Landmark Trials in Membranous Nephropathy

First Posted on RFN: October 8, 2019

Updated: January 2021

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in the Caucasian adult population with an estimated incidence of 8–10 cases per 1 million and commonly seen in males above the age of 40. It is an immune-mediated disease that is pathologically characterized by thickening of the glomerular basement membrane and granular subepithelial deposits of immunoglobulins and complement (C3) along the capillary walls. It is typically characterized by sub nephrotic to nephrotic-range proteinuria, edema, hypoalbuminemia, and hyperlipidemia. Approximately 75%–80% of patients have primary membranous nephropathy (with the absence of any identifiable cause) and the remaining 20%–25% of patients have an identifiable secondary cause.

Spontaneous remission is a well-known characteristic of the disease but patients with persistent nephrotic range are at risk of progression to end stage renal disease and may require immunosuppression therapy. Over the years, many different immunosuppressive regimens have been studied.

This post reviews the landmark studies that have shaped our modern-day management of this condition.

PLA2R Antibody in the Diagnosis and Management of Primary Membranous Nephropathy

Initial studies of membranous nephropathy used the Heymann nephritis animal model to demonstrate that the subepithelial immune deposits that are characteristic of the condition are formed in situ, but the target antigen was unknown. In 2009, Beck et al. identified the M-type phospholipase A2 receptor 1 (PLA2R1) as the target antigen in 70% of primary membranous nephropathy (PMN) cases. Interestingly, because these receptors constantly undergo endocytic recycling, they provide an ongoing source of surface-accessible antigen.  The PLA2R antibody (as it is commonly referred to in the Nephrology community) can be detected in serum as well as in renal biopsy specimens and thus the discovery of this antibody has revolutionized the diagnosis and monitoring of primary membranous nephropathy.  The presence of the PLA2R antibody makes the diagnosis of primary membranous nephropathy much more likely (though evaluation for secondary causes is still recommended), and serial monitoring of antibody titers has served as a marker to guide treatment. Clinically, decreasing antibody titers suggest immunological remission which is generally followed by remission of proteinuria. Beck and Salant also observed that titers of PLA2R antibodies may become undetectable prior to complete remission of proteinuria.

Treatment Options

Although spontaneous remission of primary membranous nephropathy occurs in approximately 30% of patients, patients with nephrotic syndrome who do not undergo remission are at risk of progression to end-stage renal disease.  Kidney Disease Improving Global Outcomes (KDIGO) recommends initial treatment with an ACE inhibitor (ACEi) or angiotensin receptor II blocker (ARB) as well as optimal management of hypertension, hyperlipidemia, edema, hypercoagulability, and infection risk.  Patients with persistent nephrotic-range proteinuria may require immunosuppressive therapy and given the variable clinical course of the disease and often indolent progression rate, monitoring disease progression and balancing risks and benefits of treatment can be challenging.

1. Steroids

 In 1979, Coggins et al, compared steroids with placebo. They demonstrated that in patients with nephrotic syndrome and preserved renal function, use of steroids for at least 8 weeks slowed deterioration of glomerular filtration rate (GFR).  Steroids are now commonly used in treatment of PMN, in combination with other agents discussed below.

2. Alkylating therapy

In 1984, Ponticelli et al showed that preservation of renal function for at least 2 years was superior in patients treated with alkylating therapy (chlorambucil) alternated with steroids, compared to supportive care alone.  In 1992 the comparison was done but this time in between Ponticelli’s regimen and steroids alone. Here, Ponticelli’s regimen was again superior (58% bs 26% rate of complete or partial remission p =0.002 ) but difference in outcomes started to shrink at 4 years of follow up. With the growing use of cyclophosphamide amongst nephrologists,  in 1998, Ponticelli and colleagues went on to compare chlorambucil with cyclophosphamide, with both groups receiving initial IV steroids plus oral steroids every other month.  Both treatments were effective, and per study authors, both were limited by adverse effects including herpes zoster (in 2 of the 36 patients who received chlorambucil) and cancer (occurring in one patient in each treatment group). 

3. Calcineurin inhibitors

Given the greater familiarity Nephrologists have with calcineurin inhibitors, both cyclosporine and tacrolimus have been used as potential treatments. It was seen that the combination of cyclosporine with steroids was superior to steroids alone. Evidence also supports the use oftacrolimus in inducing remission but no long-term remission data is available and a higher rate of relapse was seen on discontinuation.These studies highlight the fact that CNIs can be used as an alternative to alkylating agents specially in cases in which there is patient preference or when this medication class is not suitable (woman of child bearing age, patients with increased cancer risk due to tobacco exposure, hx of prior cyclophosphamide use). Both of the studies also illustrate the high rate of recurrence once the CNI regimen is completed.

4. Rituximab

Rituximab has been the focus of investigation recently in PMN and two major randomized control trials have garnered a lot of attention. Published in 2017, GEMRITUX trial compared two 375 mg/m2 doses of rituximab to non-immunosuppressive anti-proteinuric treatment (NIAT), in patients who had persistent nephrotic syndrome after 6 months of NIAT. At 6 months, more patients in the rituximab group than in the control group reached the primary endpoint (complete or partial remission of proteinuria), but this difference was not significant. By 17 months, however, the rate of complete or partial remission in rituximab group was almost twice that of controls (64.9% versus 34.2%). This makes sense, as the majority of trials does show that proteinuria as an endpoint is only affected in the long term (think more 24-36 months to reach proteinuria nadir). Interestingly, when one examines the anti-PLA2R levels, the differences between both groups becomes evident three months after treatment (depletion in Rituximab 56% vs 4.3% NIAT only group at 3 months p<0.001 and 50% vs 12% at 6 months p=0.004).

In the MENTOR TRIAL the comparison was then between Rituximab vs Cyclosporin. The anti-CD20 approach with Rituximab was found non inferior to cyclosporin at 12 months, but, more importantly, was superior at 24 months in maintaining remission (60% in the Ritux group vs 20% in the cyclosporin group). Additionally, anti-PLA2R levels dropped quicker and to a greater degree in the Ritux group. To finish it all progressive loss of eGFR was also slower with rituximab –  probably because of chronic nephrotoxic effects caused by cyclosporine. Because of its remarkable safety profile, some nephrologists are more inclined to use rituximab as first-line therapy.

Before we move forward, we should acknowledge that the studies above were completed in the post anti- PLA2R era and did show that not only rituximab did decrease antibody levels but that the decrease in antibodies preceded and helped predict clinical response. This has been consequently used to assess response to therapy and predict relapses in further studies and clinical practice.

STARMEN chose to make a different comparison than MENTOR. They compared a regimen of tacrolimus and rituximab versus steroids and cyclophosphamide (Ponticelli regimen). The group compared patients which, after a 6-month run in period, were randomized to either receive cyclical doses of methylprednisolone + cyclophosphamide versus tacrolimus (target blood levels 5-7ng/mL) and 1g of rituximab on day 180. At 24 months more patients achieved complete or partial remission in the steroids + cyclophosphamide group when compared to the tacrolimus + rituximab group. This remained true however you slice it -intention to treat or per-protocol analysis. There were more adverse events in the cyclophosphamide group (mainly infections), but no difference in terms of serious adverse events. While Ponticelli remained king in this trial, we should acknowledge that the Tacro+Ritux group did have a higher baseline level of anti-PLA2R and proteinuria. An important information that the trial did bring is that the rate of relapses in the Ritux + tacro group was not as high as historically known with tacro alone.

The RY-CYCLO study has had some data reported at ASN 2020 and might shed further light in this mater, comparing rituximab as a monotherapy vs steroids + cyclophosphamide (modified Ponticelli). With the data available so far, there appears to be no difference in rate of remission or side effects this far.

5. MMF

MMF has been studied. In a study comparing MMF vs historical controls, mycophenolate seemed to lead to decrease to proteinuria and improvement in renal function but did not appear as effective or better tolerated than cyclophosphamide. Subsequent RCTs were unable to show that MMF lead to a decrease in proteinuria. Currently MMF is not indicated as a first line treatment for PMN, but can be considered in resistant cases and in patients which do not tolerate the side effect profile of other medications.

6. ACTH

The drug H.P. Acthar® Gel (ACTH) is a natural form of ACTH and is obtained from processing porcine pituitary gland. The efficacy and utility of this drug is being studied.  In a pilot study in 2014 Hladunewich et al, evaluated its use in dose of 40 or 80 IU twice weekly in a pilot study and it was found effective in improvement in proteinuria, serum albumin, and lipid profile. The medication was not compared against any specific type of treatment.  Interestingly, in 2006, Ponticelli also conducted and RCT comparing ACTH versus steroids + chlorambucil versus cyclophosphamide amongst 32 patients over a 2 year period. The trial showed no difference between the groups when compared for rate of remission and proteinuria levels at 24 months.  In more recent years, a comparison of historical controls vs ACTH did favor cyclophosphamide. Currently, ACTH is not recommended unless all other first line therapies have been attempted and its role remains unclear.

Post by:
Priti Meena , Het Patel

Reviewed by:

Dr. Laurence Beck