Peripheral kynurenine/tryptophan ratio is not a reliable marker of systemic indoleamine 2,3-dioxygenase: A lesson drawn from patients on hemodialysis
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Yuanhan Chen1, Zhen Xie2, Chenggen Xiao1,3, Min Zhang4, Zhilian Li1, Jianteng Xie1, Yusheng Zhang5, Xingchen Zhao1,6, Pengfei Zeng5, Liyi Mo1,7, Xinling Liang1, Wei Shi1
1Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
2Department of Dermatology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China
3Division of Nephrology, Xiangya Hospital, Central South University, Hunan, China
4Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
5Second Division of Internal Medicine, Wuhua People’s Hospital, Guangdong, China
6Southern Medical University, Guangzhou, China
7Department of Nephrology, Dongguan People’s Hospital, Guangdong Province, China
Wei Shi, email: [email protected]
Xinling Liang, email: [email protected]
Keywords: indoleamine 2,3-dioxygenase, kynurenine to tryptophan ratio, hemodialysis, immune tolerance, infection
Received: September 18, 2016 Accepted: January 24, 2017 Published: February 25, 2017
Indoleamine 2,3-dioxygenase (IDO) has emerged as a pivotal enzyme for mediating immune tolerance. Because IDO metabolizes tryptophan into kynurenine, the plasma kynurenine/tryptophan (Kyn/Trp) ratio has been widely used as a marker of systemic IDO. Here, we evaluated the clinical value of using the plasma Kyn/Trp ratio to estimate cell-mediated immune responses to tuberculin skin testing and risk of new bacterial infection. We also compared the Kyn/Trp ratio to a novel IDO marker, the IDO median fluorescence index (MFI) of peripheral blood mononuclear cells, which was determined by flow cytometry. In 228 patients from two hemodialysis centers, the two IDO markers were higher in patients than in healthy controls but were not correlated with each other. In vitro experiments demonstrated that peripheral blood mononuclear cells could not metabolize tryptophan into kynurenine, indicating that the increased Kyn/Trp ratio was IDO-independent. Skin induration diameters of tuberculin skin testing were correlated with the IDO MFI (negatively), but not the Kyn/Trp ratio. Further, in a 24-month prospective cohort, the Kyn/Trp ratio was not correlated with clinical infection. Alternatively, patients with a higher IDO MFI had a lower accumulative infection-free survival rate. Using a Cox proportional hazard model, it was also revealed that a higher IDO MFI was significantly associated with new bacterial infection. Taken together, these results indicate that the Kyn/Trp ratio is not a reliable circulating IDO marker in hemodialysis patients. However, the IDO MFI reflects an immunocompromised state and thus might be a potential clinical marker of bacterial infection.
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