El Chamieh Carolla, Liabeuf Sophie, Larabi Islam Amine, De Pinho Natalia Alencar, Costes-Albrespic Margaux, Frimat Luc, Lange Céline, Herpe Yves-Édouard, Martin Jean-Charles, Letourneau Pierre, Bérengère Benoit, Soulage Christophe, Burtey Stéphane, Alvarez Jean-Claude, Koppe Laetitia, Massy Ziad A
Centre for Research in Epidemiology and Population Health (CESP), INSERM UMRS 1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, France.
Pharmacoepidemiology Unit, Department of Clinical Pharmacology, Amiens-Picardie University Medical Center, Amiens, France.
Kidney Int Rep. 2025 Mar 3;10(5):1404-1414. doi: 10.1016/j.ekir.2025.02.024. eCollection 2025 May.
Recent studies have focused on some uremic toxins, particularly those derived from tryptophan, as potential modifiable risk factors of chronic kidney disease (CKD) progression. The kynurenine pathway is the major enzymatic pathway for sequentially catabolizing tryptophan, resulting in key metabolites including kynurenine and kynurenic acid (KA) by the aminoadipate aminotransferase. We aimed at evaluating the association of serum KA levels and KA-to-kynurenine ratio (as indicators of aminoadipate aminotransferase activity) with kidney failure.
The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) study is a prospective cohort of patients with CKD having an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m. Baseline samples of uremic toxins were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for our outcome. The kidney gene expression of the kynurenine pathway was evaluated in 5 or 6 nephrectomy CKD mice and adenine-diet CKD mice under nephroprotective low protein diet (5% w/w).
Over a median follow-up period of 5 years, 608 out of the 2406 patients progressed to kidney failure. A 2-fold increase in serum KA levels and KA-to-kynurenine ratio were respectively associated with a 22% and 20%-increase in the hazard of kidney failure after multiple adjustments. In the mouse model, positive correlation was found between aminoadipate aminotransferase expression and fibrosis-related genes and kidney fibrosis. A low-protein diet was associated with a decrease in aminoadipate aminotransferase expression in the kidney as well as in inflammatory and fibrosis markers.
Our findings suggest that the kynurenine pathway is associated with kidney failure, and that the inhibition of aminoadipate aminotransferase and the subsequent reduction of KA accumulation is a promising target to mitigate kidney disease progression.
近期研究聚焦于某些尿毒症毒素，尤其是那些源自色氨酸的毒素，将其视为慢性肾脏病（CKD）进展中潜在的可改变风险因素。犬尿氨酸途径是色氨酸依次分解代谢的主要酶促途径，通过氨基己二酸转氨酶作用产生包括犬尿氨酸和犬尿酸（KA）在内的关键代谢产物。我们旨在评估血清KA水平及KA与犬尿氨酸比值（作为氨基己二酸转氨酶活性指标）与肾衰竭的关联。
慢性肾脏病 - 肾脏流行病学和信息网络（CKD - REIN）研究是一项针对估算肾小球滤过率（eGFR）<60 ml/min per 1.73 m²的CKD患者的前瞻性队列研究。使用经过验证的液相色谱串联质谱技术测量尿毒症毒素的基线样本。采用病因特异性Cox模型估计我们所关注结局的风险比（HRs）。在5或6只肾切除的CKD小鼠以及腺嘌呤饮食诱导的CKD小鼠中，于肾保护低蛋白饮食（5% w/w）条件下评估犬尿氨酸途径的肾脏基因表达。
在中位随访期5年期间，2406例患者中有608例进展至肾衰竭。经过多次调整后，血清KA水平和KA与犬尿氨酸比值分别升高2倍，与肾衰竭风险分别增加22%和20%相关。在小鼠模型中，发现氨基己二酸转氨酶表达与纤维化相关基因及肾脏纤维化之间呈正相关。低蛋白饮食与肾脏中氨基己二酸转氨酶表达以及炎症和纤维化标志物的降低相关。
我们的研究结果表明，犬尿氨酸途径与肾衰竭相关，抑制氨基己二酸转氨酶并随后减少KA蓄积是减缓肾脏疾病进展的一个有前景的靶点。
