Key Points

N-acetyl-tryptophan (NAT) was elevated in plasma of patients with cardiac surgery–associated AKI compared with those who do not develop AKI after surgery.NAT exhibited kidney-protective effects in ischemia-reperfusion–, cisplatin-, and unilateral ureteral obstruction–induced kidney injury mouse models and epithelial cellular models.NAT interacted with Kelch-like ECH-associated protein 1 at 483 and 508 sites, resulting in Nrf2 nuclear translocation and proteasome genes transcription, respectively.

Background

Cardiac surgery–associated AKI is a common serious complication after cardiac surgery. Currently, there are no specific pharmacological therapies. Our understanding of its pathophysiology remains preliminary.

Methods

A total of 2504 patients with and without AKI after cardiac surgery were enrolled. High-performance liquid chromatography coupled with mass spectrometry was used for untargeted analysis of metabolites in plasma, identifying significant differential metabolites. Subsequently, a liquid chromatography–tandem mass spectrometry–based approach using isotope-labeled standard addition was performed for targeted analysis of the metabolic marker N-acetyl-tryptophan (NAT). The function of NAT was determined using different kidney injury mouse models and epithelial cellular models. Transcriptome sequencing, surface plasmon resonance, and protein mutation were used to explore the mechanism of NAT on the kidney.

Results

We identified a total of 32 differential metabolites related to AKI occurrence on the basis of a cohort of 1042 patients. Among them, NAT was elevated in plasma of patients with cardiac surgery–associated AKI compared with those who did not develop AKI after cardiac surgery. The higher level of NAT in plasma was confirmed by accurate targeted quantification. NAT exhibited kidney-protective effects in ischemia-reperfusion–, cisplatin-, and unilateral ureteral obstruction–induced kidney injury mouse models. Mechanistically, NAT exerted kidney-protective effects by interacting with Kelch-like ECH-associated protein 1 at 483 and 508 sites, resulting in Nrf2 nuclear translocation and the transcription of proteasome genes, respectively.

Conclusions

NAT plays a key role in kidney protection.