Clinical Research Unit, Khoo Teck Puat Hospital, Singapore.
Duke-NUS Medical School, Singapore.
Diabetes Care. 2023 Dec 1;46(12):2223-2231. doi: 10.2337/dc23-1147.
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.
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.
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]).
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.
我们旨在研究色氨酸-犬尿氨酸途径中的血浆代谢物与 2 型糖尿病患者进展为终末期肾病（ESKD）的风险之间的关联。
在发现队列（n=1915）和复制队列（n=346）中测量了血浆色氨酸、犬尿氨酸、3-羟基犬尿氨酸、犬尿酸和黄尿酸的浓度。在患有糖尿病的慢性肾功能不全队列（CRIC）参与者中进行了外部验证（n=1312）。主要结局是复合终点事件，包括新发 ESKD（估算肾小球滤过率[eGFR]＜15mL/min/1.73m2、持续透析或肾脏死亡）。次要结局是每年 eGFR 下降情况。
在发现队列中，色氨酸与 ESKD 风险呈负相关，犬尿氨酸/色氨酸比值（KTR）在调整临床危险因素（包括基线 eGFR 和白蛋白尿）后与 ESKD 风险呈正相关，调整后的危险比（HR）分别为 0.62（95%CI 0.51，0.75）和 1.48（1.20，1.84）/SD。高水平的犬尿酸和黄尿酸与 ESKD 风险降低相关（0.74[0.60，0.91]和 0.74[0.60，0.91]）。同样，高水平的色氨酸、犬尿酸和黄尿酸与 eGFR 下降速度较慢独立相关，而高 KTR 则与 eGFR 下降速度较快相关。在复制队列中也得到了相似的结果。此外，在患有糖尿病的 CRIC 参与者中，犬尿酸与 ESKD 风险之间的负相关关系在外部得到了验证（调整后的 HR 0.78[0.65，0.93]）。
色氨酸在犬尿氨酸途径中的分解代谢加速可能与肾功能进行性丧失有关。然而，将犬尿氨酸途径转向犬尿酸分支可能会减缓肾脏进展。
