AA amyloidosis as a renal immune-related adverse event of immune checkpoint inhibitors: mechanisms, diagnosis, and management

Abstract

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but produced immune-related adverse events across multiple organs. Renal toxicities are uncommon yet significant, and secondary serum amyloid A (AA) amyloidosis has emerged as a rare, underrecognized complication reflecting sustained systemic inflammation rather than direct immune-mediated kidney injury. AREAS COVERED: This review summarizes evidence on AA amyloidosis as a renal adverse event of checkpoint inhibition, drawing on case reports, a systematic pharmacovigilance (FAERS) analysis, and mechanistic extrapolation from AA amyloidosis biology and cytokine signaling. Proposed mechanisms linking PD-1/PD-L1 blockade to cytokine activation, hepatic amyloid A production, and deposition are discussed as hypotheses rather than confirmed pathways. Clinical features, diagnostic challenges, and outcomes are characterized, emphasizing limits of creatinine-based monitoring, biopsy's importance, and limited reversibility once nephrotic syndrome develops. EXPERT OPINION: ICI-associated AA amyloidosis is a severe, inflammation-driven toxicity likely underdiagnosed. Management remains empirical, grounded in mechanistic rationale and case experience rather than trials, often ineffective once nephrotic syndrome is established. Greater awareness, early nephrology referral, and a low threshold for biopsy should become routine for ICI-treated patients with unexplained proteinuria. Evidence remains scarce (11 cases, 26 pharmacovigilance reports), so recommendations reflect expert opinion pending validation; causality with amyloidogenesis remains unestablished.