New Treatments for Idiopathic Membranous Nephropathy

The treatment of idiopathic membranous nephropathy (IMN) has been a matter of discussion for many years. Given the variable clinical course and potential toxicity of current regimens, the main issue nephrologists face at the moment are who to treat and with what regimen. Conservative management is justified for patients with subnephrotic proteinuria, inasmuch as spontaneous remission occurs more frequently in these patients, and their long-term prognosis is usually excellent.

By contrast, patients with nephrotic syndrome (NS) may show a progression to ESRD and are more frequently affected by any of several extrarenal complications. Thus, initiation of specific therapy is indicated for patients with declining renal function or full-blown NS (1). The guidelines of Kidney Disease: Improving Global Outcome (KDIGO) recommend a 6-month course of alternating monthly cycles of oral and intravenous corticosteroids, and oral alkylating agents. The continuous use of alkylating agents may also be effective but is associated with a greater risk of severe adverse events. Cyclosporine or tacrolimus have been suggested as alternative options in nonresponders or in patients who do not tolerate treatment with steroids and cytotoxic drugs (2).

In the past few years, the discovery that most patients with IMN have circulating antibodies directed against the M-type phospholipase A2 receptor provided important insights into the mechanistic interpretation of IMN (3). Further studies confirmed that this receptor represents the main antigen involved, although other podocyte antigens may also play a role in the pathogenesis of this disease.

In the same period of time, new drugs have been used for IMN, three of which show a potential beneficial effect: mycophenolate mofetil (MMF), adrenocorticotropic hormone (ACTH), and rituximab.

Mycophenolate mofetil

Retrospective studies and three small randomized controlled trials (RCTs) evaluated the effects of MMF in IMN. Only a small rate of remission was reported by observational studies when MMF was used as monotherapy, and negative results were reported by a French trial. That trial randomized 36 patients to either MMF alone (2 g per day for 12 months) or symptomatic therapy, and the rates of remission were similar (4). Still, a response in about two-thirds of patients (predominantly partial remission) was reported by a retrospective study in which MMF was combined with oral prednisone and methylprednisolone pulses. However, patients with NS frequently experienced relapse after treatment was interrupted (5). Two small RCTs with short-term follow-up reported remissions in about 70 percent of patients treated with MMF and steroids—a rate similar to that observed in patients assigned to a steroid/cytotoxic drug regimen (6, 7).

These data are insufficient to enable any firm conclusion to be drawn. Trials with adequate sample size and follow-up are needed to better clarify the efficacy and safety of MMF with corticosteroids in IMN. At present, this therapy may be considered for patients who do not respond to other treatments. To prevent relapses, this therapy should be given for at least 1 year if well tolerated.

Adrenocorticotropic hormone

Berg et al. (8) first showed that prolonged administration of synthetic ACTH (Synacthen) could obtain remission in patients with IMN and NS. A small RCT compared a 12-month course of Synacthen, 1 mg twice a week for 1 year, with a 6-month regimen based on steroids alternated with a cytotoxic drug every month. After a mean follow-up time of 23 months, no difference in the rate of remission or in the mean decline in proteinuria was seen between the groups (9). In an observational study, natural ACTH (Acthar gel), given at a dose of 80 units subcutaneously twice a week for 6 months, was used in 11 patients with IMN and NS. Three complete remissions and six partial remissions were observed (10). No relevant side effects have been reported in patients treated with synthetic or natural ACTH, but it should be taken into account that prolonged treatment may be complicated by diabetes, osteoporosis, or hypertension.

The available small studies suggest a potential role for ACTH in IMN. Yet, synthetic ACTH is no longer commercially available, whereas natural ACTH is burdened by an excessively high cost. Given that the mechanism of action of ACTH is related to the stimulation of melanocortin receptors (11), it is possible that less expensive and more specific synthetic melanocortin receptor agonists will be developed in the near future.

Rituximab

Recently, Ruggenenti et al. (12) reported their cumulative experience with rituximab in 100 patients with MN. After a mean follow-up time of 29 months, 27 patients showed complete remission and 38 partial remission, the median time to response being around 7 months. The response to treatment did not change whether rituximab was used in treatment-naïve patients or in patients previously treated with ineffective regimens. No severe side effects were reported. However, 4 patients died, cancer developed in 3, and progression to ESRD occurred in 4. The authors attributed these events to previous treatment, but a direct or indirect role of rituximab cannot be excluded. Good results have also been reported in other observational studies. In a multicenter study of 20 patients treated with four weekly courses of rituximab repeated after 6 months, 2 patients did not respond, 4 entered complete remission, 12 underwent partial remission, 1 patient had limited response, and 1 experienced relapse. No severe adverse events were reported (13).

From the available reports it can be extrapolated that 65 percent to 80 percent of patients may have a complete or partial (more frequent) response to rituximab. However, apart from the high cost, the optimal dose, timing, and duration of re-treatment and the long-term benefit-to-harm ratio of rituximab remain incompletely explored. It is also unclear whether patients with renal dysfunction, tubulointerstitial lesions, or both will be sensitive or resistant to such treatment.

Summary and conclusions

At present, there are at least five different options for treating nephrotic patients with IMN. Therapies based on cycling cytotoxic agents/steroid administration or calcineurin inhibitors have been tested by RCTs, meta-analyses, and retrospective clinical studies to assess their effectiveness and safety profile. It is more difficult to determine the role of new treatments in IMN in the absence of rigorous studies and long-term follow-up times.

MMF associated with corticosteroids might be an alternative therapy in patients with contraindications or poor response to cytotoxic therapy. However, solid studies are required to confirm the efficacy of this association and to indicate the optimal dosage and duration of therapy.

The mechanism of action of ACTH is completely different from that of immunosuppressive agents. Only a few small studies have been conducted with ACTH. The results are interesting, but Synacthen has been retired, and the exceedingly high cost of gel ACTH may impede further development of this treatment in IMN.

The results with rituximab are impressive. However, as discussed above, more answers are needed. Trials comparing the efficacy and toxicity of rituximab with regimens based on cytotoxic/steroid administration will be welcome. The decision on whom, when, and how to treat is completely up to each clinician. However, it should be kept in mind that whatever the treatment, an early response is seldom observed. In many cases, remission can develop months or even years after the therapy has been completed.

References

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Branten AJ, et al. Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide. Am J Kidney Dis 2007; 50:248–256.

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Chan TM, et al. Prospective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome. Nephrology (Carlton) 2007; 12:576–581.

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Senthil Nayagam L, et al. Mycophenolate mofetil or standard therapy for membranous nephropathy and focal segmental glomerulosclerosis: a pilot study. Nephrol Dial Transplant 2008; 23:1926–1930.

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Berg AL, et al. Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy. Kidney Int 1999; 56:1534–1543.

9. 

Ponticelli C, et al. A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy. Am J Kidney Dis 2006; 47:233–240.

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Bomback AS, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther 2011; 5:147–153.

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Lindskog Jonsson A, et al. Effects of melanocortin 1 receptor agonists in experimental nephropathies. PLoS One 2014; 9:e87816.

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Ruggenenti P, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012; 23:1416–1425.

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Fervenza FC, et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol 2010; 5:2188–2198.