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Abstract

Idiopathic membranous nephropathy has been recently recognized as an autoimmune disease that may recur or develop de novo posttransplant, whereby specific auto-or alloantibodies are directed against recently recognized podocyte structures such as the phospholipase receptor PLAR2 and the throm bospondin receptor THSD7A. The observed inconsistencies in therapeutic responses with all presently recognized therapies irrespective of immuno suppressive regimen used and the superiority of complete and sustained remission rates in recurrent disease after kidney transplant compared with native disease imply the existence of different immunopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of membranous nephropathy. These pathogenic mechanisms involve primarily B-cell-mediated pathways with a T-cell help component and distinct auto-and alloantibody-secreting mechanisms involving different B cells. These pathways are present in separate compartments such as in CD20+-activated B cells found in spleen and lymph nodes, CD19+/CD20-plasmablasts and shortlived plasma cells in the blood, and CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney. These latter nonproliferating plasma cells lacking CD19 and CD20 markers would be resistant to in vivo B-cell depletion by anti-CD20 monoclonal therapies. They produce considerable amounts of immunoglobulin G (IgG) autoantibodies and alloantibodies and provide the basis for humoral memory and refractory autoimmune diseases. This may explain the limited rate of sustained complete remission, which, as observed in most studies, does not exceed a rate of 20% in all rituximabtreated patients despite total B-cell eradication. There is an important need for the development of new biomarkers to help identify and predict therapeutic responses. Potential new therapeutic targets against plasma cells such as proteasome inhibitors, anti-CD38 monoclonal antibodies, and autoreactive pathogenic B-cell-specific depleting regimens, as well as new anti-CD20 monoclonal antibodies, may help tailor therapy to the individual need for optimal outcome. Key words: Autoimmune disease, Plasma cell, Proteasome inhibitors IntroductionIn patients with idiopathic membranous glomerulonephritis (iMGN), therapeutic responses to conventional therapies such as alkylating agents and steroids, T-cell-targeted therapies such as calcineurin inhibitors, and B-cell-directed therapies such as mycop henolate mofetil and the recently introduced anti-CD20 monoclonal antibody (MAb) as rescue therapy in cases of primary resistance or partial disease remission or as first-line treatment, irres pective of immunosuppressive regimen used, have been inconsistent. 1 These inconsistencies coupled with the superior complete and sustained remission rates in recurrent disease after kidney transplant versus rates of complete and partial remission, relapse, and resistance in the native kidney with iMGN2...

Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management

“…Recently, low levels of regulatory T cells and increases in circulating plasmablasts as well as in plasma cells have also been suggested as an additional new biomarker of MN activity and responsiveness to treatment [ 110 – 113 ].…”

“…Anti-CD20 antibodies [ 164 ] and adrenocorticotropic hormone (corticotropin) [ 165 ] offer new therapeutic opportunities that appear to be promising. A novel therapy based on proteasome inhibitor has been used with benefit in rituximab-resistant or partially responsive recurrent posttransplant membranous nephropathy [ 113 ].…”

Comprehensive identification of immune-associated biomarkers based on network and mRNA expression patterns in membranous glomerulonephritis

“…Membranous glomerulonephritis (MGN) is one of immune-mediated and more common forms of nephrotic syndrome in the adult population [ 1 , 2 ]. MGN shows a special type of immune complex glomerulonephritis and had the symptoms of glomerular subepithelial IgG-containing immune complex deposits and usually heavy proteinuria [ 3 , 4 ].…”

Continuing the paradigm shift in the treatment of idiopathic membranous nephropathy

“…I agree that use of plasma-cell-depleting therapies, such as the newly introduced anti-CD38 monoclonal antibodies and the less specific proteasome inhibitors with anti-B cell and anti-T cell activities 13 , might offer novel therapeutic alternatives for patients with idiopathic membranous nephropathy, at least in those who are refractory or only partially respond to combined conservative treatment plus rituximab therapy 12 . Whether new second and third generation anti-CD20 monoclonal antibodies can achieve higher rates of sustained complete remission than rituximab 1 remains to be determined, but such agents do not target long-lived memory plasma cells 8,14 . Surprisingly, another anti-CD20 monoclonal antibody, ofatumumab, failed to demonstrate superiority over rituximab as salvage chemotherapy in patients with relapsed or refractory diffuse large B cell lymphoma 15 .…”

“…Surprisingly, another anti-CD20 monoclonal antibody, ofatumumab, failed to demonstrate superiority over rituximab as salvage chemotherapy in patients with relapsed or refractory diffuse large B cell lymphoma 15 . New immunologic biomarkers are needed to help to identify patients who are likely to respond to T cell 3 , B cell 7,8 , or combination therapy 12,14 . In addition to measuring CD19 and CD20 (REFS 1,4,5,9,11), assessment of patients with membranous nephropathy should include measurement of the longlived memory plasma cell markers, CD38 and CD138, particularly in patients with relapsing or rituximab-resistant disease [7][8][9][10]12,14 .…”