Topic: Tox / TDM / Endocrine
Podium Presentation in Room 1 on Thursday at 9:20 (Chair: Richard Van Breemen / Ruben Luo)
Authors: Chia-Ni Lin, I-Wen Wu, Yung-Chang Chen, Yun-Fen Huang, Ya-Ching Huang
Introduction: Uremic toxins are normally excreted in urine via tubular anion organic transporters, but accumulate in chronic kidney disease (CKD) patients. Indoxyl sulphate (IS) and p-cresyl sulphate (pCS) are representative uremic toxins and have been identified as potentially important nephrovascular toxins.
Objectives: The primary objective of this study was to assess whether IS and pCS levels were correlated with CKD stage and used to predict adverse cardiovascular events in CKD patients.
Methods: UPLC-MS/MS method was developed and validated for quantitating IS and pCS in serum. The calibration curves were linear in the range of 0.05–5 mg/L. The three controls were prepared by pooling patient serum samples to reach 0.2, 2, and 4 mg/L separately, and the coefficient of variation ranged from 1.1% to 6.4% within each run (n=20) and 3.6%–10.6% between runs (n=26 ). A total of 45 healthy volunteers and 351 patients at various stages of CKD patients were recruited in this study.
Results: The reference interval was ≤0.05–1.15 mg/L for IS, ≤0.05–5.33 mg/L for pCS. The average IS level was 1.03±0.85 mg/L in CKD stage 1, 1.54±1.11 mg/L in CKD stage 2; 2.22±1.79 mg/L in CKD stage 3; 4.74±4.34 mg/L in CKD stage 4; 18.21±15.06 mg/L in CKD stage 5. The average pCS level was 2.69±4.34 mg/L in CKD stage 1, 4.42±4.47 mg/L in CKD stage2; 6.45±7.12 mg/L in CKD stage 3; 16.10±13.98 mg/L in CKD stage 4; 27.00±17.66 mg/L in CKD stage5. Serum IS and pCS levels in CKD patients were significantly higher than in healthy, and were positively correlated with disease severity. We further studied 147 patients with CKD stage 1-5 over a 3-year follow period and 47 patients had major adverse cardiovascular events (MACEs). Serum IS level was significant associated with MACEs, the area under the receiver operating characteristic curve for IS levels was 0.708 (95% confidence interval : 0.618-0.798).
Conclusions: Accurate measurements of the IS and pCS have not only diagnostic and predictive significance but also important role on CKD treatment. Our sensitive UPLC-MS/MS method for quantifying total and free-form IS and pCS in serum can be used to monitor the progression of CKD in clinical settings, predict adverse cardiovascular events and facilitates better understanding for the development of further therapies for this devastating disease.
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