Tacrolimus Formulations and African American Kidney Transplant Recipients: When Do Details Matter?

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From Nonadherence to Adherence

Medication nonadherence (MNA) after solid organ transplantation is highly prevalent and associated with (late) (sub)clinical acute rejection, graft dysfunction and graft loss, development of donor-specific anti-HLA antibodies, and antibody-mediated rejection. MNA is predominantly unintentional and originates from barriers to adherence that are often multifactorial and complex. Tools to establish an early diagnosis of MNA include incorporation of MNA as a vital sign in daily clinical practice, self-reporting using validated questionnaires, calculating intrapatient variability in drug exposure and applying electronic monitoring, and recent audio and video technologies such as in home telemonitoring. MNA is a modifiable risk factor after organ transplantation, and treatment is most effective if a multimodal approach is used. Management of MNA comprises education (cognitive) and counseling (behavioral) that require the involvement of a trained multidisciplinary team [ideally physician, nurse (specialist), social worker, transplant coordinator, psychologist, clinical pharmacist], electronic reminder and support systems (eg, Medication Event Monitoring System, smartphone), and different types of novel mobile health applications as well as simplification of the medication dosing regimen. Future studies that evaluate novel therapeutic approaches for MNA should assure the use of reliable MNA measures, focus on multimodal individualized therapy for enriched nonadherent target populations (eg, adolescents), and incorporate clinically relevant endpoints. Costs, time, and personnel investments should be taken into account when assessing scalability and cost-effectiveness of novel therapeutic strategies. This review provides suggestions how different types of transplant centers can set up a dedicated MNA program according to available resources to define and achieve realistic clinical goals in managing MNA.status: publishe

Determinants of the magnitude of interaction between tacrolimus and voriconazole/posaconazole in solid organ recipients

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n=100) or posaconazole (n=26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus - azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, P=0.017) and affected by hematocrit (+8% per %, P=0.004), baseline C/D (-14% per 100% increase, P<0.001) and age (+1%, P=0.008). However, the final model explained only 22% of inter-individual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus - azole interaction, but these did not permit accurate predictions in individual patients This article is protected by copyright. All rights reserved.status: publishe

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.status: publishe

Dose-dependent therapeutic effects of FK506 on dopaminergic neurodegeneration and neuroinflammation in a viral vector-based α-synuclein rat model for Parkinson’s disease

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High rates of denitrification and nitrous oxide emission in arid biological soil crusts from the Sultanate of Oman

Using a combination of process rate determination, microsensor profiling and molecular techniques, we demonstrated that denitrification, and not anaerobic ammonium oxidation (anammox), is the major nitrogen loss process in biological soil crusts from Oman. Potential denitrification rates were 584±101 and 58±20??mol N?m?2?h?1 for cyanobacterial and lichen crust, respectively. Complete denitrification to N2 was further confirmed by an 15NO3? tracer experiment with intact crust pieces that proceeded at rates of 103±19 and 27±8??mol N?m?2?h?1 for cyanobacterial and lichen crust, respectively. Strikingly, N2O gas was emitted at very high potential rates of 387±143 and 31±6??mol N?m?2?h?1 from the cyanobacterial and lichen crust, respectively, with N2O accounting for 53–66% of the total emission of nitrogenous gases. Microsensor measurements revealed that N2O was produced in the anoxic layer and thus apparently originated from incomplete denitrification. Using quantitative PCR, denitrification genes were detected in both the crusts and were expressed either in comparable (nirS) or slightly higher (narG) numbers in the cyanobacterial crusts. Although 99% of the nirS sequences in the cyanobacterial crust were affiliated to an uncultured denitrifying bacterium, 94% of these sequences were most closely affiliated to Paracoccus denitrificans in the lichen crust. Sequences of nosZ gene formed a distinct cluster that did not branch with known denitrifying bacteria. Our results demonstrate that nitrogen loss via denitrification is a dominant process in crusts from Oman, which leads to N2O gas emission and potentially reduces desert soil fertility