Plasma tryptophan- kynurenine pathway metabolites and risk for progression to end stage kidney disease in patients with type 2 diabetes

Objective: We sought to study the associations between plasma metabolites in tryptophan-kynurenine pathway and the risk of progression to end stage kidney disease (ESKD) in patients with type 2 diabetes. Design and Methods: Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid and xanthurenic acid concentrations were measured in discovery (N=1915) and replication (N=346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (N=1312). The primary outcome was a composite of incident ESKD (progression to eGFR < 15 ml/min/1.73m2, sustained dialysis or renal death). The secondary outcome was annual eGFR decline. Results: In discovery cohort, tryptophan was inversely associated with risk for ESKD and kynurenine-to-tryptophan ratio (KTR) was positively associated with risk for ESKD after adjustment for clinical risk factors including baseline eGFR and albuminuria (adjusted HR [95% CI], 0.62 [0.51-0.75] and 1.48 [1.20-1.84], per one SD). High levels of kynurenic acid and xanthurenic acid were associated with low risks of ESKD (0.74 [0.60-0.91] and 0.74 [0.60-0.91]). Consistently, high levels of tryptophan, kynurenic acid and xanthurenic acid were independently associated with a slower eGFR decline whilst a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in replication cohort. Furthermore, the inverse association between kynurenic acid and risk of ESKD was externally validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65-0.93]). Conclusion: Accelerated catabolism of tryptophan in kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward kynurenic acid branch may potentially slow renal progression.