Urinary metabolomic profiling for noninvasive diagnosis of acute T cell-mediated rejection after kidney transplantation

Kim, Sun‐Young; Kim, Bo Kyung; Gwon, Mi‐Ri; Seong, Sook Jin; Ohk, Boram; Kang, Woo Youl; Lee, Hae Won; Jung, Hee-Yeon; Cho, Jang‐Hee; Chung, Byung Ha; Lee, Sang-Ho; Kim, Yeong Hoon; Yoon, Young‐Ran; Kim, Chan‐Duck; Cho, Seung Il

doi:10.1016/j.jchromb.2019.04.047

Cited by 13 publications

(14 citation statements)

References 31 publications

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“…Urinary untargeted metabolomic profiling led to identification of a panel of five potential biomarkers (guanidoacetil acid, methylimidazolacetic acid, dopamine, 4-guanidobutyric acid, and L-tryptophan), which discriminated between TCMR and stable graft (ROC curve AUC: sensitivity 90%; specificity 84.6%) [ 106 ].…”

Section: Armentioning

confidence: 99%

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Quaglia

Merlotti

Guglielmetti

et al. 2020

IJMS

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New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

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Section: Armentioning

confidence: 99%

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Quaglia

Merlotti

Guglielmetti

et al. 2020

IJMS

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“…Kim et al detected five urinary biomarkers related to T-cell mediated kidney allograft rejection by using a metabolomics approach: a positive association was found with guanidoacetic acid, methylimidazoleacetic acid and dopamine and a negative one with 4-guanidinobutyric acid and L-tryptophan. Together, these metabolites predicted acute T-cell-mediated rejection with an accuracy of 87% for the training set; however, in the validation set, the accuracy decreased to 62.5% [ 146 ]. In another targeted metabolomics study that investigated urinary metabolites, kynurenine was found as one of the top 10 metabolites able to identify acute T-cell-mediated rejection in pediatric kidney Tx recipients [ 147 ].…”

Section: Diagnostic and Prognostic Role Of Tryptophan And Its Metamentioning

confidence: 99%

“…The most suitable and reliable chromatographic method for the simultaneous multi-compound analysis of tryptophan and kynurenine pathway metabolites is LC-MS, which allows the accurate quantification of analytes in a wider range of concentrations. However, due to the necessity of costly equipment, expensive isotope-labeled internal standards and precise sample preparation process, its utility in daily clinical practice is limited as well [ 11 , 146 , 147 , 149 , 152 , 158 ]. Nuclear magnetic resonance (NMR) is another promising technique that allows not only the rapid and precise quantification of various biochemical analytes in biological fluids or tissues but, also, the noninvasive in vivo analysis of metabolism in spectroscopic images and have also been successfully used to determine the levels of tryptophan-kynurenine pathway compounds [ 11 , 160 ].…”

Section: Diagnostic and Prognostic Role Of Tryptophan And Its Metamentioning

confidence: 99%

Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation

Žulpaitė

Miknevicius

Leber

et al. 2021

IJMS

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Solid organ transplantation is a gold standard treatment for patients suffering from an end-stage organ disease. Patient and graft survival have vastly improved during the last couple of decades; however, the field of transplantation still encounters several unique challenges, such as a shortage of transplantable organs and increasing pool of extended criteria donor (ECD) organs, which are extremely prone to ischemia-reperfusion injury (IRI), risk of graft rejection and challenges in immune regulation. Moreover, accurate and specific biomarkers, which can timely predict allograft dysfunction and/or rejection, are lacking. The essential amino acid tryptophan and, especially, its metabolites via the kynurenine pathway has been widely studied as a contributor and a therapeutic target in various diseases, such as neuropsychiatric, autoimmune disorders, allergies, infections and malignancies. The tryptophan-kynurenine pathway has also gained interest in solid organ transplantation and a variety of experimental studies investigating its role both in IRI and immune regulation after allograft implantation was first published. In this review, the current evidence regarding the role of tryptophan and its metabolites in solid organ transplantation is presented, giving insights into molecular mechanisms and into therapeutic and diagnostic/prognostic possibilities.

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“…Unbiased metabolomic analysis and untargeted profiling revealed multiple urinary metabolites as potential biomarkers of AR: nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid, 1-methylnicotinamide (MNA), gamma-aminobutyric acid (GABA), cholesterol sulfate, homocysteine [18], the combination of alanine, citrate, lactate, and urea [21,27], and the combination of guanidoacetic acid, methylimidazoleacetic acid, dopamine, 4-guanidinobutyric acid, and l-tryptophan [25].…”

Section: Scores and Formulasmentioning

confidence: 99%

“…Results confirmation in at least one validation cohort was available in less than one third of studies (7/29, 24%). Of these, two were case-control studies [25,33], while the others were the previously mentioned five cross-sectional studies with the lowest risk of bias score [16,17,21,41,45]. Sensitivity and specificity values were highly variable between studies, ranging from 9% to 100% and from 34% and 100%, respectively.…”

Section: Quality Assessmentmentioning

confidence: 99%

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review

Guzzi

Cirillo

Buti

et al. 2020

IJMS

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Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from 1 January 2015 to 31 May 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies.

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Urinary metabolomic profiling for noninvasive diagnosis of acute T cell-mediated rejection after kidney transplantation

Cited by 13 publications

References 31 publications

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review

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