A Randomized, Controlled Trial of Steroids and Cyclophosphamide in Adults with Nephrotic Syndrome Caused by Idiopathic Membranous Nephropathy

Abstract

Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Universal consensus regarding the need for and the modality of therapy has not been formed because of a lack of controlled trials of sufficient size, quality, and duration. This study compared the effect of a 6-mo course of alternating prednisolone and cyclophosphamide with supportive treatment in adults with nephrotic syndrome caused by IMN on doubling of serum creatinine, development of ESRD, and quality of life in a randomized, controlled trial. Patients were followed up for 10 yr. Data were analyzed on an intention-to-treat basis. A total of 93 patients completed the study. Of the 47 patients who received the experimental protocol, 34 achieved remission (15 complete and 19 partial), compared with 16 (five complete, 11 partial) of 46 in the control group (P < 0.0001). The 10-yr dialysis-free survival was 89 and 65% (P ‫؍‬ 0.016), and the likelihood of survival without death, dialysis, and doubling of serum creatinine were 79 and 44% (P ‫؍‬ 0.0006) in the two groups. Treated patients exhibited significantly lower prevalence of edema, hypertension, hypoalbuminemia, hyperlipidemia that required therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use, and better quality of life on follow-up. The incidence of infections was similar in the two groups. In conclusion, untreated IMN with nephrotic syndrome is associated with a high risk for deterioration of renal function. A 6-mo regimen of cyclophosphamide and steroids induces remissions in a high proportion, arrests progression of renal insufficiency, and improves quality of life. 18: 189918: -190418: , 200718: . doi: 10.1681 I diopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults (1). Although clinical trials on therapy for this disease have spanned more than two decades, universal consensus regarding the need for and the modality of therapy to decrease proteinuria and halt the progression of renal disease does not exist (2). A number of therapeutic measures have been tried, including nonspecific antiproteinuric agents; corticosteroids, either alone or with alkylating agents; cyclosporine; intravenous Ig; mycophenolate mofetil; and rituximab (3-16). The only regimen that showed a clear short-and long-term benefit is the one that consists of a 6-mo course of alternating months of oral chlorambucil and corticosteroids (15,17). Others, however, have pointed to the relatively benign course of IMN (18) and favor a conservative approach. A recent systematic review (19) failed to find a beneficial effect of treatment on renal or patient survival. J Am Soc NephrolA major lacuna that limits the value of this meta-analysis is the lack of controlled trials of sufficient size, quality, and duration. Because ESRD usually develops only after 5 to 10 yr, studies that aim to evaluate the effect of treatment on development of ESRD need a sufficiently long follow-up. We conducted a randomized, controlled trial (R...

Have We Changed the Outcome in Membranous Nephropathy? A Propensity Study on the Role of Immunosuppressive Therapy

“…The immunosuppressive recommendations for MGN based on RCTs include cyclophosphamide, chlorambucil, and cyclosporine regimens (5,18,(33)(34)(35). Most of these, but not all, concomitantly used corticosteroids.…”

“…The design and conduct of therapeutic studies for treatment of MGN remains a challenge because of its relatively slow evolution and highly variable natural history. Long-term follow-up publications of randomized controlled trials (RCTs) on cytotoxic therapy have demonstrated a reduction of ESRD in some (4,5) but not all studies (6). The effect of calcineurin inhibitors on remission of proteinuria is clear, but their effect on renal survival is uncertain (7).…”

Rituximab Therapy for Membranous Nephropathy

“…The decision to treat with immunosuppressive medications is complicated by the well known natural history of disease: about one-third of patients spontaneously remit, one-third remain proteinuric but with stable renal function, and one-third progress to renal failure over a period of 5 to 10 yr (1,32,33). Recent quantitative systematic reviews have found no significant difference in renal outcomes between immunosuppressive therapy, placebo, and no treatment (4,34), although these analyses antedate a recent, large randomized trial that reported significant improvement in 10-yr dialysis-free survival among patients treated with cyclophosphamide and corticosteroids (35). Speculatively, MN outcomes may not have substantially changed because alkylating agents and calcineurin inhibitors-the current therapies for patients who do not spontaneously remit or respond to RAS blockade-are nonspecific and potentially toxic.…”

Clinicopathological analysis of idiopathic membranous nephropathy in young adults

“…Etiological treatments include immunosuppressive therapies such as glucocorticoids, cyclophosphamide, MMF, cyclosporin A, FK506, and azathioprine. Currently, the consistent view towards the treatment of IMN is that hormone therapy alone has a non-significant effect on IMN (Cattran et al, 1989;Beck et al, 2013), and many scholars advocate the combined use of immunosuppressant therapy (Ponticelli et al, 1998;Goumenos et al, 2006;Jha et al, 2007;Ponticelli, 2007;Dussol et al, 2008;Quaglia and Stratta, 2009;Kalliakmani et al, 2010;Polanco et al, 2010;Cattran et al, 2011;Howman et al, 2013). It is suggested that high-risk patients with deteriorated renal function should be given an active combination therapy of glucocorticoids and immunosuppressant, whereas in low-risk IMN patients, the adverse effects of glucocorticoid and immunosuppressant therapy should be avoided where possible (Quaglia and Stratta, 2009).…”