CFHR5 Nephropathy and Complement in Kidney Diseases.

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

Stenting for atherosclerotic renal artery stenosis: Another nail in the coffin

Despite a lack of strong evidence, angioplasty and stenting of atherosclerotic renal artery stenosis (RAS) became a common intervention in the last decade. It was often performed on incidental lesions discovered  during “drive-by” angiography in cardiac procedures. In the last few years, enthusiasm has cooled as two randomized trials; the ASTRAL and STAR trials have failed to show any benefit of the procedure.The ASTRAL trial received significant criticism in some corners of the medical press –as headlines like this show! 

The CORAL trial recently reported in the NEJM has added to the weight of evidence against the procedure. It included 947 patients with either systolic hypertension >155mmHg on two agents or an eGFR <60ml/min and RAS of >80% or >60% with a pressure gradient > 20mmHg. All patients received, amlodipine, atorvastatin, and candesartan +/- hydroclorothiazide.

In short there was no difference in the primary and composite endpoints of Death, MI, Stroke, heart failure, progression of CKD and need for RRT. The only exception was for that of BP in which a significant but minor (2mmHg) drop in the intervention arm.

This is another large, RCT demonstrating a lack of benefit or renal artery stenting, therefore for the vast majority of patients with RAS and either hypertension or CKD, management of RAS should be limited to medical therapy.

There remains uncertainty around patient groups in which their may still be benefit such as those with severe stenosis to a single functioning kidney, severe stenosis and AKI and patients flash pulmonary oedema. It is hard to imagine recruitment of these groups in numbers sufficient to adequately power a clinical trial.

Posted by Jonathan Dick

Aristolochic Acid Nephropathy

Aristolochic acids (AA) are found in products derived from the aristolochia genus of plants which are used extensively in herbal medicines, particularly in Asia. Nephrotoxicity resulting from AA exposure was originally described in a case series of women taking diet supplements in Belgium but has subsequently been identified in the US, Europe and Asia. Consumption of products containing AA remains endemic in some areas with an estimated exposure in up to 40% of the Taiwanese population. The disease known as Balkan endemic nephropathy – described the population living around tributaries of the Danube river- is now thought to result from contamination of wheat flour with seeds of plants containing AA.

Patients with AA nephropathy typically present with renal insufficiency and anemia. Urinalysis reveals a few red cells and mild proteinuria. The rate of decline of renal function varies but may depend on the cumulative dose of AA. Renal histology is characterized by extensive interstitial fibrosis with tubular atrophy and low numbers of inflammatory cells. There is a very high incidence of urothelial atypia and carcinoma. Exposure to AA can be confirmed by the presence of AA-DNA in biopsy tissue. 

Therapy consists of routine management of CKD alongside regular screening for urothelial malignancy. A trial of steroids can be considered in selected patients. The risk of urothelial malignancy is so high that some consider patients for bilateral nephrouretecomy once RRT as been established.

Despite being banned in many countries, products containing AA remain available. The true incidence of CKD and urothelial malignancy resulting from AA exposure remains unknown. It is possible that a lack of awareness means that a significant proportion of AA resulted morbidity remains undiagnosed.  For a comprehensive review of the subject see here.

Image from Wikipedia.

Posted by Jonathan Dick