Immune checkpoint inhibitor-associated acute interstitial nephritis: Pathogenesis and heterogeneity

Immune checkpoint inhibitor (ICI)-associated acute kidney injury is a significant complication of cancer immunotherapy, with acute interstitial nephritis (AIN) being the most common pathological type. This review systematically elaborates on the core pathogenesis, spectrum of pathological heterogeneity, and the distinct immunological underpinnings of ICI-associated AIN (ICI-AIN). The typical mechanism of ICI-AIN involves abnormal activation of the adaptive immune system, activating resident autoreactive CD8⁺ tissue-resident memory T cells. This triggers an interferon-gamma-driven inflammatory cascade, which subsequently recruits and activates myeloid cells, establishing a self-amplifying immune injury network. This type of mechanism can sometimes also form a tertiary lymphoid structure. Further research has unveiled a highly heterogeneous immunopathological spectrum of ICI-AIN, encompassing distinct subtypes often accompanied by features such as a dominant neutrophil infiltration and granulomatous interstitial nephritis. These subtypes correspond to differential immunopathogenic pathways and are closely associated with responses to glucocorticoid therapy and long-term renal outcomes. Future directions necessitate the integration of spatial multi-omics technologies and clinical studies to deeply dissect the immune cell interaction networks. Such efforts are critical to advancing the development of non-invasive diagnostics and targeted therapies, ultimately enabling precision clinical management of ICI-AIN.