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Treatment of membranous nephropathy: time for a paradigm shift
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Journal Article
Treatment of membranous nephropathy: time for a paradigm shift
2017
Overview
Key Points
Steroids and alkylating agents increase the rate of remission in patients with membranous nephropathy but can cause diabetes mellitus, myelotoxicity, infections, cancer, and other adverse events
Calcineurin inhibitors can reduce proteinuria in patients with membranous nephropathy but are nephrotoxic, and these agents should be avoided in patients with abnormal kidney function
The discovery of nephritogenic autoantibodies provided a clear rationale for interventions specifically aimed at preventing formation of antigen–antibody immunocomplexes with secondary complement activation, podocyte damage, and proteinuria
B cell-targeted therapy with rituximab is at least as effective as steroids and alkylating agents in achieving remission in membranous nephropathy, and available evidence suggests that it is safer and better tolerated
In patients with anti-PLA
2
R-related membranous nephropathy and overt nephrotic syndrome, evaluation of serum autoantibody titre and albumin levels, as well as assessment of proteinuria could guide tailored therapy
Traditional immunosuppressive regimens will be replaced by specific, nontoxic agents such as B cell-targeting monoclonal antibodies; modulation of B-cell immunity could lead to a novel therapeutic paradigm in membranous nephropathy
Membranous nephropathy is an immune-mediated disease and is the leading cause of nephrotic syndrome in adults. Here, the authors discuss the role of B cell-depleting regimens in the treatment of this disease and the potential use of rescue therapy with agents that target plasma cells, which might prevent antigen–antibody interactions and immune complex-mediated complement activation.
In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA
2
R) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition. The anti-CD20 monoclonal antibody rituximab is safe and achieves remission of proteinuria in approximately two-thirds of patients with membranous nephropathy. In those with PLA
2
R-related disease, remission can be predicted by anti-PLA
2
R antibody depletion and relapse by antibody re-emergence into the circulation. Thus, integrated evaluation of serology and proteinuria could guide identification of affected patients and treatment with individually tailored protocols. Nonspecific and toxic immunosuppressive regimens will fall out of use. B-cell modulation by rituximab and second-generation anti-CD20 antibodies (or plasma cell-targeted therapy in anti-CD20 resistant forms of disease) will lead to a novel therapeutic paradigm for patients with membranous nephropathy.
Publisher
Nature Publishing Group UK,Nature Publishing Group
