Integrated spatial and functional metabolic profiling identified the thick ascending limb as a mitochondrial vulnerability hub in acute kidney injury

Abstract

Introduction: Acute kidney injury (AKI) is a common complication in critically ill patients and often progresses to chronic kidney disease (CKD), increasing morbidity and mortality. Despite its clinical relevance, the metabolic mechanisms underlying kidney injury remain poorly understood.

Methods: To help define this, we used an integrated approach combining spatial and single-cell transcriptomics, immunofluorescence, and isotope tracing imaging to investigate the spatial distribution of kidney energy metabolism in murine models and in human kidney allografts following transplantation.

Results: The outer medullary thick ascending limb (TAL) was identified as the most metabolically active nephron segment, characterized by a high reliance on oxidative phosphorylation and fatty acid oxidation for ATP production. This metabolic profile renders TAL cells particularly vulnerable to injury, a finding confirmed in both murine and human models of AKI and CKD. We further examined the effect of propofol, a widely used sedative in critical care, on kidney metabolism. Propofol impaired oxidative phosphorylation, especially within the outer medulla, inducing a metabolic shift toward anaerobic glycolysis. In a murine ischemia-reperfusion model, propofol preconditioning exacerbated tubular injury in the outer medulla. In kidney transplant recipients, higher intraoperative exposure to propofol was associated with reduced oxidative metabolism, increased tubular injury and poorer long-term kidney outcomes.

Conclusions: Our findings identify the TAL as a metabolic hotspot and a major site of injury in AKI. The selective vulnerability of this segment to propofol-induced mitochondrial dysfunction suggests that sedation strategies should be reconsidered in high-risk patients to mitigate kidney injury and improve clinical outcomes.

Keywords: acute kidney injury; ischemia-reperfusion; mitochondria.