Peripheral kynurenine/tryptophan ratio is not a reliable marker of systemic indoleamine 2,3-dioxygenase: A lesson drawn from patients on hemodialysis

Abstract

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.

The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal

“…An increase in the ratio in alcohol-dependent subjects, 8 weeks after withdrawal, does not correlate with neopterin, 14 a marker of IDO induction, as IFN-γ also induces the key enzyme of neopterin synthesis, GTP cyclohydrolase I. In a study 15 . That the increase in the ratio in this study was independent of IDO activity is further suggested by the failure of these PBMCs to metabolise Trp to Kyn.…”

“…An increase in the ratio in alcohol-dependent subjects, 8 weeks after withdrawal, does not correlate with neopterin, 14 a marker of IDO induction, as IFN-γ also induces the key enzyme of neopterin synthesis, GTP cyclohydrolase I. In a study 15 of patients with haemodialysis from 2 separate centres, the significant increase in the plasma [Kyn]/[Trp] ratio caused by a significant increase in [Kyn] and a significant decrease in [Trp], does not correlate with IDO activity measured directly in peripheral blood mononuclear cells (PBMCs). That the increase in the ratio in this study was independent of IDO activity is further suggested by the failure of these PBMCs to metabolise Trp to Kyn.…”

“…That the increase in the ratio in this study was independent of IDO activity is further suggested by the failure of these PBMCs to metabolise Trp to Kyn. 15 A more likely explanation of the changes in this ratio and its 2 components is enhancement of hepatic TDO activity, which has been demonstrated in rat models of renal failure by 2 independent groups. 16,17 By contrast, IDO activity directly measured in 5 tissues 16 including lung 17 is not altered in these 2 models.…”

Tryptophan Metabolism, Inflammation, and Oxidative Stress in Patients with Neurovascular Disease

“…Recently, it was shown that peripheral KTR is influenced by various factors and is not a reliable marker of IDO activity [16,46]. KTR is reliable for measurement of IDO activity in isolated cells or cell cultures of cells capable of producing functional IDO, e.g., in endothelial cells, antigen-presenting cells, fibroblasts, macrophages, and dendritic cells [10,46]. In plasma, IDO-independent loss of TRP (enhancing KTR) may be caused by decreased dietary intake of TRP or due to the action of liver TDO increase for instance in renal diseases [43].…”

Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging

“…IDO1 expression is known to induce the suppression of effector T cells, promoting T reg activation and tolerance. Recently, IDO1 activity has been identified as a potential clinical marker of bacterial infection in hemodialysis patients [41], linking dysregulation of the immune system to hemodialysis chronic microinflammation and risk of infection. Experimental data support the hypothesis that IDO1 suppresses innate and adaptive immune responses, confirming its relevance to promote chronic inflammatory syndromes [42].…”