October 5, 2023Open Access
Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes
Key Result
Higher plasma tryptophan was associated with a lower risk of ESKD (HR 0.62; 95% CI 0.51-0.75), whereas a higher kynurenine-to-tryptophan ratio increased the risk (HR 1.48; 95% CI 1.20-1.84).
Study Design
Type
Cohort (n=3,573)
Multicenter
Yes
Structured PICO
Are plasma tryptophan-kynurenine pathway metabolites associated with the risk of progression to end-stage kidney disease in patients with type 2 diabetes?
P
Population
3,573 patients with type 2 diabetes across discovery, replication, and external validation cohorts assessed for progression to end-stage kidney disease.
E
Exposure
Plasma tryptophan-kynurenine pathway metabolites (tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, xanthurenic acid)
O
Outcome
Composite of incident ESKD (progression to estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, sustained dialysis, or renal death)composite
Accelerated catabolism of tryptophan in the kynurenine pathway is associated with progressive loss of kidney function in type 2 diabetes, while shunting toward kynurenic acid may be protective.
Main Result
Hazard Ratio: 0.62 (95% CI 0.51–0.75)
Abstract
OBJECTIVE: We sought to study the associations between plasma metabolites in the tryptophan-kynurenine pathway and the risk of progression to end-stage kidney disease (ESKD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, and xanthurenic acid concentrations were measured in discovery (n = 1,915) and replication (n = 346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (n = 1,312). The primary outcome was a composite of incident ESKD (progression to estimated glomerular filtration rate eGFR <15 mL/min/1.73 m2, sustained dialysis, or renal death). The secondary outcome was annual eGFR decline. RESULTS: In the 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 hazard ratios HRs 0.62 95% CI 0.51, 0.75 and 1.48 1.20, 1.84 per 1 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, while a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in the 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). CONCLUSIONS: Accelerated catabolism of tryptophan in the kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward the kynurenic acid branch may potentially slow renal progression.