Abstract Introduction Immune checkpoint inhibitors (ICIs) have revolutionized oncology by restoring antitumor T-cell activity through the blockade of PD-1 and CTLA-4. However, unchecked immune activation may trigger severe immune-related adverse events (irAEs) involving nearly every organ system. Renal toxicity occurs in 1% of treated patients, typically as acute interstitial nephritis. Pauci-immune necrotizing glomerulonephritis (GN) with pulmonary-renal syndrome is exceedingly rare but potentially fatal. We report a fulminant case of pembrolizumab-induced ANCA-associated vasculitis complicated by diffuse alveolar hemorrhage, underscoring the need for early recognition and rapid intervention. Case Presentation An 81-year-old woman with Müllerian carcinosarcoma, status post hysterectomy and bilateral salpingo-oophorectomy, completed pembrolizumab therapy in November 2024. Four months later, she developed oliguria and acute renal failure requiring hemodialysis. During dialysis, she experienced acute dyspnea and hemoptysis. Chest imaging revealed diffuse bilateral alveolar infiltrates consistent with pulmonary hemorrhage. Laboratory testing showed hemoglobin 5.4 g/dL, creatinine 7.45 mg/dL, positive c-ANCA (PR3), and negative ANA, p-ANCA, and anti-GBM antibodies. Renal biopsy demonstrated pauci-immune necrotizing GN with crescents in 50% of glomeruli. Despite high-dose intravenous methylprednisolone, plasmapheresis, and cyclophosphamide, her respiratory failure worsened, and she succumbed shortly thereafter. Discussion This case highlights one of the most aggressive renal irAEs associated with PD-1 inhibition. The proposed mechanism involves loss of self-tolerance through aberrant T-cell activation and secondary autoantibody formation, producing small-vessel vasculitis. In patients on ICIs, concurrent acute kidney injury and hemoptysis should prompt immediate evaluation for pulmonary-renal syndrome. Biopsy remains diagnostic gold standard but may be limited by clinical instability. Management requires prompt discontinuation of the ICI, initiation of high-dose corticosteroids, and often cyclophosphamide or rituximab; plasmapheresis may benefit those with diffuse alveolar hemorrhage. Multidisciplinary collaboration between oncology, nephrology, and critical care is essential. Conclusion Pembrolizumab can rarely precipitate life-threatening ANCA-associated vasculitis with necrotizing GN and pulmonary hemorrhage. Vigilance for irAEs, early immunosuppression, and coordinated multidisciplinary management are critical to improving outcomes, though prognosis in fulminant cases remains poor. This abstract is funded by: None
Rodriguez et al. (Fri,) studied this question.