Marie Christelle Saade
Amanda J. Clark1,2- 1Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, TX, United States
- 2Division of Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, United States
- 3Department of Pharmacology, University of Texas Southwestern, Dallas, TX, United States
Introduction: Quinolinic acid is an intermediate compound derived from the metabolism of dietary tryptophan. Its accumulation has been reported in patients suffering a broad spectrum of diseases and conditions. In this manuscript, we present the results of a systematic review of research studies assessing urinary quinolinic acid in health and disease.
Methods: We performed a literature review using PubMed, Cochrane, and Scopus databases of all studies reporting data on urinary quinolinic acid in human subjects from December 1949 to January 2022.
Results: Fifty-seven articles met the inclusion criteria. In most of the reported studies, compared to the control group, quinolinic acid was shown to be at increased concentration in urine of patients suffering from different diseases and conditions. This metabolite was also demonstrated to correlate with the severity of certain diseases including juvenile idiopathic inflammatory myopathies, graft vs. host disease, autism spectrum disorder, and prostate cancer. In critically ill patients, elevated quinolinic acid in urine predicted a spectrum of adverse outcomes including hospital mortality.
Conclusion: Quinolinic acid has been implicated in the pathophysiology of multiple conditions. Its urinary accumulation appears to be a feature of acute physiological stress and several chronic diseases. The exact significance of these findings is still under investigation, and further studies are needed to reveal the subsequent implications of this accumulation.
Introduction
Quinolinic acid, or pyridine-2,3-dicarboxylic acid, was originally described in 1949 by Henderson et al. as a normal component of urine and a possible substrate of tryptophan (1). More recently, quinolinic acid has been recognized as a metabolite of the kynurenine pathway, also known as the de novo nicotinamide adenine dinucleotide (NAD+) synthesis pathway. This pathway catabolizes dietary tryptophan into NAD+ and is one of the three independent pathways for NAD+ biosynthesis (Figures 1, 2). In times of stress and inflammation, quinolinic acid accumulates (3, 4). This accumulation was hypothesized to result from two phenomena. First, pro-inflammatory cytokines activate the first and rate-limiting enzyme of the kynurenine pathway, indoleamine 2,3-dioxygenase (IDO), inducing the accumulation of downstream metabolites (5). Second, the quinolinate phosphoribosyl transferase (QPRT) enzyme which catalyzes quinolinic acid and commits the pathway to NAD+ biosynthesis declines or saturates with inflammation (6, 7).
Figure 1. NAD+ biosynthetic pathways. IDO, indoleamine-pyrrole 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; QPRT, quinolinate phosphoribosyltransferase; NAD, nicotinamide adenine dinucleotide; NADS, nicotinamide adenine dinucleotide synthetase 1; NMNAT, nicotinamide mononucleotide adenylyl transferase; NAPRT, nicotinate phosphoribosyltransferase; NAMPT, nicotinamide phosphoribosyltransferase.
Figure 2. Studies selection flow diagram.
The redox cofactor nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in cellular energy production by carrying high energy electrons and driving oxidative phosphorylation (8). In addition to the de novo NAD+ biosynthesis pathway, NAD+ is biosynthesized from two additional pathways including the Preiss–Handler pathway, which makes NAD+ from dietary niacin, and the NAD+ salvage pathway which makes NAD+ from dietary or recycled niacinamide (Figures 1, 2). Despite the alternative pathways of NAD+ production, quinolinic acid accumulation is frequently accompanied by NAD+ reduction (9).
Over the past decade, a growing number of reports has described quinolinic acid accumulation during inflammation and has hypothesized that quinolinic acid may play a role in many disease processes. Inflammation triggers a complex cascade of cytokines which can activate the kynurenine pathway and cause quinolinic acid accumulation. In fact, IDO, the enzyme responsible for the first and rate-limiting step of this pathway, is induced by many inflammatory cytokines (10, 11). Interferon-γ (IFN-γ), specifically, is a powerful IDO-activating cytokine (12). Quinolinic acid seems to have a controversial and unclear role during inflammation. In some instances, quinolinic acid appears to have an anti-inflammatory role by reducing Th1-like cells and increasing the Th2-like cells, which limits adaptive immunity overactivation (13). However, quinolinic acid accumulation has also been considered a deleterious feature of inflammation, and its increased concentration can be responsible for cytotoxicity, particularly in neurologic diseases through numerous proposed mechanisms (2).
Quinolinic acid has been noted to accumulate in several organs, blood, cerebrospinal fluid (CSF), and urine during pathological conditions. This accumulation could be interpreted as either evidence of a high-flux state or as suppression of pathway enzymes, including QPRT activity, during inflammation and stress, leading to altered NAD+ biosynthesis (7, 14). Quinolinic acid accumulation has been associated with a spectrum of diseases including neurodegenerative conditions, psychiatric diseases, acute illness, kidney failure, and liver failure. The exact implication of quinolinic acid accumulation as well as its correlation with the disease severity is still uncertain. Urinary measurement of quinolinic acid is a convenient diagnostic test of this metabolite as it is a non-invasive and easily collected. Additionally, there is evidence that urinary quinolinic acid levels correspond with systemic levels (15). Several studies have assessed urinary quinolinic acid levels as markers of various pathologies. However, until now, a broad examination of urinary quinolinic acid excretion has not been undertaken. In this review, we categorize and summarize primary research that has reported quinolinic acid in human urine.
Materials and methods
Literature search
This study was guided by the Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA) statement issued in 2020. The search was restricted to English language journal articles with human subjects, published between December 1949 and January 2022.
The search of the literature was conducted using electronic databases PubMed, Cochrane, and Scopus. The following keywords were used to perform the search: ((Quinolinic Acid) OR (Quinolinate)) AND ((Urine) OR (Urinary) OR (Urine analysis)).
Inclusion and exclusion criteria
Eligible studies were included if they were (i) peer reviewed primary scientific articles and (ii) reported quinolinic acid measurement in the urine of human subjects irrespective of study aim. Studies were excluded if they were (i) reviews or meta-analyses, (ii) articles written in languages other than English, (iii) assessments of quinolinic acid in body fluids other than urine, and (iv) studies performed exclusively on animals.
Study selection and data extraction
Two investigators performed the literature search and selected qualified studies according to the inclusion and exclusion criteria. The study selection was performed in a two-step process, beginning with a title and abstract screening followed by full-text screening. The data extracted from each study included the general aim of the study, study method and design for measuring metabolites, and the results concerning quinolinic acid measurement in urine. Included studies were categorized in a system-based classification: endocrinology, gastroenterology, hematology, infectious diseases, nephrology, neurology, obstetrics and gynecology, oncology, psychiatry, rheumatology, and other conditions. A descriptive analysis of the results was presented.
Results
The electronic database search yielded a total of 512 articles. Based on title and/or abstract, 90 articles were deemed potentially relevant, and after the full text viewing, 54 articles were included in the review (Figure 2).
Studies measuring urinary quinolinic acid in humans are shown in Table 1. Various methods were used to measure urinary quinolinic acid. However, most studies described chromatography-spectrometry techniques. Additionally, human urine exhibits significant variability in concentration and composition within an individual arising from various external and internal factors such as hydration, solute intake, and kidney function. To avoid false data interpretation, several normalization methods exist for urinary metabolomic studies (16). We specified for each study which normalization technique was used (if any) to insist on the validity of the results and to facilitate the interpretation of the data.
Table 1. Studies measuring urinary quinolinic acid in humans.
Urinary quinolinic acid was measured in multiple pathological conditions. Compared to control groups, this metabolite was shown to be higher in urine of patients suffering from premature rupture of membranes during labor (17), juvenile idiopathic inflammatory myopathies (18), Sjögren’s Syndrome (19), mitochondrial oxodicarboxylate carrier deficiency (20), kidney cancer (21), breast cancer (22), prostate cancer (23), graft versus host disease (GVHD) (24), major depressive disorder (25), autism spectrum disorder (26), attention-deficit/hyperactivity disorder (ADHD) (27), tuberculous meningitis (28), kidney transplant rejection, acute kidney injury (AKI) (6), and metabolic syndrome including hyperlipidemia, obesity, hypertension, and diabetes (29, 30). In some cases, urinary quinolinic acid was even demonstrated to correlate with disease severity. In juvenile idiopathic inflammatory myopathies, urinary quinolinic acid was shown to increase with several aspects of disease activity including physician and parent global assessments of disease activity, manual muscle testing total score, Childhood Myositis Assessment Scale, and Childhood Health Assessment Questionnaire (18). In GVHD, urinary quinolinic acid was significantly higher in patients with GVHD grade 3 or 4 compared to those with grade 1 and 2 (24). Moreover, in a critically ill population, urinary quinolinic acid to tryptophan ratio was not only associated with higher risk of AKI development, but also increased probability of global adverse outcomes, including hospital mortality (6). In a study on patients with autism spectrum disorder comparing urine metabolomics of patients with severe autism spectrum disorder symptoms to those with mild-to-moderate symptoms, quinolinic acid was significantly higher in patients with severe symptoms (31). In patients with prostate cancer, quinolinic acid to tryptophan ratio level in urine significantly correlated with their Gleason score.
Conversely, Heyes et al. found no significant difference in urinary quinolinic acid in patients with Huntington’s disease compared to the control group (32). Patients suffering from acute on chronic liver failure showed no significant difference in their urinary quinolinic acid during acute kidney failure (33). And, one study investigating patients with bladder cancer showed a lower ratio of urinary tryptophan to quinolinic acid compared to the healthy control group (34).
Urinary quinolinic acid is increased in several non-disease settings as well. Quinolinic acid is reportedly higher in urine of patients who were administered deoxypyridoxine (a vitamin B6-antagonist), oral contraceptive (35), tryptophan (1, 36–38), high-protein diet (39), and those who were exposed to phthalate (an industrial chemical) (40; Table 1).
Discussion
To our knowledge, this is the first systematic review evaluating urinary quinolinic acid in humans. There is abundant evidence that urinary quinolinic acid is increased in various disease states including cancer, infections, autoimmune diseases, metabolic syndrome, and psychiatric conditions, and in many instances quinolinic acid levels correlate with disease severity (41). While this review focused primarily on human urine, given its ease of measurement, this metabolite has also been investigated in blood, CSF, and tissue biopsies and has been implicated in the pathophysiology of different diseases in animals as well.
The included articles described a wide spectrum of settings in which quinolinic acid is increased with different methods and units of measurement. These variations limited our ability to compare findings. Another limitation to our systematic review is the difficulty of assessing bias in the included studies since the quinolinic acid data is not always primary outcome of the studies presented. We recognize that undetected biases may have been present in the articles described here. We also acknowledge that focusing on urinary-based quinolinic acid studies and excluding plasma and tissue-based quinolinic acid studies is an additional limitation to our results, but this was an indispensable filter for the purpose and feasibility of our study.
Overall, we were able to demonstrate build-up of quinolinic acid in urine in a wide spectrum of settings. Quinolinic acid increase during inflammation cannot be analyzed independently from its biochemical pathway, and the exact implication of its build-up is yet unrevealed. Acting as a double-edged sword, quinolinic acid is both an essential precursor for nicotinamide adenine dinucleotide (NAD+) biosynthesis and a potentially toxic metabolite at high concentrations. Quinolinic acid accumulation has been observed in numerous pathologic conditions. While most of the reported studies are observational in nature, they have highlighted that urinary measurement of quinolinic acid is an easy value to obtain that may reveal useful information about systemic disease processes. The true significance of its accumulation and its correlation with the severity of disease are still uncertain. Further studies are needed to investigate potential diagnostic, prognostic, and therapeutic implications of quinolinic acid.
Data availability statement
The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
SP planned, designed, and supervised the project. AC and MS performed the literature search and collected the qualified studies according to the inclusion and exclusion criteria. All authors discussed the results, wrote the manuscript, and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: quinolinic acid (QA), tryptophan, urine, NAD+, inflammation, NAD+ biosynthesis, metabolism, quinolinate phosphoribosyl transferase (QPRT)
Citation: Saade MC, Clark AJ and Parikh SM (2022) States of quinolinic acid excess in urine: A systematic review of human studies. Front. Nutr. 9:1070435. doi: 10.3389/fnut.2022.1070435
Received: 17 October 2022; Accepted: 28 November 2022;
Published: 16 December 2022.
Edited by:
Hui-Xin Liu, China Medical University, ChinaReviewed by:
Shayne Mason, North-West University, South AfricaIman Zarei, University of Eastern Finland, Finland
Copyright © 2022 Saade, Clark and Parikh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Samir M. Parikh, ✉ samir.parikh@utsouthwestern.edu