Case Presentation: Patient is an 82-year-old male with a past medical history of primary epithelial mesothelioma secondary to asbestos exposure while on active duty in the Navy. Patient was initially treated with neoadjuvant chemotherapy with carboplatin pemetrexed for 4 cycles followed by pleurectomy and talc pleurodesis. Patient had recurrent disease after surgery and was started on palliative nivolumab. He presented to the office with dyspnea and lower extremity edema that began post-cycle 3 on June 23. Outpatient blood work returned with acutely abnormal renal function, so he was instructed to report to the community hospital. On physical exam, the patient was hypertensive with anasarca. Hospital labs showed creatinine of 3.27 mg/dL, albumin of 2.1 mg/dL and urine protein over 10 g consistent with nephrotic syndrome. Patient did have a PET/CT prior to admission which showed response to nivolumab with decrease in the volume and FDG uptake of the pleural nodules. Patient was admitted on July 20 for close follow-up with nephrology and oncology and maintained on oral corticosteroids and IV diuretics. Patient subsequently had a CT-guided kidney biopsy on July 26. Biopsy showed diffuse effacement of the foot processes and consistent with immune-mediated nephropathy, with no evidence of glomerulonephritis or immune complex-mediated glomerulopathy. After resolution of dyspnea, anasarca, and stabilization of creatinine levels to 2.13 mg/dL and albumin to 2.9 mg/dL, he was discharged home on July 27.
Discussion: This case illustrates a rare potential adverse renal side effects of nivolumab in the treatment of mesothelioma. Nivolumab is a IgG4 monoclonal antibody that inhibits programmed death-1 protein (PD-1) receptors on T-cells. Certain cancer cells express programmed death ligand 1 (PD-L1) that can bind to PD-1 on immune cells, effectively neutralizing tumor destroying lymphocytes. Nivolumab is typically used in the treatment for unresectable mesothelioma alongside ipilimumab. In this patient, ipilimumab was deferred due to age and increased toxicity. Immune checkpoint inhibitors, which are very effective at targeting cancer cells, are known to cause a variety of autoimmune conditions because of their nature in deactivating the recognition of self vs. foreign that is typically provided by checkpoint receptors like PD-L1. While rare, the reported incidence of renal toxicity in single agent checkpoint inhibitors is approximately 2-5% and has the potential to cause the nephrotic syndrome visualized here. Nephrotic syndrome is classified as proteinuria of at least 3.5 g over 24 hours and leads to hypoalbuminemia and symptoms of edema. The treatment for nephrotic syndrome is steroids to prevent destruction of the basal membrane, as well as diuretics to clear out the excess fluid retained from low colloid osmotic pressure from hypoalbuminemia. Other more common renal side effects from immunotherapy include acute tubulointerstitial nephritis, as well as immune complex glomerulonephritis or thrombotic microangiopathy.
Conclusions: Nivolumab-induced nephrotic syndrome is a rare adverse drug reaction not widely documented outside of case reports. Nephrotic syndrome as a result of nivolumab treatment for mesothelioma was not reported prior to this incidence. Although unusual, hospitalists should consider this complication in patients with symptoms of nephrotic syndrome such as renal insufficiency, hypoalbuminemia, or proteinuria, and with a prior treatment history of PD-1 inhibitors.