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Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant.

ABSTRACT: AIMS:Nephrotoxicity of calcineurin inhibitors (CNIs) is associated with adverse events in patients undergoing heart transplant (HTx), although studies directly comparing tacrolimus (TAC) versus cyclosporin A (CsA), especially in combination with everolimus and low-dose CNIs approach, are limited. Thus, we sought to investigate the associations of TAC and CsA with clinical outcomes in HTx recipients, with specific focus on renal function. METHODS AND RESULTS:From August 2007 to February 2017, 72 consecutive patients (39 treated with TAC vs. 33 with CsA) receiving de novo HTx in a single transplant centre were retrospectively evaluated. We used the instrumental variable method to account for unmeasured confounding. The study outcomes were percentage change in estimated glomerular filtration rates (eGFR) (safety endpoint) and biopsy-proven acute rejection (efficacy endpoint) within the first year after HTx. The enrolled patients (median age 40 years) were predominantly men (68%). There were no significant differences in baseline characteristics, including eGFR (64.8 [45.7-96.4] mL/min/1.73 m2 in TAC vs. 65.6 [57.9-83.0] mL/min/1.73 m2 for CsA; P = 0.48), other than sex (male, 49% for TAC vs. 91% for CsA; P < 0.001) between the two groups. Within the first year after HTx, 23 (59%) in the TAC group switched mycophenolate mofetil to everolimus, whereas 16 (48%) in the CsA group (P = 0.52). At 12 months, the rates of mortality and end-stage renal disease requiring renal replacement therapies were both 0%. In the instrumental variable analysis, no differences in renal function as well as graft rejection for 1 year after HTx existed between the TAC and CsA groups. These results were similar when taking into account of everolimus use. CONCLUSIONS:Irrespective of everolimus use with low-dose CNIs, our analysis using the instrumental variable method showed no differences in renal function as well as graft rejection during the first year after HTx between HTx recipients who received TAC or CsA.

SUBMITTER: Shiraishi Y

PROVIDER: S-EPMC7373882 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant.

Shiraishi Yasuyuki Y Amiya Eisuke E Hatano Masaru M Katsuki Toshiomi T Bujo Chie C Tsuji Masaki M Nitta Daisuke D Maki Hisataka H Ishida Junichi J Kagami Yukie Y Endo Miyoko M Kimura Mitsutoshi M Ando Masahiko M Shimada Shogo S Kinoshita Osamu O Ono Minoru M Komuro Issei I

ESC heart failure 20200523 4

<h4>Aims</h4>Nephrotoxicity of calcineurin inhibitors (CNIs) is associated with adverse events in patients undergoing heart transplant (HTx), although studies directly comparing tacrolimus (TAC) versus cyclosporin A (CsA), especially in combination with everolimus and low-dose CNIs approach, are limited. Thus, we sought to investigate the associations of TAC and CsA with clinical outcomes in HTx recipients, with specific focus on renal function.<h4>Methods and results</h4>From August 2007 to Feb ...[more]

PMID: 32445260

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Project description:PurposeCYP3A5 genotype is a significant contributor to inter-individual tacrolimus exposure and may impact the time required to achieve therapeutic concentrations and number of tacrolimus dose adjustments in transplant patients. Increased modifications to tacrolimus therapy may indicate a higher burden on healthcare resources. The purpose of this study was to evaluate whether CYP3A5 genotype was predictive of healthcare resource utilization in pediatric renal and heart transplant recipients.Patients and methodsPatients <18 years of age with a renal or heart transplant between 6/1/2014-12/31/2018 and tacrolimus-based immunosuppression were included. Secondary use samples were obtained for CYP3A5 genotyping. Clinical data was retrospectively collected from the electronic medical record. Healthcare resource utilization measures included the number of dose changes, number of tacrolimus concentrations, length of stay, number of clinical encounters, and total charges within the first year post-transplant. Rejection and donor-specific antibody (DSA) formation within the first year were also collected. The impact of CYP3A5 genotype was evaluated via univariate analysis for the first year and multivariable analysis at 30, 90, 180, 270, and 365 days post-transplant.ResultsEighty-five subjects were included, 48 renal transplant recipients and 37 heart transplant recipients. CYP3A5 genotype was not associated with any outcomes in renal transplant, however, a CYP3A5 expresser phenotype was a predictor of more dose changes, more tacrolimus concentrations, longer length of stay, and higher total charges in heart transplant recipients. CYP3A5 genotype was not associated with rejection or DSA formation. Age and induction therapy were associated with higher total charges.ConclusionCYP3A5 genotype may predict healthcare resource utilization in the first year post-transplant, although this may be mitigated by differences in tacrolimus management. Future studies should evaluate the impact of genotype-guided dosing strategies for tacrolimus on healthcare utilization resources.

Project description:Key Points eGFR at 1 year post transplant is an established predictor of graft failure, but the effects of major intercurrent events are not fully known. We assessed the link between 12-month eGFR and long-term graft failure accounting for intercurrent events and competing mortality risks. Acute rejection, cardiovascular events, and infectious events were significant risks; 12-month eGFR remained the dominant driver of graft failure. Visual Abstract Background Estimated glomerular filtration rate (eGFR) at 1 year post transplantation has been shown to be a strong predictor of long-term graft survival. However, intercurrent events (ICEs) may affect the relationship between eGFR and failure risk. Methods The OPTN and USRDS databases on single-organ kidney transplant recipients from 2012 to 2016 were linked. Competing risk regressions estimated adjusted subhazard ratios (SHRs) of 12-month eGFR on long-term graft failure, considering all-cause mortality as the competing risk, for deceased donor (DD) and living donor (LD) recipients. Additional predictors included recipient, donor, and transplant characteristics. ICEs examined were acute rejection, cardiovascular events, and infections. Results Cohorts comprised 25,131 DD recipients and 7471 LD recipients. SHRs for graft failure increased rapidly as 12-month eGFR values decreased from the reference 60 ml/min per 1.73 m2. At an eGFR of 20 ml/min per 1.73 m2, SHRs were 13–15 for DD recipients and 12–13 for LD recipients; at an eGFR of 30 ml/min per 1.73 m2, SHRs were 5.0–5.7 and 5.0–5.5, respectively. Among first-year ICEs, acute rejection was a significant predictor of long-term graft failure in both DD (SHR=1.63, P<0.001) and LD (SHR=1.51, P=0.006) recipients; cardiovascular events were significant in DD (SHR=1.24, P<0.001), whereas non-CMV infections were significant in the LD cohort (SHR=1.32, P=0.03). Adjustment for ICEs did not significantly reduce the association of eGFR with graft failure. Conclusions Twelve-month eGFR is a strong predictor of long-term graft failure after accounting for clinical events occurring from discharge to 1 year. These findings may improve patient management and clinical evaluation of novel interventions.

Project description:AIMS:Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUCss,0-12h ). METHODS:All recipients receiving tacrolimus and mycophenolic acid ?6 months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients. RESULTS:Dose-normalized tacrolimus AUCss,0-12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose-normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error < 10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%). CONCLUSIONS:Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUCss,0-12h and clearance. Skin changes and acne were associated with dose-normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUCss,0-12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.

Project description:Background:Prevalence of immunosuppressant nonadherence in renal transplant recipients is high despite negative clinical outcomes associated with nonadherence. Simplification of dosing has been demonstrated to improve adherence in renal transplant recipients as measured through electronic monitoring and self-report. Objective:The purpose of this study was to replicate and extend previous findings by measuring adherence with multiple methods in a Canadian sample. Design:The study design was a randomized controlled medication dosing trial in adult renal transplant patients. The trial length was 4 months. Setting:This study was conducted within the Solid Organ Transplant (SOT) Clinic at Vancouver General Hospital (VGH; Vancouver, Canada). Patients:A total of 46 adult renal recipients (at least 1 year post-transplant) were recruited through the SOT clinic. With 8 withdrawals, 38 individuals completed all phases of the study. Measurements:Medication adherence was measured for a period of 4 months using multiple methods, including electronic monitoring (MEMS [Medication Event Monitoring System]), pharmacy refill data (medication possession ratio [MPR]), and by self-report using the Adherence subscale of the Transplant Effects Questionnaire (TEQ). Methods:Participants were randomized to twice-daily (n = 19) or once-daily tacrolimus dosing (n = 19) and followed over a 4-month period via monthly clinic study visits. Comparisons between the treatment groups were performed using the Mann-Whitney U and chi-square tests, for continuous and categorical variables, respectively. Results:As outlined in Table 3, the once-daily dosing group showed significantly better MEMS Dose Adherence (P = .001), whereas MEMS Timing Adherence showed a tendency toward better adherence for this group, but was not significant (P = .052). MEMS Days Adherent (P = .418), MPR% (P = .123), and self-reported adherence (P = .284) did not differ between the once- and twice-daily dosing groups when measured as continuous variables. The MPR% was significantly better for the once-daily dosing group when measured dichotomously but not continuously (P = .044). Notably, most of those exposed to once-daily dosing (63.2%) preferred this to the twice-daily regimen. Limitations:Limitations included small sample size and short follow-up period, precluding the examination of clinical outcome differences. Conclusions:Results for dose adherence replicate the finding that dose simplification increases adherence to immunosuppressants as measured through electronic monitoring. Such an advantage for the once-daily dosing group was not seen across the 2 other electronic monitoring measurement variables (days and timing adherence). This study extends previous research by examining adherence in once versus twice-daily dosing via prescription refill data in a Canadian sample. Given the gravity of potential health outcomes associated with nonadherence, although results indicate inconsistencies in significance testing across measurement methods, the medium to large effect sizes seen in the data favoring better adherence with once-daily dosing provide an indication of the potential clinical significance of these findings. Trial registration:This study was registered with ClinicalTrials.gov (NCT01334333) on April 11, 2011.

Dataset Information

Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant.

Publications

Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant.

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