Daratumumab in Refractory Membranous Nephropathy: A Report of Four Cases

Introduction: Membranous nephropathy (MN) is a leading cause of adult nephrotic syndrome, characterized by subepithelial immune complex deposition and podocyte injury. Several autoantibodies are implicated in pathogenesis and B-cell depletion using anti-CD20 monoclonal antibodies (mAb) are the cornerstone of therapy. A subset of patients remains refractory to rituximab or obinutuzumab. Daratumumab, an anti-CD38 mAb, is emerging as a promising therapy for several B-cell mediated diseases by targeting long-lived plasma cells. Case Description: We report a case series of four patients with biopsy-proven anti-PLA2R-associated MN refractory to at least two agents, rituximab, obinutuzumab or cyclophosphamide, and who received daratumumab with hyaluronidase-fihj 1800 mg s/c weekly. Treatment course and outcomes are summarized in the table. All 4 patients were classified as high-risk disease with nephrotic syndrome and progressive kidney dysfunction. In three patients, we observed quick immunologic remission with undetectable anti-PLA2R within the first month. Patient #4 had very low levels of anti-PLA2R by ELISA and IFA and is still undergoing therapy with variable response. The therapy was associated with 2 infectious complications: ophthalmic zoster for one patient who was not on acyclovir prophylaxis and pneumonia that did not require hospitalization. Discussion: Daratumumab has shown effectiveness in reducing proteinuria and improving serologic markers in patients with refractory MN. Additionally, it demonstrated a favorable safety profile in a small cohort. These promising findings support the need for further investigations through clinical trials to better understand the potential benefits and broader applicability of anti-CD38 mAb in treating MN.Summary of patient demographics, treatment course and outcomes.