CD38(hi) macrophages promote fibrotic transition following acute kidney injury by modulating NAD(+) metabolism.

Acute kidney injury (AKI) encompasses a spectrum of conditions, varying from mild and self-limiting to severe cases that can lead to chronic kidney disease (CKD). Macrophages are crucial in the progression from AKI to CKD, yet the diversity of macrophage subsets complicates the identification of key functional types. We established a detailed single-cell atlas of mononuclear macrophages from the onset of AKI through its progression to CKD. Our results indicate that a macrophage subset with high CD38 expression is closely linked to renal fibrosis following AKI in both mouse model and AKI patients. These CD38(hi) macrophages, derived from resident macrophages via Csf1 signaling, secrete the NAD-depleting enzyme CD38, inducing senescence in renal tubular cells and promoting chronic inflammation and renal fibrosis. Knocking out CD38 in macrophages elevated renal NAD levels, reducing senescence and fibrotic responses. Furthermore, we initiated a dosing regimen for a CD38 inhibitor, demonstrating its potential to reduce fibrosis post-AKI, suggesting that targeting CD38(hi) macrophages-mediated NAD(+) metabolism could be a promising therapy to halt AKI to CKD progression.