Department of Nephrology, Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Chemistry, Sharif University of Technology, Tehran, Iran.
OMICS. 2020 Mar;24(3):140-147. doi: 10.1089/omi.2019.0158.
Acute T cell-mediated rejection (TCMR) is a major complication after renal transplantation. TCMR diagnosis is very challenging and currently depends on invasive renal biopsy and nonspecific markers such as serum creatinine. A noninvasive metabolomics panel could allow early diagnosis and improved accuracy and specificity. We report, in this study, on urine metabolome changes in renal transplant recipients diagnosed with TCMR, with a view to future metabolomics-based diagnostics in transplant medicine. We performed urine metabolomic analyses in three study groups: (1) 7 kidney transplant recipients with acute TCMR, (2) 15 kidney transplant recipients without rejection but with impaired kidney function, and (3) 6 kidney transplant recipients with stable renal function, using H-nuclear magnetic resonance. Multivariate modeling of metabolites suggested a diagnostic panel where the diagnostic accuracy of each metabolite was calculated by receiver operating characteristic curve analysis. The impaired metabolic pathways associated with TCMR were identified by pathway analysis. In all, a panel of nine differential metabolites encompassing nicotinamide adenine dinucleotide, 1-methylnicotinamide, cholesterol sulfate, gamma-aminobutyric acid (GABA), nicotinic acid, nicotinamide adenine dinucleotide phosphate, proline, spermidine, and alpha-hydroxyhippuric acid were identified as novel potential metabolite biomarkers of TCMR. Proline, spermidine, and GABA had the highest area under the curve (>0.7) and were overrepresented in the TCMR group. Nicotinate and nicotinamide metabolism was the most important pathway in TCMR. These findings call for clinical validation in larger study samples and suggest that urinary metabolomics warrants future consideration as a noninvasive research tool for TCMR diagnostic innovation.
急性 T 细胞介导的排斥反应（TCMR）是肾移植后的主要并发症。TCMR 的诊断极具挑战性，目前依赖于有创性的肾活检和非特异性标志物，如血清肌酐。非侵入性代谢组学分析可能可以实现早期诊断，并提高准确性和特异性。在本研究中，我们报告了诊断为 TCMR 的肾移植受者尿液代谢组的变化，以期在移植医学中实现基于代谢组学的诊断。我们在三个研究组中进行了尿液代谢组学分析：（1）7 例诊断为急性 TCMR 的肾移植受者；（2）15 例无排斥反应但肾功能受损的肾移植受者；（3）6 例肾功能稳定的肾移植受者，使用 H-核磁共振。对代谢物进行多元建模表明，存在一个诊断性标志物面板，通过接收者操作特征曲线分析计算每个标志物的诊断准确性。通过途径分析确定了与 TCMR 相关的受损代谢途径。总之，一组 9 种差异代谢物，包括烟酰胺腺嘌呤二核苷酸、1-甲基烟酰胺、硫酸胆固醇、γ-氨基丁酸（GABA）、烟酸、烟酰胺腺嘌呤二核苷酸磷酸、脯氨酸、亚精胺和α-羟基苯乙酸，被鉴定为 TCMR 的潜在新型代谢物生物标志物。脯氨酸、亚精胺和 GABA 的曲线下面积（AUC）最高（>0.7），并且在 TCMR 组中含量较高。烟酸和烟酰胺代谢是 TCMR 中最重要的途径。这些发现需要在更大的研究样本中进行临床验证，并表明尿液代谢组学值得进一步考虑作为 TCMR 诊断创新的非侵入性研究工具。
