MON-013 A CASE OF MEMBRANOUS NEPHROPATHY THAT DEVELOPPED AFTER USE OF NIVOLUMAB

Abstract

Immune checkpoint inhibitors (ICIs) are novel medicines for cancer immunotherapy that have increasingly been used in recent years.Nivolumab is a human anti-programmed cell death 1(PD-1) monoclonal antibody that serves as an ICI. It activates anti-tumor immunity by interfering with the interaction between PD-1 and PD-1 ligand. However, by activating the immune system, ICIs also cause unique side effects, termed immune-related adverse events (irAE). Although renal irAEs are considered less common, case reports related to renal irAEs are becoming more frequent with the increasing use of ICIs. Most renal irAEs involve acute interstitial nephropathy, and glomerulonephritis is rarely reported. Here, we present the first case of membranous nephropathy (MN) that developed after use of nivolumab. ［HPI］ A 69-year-old man was referred to our hospital with nephrotic syndrome. Sixteen months previously, he commenced chemotherapy with docetaxel for stage IV non-small cell lung carcinoma. However, docetaxel was discontinued because of drug-induced lung injury and immunotherapy with nivolumab was initiated 5 months previously. He subsequently developed leg edema and increasing proteinuria. Despite discontinuation of nivolumab after the seventh course, his symptoms did not improve. He was admitted and underwent renal biopsy. ［Investigations］ His urine protein/creatinine ratio was 19 g/g Cre and serum albumin was 2.3 g/dL. Light microscopic examination of the biopsy specimen, which contained 19 glomeruli, showed global sclerosis in one of the glomeruli. The remaining glomeruli demonstrated diffuse thickening and spikes in the glomerular basement membrane. There was no evidence of acute interstitial nephritis. Immunofluorescence staining showed IgG and C3 deposition on the capillary walls. IgA, IgM, C4, and Ciq were not stained. These observations led to the diagnosis of MN. Staining for IgG subclasses and phospholipase A2 receptor (PLA2R), a membrane protein expressed on podocytes, indicated only IgG1 deposition on the capillary wall. ［In-hospital course］ Glucocorticoid therapy was started with 50 mg/day prednisolone as the standard treatment for irAEs, with recovery of proteinuria from the nephrotic range in 4 weeks. During tapering of glucocorticoids, proteinuria decreased and he attained incomplete remission in 7 months. Thereafter, chemotherapy was resumed with pemetrexed, anantimetabolic drug, which maintained the lung carcinoma at a steady disease state. ［Discussion］ It is well-documented that about 10% of MN cases are associated with malignancy. In previous studies, the absence of IgG4 and PLA2R deposition was a common finding in malignancy-associated MN (M-MN) and was useful for distinguishing M-MN from idiopathic MN. Our case was considered as M-MN because of the staining pattern. Although previous reports show that M-MN improves after successful treatment of malignancy, our patient’s proteinuria increased even though his lung carcinoma remained stable during chemotherapy with nivolumab. This suggests that his M-MN was induced by immune activation caused by nivolumab. Additionally, the favorable response to glucocorticoid therapy supports the association between nivolumab and MN. With the increasing use of ICIs, renal irAEs will likely increase. Our case report demonstrates that ICIs can cause M-MN, which can be successfully treated with glucocorticoids.