CD38hi Macrophages Drive Kidney Fibrosis by Depleting NAD+ After Acute Injury

Acute kidney injury (AKI) affects millions globally and frequently progresses to chronic kidney disease (CKD), yet the molecular drivers of this transition remain incompletely understood. Macrophages are central orchestrators of both injury and repair in the kidney, but their heterogeneity has made it difficult to pinpoint which subsets are harmful versus helpful during the AKI-to-CKD transition.

This study by Yao, Liu, and colleagues at Peking University First Hospital constructed a detailed single-cell transcriptomic atlas of mononuclear macrophages spanning the full temporal arc from AKI onset through CKD establishment, using both mouse ischemia-reperfusion injury models and kidney biopsy samples from AKI patients. Through clustering and trajectory analyses, they identified a macrophage subset characterized by high CD38 expression — a surface enzyme known to catalyze NAD+ hydrolysis — as disproportionately enriched during the fibrotic transition phase.

Lineage tracing and Csf1 signaling analyses showed that CD38hi macrophages derive primarily from tissue-resident kidney macrophages rather than recruited monocytes, and their expansion is driven by CSF1 pathway activation. These cells secrete CD38 protein into the extracellular milieu, where it degrades NAD+ in neighboring renal tubular epithelial cells. The resulting NAD+ depletion activates cellular senescence programs in tubular cells, evidenced by p21/p16 upregulation and senescence-associated secretory phenotype (SASP) markers, which in turn sustain chronic inflammation and activate pro-fibrotic pathways including TGF-β signaling.

To establish causal relationships, the team generated macrophage-specific CD38 knockout mice. These animals showed markedly elevated renal NAD+ levels after AKI, significantly reduced tubular cell senescence, diminished inflammatory cytokine production, and attenuated interstitial fibrosis compared to wild-type controls. Complementary pharmacological experiments used a small-molecule CD38 inhibitor delivered on an optimized dosing schedule, which recapitulated the genetic knockout phenotype — reducing fibrosis endpoints and preserving renal function in the post-AKI period.

The findings are clinically significant because they identify a specific, druggable macrophage population and a clear metabolic mechanism (NAD+ depletion) linking innate immune activation to long-term organ damage. CD38 inhibitors are already in clinical development for hematologic malignancies and other conditions, lowering the translational barrier. However, the study relies predominantly on murine models, and whether the precise CD38hi macrophage subset identified here maps cleanly onto human kidney macrophage biology requires further validation in larger human cohorts. The interplay between CD38-mediated NAD+ depletion and other NAD+ salvage pathways (e.g., NAMPT-driven biosynthesis) also warrants further investigation to optimize therapeutic windows.