Ruxolitinib-Associated Karyomegalic Interstitial Nephritis without FAN1 Mutation: Expanding the Etiology to Janus-Associated Kinase Inhibitors

INTRODUCTION: Karyomegalic interstitial nephritis (KIN) is a rare entity characterized by enlarged, hyperchromatic, and pleomorphic tubular epithelial nuclei within the setting of chronic tubulointerstitial nephritis. Although classically associated with hereditary mutations in the FAN1 gene, acquired forms have been described, generally linked to the use of cytotoxic or immunomodulatory agents that presumably act as a "second hit." CASE PRESENTATION: We report the case of a 53-year-old male with a history of acute myeloid leukemia in complete remission after allogeneic stem cell transplantation, who developed acute kidney injury following prolonged treatment with ruxolitinib for graft-versus-host disease. Renal biopsy revealed characteristic features of KIN, while genetic testing was negative for FAN1 mutations. After ruxolitinib withdrawal, progressive improvement in renal function was observed. CONCLUSION: This represents the first reported case of KIN associated with JAK inhibitors. We propose that ruxolitinib may induce DNA repair defects in the absence of known genetic predisposition, highlighting the need to consider this entity in patients with unexplained chronic interstitial nephropathy under complex immunomodulatory therapies.