment for a similar complement mediated renal disease, called atypical haemolytic uraemic syndrome. We envisage similar benefits in MPGN.

Membranoproliferative glomerulonephritis (MPGN) accounts for ~10% of biopsy proven glomerulonephritis and of the primary glomerulonephritides, is the third commonest cause of End Stage Renal Disease (ESRD). It is well established that MPGN is associated with activation of the alternative pathway (AP) of complement. Preliminary data from our lab and others suggests that autoantibodies and mutations affecting the complement system may predispose to disease.

The aims of this project are to:-

1) Establish the prevalence of inherited and acquired complement abnormalities in MPGN.

2) Analyse their functional consequences.

3) Define clinical and pathological correlates with specific complement abnormalities.

In both the Newcastle cohort of MPGN patients (currently n=40) and the MPGN cohort of RaDaR (renal Rare Disease Registry), I will screen the genes encoding factor H, factor I, membrane cofactor protein, factor B and C3 for mutations. I will also screen serum samples for autoantibodies against factor H, factor I, membrane cofactor protein, and the complement factor H related proteins.

I will assess the functional significance of identified genetic variants in CFH using recombinantly produced protein in C3b binding assays (surface plasmon resonance (SPR)), decay acceleration assays (cell surface; SPR) and in cofactor assays (fluid phase; cell surface). Complement haemolytic assays will be used to assess the functional consequences of autoantibodies to complement components.

In these patients with complement abnormalities I will determine if there are clinical and pathological correlates. Similar studies in Newcastle on the role of the AP in pathogenesis of atypical haemolytic uraemic syndrome (aHUS) led to successful clinical trials of the complement inhibitor Eculizumab. Given the similarities with aHUS, a characterisation of the role of complement in MPGN, is likely to lead to similar translation benefits.

Patients
Membranoproliferative Glomerulonephritis (MPGN) accounts for ~10% of biopsy proven glomerulonephritis and of the primary glomerulonephritides, is the third commonest cause of End Stage Renal Disease (ESRD). Presently, there are no specific treatments for idiopathic MPGN and consequently there is progression to ESRD requiring long term dialysis treatment. Although renal transplantation is undertaken, MPGN usually recurs in the transplant leading to graft failure. It is therefore important to understand the mechanisms that lead to the development of idiopathic MPGN in order to implement a rational treatment strategy.
Since the late 1990s, the Renal Genetics group in Newcastle has elucidated the role of the complement AP in the pathogenesis of aHUS. This led to successful clinical trials of the complement inhibitor Eculizumab in aHUS and its anecdotal use has now also been reported in MPGN. Given the similarities with aHUS, a characterisation of the role of complement in MPGN, is likely to lead to similar translation benefits.

NHS Screening
The NHS Northern Genetics Service is based in the Institute for Genetic Medicine. It hosts the national genetic screening service for complement genes in atypical haemolytic syndrome (aHUS). This screening service will expand to cover genetic screening in MPGN, another complement mediated renal disease.
The accommodation of both the NHS Northern Genetics Service and the Renal Genetic research group under one roof at the Institute for Genetic Medicine results in symbiotic gains. The two groups meet on a weekly basis to discuss the likely functional significance of variants of unknown significance in the light of the research team's knowledge. Additionally, research techniques, once optimised, can rapidly be transferred to the NHS lab.

Clinicians
By establishing the underlying genetic / acquired abnormality we will subsequently be able to derive genotype:phenotype correlations This will allow clinicians to better inform decisions with regards to recurrence following renal transplantation. It will also allow clinicians to screen potential familial kidney donors prior to donation.

Pharma
Currently, several pharmaceutical companies have complement inhibitors at various stages of development. The availability of a fully characterised cohort of patients with MPGN will facilitate a clinical trial of complement inhibitors in these patients.

Economic
This research will result in long term economic benefits to the NHS and to the Country. The ability to predict recurrence of MPGN following renal transplantation will allow physicians to delay transplantation until suitable agents are in place to prevent recurrence. In addition to preventing morbidity and mortality associated with transplant recurrence, it will allow better utilization of the transplant donor pool. This has cost savings for the NHS.
Clinical trials of complement inhibitors are to be expected in these patients, with the hope of preventing renal failure in those who first present and allowing renal transplantation without recurrence in those on dialysis. Long term economic benefits will accrue from patients working and being productive for longer. The ability to host such a trial in the UK will have economic benefits associated with collaboration with the pharmaceutical industry.

Policy Makers
By establishing the underlying potential future requirement for treatment with complement inhibitors, policy makers will be able to plan for the cost of these agents with more certainty.