Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

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.

Cancer risks in recipients of renal transplants: a meta-analysis of cohort studies.

Renal transplantation is associated with an increased risk of cancers at multiple sites; however, the relationships between increased cancer risk and participant characteristics remain unclear. We searched PubMed, Embase, and the Cochrane Library to identify prospective observational studies performed up to July 2017. Totally 11 prospective studies reported data on 79,988 renal transplant recipients were included. Renal transplant recipients were found to display a higher risk of all cancers (standard incidence ratio [SIR]: 2.89; 95% CI: 2.13-3.91; P < 0.001), gastric cancer (SIR: 1.93; 95% CI: 1.60-2.34; P < 0.001), colon cancer (SIR: 1.85; 95% CI: 1.53-2.23; P < 0.001), pancreatic cancer (SIR: 1.53; 95% CI: 1.23-1.91; P < 0.001), hepatocellular carcinoma (SIR: 2.45; 95% CI: 1.63-3.66; P < 0.001), lung cancer (SIR: 1.68; 95% CI: 1.29-2.19; P < 0.001), thyroid cancer (SIR: 5.04; 95% CI: 3.79-6.71; P < 0.001), urinary bladder cancer (SIR: 3.52; 95% CI: 1.48-8.37; P = 0.004), renal cell cancer (SIR: 10.77; 95% CI: 6.40-18.12; P < 0.001), non-melanoma skin cancer (SIR: 12.14; 95% CI: 6.37-23.13; P < 0.001), melanoma (SIR: 2.48; 95% CI: 1.08-5.67; P = 0.032), Hodgkin's lymphoma (SIR: 4.90; 95% CI: 3.09-7.78; P < 0.001), non-Hodgkin lymphoma (SIR: 10.66; 95% CI: 8.54-13.31; P < 0.001), lip cancer (SIR: 29.45; 95% CI: 17.85-48.59; P < 0.001), breast cancer (SIR: 1.11; 95% CI: 1.00-1.24; P = 0.046), and ovarian cancer (SIR: 1.60; 95% CI: 1.23-2.07; P < 0.001). However, renal transplantation did not significantly influence the risks of uterine cancer (P = 0.171), and prostate cancers (P = 0.188). Our findings suggest that patients who receive renal transplantation have an increased risk of cancer at most sites, apart from uterine and prostate cancers patients.

[Slowing progression of chronic allograft nephropathy by conversion from cyclosporin A to tacrolimus].

OBJECTIVE: To investigate the feasibility and safety of substituting tacrolimus(FK506) for cyclosporin A(CsA) on delaying the pace of renal dysfunction in patients with biopsy-proven chronic allograft nephropathy(CAN). METHODS: Seventy-three renal transplantation patients with CAN proved by allograft biopsy were collected in this study. Patients were randomly divided into 2 groups. Patients were either converted to FK506(FK506 group, n=43) or remained on their initial CsA-based immunosuppression(CsA group, n=30). The clinical data at study entry and after 12 months including blood urea nitrogen(BUN), serum creatinine(SCr), glomerular filtration rate(GFR), 24-hour urine protein excretion, serum total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL) and the side effects of calcineurin inhibitors were monitored during a follow-up of over 12 months. RESULTS: Twelve months later, the level of SCr was statistically reduced and GFR levels were obviously elevated in the FK506 group as compared with CsA group [(194.8+/-42.5)micromol/L vs. (245.4+/-52.8)micromol/L and (50.14+/-3.92)mL/(min.1.73 m(2)) vs. (40.58+/-2.49)mL/(min.1.73 m2), P<0.01]. Quantity of 24-hour urine protein excretion in the FK506 group was (2.0+/-0.5)g which is significantly lower than (3.9+/-0.7)g in the CsA group(P<0.01). TC, TG, and LDL levels remained unchanged in the CsA group, while those were statistically reduced in the FK506 group respectively [(5.19+/-0.73)mmol/L vs. (6.94+/-1.37)mmol/L, (1.86+/-0.84)mmol/L vs. (3.14+/-1.38)mmol/L, (3.03+/-0.71)mmol/L vs. (3.82+/-0.89)mmol/L, P<0.01]. Tremor obviously increased (P<0.01) and hypertension obviously decreased (P<0.05) in the FK506 group compared with the CsA group. CONCLUSION: FK506 treatment can greatly improve the proteinuria and hyperlipidemia. Conversion from CsA to FK506 is an effective and safe alternative therapy for delaying the progression of renal dysfunction induced by CAN.

Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management.

Improved survival following organ transplantation has brought to the forefront some long-term complications, among which osteoporosis and associated fractures are the major ones that adversely affect the quality of life in recipients. The pathogenesis of osteoporosis in transplant recipients is complex and multifactorial which may be related to increased bone resorption, decreased bone formation, or both. Studies have shown that the preexisting underlying metabolic bone disorders and the use of immunosuppressive agents are the major risk factors for osteoporosis and fractures after organ transplantation. And rapid bone loss usually occurs in the first 6-12 months with a significant increase in fracture risk. This paper will provide an updated review on the possible pathogenesis of posttransplant osteoporosis and fractures, the natural history, and the current prevention and treatment strategies concerning different types of organ transplantation.

[Surgical strategy for ectopic kidneys: analysis of 35 cases].

OBJECTIVE: To explore the surgical strategy for ectopic kidney and evaluate the clinical outcomes. METHODS: From January 2000 to October 2009, 35 cases of ectopic kidney were treated surgically in our hospital. Definite diagnoses were established in all the cases by ultrasound, intravenous urography (IVU), cystoscope, CT, magnetic resonance urography (MRU) and radionuclide imaging before the surgery. In these patients, 26 had ipsilateral ectopic ureteral orifice (including 5 with bilateral duplicated kidneys and ureter), 9 had moderate or severe hydronephrosis (including 3 with ectopic kidney calculi), and 24 had dysplastic kidney (24/35). All the patients underwent operations, including 26 with ectopic nephrectomy, 7 with ectopic ureterovesical reimplantation, and 3 with ectopic renal pelvis incision. RESULTS: The clinical effect was satisfactory in all the cases during the follow up of 7 to 29 months. CONCLUSION: Appropriate surgical approaches according to the concurrent deformities and complications can achieve good clinical results in patients with ectopic kidneys.