Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab

Abstract

The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.

Keywords: autoimmunity; case reports; immunotherapy.

Figure 1

Renal biopsy 2011. (A) Periodic acid–Schiff (PAS) stain of glomerulus with thick capillary walls. (B) Jones methenamine silver (silver): basement membrane pits and spikes. (C) Electronic micrograph (EM): thickened glomerular basement membrane (GBM) ~1000 nm, subepithelial, intramembranous deposits (green arrows) and electron-lucent intramembranous spaces (purple arrows). Renal biopsy 2019. (D) Hematoxylin and eosin (H&E) stain thick glomerular capillaries with patchy mild to focally moderate infiltration by lymphocytes. (E) Phospholipase A2 receptor (PLA2R) stain is diffuse and granular with capillary distribution. (F) EM thickened GBM measuring >3000 nm (normal 230–430 nm). Electron-dense subepithelial deposits (green arrow). Diffuse podocyte effacement. Scale bar: 50 μm (A–E) and 1 μm (C, F).

Figure 2

Timeline of events: (A) 24-hour urine protein was <1 g/24 hours prior to during time of diagnosis and prior to nivolumab therapy. In November 2019, proteinuria peaked at 13.4 g/24 hours. (B) Serum albumin level nadired at 1.9 g/dL. (C) Serum creatinine peaked at 1.26 mg/dL. *Nivolumab 480 mg intravenous every month. †Rituximab 1 g intravenous administered on days 1 and 15. MDACC, University of Texas MD Anderson Cancer Center (MDACC); T1DM, type 1 diabetes mellitus.

Figure 3

(A) Positron emission tomography/computed tomography (PET/CT) (left) demonstrates hypermetabolic lesion in the pleura of the right anterior rib space (red arrow). Maximum intensity projection (MIP, right) with multifocal lesions (blue arrow). (B) Follow-up PET/CT (left) and MIP (right) with complete metabolic response.