COVID-19 Vaccination Response in Kidney Transplant Recipients With and Without Mycophenolate Mofetil: Follow-up of a Randomized Controlled Trial.
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ABSTRACT:
SUBMITTER: Al Fatly Z
PROVIDER: S-EPMC8988620 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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COVID-19 Vaccination Response in Kidney Transplant Recipients With and Without Mycophenolate Mofetil: Follow-up of a Randomized Controlled Trial.
Al Fatly Zainab Z Betjes Michiel G H MGH Messchendorp A Lianne AL Sanders Jan-Stephan F JF Reinders Marlies E J MEJ Kho Marcia Mu Lan MML de Weerd Annelies E AE
Kidney international reports 20220407 6
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Project description:Background Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is the immunosuppressive regimen in the majority of solid organ transplant recipients. Gastrointestinal complaints are frequent, which is considered predominantly a side effect of MMF. However, systematic research in this field is lacking. The aim of this study is to systematically investigate the burden of gastrointestinal complaints in TAC-treated kidney transplant recipients with and without MMF. Methods In a single-center, open-label, randomized controlled trial, low immunological risk recipients were randomized to either TAC and MMF or to TAC monotherapy from 6 months after kidney transplantation onwards [NTR4672],. They filled in the Gastrointestinal Symptom Rating Scale questionnaire, which covers five dimensions (abdominal pain, reflux, indigestion, constipation, and diarrhea), 6, 12, and 15 months after transplantation. Results Seventy-nine recipients were randomized and 72 completed all questionnaires (34 TACmono and 38 TAC/MMF). At baseline, the mean age was 59 years with 72% male, mean BMI 28 kg/m2, eGFR 55 ml/min/1.73m2, mean daily dose MMF 1200 mg and TAC 5.8 mg, with trough levels of 2.1 mg/L and 7.4 ug/L. Six months after transplantation, 75% of recipients reported troublesome symptoms (score ≥3). Diarrhea was the most troublesome (mean 3.3) and discontinuing MMF significantly reduced it (mean Δ score between month 6 and 15 TAC/MMF -0.9 vs. TACmono -1.8, p=0.03). In recipients with troublesome symptoms, abdominal pain (2.7 to 1.8, p=0.003), indigestion (2.8 to 2.3, p=0.012), and reflux (2.9 to 1.7, p=0.007) significantly decreased over time, independent of MMF use. Conclusion The majority of kidney transplant recipients with TAC and MMF experienced troublesome gastrointestinal symptoms 6 months after transplantation. While constipation remained troublesome, indigestion, abdominal pain, and reflux improved over time by month 15. Diarrhea only improved after discontinuing MMF.
| S-EPMC10479617 | biostudies-literature
Project description:We compared steady-state pharmacokinetics of mycophenolate mofetil (MMF) - Myfenax(®) (Teva) and CellCept(®) (Roche) - in stable kidney transplant recipients (KTRs). This was an international, multi-centre, randomized, open-label, two-treatment, two-sequence crossover study with a 3-month follow-up. We included KTRs at least 12 months post-transplantation with stable renal graft function for at least 3 months. The maintenance treatment consisted of MMF in combination with tacrolimus with or without steroids. At the end of the two treatment periods, 6-h or 12-h PK studies of mycophenolic acid (MPA) were performed. A total of 43 patients (mean age: 50.7 ± 13.5 years; 19 females, 24 males) were randomized. Estimates of test to reference ratios (90% CIs) were 0.959 (0.899; 1.023) h*μg/ml for AUC((0-tau)) and 0.873 (0.787; 0.968) μg/ml for C(max). Estimates for AUC((0-6h)) were 0.923 (0.865; 0.984) h*μg/ml and 0.985 (0.877; 1.106) μg/ml for C(min). Thus, AUC((0-tau)), AUC((0-6h)), and C(min) of MPA were within the predefined margins. C(max) was somewhat outside of these margins in this set of patients. The numbers and types of adverse events were not different between the two treatments. The steady-state pharmacokinetics of MPA as well as adverse events are comparable for Myfenax(®) and CellCept(®) in tacrolimus-treated stable KTRs.
| S-EPMC3528070 | biostudies-literature
Project description:Modification of vaccination strategies is necessary to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs). This multicenter observational study analyzed the effects of the third SARS-CoV-2 vaccination in previously seronegative KTRs with the focus on temporary mycophenolate mofetil (MMF) dose reduction within propensity matched KTRs. 56 out of 174 (32%) previously seronegative KTRs became seropositive after the third vaccination with only three KTRs developing neutralizing antibodies against the omicron variant. Multivariate logistic regression revealed that initial antibody levels, graft function, time after transplantation and MMF trough levels had an influence on seroconversion (P < .05). After controlling for confounders, the effect of MMF dose reduction before the third vaccination was calculated using propensity score matching. KTRs with a dose reduction of ≥33% showed a significant decrease in MMF trough levels to 1.8 (1.2-2.5) μg/ml and were more likely to seroconvert than matched controls (P = .02). Therefore, a MMF dose reduction of 33% or more before vaccination is a promising approach to improve success of SARS-CoV-2 vaccination in KTRs.
| S-EPMC9539238 | biostudies-literature
Project description:BackgroundThere are no high-quality data to guide long-term mycophenolate mofetil (MMF) dosing in kidney transplant recipients (KTRs) to balance the long-term risks of allograft rejection with that of infections and malignancy. At our center, KTRs are managed with either a "preemptive" dose reduction strategy, where the MMF dose is reduced after the first year before the development of adverse events, or with a "reactive" dosing strategy, where they are maintained on the same MMF dose and only reduced if they develop an adverse event. We hypothesized that a preemptive MMF dosing strategy after the first year of transplantation is associated with decreased infections without increasing alloimmune complications.MethodsWe conducted a retrospective cohort study of all KTRs receiving MMF from January 1, 2015, to December 31, 2020. The primary outcome was the incidence of infections requiring hospitalization.ResultsOne hundred forty-two KTRs met the inclusion criteria, of whom 44 (31%) were in the preemptive group and 98 (69%) were in the reactive group. The median follow-up was 4 y (interquartile range, 3.8-4.0). Multivariable analysis showed that a preemptive MMF dose reduction strategy was associated with a lower risk of infections requiring hospitalization (adjusted hazard ratio = 0.39; 95% confidence interval, 0.16-0.92). There was no difference in graft loss, rejection, or estimated glomerular filtration rate slope.ConclusionsPreemptive MMF dose reduction in KTRs may be an effective strategy to prevent infections without increasing the risk of allograft rejection. Randomized clinical trials are needed to confirm these findings.
| S-EPMC11365660 | biostudies-literature
Project description:BackgroundElderly kidney transplant recipients (KTRs) represent almost one third of the total kidney transplant population. These patients have a very high coronavirus disease 2019 (COVID-19)-related mortality, whereas their response to COVID-19 vaccination is impaired. Finding ways to improve the COVID-19 vaccination response in this vulnerable population is of uttermost importance.MethodsIn the OPTIMIZE trial, we randomly assign elderly KTRs to an immunosuppressive regimen with standard-exposure calcineurin inhibitor (CNI), mycophenolate mofetil, and prednisolone or an adapted regimen with low dose CNI, everolimus, and prednisolone. In this substudy, we measured the humoral response after 2 (N = 32) and 3 (N = 22) COVID-19 mRNA vaccinations and the cellular response (N = 15) after 2 vaccinations.Results. The seroconversion rates of elderly KTRs on a standard immunosuppressive regimen were only 13% and 38% after 2 and 3 vaccinations, respectively, whereas the response rates of KTRs on the everolimus regimen were significantly higher at 56% ( P = 0.009) and 100% ( P = 0.006). Levels of severe acute respiratory syndrome coronaVirus 2 IgG antibodies were significantly higher at both time points in the everolimus group ( P = 0.004 and P < 0.001). There were no differences in cellular response after vaccination.ConclusionsAn immunosuppressive regimen without mycophenolate mofetil, a lower CNI dose, and usage of everolimus is associated with a higher humoral response rate after COVID-19 vaccination in elderly KTRs after transplantation. This encouraging finding should be investigated in larger cohorts, including transplant recipients of all ages.
| S-EPMC9311282 | biostudies-literature
Project description:Impaired kidney function is associated with increased morbidity and mortality in patients undergoing liver transplantation. Although immunosuppressants are essential in these patients, they impair kidney function. This study aimed to compare adverse kidney outcomes between patients treated with a reduced dose of tacrolimus (calcineurin inhibitor) plus sirolimus or mycophenolate mofetil (MMF) in the liver transplant center at Kaohsiung Chang Gung Memorial Hospital between April 2011 and December 2017. Propensity score matching was used to identify 232 patients. The risk of adverse kidney outcomes was estimated using Cox proportional hazards regression, and changes in kidney function over time were analyzed using linear mixed modeling. Acute kidney disease risks in this study cohort were not significantly different for the two immunosuppressants (aHR 1.04; 95% CI: 0.70-1.55, p = 0.8328). However, sirolimus use was significantly associated with a higher risk of estimated glomerular filtration rate decline > 30% than MMF (aHR, 2.09; 95% CI: 1.33-3.28; p = 0.0014). Our results demonstrate that sirolimus use may have worsened long-term kidney outcomes compared to MMF. Close monitoring of kidney function, dose adjustment, and timely transition to MMF is necessary for LT patients receiving sirolimus.
| S-EPMC10457954 | biostudies-literature
Project description:BackgroundWe compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.Methods and findingsATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.ConclusionsIn this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.Trial registrationClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
| S-EPMC8224852 | biostudies-literature
Project description:This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.
| S-EPMC6692323 | biostudies-literature
Project description:AimsVarious mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors.MethodsThe external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated.ResultsFifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models.ConclusionsThe published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.
| S-EPMC6422729 | biostudies-literature
Project description:There are data available in the literature on bioelement concentrations in the serum of various groups of patients; however, very little is known about the serum concentration of selenium (Se), iron (Fe), zinc (Zn), and copper (Cu) in renal transplant patients treated with immunosuppressive drugs, including mycophenolate mofetil (MMF). Monitoring of serum bioelement concentrations in renal transplant recipients is of profound importance, as the proper bioelement levels seem to prolong the normal function of the transplanted organ. Thus, the aim of this current study was to examine and carry out comparative analysis involving serum concentrations of Se, Fe, Cu, and Zn of renal transplant recipients treated with MMF and without MMF. The material consisted of blood samples from 115 patients of the Department of Nephrology, Transplantology, and Internal Medicine of Independent Public Clinical Hospital No. 2, Pomeranian Medical University, in the city of Szczecin in the northwestern Poland. Serum Se, Fe, Cu, and Zn levels were quantified by inductively coupled mass spectroscopy (ICP-MS). Taking into account all patients, MMF increases Cu level. Cu and Fe concentrations were significantly higher in women treated with MMF; in group of younger patients treated with MMF, Se level was significantly lower comparing with those whose regimen did not include MMF. Additionally, MMF in combination with prednisone increased Se concentration in blood of transplant recipients. Our study highlights that trace elements should be monitored to allow for an early detection of trace elements deficits, which can easily be corrected for by an adjusted diet or supplemental intake.
| S-EPMC7561557 | biostudies-literature