This is the first report demonstrating that ABCB1 polymorphisms influence cyclosporine intracellular concentration. Interestingly, its influence on intracellular concentration is significantly higher than on blood concentration (P<0.002). This may therefore modulate cyclosporine immunosuppressive activity.
Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight (P < 0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.
tients in the Grossberg study) is unjustifiable.Furthermore, the results by quintile presented in Table 1, abstracted from text in the Grossberg paper and corrected by the corresponding author, indicate that the proportion of patients with predicted probability less than 0.20 is 0.065 (95% confidence interval: 0.028 -0.102). This is in sharp contrast to the proportion of patients with predicted probability less than 0.20 calculated from Irish and colleagues, 0.453. Because the predicted probability is conditional on observed covariates measured at time of transplantation (e.g., donor age and cold ischemia time), any difference in predicted probability is related to differences in study sample characteristics. Thus, the sample used by Grossberg cannot be used to validate or disprove the Irish DGF nomogram.The authors conclusion that the Irish nomogram is "weakly predictive" is based on misinterpretation of the numeric degree of difference between mean values.The mean difference between the DGF group and the No-DGF group is reported as 0.04. If we multiply the DGF risk score by 1,000, for example, then the mean difference between the two groups is 40. Although the magnitude of the difference has increased 1,000-fold, the sensitivity and specificity of the model, or its ability to discriminate, have not changed.Thus, we believe that, based on inappropriate use of validation methods and disparate study sample characteristics, the Grossberg study does not invalidate the Irish DGF nomogram. The Irish DGF nomogram remains useful for prediction of the likelihood of DGF but not its absolute occurrence.
In elective cases of surgery with CPB and hypothermia, temperature-dependent differential serum cryoprecipitation profile may be an easy and efficient way to assess a safe peroperative level of temperature to avoid complications due to cryoglobulins, without enhancing the patient's tissue ischemia risks.
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