Journal
BIOMEDICAL CHROMATOGRAPHY
Volume 32, Issue 7, Pages -Publisher
WILEY
DOI: 10.1002/bmc.4198
Keywords
amino acid; HPLC-MS; MS; metabolomics; nephrotoxicity; tacrolimus; transplantation; urine
Categories
Funding
- Shanghai Key Specialty Project of Clinical Pharmacy [2016-40044-002]
- Beijing Medical Award Foundation [YJHYXKYJJ-122]
- Shanghai Shenkang Hospital Development Center Project [SHDC12015120]
- Program of International ST Cooperation [2015DFA31810]
- National Natural Science Foundation of China [81573793]
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Calcineurin inhibitor nephrotoxicity, especially for the widely used tacrolimus, has become a major concern in post-transplant immunosuppression. Multiparametric amino acid metabolomics is useful for biomarker identification of tacrolimus nephrotoxicity, for which specific quantitative methods are highlighted as a premise. This article presents a targeted metabolomic assay to quantify 33 amino acids and biogenic amines in human urine by high-performance liquid chromatography coupled with tandem mass spectrometry. Chromatographic separation was carried out on an Agilent Zorbax SB-C-18 column (3.0 x 150mm, 5m) with addition of an ion-pairing agent in the mobile phase, and MS/MS detection was achieved in both the positive and negative multiple reaction monitoring modes. Good correlation coefficients (r(2) > 0.98) were obtained for most analytes. Intra- and inter-day precision, stability, carryover and incurred sample reanalysis met with the acceptance criteria of the guidance of the US Food and Drug Administration. Analysis on urine from healthy volunteers and renal transplantation patients with tacrolimus nephrotoxicity confirmed symmetric dimethylarginine and serine as biomarkers for kidney injury, with AUC values of 0.95 and 0.81 in receiver operating characteristic analysis, respectively. Additionally, symmetric dimethylarginine exhibited a tight correlation with serum creatinine, and was therefore indicative of renal function. The targeted metabolomic assay was time and cost prohibitive for amino acid analysis in human urine, facilitating the biomarker identification of tacrolimus nephrotoxicity.
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