Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial

Abstract

SummaryBackgroundMembranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function.MethodsThis randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18–75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692.FindingsWe randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard ratio [HR] 0·44 [95% CI 0·24–0·78]; p=0·0042); risk did not differ between the ciclosporin (29 [81%] of 36) and supportive treatment only groups (HR 1·17 [0·70–1·95]; p=0·54), but did differ significantly across all three groups (p=0·003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p=0·048).InterpretationFor the subset of patients with idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months' therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence. Ciclosporin should be avoided in this subset.FundingMedical Research Council, Novartis, Renal Association, Kidney Research UK.

Glomerular Diseases

“…At 3 years, the risk of further 20% decline in creatinine clearance was significantly lower in the prednisolone and chlorambucil group than in the supportive care group and this risk did not differ between the cyclosporine and supportive treatment-only groups. Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care-only group (50). It is well known that cyclosporine may be contraindicated in nephrotic patients with serum creatinine .2.00 mg/dl (estimated creatinine clearance around 50 ml/min per 1.73 m 2 ), due to the possibility of nephrotoxicity.…”

“…The results of a randomized controlled trial that compared the effects of three different therapeutic approaches in adult patients with biopsy proven idiopathic MN and declining renal function were recently published (50). Criteria for inclusion included an initial serum creatinine level ,300 mmol/L (3.4 mg/dl) and at least a 20% decline in creatinine clearance measured in the 2 years before study entry.…”

Cancer Risk after Cyclophosphamide Treatment in Idiopathic Membranous Nephropathy

“…For a 55-year-old patient, this result translates into an increase in annual cancer risk from approximately 0.3% to 1.0% (13). Previous studies have shown that treatment with alkylating agents reduced the incidence of ESRD 3-to 5-fold (14)(15)(16)(17). At first glance, this decreased renal risk is matched by an increased risk of cancer.…”

Partial remission by cyclosporine monotherapy in a patient with membranous nephropathy superimposed diabetic nephropathy

“…These results suggest therapy and prognosis of MN are different in Japan and American or European countries. Recently, it was reported that 6 months' therapy with prednisolone and chlorambucil, but not with Cs A monotherapy, was effective for maintaining renal function in patients with IMN, and thus CsA monotherapy should be avoided in MN [6]. Nevertheless, in this study we administered our patient CsA as Irbesartan 100mg…”