Deceased donor kidney function is determined by branch chained amino acid metabolism during ex vivo normothermic perfusion

Abstract

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion (EVNP) may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. We assessed the association of tissue metabolic changes with changes in kidney injury biomarkers and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12-hour ex vivo normothermic perfusion (EVNP). The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean (SD) age of the deceased kidney donors was 43 (16) years with an average cold ischemia time of 37 (12) hours. Urine output and creatinine clearance progressively increased and peaked at 6 hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% CI 1.5, 140) urinary neutrophil gelatinase-associated lipocalin (NGAL) at 6 hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branch-chained amino acid (BCAA) metabolism. Tissue BCAA levels negatively correlated with urine output among all kidneys at 6 hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Overall, we showed that 6 hours is needed for kidney functional recovery during ENVP and that BCAA metabolism may be a major determinant of organ function and resilience.