Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome, which may present as a sub-nephrotic or nephrotic range proteinuria with hypoalbuminemia, hyperlipidemia, and edema. It is an immune-mediated glomerular disease that is pathologically characterized by glomerular intra-membranous and sub-epithelial immune complex deposits (immunoglobulin G4 [IgG4] and complement 3 [C3]) causing membrane thickening.
The pathophysiology of MN was first described by the Heymann nephritis rat model in 1959 (1). Although the target antigen described in that model was “megalin,” which does not play a major role in humans, it set the path for subsequent discoveries of many other target antigens. In 2009, Beck et al. (2) revolutionized the diagnosis and monitoring of this disease by discovering the M-type phospholipase A2 receptor 1 (PLA2R1) as the target antigen in 70% of cases, followed by the discovery of THSD7A (thrombospondin type 1 domain-containing 7a) in 2014 (3). This year, we saw the advent of four new target antigens, including EXT1 (exotosin 1) and EXT2 (exotosin 2), NELL1 (neural epidermal growth factor-like 1 protein), Sema3B (semaphorin 3b), and PCDH7 (protocadherin 7) (4). These discoveries have helped elucidate the pathophysiology of MN and may help in designing more specific antigen-targeted therapy in the future.
In 1979, a study showed that the use of steroids was significantly better for remission of proteinuria and to slow down the decline of kidney function as compared to placebo (5). However, in 1984, Ponticelli et al. (6) showed that the use of cyclic steroids and chlorambucil over a 6-month period was superior in achieving remission with improved kidney function. Following this trial, the use of only steroids in primary MN lost favor. In 1998, once again, Ponticelli et al. (7) went ahead and compared cyclic steroids and chlorambucil with cyclic steroids and cyclophosphamide (the modified Ponticelli regimen) and showed a comparable remission rate and preservation of glomerular filtration rate (GFR) along with the side-effect profile. There has been limited literature for the use of calcineurin inhibitors alone (tacrolimus monotherapy) or with steroids (cyclosporine with steroids) (8−10). These agents tend to show a higher rate of relapse after discontinuation, as compared to alkylating agents (11), and may be used as an alternative if contraindications for alkylating agent use exist. The use of mycophenolate mofetil in MN still lacks the backing of good quality evidence and continues to be used in instances where alkylating agents are not well tolerated.
The new kid on the block for the treatment of MN is rituximab, an anti-CD20 monoclonal antibody. Two recently published trials, Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX; 2017), which compared rituximab to anti-proteinuric therapy (12), and Membranous Nephropathy Trial of Rituximab (MENTOR; 2019), which compared rituximab to cyclosporine with superiority at a 24-month follow-up (13), garnered a lot of attention and have made rituximab the first-line therapy for many cases of MN. The recent Sequential Treatment with Tacrolimus and Rituximab Versus Alternating Corticosteroids and Cyclophosphamide in [Primary Membranous Nephropathy] PMN (STARMEN; 2020) showed that the time-tested cyclic steroid and cyclophosphamide therapy showed significantly greater remission of the disease as compared to tacrolimus with rituximab, albeit with more side effects (14). The hot-off-the-press trial, Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), finds no significant benefit, or less harm, of rituximab over the modified Ponticelli regimen in the treatment of MN too (15). We wait patiently to see if the newly introduced obinutuzumab, a CD20-directed cytolytic monoclonal antibody, or adrenocorticotropic hormone (ACTH; synthetic corticotropin) does bring in better results for the treatment of MN with a better side-effect profile. Table 1 summarizes the broad treatment guidelines from the 2020 KDIGO glomerular diseases update (16).
Given the fact that the modified Ponticelli regimen has withstood the test of time over 30 years for the treatment of MN and with the advent of some newly described target antigens of MN, we hope to welcome new targeted therapies (Table 2). Until that happens, old is gold!
References
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