Background: Elevated levels of circulating Tumor-Necrosis-Factor-Receptors 1 and 2 (cTNFR1/2) predict CKD progression. Whether acute kidney injury drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remains unknown. Methods: We used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, toxic) and progression to fibrosis, nephrectomy, and related single cell RNA-sequencing datasets. Results: We show that TNFR1/2 serum and urine levels are highly elevated in all mouse models of kidney injury tested, beginning within one-hour post-injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with severity of kidney failure. Interestingly, the extracellular vesicle (EV)-bound forms of cTNFR1/2 correlate with renal function better than their soluble forms. TNF neutralization does not affect early cTNFR1/2 elevations, suggesting that cTNFR1/2 levels do not reflect injury-induced TNF activity. Kidney tissue expression of TNFR1/2 after AKI is only mildly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting release of these receptors by extrarenal sources. cTNFR1/2 remain elevated for weeks after severe kidney injury and at these later timepoints cTNFR1/2 correlate to remaining kidney injury. During AKI-to-CKD transition, kidney expression of TNFR1/2 and cTNFR2 levels, correlate with development of fibrosis. Conclusions: Our data demonstrate that AKI drives acute increases in cTNFR1/2 serum levels which negatively correlate with kidney function, in particular their EV-bound forms. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition correlate with persistent tissue injury and progression to kidney fibrosis.

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