Diabetes care · 2023
Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Liu Jian-Jun, Ching Jianhong, Wee Hai Ning, Liu Sylvia, Gurung Resham L, Lee Janus, M Yiamunaa, Zheng Huili, Lee Lye Siang, Ang Keven, Shao Yi Ming, Kovalik Jean-Paul, Subramaniam Tavintharan, Sum Chee Fang, Sharma Kumar, Kestenbaum Bryan R, Lim Su Chi
Аннотация
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.
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.