Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy

Abstract

Introduction: B-cell depletion has been shown to be an effective strategy for the majority of patients with membranous nephropathy (MN), and in PLA2R-positive MN, immunologic remission (improvement or elimination of measurable serum anti-PLA2R antibodies) precedes renal remission. Yet, cases exist of patients who do not achieve immunologic remission despite achieving peripheral B-cell depletion. This has led to the hypothesis that some patients have plasma cells that are responsible for producing anti-PLA2R antibodies. Case Presentation: A 66-year-old man with a past medical history of hypertension, hyperlipidemia, and cerebrovascular disease presented with nephrotic syndrome and was diagnosed with PLA2R-positive MN on kidney biopsy. He was refractory to multiple therapies including tacrolimus, and was resistant to rituximab despite having achieved B-cell depletion. He also did not enter into remission with plasmapharesis and cyclophosphamide. He then achieved immediate immunologic remission after treatment with the proteasome inhibitor bortezomib, which is used as first-line therapy for multiple myeloma. Discussion/Conclusion: This case suggests that considering the source of PLA2R antibody production could lead to individualized and targeted therapies for MN.

Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy

“…Four doses of bortezomib (1.6 mg at days 1, 4, 8, and 11) induced complete remission at 12 months in one patient with primary MN with severe nephrotic syndrome that did not respond to RAS blockade or high-dose corticosteroids, and decreased anti-PLA2R titers, with few AEs [ 57 ]. Similar results with bortezomib plus dexamethasone have been reported in severe and refractory cases to RTX and/or cyclophosphamide [ 58 , 59 ]. However, this therapeutic approach has not been formally tested, and RCTs are required to give more robust recommendations.…”

A Case of M-Type Phospholipase A2 Receptor-Associated Membranous Nephropathy With IgG4-Positive Cells Infiltration in the Interstitium

“…17 Recently, the potential of proteasome inhibitor bortezomib in treating patients with rituximab-resistant PLA2R-associated MN has been reported. 18 It suggested that plasma cells also produce autoantibodies against podocyte antigens. However, the kidneys may not be main location of IgG4 production because IgG4-positive interstitial cells are rare even in MN with IgG4-positive staining in the glomeruli.…”

Membranous nephropathy: pathogenesis and treatments

“… 196 Additionally, case reports have demonstrated that bortezomib usage in refractory MN has resulted in immune and clinical remission. Furthermore, bortezomib treatment has been linked to a reduction in the number of cells producing autoantibodies 197 , 198 , 199 (Figure 6 ).…”