The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease

Abstract

<b><i>Background:</i></b> The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD<sup>+</sup>) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington’s disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. <b><i>Summary:</i></b> This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD<sup>+</sup> production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. <b><i>Key Messages:</i></b> KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.

Network Pharmacology Combined with Metabolomics Approach to Investigate the Toxicity Mechanism of Paclobutrazol

“…33 The complex enzyme systems in the kidney could be involved in the kynurenine pathway, and the kidney injury can affect metabolic enzyme activities, which has a direct impact on metabolic disorder. 34 There are some literature reports that chronic nephrosis is often accompanied by the disorder of tryptophan metabolism, and the results of our research show that, compared with the control group, the tryptophan levels in the PBZ-exposed rats showed a significant decrease. 34 4,6-Dihydroxyquinoline is a downstream product of the kynurenine pathway.…”

Metabolomic profiling demonstrates evidence for kidney and urine metabolic dysregulation in a piglet model of cardiac surgery-induced acute kidney injury

“…During pathological inflammatory states, flux through the KP is increased due to the upregulation of the first pathway enzyme (indolamine 2,3-dioxygenase) across multiple organs ( 45 – 48 ). Evidence points to a potential role for the KP in noncardiac surgery-associated AKI ( 49 ). Observational studies in adults with AKI from a mix of etiologies have identified increased circulating kynurenic acid and kynurenine/tryptophan ratios in subjects with AKI ( 50 – 54 ).…”

“…Administration of exogenous kynurenic acid decreases ischemia-reperfusion-induced AKI in mice ( 58 ), and blockade of the KP at kynurenine 3-monooxygenase with shunting toward kynurenic acid has a similar effect ( 29 ). These findings suggest that kynurenic acid may be protective in isolated ischemia-reperfusion injury, likely through a combination of antioxidant, anti-inflammatory, and N -methyl- d -aspartate receptor antagonist properties ( 49 ). Reduction of downstream oxidant, proapoptotic, N -methyl- d -aspartate receptor agonist KP metabolites may also be beneficial.…”

Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial

“…The TRP-KYN pathway is activated in AKI, showing usually an increase in its metabolites [ 17 , 18 ]. Upregulation of the TRP-KYN pathway in AKI can be explained by the higher concentrations of IFN-γ and other pro-inflammatory cytokines following IR injury, which in turn activate the TRP-KYN pathway via its rate-limiting enzyme IDO [ 19 ]. In our study a strong linear correlation of change in the kynurenine/tryptophan ratio with change in cystatin C and beta-2-microglobulin was seen in the RIPC group.…”