It is fair to say that unless you a nephrologist practicing in Cyprus you are unlikely to ever see a case of CFHR5 (Complement factor H related protein 5) nephropathy. It does however give an insight into the growing appreciation of the role of complement in renal disease. The culprit mutation in CFHR5 is thought to affect around 1 in 6000 Cypriots and is associated with autosomal dominant glomerulonephritis and renal failure.The disease seems to predominantly affects males (why is not well understood) and is characterised by microscopic haematuria with mild proteinuria. Macroscopic haematuria can occur, particularly during episodes of infection. Serum C3 and C4 levels are normal. Progressive decline in renal function leads to ESRD. Biopsy findings are of MPGN with C3, C5 and C9 deposition.
The alternative pathway is both one of the three complement pathways by which C3 can be generated and also provides an amplification loop for C3 generation by the other pathways. Complement factor H is a key regulator of alternative pathway activity. Inherited or acquired deficiencies in CFH can lead to the catastrophic consequences of uncontrolled complement act
ivation seen in aHUS. CFHR5 is also thought to be a regulator of the alternative pathway, though it is probably more important at membrane surfaces rather than in the fluid phase- hence the normal C3 and C4 levels. Defective CFHR5 fails to inhibit accumulation of C3 metabolites at the glomerular surfaces resulting in their accumulation.
CFHR5 nephropathy is one of a group of diseases recently included under the definition of “C3 glomerulonephritis”. These include dense deposit disease, C3 glomerulonephritis and CFHR5 nephropathy. An absence of immunoglobulin deposition differentiates them from immune-complex mediated GN. The C3 glomerulopathies, aHUS, Lupus nephritis, IgA nephropathy, ANCA-associated vasculitis and renal ischemia-reperfusion injury are just some of the diseases where complement is thought play an injurious role.
At present eculizimab –an anti-C5 mAb- is the only licensed complement inhibitor. A large number of other drugs are under development, many of which have other targets in the complement system.
Posted by Jonathan Dick
The most recent C3 glomerulopathy consensus statement defines it C3 staining at least 2 orders of magnitude greater than immunoglobulin on IF, but immunoglobins can be present as well.
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