Anti-phospholipase A2 Receptor (PLA2R)-Positive Membranous Nephropathy Triggered by Sunitinib in Patients with Gastrointestinal Stromal Tumor (GIST): A New Association?

Introduction: Tyrosine Kinase Inhibitors are classically associated with hypertension and proteinuria due to thrombotic microangiopathy. We report the second case of Membranous Nephropathy associated with anti-PLA2R antibody in the literature, developed shortly after starting Sunitinib, in patients with metastatic GIST. Case Description: A 55-year-old female was diagnosed with metastatic duodenal GIST in May 2018, and treated with Imatinib 400 mg/day. Oral Sunitinib was started in September 2023 due to disease progression. She developed proteinuria (1450 mg/24 hours) after two doses, leading to treatment discontinuation. Despite that, proteinuria increased to nephrotic levels with urine protein/creatinine ratio (UPCR) of 11 g/g of creatinine. A renal biopsy revealed Membranous Nephropathy and serum anti-PLA2R was positive at 259 UR/ml (<14). The patient was treated with Rituximab, with serologic remission and a marked improvement in proteinuria (UPCR 2.6 g/g of creatinine) shortly after (1 week) completion of treatment. Discussion: In 2021, Zonoozi et al (BMJ Case Rep 2021;14:e243567) reported a very similar case: proteinuria developed after a few weeks of treatment with Sunitinib in a patient with metastatic GIST that progressed on Imatinib. As in the case reported here, renal biopsy revealed Membranous Nephropathy with serology and tissue IF positive for anti-PLA2R. Both patients were treated with Rituximab, with complete serologic remission. To our knowledge, this is the second case reported of anti-PLA2R Membranous Nephropathy associated with Sunitinib in the literature, coincidentally or not, in patients with GIST. Since there is no known association between Membranous Nephropathy and GIST, and anti-PLA2R antibodies are usually associated with “primary” Membranous Nephropathy, we hypothesize that the Tyrosine Kinase Inhibitor Sunitinib elicited the production of anti-PLA2R antibodies in both cases