Abstract / Summary
Abstract Introduction: Pembrolizumab (PB), a PD-1 immune checkpoint inhibitor, and enfortumab vedotin (EV), a Nectin-4 targeting antibody-drug conjugate delivering the microtubule-disrupting payload MMAE, represent the current standard of care for advanced urothelial carcinoma. While PB-associated glomerulopathy is a recognized rare complication, rapid one-month progression to end-stage renal disease (ESRD) following the EV-PB combination has not been previously described. Case Presentation: A 76-year-old male with high-grade urothelial carcinoma and baseline Stage 4 CKD (eGFR 25 mL/min/1.73 m^2, creatinine 2.5 mg/dL) secondary to prior cisplatin exposure was initiated on PB 200 mgIV and EV 1 mg/kg IV on a 21-day cycle. Within one month, he developed AKI presenting with a creatinine of 3.1 mg/dL, eGFR of 20 mL/min/1.73 m^2, and nephrotic-range proteinuria of 13.1 g/24 hours. Renal biopsy confirmed cFSGS with 53% global glomerulosclerosis and 70% cortical fibrosis. Both agents were discontinued, and rituximab was initiated; however, renal function still deteriorated. Six months later he presented with labs of: creatinine 8.4 mg/dL, eGFR 6 mL/min/1.73 m^2; requiring emergent hemodialysis. Renal function did not recover, and the patient progressed to permanent ESRD. Discussion/Conclusion: This case highlights three key teaching points. First, pre-existing CKD from prior nephrotoxic chemotherapy amplifies the risk of irreversible cFSGS progression following ADC-immunotherapy, underscoring the need for baseline nephrology evaluation in this population. Second, we propose a novel synergistic mechanism whereby PB-induced podocyte dedifferentiation and cell-cycle re-entry renders those podocytes selectively vulnerable to MMAE-mediated cytotoxicity which can potentially explain the unusually rapid deterioration observed. Third, once advanced interstitial fibrosis is established, immunosuppressive salvage is unlikely to alter the trajectory, and its toxicity must be weighed against a negligible probability of benefit. Notably, PB-induced cFSGS typically remits within 2–3 months of drug discontinuation; however, the literature on dual therapy with EV remains limited.