N-acetyl-tryptophan in Acute Kidney Injury after Cardiac Surgery

Cardiac surgery-associated acute kidney injury is a common serious complication after cardiac surgery. Currently, there are no specific pharmacological therapies. Our understanding of its pathophysiology remains preliminary. A total of 2504 patients with and without acute kidney injury (AKI) following 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 tandem liquid chromatography-mass spectrometry-based approach using isotope-labeled standard addition was performed for targeted analysis of the metabolic marker N-acetyl-tryptophan. The function of N-acetyl-tryptophan was determined using different kidney injury mouse models and epithelial cellular models. Transcriptome sequencing, surface plasmon resonance and protein mutation were employed to explore the mechanism of N-acetyl-tryptophan on the kidney. We identified a total of 32 differential metabolites related to AKI occurrence based on a cohort of 1042 patients. Among them, N-acetyl-tryptophan was elevated in plasma of patients with cardiac surgery-associated acute kidney injury compared with those who do not develop AKI after cardiac surgery. The higher level of N-acetyl-tryptophan in plasma was confirmed by accurate targeted quantification. N-acetyl-tryptophan exhibited kidney protective effects in ischemia/reperfusion-, cisplatin-, and unilateral ureteral obstruction-induced kidney injury mouse models. Mechanistically, N-acetyl-tryptophan exerted kidney protective effects by interacting with KEAP1 at 483 and 508 sites, resulting in Nrf2 nuclear translocation and the transcription of proteasome genes. N-acetyl-tryptophan plays a key role in kidney protection.