慢性肾病患者吲哚胺2,3-双加氧酶（IDO）活性增加及血清色氨酸分解代谢产物水平升高：慢性炎症与尿毒症症状之间的可能联系

Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms.

作者信息

Schefold Jörg C, Zeden Jan-Philip, Fotopoulou Christina, von Haehling Stephan, Pschowski Rene, Hasper Dietrich, Volk Hans-Dieter, Schuett Christine, Reinke Petra

机构信息

Department of Nephrology and Intensive Care, Charité University Medicine, Campus Virchow Clinic, Berlin, Germany.

出版信息

Nephrol Dial Transplant. 2009 Jun;24(6):1901-8. doi: 10.1093/ndt/gfn739. Epub 2009 Jan 20.

DOI:10.1093/ndt/gfn739

PMID:19155537

Abstract

BACKGROUND

Tryptophan (Trp) is catabolized by indoleamine 2,3-dioxygenase (IDO). Changes in Trp metabolism and IDO activity in chronic kidney disease (CKD) have not been widely studied, and the impact of haemodialysis is uncertain. Here we investigate Trp catabolism, IDO activity and the role of inflammation in moderate to very severe CKD and haemodialysis.

METHODS

Eighty individuals were included in a prospective blinded endpoint analysis. Using tandem mass spectrometry, serum levels of Trp, kynurenine (Kyn), kynurenic-acid (Kyna), quinolinic-acid (Quin), 5-hydroxytryptophan (OH-Trp), serotonin (5-HT), estimated IDO activity and inflammatory markers were assessed in 40 CKD patients (age 57 +/- 14 years, 21 male, creatinine 4.5 +/- 2.7, n = 17 receiving haemodialysis), and in 40 healthy controls (age 34 +/- 9 years, 26 male).

RESULTS

Trp levels were unchanged in CKD (P = 0.78 versus controls). Serum levels of Kyn, Kyna and Quin increased with CKD severity (stages 4, 5 versus controls all P < or = 0.01). IDO activity was significantly induced in CKD and correlated with disease severity (stages 3-5 versus controls, all P < or = 0.01) and inflammatory markers [high-sensitivity C-reactive protein (hsCRP), soluble TNF-receptor-1 (sTNFR-I); both P < or = 0.03]. IDO products (Kyn, Kyna, Quin) correlated also with hsCRP and sTNFR-I (all P < or = 0.04). Haemodialysis did not influence IDO activity (P = 0.26) and incompletely removed Kyn, Kyna, Quin, OH-Trp and 5-HT by 22, 26, 50, 44 and 34%, respectively. In multiple regression, IDO activity correlated with hsCRP and sTNFR-I (both P < or = 0.03) independent of serum creatinine, age and body weight.

CONCLUSIONS

IDO activity and serum levels of tryptophan catabolites of the kynurenine pathway increase with CKD severity. In CKD, induction of IDO may primarily be a consequence of chronic inflammation.

摘要

背景

色氨酸（Trp）通过吲哚胺2,3-双加氧酶（IDO）进行分解代谢。慢性肾脏病（CKD）中色氨酸代谢和IDO活性的变化尚未得到广泛研究，且血液透析的影响尚不确定。在此，我们研究中度至重度CKD及血液透析中色氨酸分解代谢、IDO活性及炎症的作用。

方法

80名个体纳入前瞻性盲法终点分析。使用串联质谱法，对40例CKD患者（年龄57±14岁，男性21例，肌酐4.5±2.7，其中17例接受血液透析）及40名健康对照者（年龄34±9岁，男性26例）的血清色氨酸、犬尿氨酸（Kyn）、犬尿酸（Kyna）、喹啉酸（Quin）、5-羟色氨酸（OH-Trp）、5-羟色胺（5-HT）、估计的IDO活性及炎症标志物进行评估。

结果

CKD患者色氨酸水平无变化（与对照组相比，P = 0.78）。犬尿氨酸、犬尿酸和喹啉酸的血清水平随CKD严重程度增加（4期、5期与对照组相比，P均≤0.01）。CKD中IDO活性显著升高，且与疾病严重程度相关（3 - 5期与对照组相比，P均≤0.01）以及与炎症标志物[高敏C反应蛋白（hsCRP）、可溶性肿瘤坏死因子受体-1（sTNFR-I）]相关（P均≤0.03）。IDO产物（犬尿氨酸、犬尿酸、喹啉酸）也与hsCRP和sTNFR-I相关（P均≤0.04）。血液透析不影响IDO活性（P = 0.26），且分别不完全清除犬尿氨酸、犬尿酸、喹啉酸、5-羟色氨酸和5-羟色胺22%、26%、50%、44%和34%。在多元回归分析中，IDO活性与hsCRP和sTNFR-I相关（P均≤0.03），独立于血清肌酐、年龄和体重。