Aims: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections.Methods: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed‐effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model.Results: A one‐compartment model with first‐order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h⁻¹, 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily.Conclusions: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.

Background: The relationship between vitamin E supplementation and the prevalence of chronic kidney disease (CKD) is unclear. We discussed the relationship between vitamin E intake and CKD prevalence and further investigated the effect on different CKD risk strata. Methods: We ultimately included 20 295 participants from the National Health and Nutrition Examination Survey (NHANES) database from 2009 to 2016. Multiple logistic regression and restricted cubic splines (RCS) were applied to explore the relationship between vitamin E intake and CKD prevalence and risk stratification. Subgroup analysis was applied to assess the stability of the association between vitamin E intake and CKD. Results: In the CKD prevalence study, we found a negative association between high vitamin E intake and CKD prevalence through an adjusted multiple logistic regression model, the odds ratio (OR) was 0.86 [95% confidence interval (CI) 0.74–1.00; P for trend = .041] and RCS showed a nonlinear negative correlation (P-nonlinear = .0002, <.05). In the CKD risk stratification study, we found that in very high–risk patients, the OR was 0.51 (95% CI 0.32–0.84; P for trend = .006) and the RCS also showed a nonlinear negative correlation (P-nonlinear <.0001, <.05). Subgroup analysis demonstrated that the correlations were stable across populations (P-values >.01 for all interactions). Conclusion: Dietary vitamin E intake was negatively associated with the prevalence of CKD in US adults. Increased vitamin E intake was a protective factor across CKD risk strata, and as vitamin E intake increased, there was a non-linear downward trend in the proportion progressing to very high–risk CKD.

Objectives: Significant increase in tacrolimus exposure was observed during co-administration with voriconazole, and no population pharmacokinetic model exists for tacrolimus in renal transplant recipients receiving voriconazole. To achieve target tacrolimus concentrations, an optimal dosage regimen is required. This study aims to develop individualized dosing parameters through population pharmacokinetic analysis and simulate tacrolimus concentrations under different dosage regimens.Methods: We conducted a retrospective study of renal transplant recipients who were hospitalized at the Second Xiangya Hospital of Central South University between January 2016 and March 2021. Subsequently, pharmacokinetic analysis and Monte Carlo simulation were employed for further analysis.Results: Nineteen eligible patients receiving tacrolimus and voriconazole co-therapy were included in the study. We collected 167 blood samples and developed a one-compartment model with first-order absorption and elimination to describe the pharmacokinetic properties of tacrolimus. The final typical values for tacrolimus elimination rate constant (Ka), apparent volume of distribution (V/F), and apparent oral clearance (CL/F) were 8.39 h⁻¹, 2690 L, and 42.87 L/h, respectively. Key covariates in the final model included voriconazole concentration and serum creatinine. Patients with higher voriconazole concentration had lower tacrolimus CL/F and V/F. In addition, higher serum creatinine levels were associated with lower tacrolimus CL/F.Conclusion: Our findings suggest that clinicians can predict tacrolimus concentration and estimate optimal tacrolimus dosage based on voriconazole concentration and serum creatinine. The effect of voriconazole concentration on tacrolimus concentration was more significant than serum creatinine. These findings may inform clinical decision-making in the management of tacrolimus and voriconazole therapy in solid organ transplant recipients.

The exact mechanism of graft dysfunction has not been fully clarified. We aimed to explore the causal effects of serum metabolites on graft dysfunction and the mediating role of inflammatory proteins. We first analyzed the causal association of 1,091 serum metabolites and 91 inflammatory proteins with graft dysfunction by Mendelian randomization (MR) to find the most important indicators and calculated the mediating role of inflammatory proteins. Second, we further intergrated the single-cell analysis, machine learning, and Shapley Additive exPlanations (SHAP) methods to validate the role of the inflammatory protein in rejected transplanted kidneys. In MR analysis, the inverse variance weighted (IVW) method showed that N-acetylaspartyl glutamate (NAAG) levels reduced the risk of graft dysfunction (OR 0.648, 95% CI 0.522-0.805). Interleukin-2 receptor subunit beta (IL-2RB) mediated the association between NAAG and graft dysfunction with a mediation ratio of 11.35% (95% CI 1.85%-24.69%). In transplanted kidneys, IL-2RB is predominantly expressed elevated in T cells from rejection samples and is associated with decreased renal function. 10 hub genes were identified based on T cells with high and low expression of IL-2RB, of which NGboost reached AUC 0.77. The SHAP method obtained the gene with the greatest model contribution: the IL-2RB gene. NAAG plays a protective role in graft dysfunction, and part of the effect is mediated by inhibition of IL-2RB, which is verified as an important gene that functions in transplant kidney rejection. NAAG and IL-2RB may be novel molecular markers and therapeutic targets for graft dysfunction.