Liu Jian-Jun, Liu Sylvia, Zheng Huili, Lee Janus, Gurung Resham L, Chan Clara, Lee Lye Siang, Ang Keven, Ching Jianhong, Kovalik Jean-Paul, Tavintharan Subramaniam, Sum Chee Fang, Sharma Kumar, Coffman Thomas M, Lim Su Chi
Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore.
Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore.
J Clin Endocrinol Metab. 2025 Jan 21;110(2):e321-e329. doi: 10.1210/clinem/dgae199.
Metabolites in the tricarboxylic acid (TCA) pathway have pleiotropic functions.
To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease progression in individuals with type 2 diabetes.
DESIGN, SETTING AND PARTICIPANTS: A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of people with type 2 diabetes in a regional hospital and a primary care facility.
Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate, and malate were measured by mass spectrometry. Chronic kidney disease progression was defined as a composite of sustained estimated glomerular filtration rate below 15 mL/min/1.73 m2, dialysis, renal death, or doubling of serum creatinine.
During a median of 9.2 (interquartile range 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate, and malate were associated with an increased risk (adjusted hazard ratio, [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82], and 1.49 [1.05-2.11], per SD), whereas citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardiorenal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites.
Urine fumarate and citrate predict the risk for progression to end-stage kidney disease independent of clinical risk factors and other urine metabolites. These 2 metabolites in TCA cycle pathway may play important roles in the pathophysiological network, underpinning progressive loss of kidney function in patients with type 2 diabetes.
三羧酸（TCA）循环中的代谢物具有多种功能。
研究2型糖尿病患者尿TCA循环代谢物与慢性肾脏病进展风险之间的关联。
设计、地点和参与者：在一家地区医院和一家初级保健机构对2型糖尿病患者进行的一项前瞻性研究，分为发现队列（n = 1826）和验证队列（n = 1235）。
通过质谱法测量尿乳酸、丙酮酸、柠檬酸、α-酮戊二酸、琥珀酸、富马酸和苹果酸。慢性肾脏病进展定义为持续估计肾小球滤过率低于15 mL/min/1.73 m2、透析、肾性死亡或血清肌酐翻倍的综合情况。
在中位随访时间9.2（四分位间距8.1 - 9.7）年和4.0（3.2 - 5.1）年期间，分别确定了213例和107例肾脏事件。Cox回归分析表明，尿乳酸、富马酸和苹果酸与风险增加相关（调整后风险比，[95%置信区间] 每标准差为1.63 [1.16 - 2.28]、1.82 [1.17 - 2.82] 和1.49 [1.05 - 2.11]），而在调整心肾危险因素后，柠檬酸与肾脏结局风险较低相关（每标准差调整后风险比为0.83 [0.72 - 0.96]）。这些发现在验证队列中具有可重复性。值得注意的是，在进一步调整其他代谢物后，富马酸和柠檬酸与肾脏结局独立相关。
尿富马酸和柠檬酸可独立于临床危险因素和其他尿代谢物预测进展至终末期肾病的风险。TCA循环途径中的这两种代谢物可能在病理生理网络中发挥重要作用，是2型糖尿病患者肾功能进行性丧失的基础。
