Blog entry by Arif Khwaja
Anyone in the world
The UK Membranous Nephropathy Trial which I had blogged on in an earlier post here has now been published in The Lancet. Most of the data was presented at The ASN and is covered in my earlier blog but its worth reiterating a few points. 108 patients who had at least a 20% decline in excretory renal function over 2 years were randomised to chlorambucil+ steroids, ciclosporin monotherapy or supportive care. No data was provided about ARBs but 82% of the cytotoxic group, 92% of the CyA group and 100% of the supportive care group were on ACEi. The primary endpoint was a further 20% decline in excretory renal function. 58 % of the cytotoxic group experienced this compared to 81-84% of the other 2 groups. The outcomes with CNI and supportive care were comparable. 36 months after randomisation the greatest mean reduction in proteinuria was in the cytotoxic group of 2.2g/24 hours. Serious adverse events were much more common in the cytotoxic group (61%) vs 49% in the CyA group and 42% in the supportive care group. Most of these adverse events were related to haematological complications from myelosuppression with chlorambucil and metabolic disturbances with steroids. Its worth noting that at randomisation the kidney function was reasonable in all three groups with a creatinine clearance of around 50mls/min.
My thoughts are as follows:
i) this is an excellent RCT that establishes that cytotoxic therapy should be the preferred therapy for those with progressive membranous nephropathy. This adds to a body of earlier work from Jha and Ponticelli that suggests that cytotoxic therapy is the treatment of choice for those with progressive disease who dont undergo spontaneous remission. There is no role for CNIs in such patients.
ii) as acknowledged in the excellent discussion the adverse events with such therapy is a problem but its also worth noting that adverse events are also pretty common in the supportive care group suggesting the disease itself can be fairly disabling
iii) there was no data presented on progression to ESRD although given the trajectory of the data presented I think its safe to assume that cytotoxic therapy would reduce the risk of progression to ESRD. Given the time it took to conduct this study I dont think one can reasonably expect there to be a study of membranous that has ESRD as its endpoint!
iv) the authors themselves state that Ponticelli has showed (subsequent to the start of the study) that cyclophosphamide and chlorambucil are equally effective.
v) Clearly as phospholipase a2 receptor antibody testing starts to be introduced into clinical practice future trials in membranous maybe able to better identify those who would benefit from immunosuppressive therapy.
vi) Finally given the positive observational data of Rituximab from the Remuzzi group and from the Mayo Clinic the next obvious trial to do in membranous would be to compare rituximab to cytotoxic therapy not only in terms of remission and progression but also evaluating safety and cost-effectiveness. Until such data is available it is difficult to justify using Rituximab as first line therapy as there have been no studies comparing it with simple supportive care or with active cytotoxic therapy.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]