<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⁺) 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⁺ 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.

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Background Health-related quality of life (HRQoL) measures are predictors of adverse health outcomes in older adults. Studies have demonstrated cross-sectional associations between HRQoL measures and blood-based biochemical markers. Acylcarnitines (ACs) are a class of metabolites generated in the mitochondria and are predictive of multiple geriatric syndromes. Changes in ACs reflect alterations in central carbon metabolic pathways. However, the prospective relationship between plasma acylcarnitines and declining HRQoL has not been examined. This study aimed to investigate both cross-sectional and longitudinal associations of baseline ACs with baseline and declining EuroQol-5 Dimension/ EuroQol Visual Analogue Scale (EQ-5D/ EQ-VAS) in community-dwelling older adults. Methods 120 community-dwelling older adults with EQ-5D/ EQ-VAS measurements at baseline and follow-up were included. We quantified ACs at baseline using targeted plasma metabolomics profiling. Multivariate regressions were performed to examine cross-sectional and longitudinal associations between the measures. Results Cross-sectionally, ACs showed no significant associations with either EQ-5D index or EQ-VAS scores. Longitudinally, multiple baseline short-chain ACs were significantly and inversely associated with declining EQ-5D index score, explaining up to 8.5% of variance in the decline. Conclusions Within a cohort of community-dwelling older adults who had high HRQoL at baseline, we showed that short-chain acylcarnitines are independent predictors of declining HRQoL. These findings reveal a novel association between central carbon metabolic pathways and declining HRQoL. Notably, dysregulation in mitochondrial central carbon metabolism could be detected prior to clinically important decline in HRQoL, providing the first evidence of objective biomarkers as novel predictors to monitor HRQoL in non-pharmacological interventions and epidemiology.

Background: Major depressive disorder (MDD) is a debilitating condition with a high disease burden and medical comorbidities. There are currently few to no validated biomarkers to guide the diagnosis and treatment of MDD. In the present study, we evaluated the differences between MDD patients and healthy controls (HCs) in terms of cortical haemodynamic responses during a verbal fluency test (VFT) using functional near-infrared spectroscopy (fNIRS) and serum amino acid profiles, and ascertained if these parameters were correlated with clinical characteristics. Methods: Twenty-five (25) patients with MDD and 25 age-, gender-, and ethnicity-matched HCs were recruited for the study. Real-time monitoring of the haemodynamic response during completion of a VFT was quantified using a 52-channel NIRS system. Serum samples were analysed and quantified by liquid chromatography-mass spectrometry for amino acid profiling. Receiver-operating characteristic (ROC) curves were used to classify potential candidate biomarkers. Results: The MDD patients had lower prefrontal and temporal activation during completion of the VFT than HCs. The MDD patients had lower mean concentrations of oxy-Hb in the left orbitofrontal cortex (OFC), and lower serum histidine levels. When the oxy-haemoglobin response was combined with the histidine concentration, the sensitivity and specificity of results improved significantly from 66.7% to 73.3% and from 65.0% to 90.0% respectively, as compared to results based only on the NIRS response. Conclusions: These findings demonstrate the use of combination biomarkers to aid in the diagnosis of MDD. This technique could be a useful approach to detect MDD with greater precision, but additional studies are required to validate the methodology.

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Introduction: We previously reported changes in the serum metabolome associated with sub-clinical diastolic dysfunction in an aged cohort. In this trial, we subjected subjects with mild diastolic dysfunction to exercise intervention and evaluated effects on cardiovascular function and serum metabolome. Methods: Thirty (83% females) middle-aged adults (53±4 years) with early diastolic dysfunction were randomly assigned to either 12 weeks of moderate intensity exercise training (n=15) or control (n=15). Central hemodynamics and echocardiography were performed pre- and post- intervention, with serum sampling for metabolomic analyses.(E/A (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s). Results: 29 adults completed once-weekly (for 12 weeks) aerobic exercise and muscle strength training for sixty minutes each in a laboratory (n=14 in intervention group, one drop-out) with n=15 controls.E/A increased by magnitude (ratio of post to pre intervention timepoints) of 1.059±0.29 in intervention (p<0.0001) and decreased by 0.969±0.225 (p<0.0001) in control groups. After 12 weeks, central pulse wave velocity) was lower in the intervention compared to control group (7.416±0.789 vs 8.117±0.642, m/s, p=0.032). There were significant accumulations of a medium chain acylcarnitine C12:2-OH/C10:2-DC, alanine and arginine (fold-change 1.825 vs 0.9376, p=0.023; 1.1733 vs 0.95344, p=0.035; 1.1379 vs 0.9501, p=0.041 respectively), with reductions in long-chain acylcarnitine C20:2-OH/C18:2-DC (fold-change 0.7136 vs 1.741, p=0.011), among intervention compared to controls. Conclusions: Our novel pilot data demonstrated reversal of mild diastolic dysfunction after exercise intervention, associated with cellular fuel oxidation and amino acid pathways. We highlight a role for exercise strategies and central carbon metabolism in treating ageing-associated cardiovascular disease.

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Major depressive disorder (MDD) is a highly prevalent and disabling condition with a high disease burden. There are currently no validated biomarkers for the diagnosis and treatment of MDD. This study assessed serum amino acid metabolite changes between MDD patients and healthy controls (HCs) and their association with disease severity and diagnostic utility. In total, 70 MDD patients and 70 HCs matched in age, gender, and ethnicity were recruited for the study. For amino acid profiling, serum samples were analysed and quantified by liquid chromatography-mass spectrometry (LC-MS). Receiver-operating characteristic (ROC) curves were used to classify putative candidate biomarkers. MDD patients had significantly higher serum levels of glutamic acid, aspartic acid and glycine but lower levels of 3-Hydroxykynurenine; glutamic acid and phenylalanine levels also correlated with depression severity. Combining these four metabolites allowed for accurate discrimination of MDD patients and HCs, with 65.7% of depressed patients and 62.9% of HCs correctly classified. Glutamic acid, aspartic acid, glycine and 3-Hydroxykynurenine may serve as potential diagnostic biomarkers, whereas glutamic acid and phenylalanine may be markers for depression severity. To elucidate the association between these indicators and clinical features, it is necessary to conduct additional studies with larger sample sizes that involve a spectrum of depressive symptomatology.