Objective: We sought to study the associations of plasma metabolites in tryptophan-kynurenine pathway with the risk for progression to end stage kidney disease (ESKD) in patients with type 2 diabetes. Design and Methods: In this prospective study, plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid and xanthurenic acid concentrations were measured in a discovery (N=1915) and a replication (N=346) cohort of type 2 diabetes. The primary outcome was incident ESKD defined as progression to eGFR < 15 ml/min/1.73m2, sustained dialysis or renal death. Association of kynurenic acid with ESKD was further validated in Chronic Renal Insufficiency Cohort (CRIC). Results: Cox regression showed that tryptophan was inversely, whilst kynurenine-to-tryptophan ratio (KTR) was positively associated with the risk for ESKD after adjustment for clinical cardio-renal risk factors (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 risk of ESKD (0.74 [0.60-0.91] and 0.74 [0.60-0.91]). Consistent outcomes were obtained in replication cohort. The inverse association of kynurenic acid with risk of ESKD was further validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65-0.93]). Conclusions: Plasma tryptophan was inversely, whilst KTR was positively associated with risk for incident ESKD. Both kynurenic acid and xanthurenic acid were inversely with risk of ESKD. Our data suggest that accelerated catabolism of tryptophan in kynurenine pathway may play a role in progressive loss of kidney function. However, shunting the kynurenine pathway towards kynurenic acid branch may potentially slow renal progression.