Area Under Trough Concentrations of Tacrolimus as a Predictor of Progressive Renal Impairment After Liver Transplantation.

BACKGROUND: Tacrolimus minimization is usually restricted to patients with pretransplant renal impairment, and this strategy could result into worse renal outcomes after liver transplantation (LT). METHODS: A consecutive cohort of 455 LT patients receiving tacrolimus-based immunosuppression was studied (2008-2013). Cumulative exposure to tacrolimus was calculated as the area under curve of trough concentrations (AUCtc). Patients were stratified as tacrolimus minimization, conventional, or high exposure, according to the thresholds based in the COMMIT consensus. Estimated glomerular filtration rates (eGFR) were assessed by the Modification of Diet in Renal Disease formula (MDRD-4) up to 5 years after LT. RESULTS: Seventy patients (15.4%) had pretransplant eGFR < 60 mL/min, which was associated with increased mortality rates, particularly within the first 5 years post-LT (31.4% versus 17.5%; Breslow P = 0.010). After LT, there was an abrupt eGFR decline within the first 3 months (median 18.6 mL/min; P < 0.001), further decreasing up to 12 months (additional 3 mL/min), without any improvement thereafter. According to AUCtc, 33.7% of patients received tacrolimus minimization, 44.8% conventional exposure, and 21.5% high exposure. Conventional/high exposure to tacrolimus resulted in a more pronounced eGFR decline within the first 3 months when compared with minimization (23.3 mL/min versus 9.5 mL/min; P < 0.001). This gap was even higher in patients with initially preserved renal function. Tacrolimus AUCtc was an independent predictor of eGFR decline within the first 3 months after controlling for potential confounders. CONCLUSIONS: AUCtc is a surrogate of cumulative exposure to tacrolimus and may be helpful for routine dose adjustments. Tacrolimus minimization should be universally attempted after LT to preserve renal function.

Evaluation of the Novel Methotrexate Architect Chemiluminescent Immunoassay: Clinical Impact on Pharmacokinetic Monitoring.

BACKGROUND: Fluorescence polarization immunoassay (FPIA) has probably been the most widely used technique for the determination of methotrexate (MTX) concentrations in clinical laboratories. After its replacement by a novel architect chemiluminescent microparticle immunoassay (CMIA), it is essential to verify that there are no differences between the methods that can induce an error in leucovorin rescue with dire consequences for the patient. The objective of our study was to compare plasma/serum MTX measurements between CMIA and FPIA (reference method in this study) in the work conditions of a clinical pharmacokinetics unit to determine whether any difference would affect clinical decisions on the management of this drug. METHODS: FPIA on TDx/FLx and CMIA on Architect ci8200 were simultaneously used to evaluate 127 clinical samples. Within-run (20 repetitions on same day) and between-run (20 repetitions on different days) imprecision was evaluated using 6 control samples provided by the manufacturer and diluting 2 of them by 50% for 0.03 and 0.22 µmol/L, respectively. The Passing-Bablok regression method, Bland-Altman plot, and concordance correlation coefficient (CCC) were used in the statistical analysis. RESULTS: Within-run imprecision was <5% (3.6%-4.39%) and between-run imprecision <11% (2.42%-10.65%). Between-assay correlation for the studied concentration range (0.05-250 µmol/L) was CMIA = -0.026 + 1.033 FPIA (n = 127), r = 0.9963, and CCC = 0.9946. For samples <1.5 µmol/L (nondiluted) included in the assay calibration curve, the correlation was CMIA = -0.009 + 0.955 FPIA (n = 54), r = 0.9819, and CCC = 0.9807. No significant difference was observed between the measurements by the 2 assays, given that the 95% confidence interval of the ordinate at the origin included "0" (-0.020 to 0.0007), and the 95% confidence interval of the slope included 1 (0.923-1.020). The interchangeability of these assays was confirmed by Bland-Altman plot results, which showed a mean difference insignificant at concentrations <10 µmol/L. CONCLUSIONS: The correlation between methods was excellent, and Passing-Bablok regression analysis detected no virtually difference in their results. Utilization of the CMIA-Architect assay to measure MTX concentrations would therefore not affect clinical decisions on MTX management, supporting its employment in routine MTX monitoring.