Everolimus In Kidney Transplant Recipients Research Articles

Replacing Mycophenolate Mofetil by Everolimus in Kidney Transplant Recipients to Increase Vaccine Immunogenicity: The PREPARE-iVAC Trial

Replacing Mycophenolate Mofetil by Everolimus in Kidney Transplant Recipients to Increase Vaccine Immunogenicity: The PREPARE-iVAC Trial

Medication adherence in kidney transplant recipients: A cross-sectional study from a nursing clinical practice perspective

Medication non-adherence is implicated as one of the major causes of early and late kidney transplant rejection. The present study aimed to evaluate medication adherence in kidney transplant recipients. The study design was cross-sectional and descriptive. The sample was 144 kidney transplant patients, and sampling was by convenience. The researchers collected data using a three-part questionnaire, including demographic characteristics, clinical features, and simplified medication adherence questionnaire (SMAQ). Findings suggest that medication adherence in participants was at the desired level (94.4%; 95% CI: 89.8-97.3; P<0.001) and the number of hospitalizations was a predictor of medication adherence in kidney transplant recipients (95% CI: 0.236-1.009; OR:0.488; P=0.053). The mean serum levels of Tacrolimus, Sirolimus, Cyclosporine, and Everolimus in kidney transplant recipients were 8.22 (SD=4.75), 59.66 (SD=82.71), 138.25 (SD=74.99), and 5.7, respectively. Glomerular filtration rate and serum levels of Tacrolimus and Cyclosporine were higher in patients with appropriate medication adherence than those with poor medication adherence (P>0.05). With the increasing number of hospitalizations, medication adherence in these patients decreased. Overall, the medication adherence in kidney transplant recipients at the Kidney Transplantation Referral Center was at the desired level. Therefore, medicating related training programs are a promising approach to improve the quality of life in kidney transplant recipients and potentially reduce the incidence of transplant rejections among kidney transplant patients.

Evaluation of factors influencing the ratio of the trough blood concentration to dose level of everolimus in Japanese kidney transplant recipients

BackgroundNo factors influencing the blood everolimus (EVL) concentrations has been identified until date. Our aim was to identify factors that can affect the ratio of the trough blood concentration to dose level (C0/D ratio) of EVL in kidney transplant recipients. MethodsWe retrospectively analyzed 448 patients who had undergone kidney transplantation and were subsequently being managed as our hospital between 2011 and 2015. Multivariate analysis were performed in an attempt to identify factors affecting the EVL C0/D ratio. ResultsThe numbers of patients receiving calcineurin inhibitor (CNI)-free regimen and regimen containing cyclosporine (CsA) or tacrolimus (TAC) were 47, 137 and 264 respectively. The EVL C0/D ratio did not differ significantly between the TAC(+) group and the CNI-free group, while it was significantly higher in the CsA(+) group than the TAC(+) group (p < 0.0001) and CNI-free group (p = 0.0003). In the multivariate analysis, age, gender, diabetes mellitus as a cause of the end-stage renal disease (ESRD), CsA, serum creatinine, and hemoglobin were selected as factors affecting the EVL C0/D ratio (R2 = 0.269, p < 0.0001). Using the stepwise method, although mycophenolate mofetil treatment was selected, did not differ significantly according to multiple linear regression analysis. Furthermore, concomitant use of CsA was identified as the most impactful factor, based on the standardized partial regression coefficients (β = 0.341). ConclusionsWe obtained an indication of patient characteristics that influences the EVL C0/D ratio. But the accuracy of the regression equation obtained from multiple regression analysis was poor (R2 = 0.269), and it was not accurate enough to predict the EVL C0/D ratio and use it for therapeutic drug monitoring.

Evidence-based practice: Guidance for using everolimus in combination with low-exposure calcineurin inhibitors as initial immunosuppression in kidney transplant patients.

The mammalian target of rapamycin (mTOR) inhibitor, everolimus, in combination with reduced-exposure calcineurin inhibitor (CNI), has been demonstrated in clinical trials to have comparable efficacy in low-to-moderate immunological risk kidney transplant recipients to the Standard of Care, mycophenolic acid (MPA) in combination with standard-exposure CNI. Current treatment guidelines consider mTOR inhibitors to be a second-line therapy in the majority of cases; however, given that everolimus-based regimens are associated with a reduced rate of viral infections after transplantation, their wider use could have great benefits for kidney transplant patients. In this evidence-based practice guideline, we consider the de novo use of everolimus in kidney transplant recipients. The main outcomes of our consideration of the available evidence are that: 1. Everolimus, in combination with reduced-exposure CNI and low dose steroids, is a suitable regimen for the prophylaxis of kidney transplant rejection in the majority of low-to-moderate immunological risk adult patients, with individualized management; 2. Induction with either basiliximab or rabbit anti-thymocyte globulin is an effective therapy for kidney transplant recipients when initiating an everolimus-based, reduced-exposure CNI regimen; and 3. An individualized approach should be adopted when managing kidney transplant recipients on everolimus-based therapy.

Conversion to Everolimus in Kidney Transplant Recipients With Calcineurin Inhibitor-Induced Nephropathy: 3 Case Reports

BackgroundCalcineurin inhibitors (CNIs), which remain the most important immunosuppressants in kidney transplant recipients, are a major cause of renal dysfunction due to CNI-induced nephropathy. However, a safe and effective CNI-sparing protocol is yet to be established. Herein, we report a case series of kidney transplant recipients experiencing CNI nephropathy, whose renal function is improved after conversion from CNIs to everolimus. CasesThe 3 kidney transplant recipients included in this study were diagnosed with CNI arteriolopathy by episode biopsy between 9 months and 11 years after transplantation. All patients received triple immunosuppressive therapy consisting of CNI (tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. All allografts were transplanted from elderly living donors to ABO-compatible and donor-specific antibody-negative recipients. All allograft biopsy specimens exhibited CNI arteriolopathy with alternative quantitative criteria for hyaline arteriolar thickening (aah score: 2 or 3), according to the Banff classification; however, histopathologic assessment did not show any evidence of allograft rejection. Conversely, total dose and blood concentrations of CNIs were within appropriate ranges. After conversion from CNIs to everolimus (1.5 mg/day, twice daily; trough level, 3–5 ng/mL), serum creatinine levels returned to baseline levels measured before the diagnosis of CNI arteriolopathy. In all patients, renal allograft function remained stable, with no evidence of donor-specific antibodies, 1 year after conversion from CNIs to everolimus. ConclusionConversion from CNIs to everolimus can safely and effectively improve renal function in kidney transplant recipients experiencing CNI-induced nephropathy.

Everolimus in kidney transplant recipients at high cardiovascular risk: a narrative review.

Kidney transplant recipients (KTRs) are at increased risk of cardiovascular (CV) morbidity and mortality, and side effects induced by immunosuppressive therapy may be a major contributor to this risk, together with traditional CV risk factors. Many strategies have been considered in order to reduce CV risk in KTRs, such as steroid and/or calcineurin inhibitor (CNI) minimization, but current data are inconclusive. The introduction of mammalian target of rapamycin (mTOR) inhibitors, the cornerstone of CNI minimization, in the immunosuppressive protocol may reduce both the incidence and severity of CNI-associated side effects; however, whether this strategy has an impact on CV risk after kidney transplantation needs to be evaluated. To this end, a panel of Italian experts in the field of transplantation was convened in a series of meetings to assess the current literature on the potential of the mTOR inhibitor everolimus as a cardioprotective agent. This narrative review summarizes the panel's round-table discussions and provides recommendations for CV risk management in KTRs.

Introduction of everolimus in kidney transplant recipients at a late posttransplant stage.

This minireview focuses on the current knowledge about the introduction of everolimus (EVL), a mammalian target of rapamycin inhibitor, with calcineurin inhibitor (CNI) elimination or minimization in kidney transplant recipients at a late posttransplant stage. Within, we have summarized two major clinical trials, ASCERTAIN and APOLLO, and seven other retrospective or nonrandomized studies. In the open-label multicenter ASCERTAIN study, the estimated glomerular filtration rate (eGFR) at 24 mo after conversion was not significantly different between three groups-EVL with CNI elimination, CNI minimization and continued CNI unchanged-at a mean of 5.4 years after transplantation. However, recipients with baseline creatinine clearance higher than 50 mL/min had a greater increase in measured GFR after CNI elimination. In the open-label multicenter APOLLO study, adjusted eGFR within the on-treatment population was significantly higher in the EVL continuation group than in the CNI continuation group at 12 mo after conversion at a mean of 7 years posttransplantation. Other studies on recipients without adverse events and already having satisfactory renal function showed favorable graft function by EVL late-induction with CNI elimination or reduction. These studies showed that chronic allograft nephropathy, CNI nephrotoxicity, CNI arteriolopathy, cancer and viral infection (especially cytomegalovirus infection) may be good indications for late conversion to EVL.

Effects of Atorvastatin on the Pharmacokinetics of Everolimus Among Kidney Transplant Recipients

BackgroundHyperlipidemia occurs in up to 50% of kidney transplant (KT) recipients who take everolimus (EVL). As a result of this, statins are the most commonly prescribed lipid-lowering drugs among these patients. However, we are concerned whether there are any drug interactions between EVL and statins, because both of these drugs use the same pharmacokinetics pathway. Therefore, we assessed the effects of concomitant use of EVL and atorvastatin. MethodsIn this randomized, open-label, crossover study, 20 KT patients were assigned (1:1) to receive EVL with or without 20 mg atorvastatin for 1 month. One-month washout period was used before crossover. Plasma EVL concentrations were measured by homogeneous particle-enhanced turbidimetric immunoassay. Twelve-hour area under the time-concentration curve (AUC0–12) of EVL was calculated with the use of whole-blood EVL concentrations from 10 different time points (0, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, and 12 hours). ResultsThe mean (SD) AUC0–12 for EVL and EVL plus atorvastatin was 155.9 (41.6) ng·h/mL and 151.3 (51.4) ng·h/mL, respectively (P > .05; paired t test). No difference of EVL Cmax or Tmax was found after atorvastatin coadministration. Even though the EVL AUC0–12 levels were not affected by atorvastatin coadministration in one-half of the subjects, for the rest of the patients, there were unpredictable changes in the EVL AUC0–12 levels. This may be due to the high intrapatient variability of EVL drug concentration (coefficient of variation ranges from 9.8% to 34.1%). ConclusionsCoadministration of atorvastatin with EVL in KT recipients did not affect the pharmacokinetics of EVL.

Conversion to Everolimus in Kidney Transplant Recipients: To Believe or Not Believe?

IntroductionImmunosuppression with calcineurin inhibitors (CNI) in renal transplantation is associated with chronic graft dysfunction, increased cardiovascular risk, and malignancies. Everolimus (EVR) appears to permit a CNI-sparing regimen among stable kidney recipients. AimThe aim of this study was to analyze the efficacy and safety of conversion from CNI to EVR. Material and MethodsThis was a retrospective registry-based study of all kidney transplant recipients converted from CNI to EVR between 2006 and 2010. One hundred fifty-one patients, including 69.5% males and with an overall mean age of 50.2 ± 12.7 years, underwent conversion to EVR at 37.0 ± 49.8 (16) months after transplantation with 33.7% during the first 6 months. Reasons for conversion included: CNI nephrotoxicity prevention (54.3%), chronic graft dysfunction (25.8%), malignant tumors (10.6%), CNI-adverse reactions (6.6%), and biopsy-proven CNI nephrotoxicity (2.6%). During a follow-up of 17.9 ± 9.9 months (range, 6–58.5), 18 patients (11.9%) were reconverted to CNI, 2 died with functioning grafts, and 2 lost kidney function. ResultsWe observed a significant (P < .001) increase in estimated glomerular filtration rate–Modification of Diet in Renal Disease (eGFR-MDRD) by 11.3% within 6 months: 56.7 ± 22.1 to 64.1 ± 23.4 mL/min/1.73 m2. At final evaluation it was 13.7%, namely, to 65.5 ± 23.0 mL/min/1.73 m2. At the end of follow-up the proportion of patients with >300 mg/d proteinuria increased from 7.9% to 23.3% (P = .001). Dyslipidemia prevalence increased from 69.5% to 77.5% (P = not significant [NS]) and arterial hypertension increased from 49% to 65.9% (P < .001) at the end of follow-up. Other reported side effects included oral ulcers (2.6%), edema (5.3%), interstitial pneumonitis (1.3%), and toxic hepatitis (1.3%), some of them leading to EVR discontinuation. ConclusionIn our population, renal function improved significantly after conversion from CNI to EVR. Although side effects were common, most were mild, withdrawal of EVR was necessary in a low percentage of cases. EVR appears to be an effective, safe alternative to CNI for maintenance therapy in selected kidney transplant recipients.

Conversion from sirolimus to everolimus in kidney transplant recipients receiving a calcineurin‐free regimen

Everolimus (EVL) and sirolimus (SRL) were introduced into immunosuppressive regimens, in an attempt to replace or reduce the dose of the nephrotoxic calcineurin inhibitors (CNI). In our institution, due to an administrative decision, conversion from SRL to EVL, was carried out, providing us the opportunity to investigate the effectiveness and safety profile of both drugs and to review the practical conversion dose between them. We retrospectively analyzed the medical records of 51 maintenance kidney transplant recipients receiving an SRL-based CNI-free regimen, who were switched to EVL. SRL dose was concentration controlled to a through level of 4-8 ng/mL. Patients were converted to a variable dose of EVL that was adjusted to achieve a trough concentration of 3-8 ng/mL. SRL mean dose at time of conversion was 2.0 ± 0.9 mg/d. Initial EVL mean dose was 1.3 ± 0.5 mg/d. Six months after conversion, mean EVL trough level was 6.2 ± 2.8 ng/mL. EVL dose at this point was 2.0 ± 0.9 mg/d, which was not statistically different from SRL dose at the time of conversion (p = 0.575), suggesting a conversion factor of 1:1. During this six month period post conversion, no significant changes were observed in serum creatinine, hematocrit level, platelet count, proteinuria or lipid levels. No patient experienced an acute rejection episode. Conversion from SRL to EVL in renal transplant recipients receiving a CNI-free immunosuppressive regimen can be performed safely with a low trough level range of EVL. We report for the first time a conversion factor between SRL and EVL.

Renal Function Outcomes in Kidney Transplant Recipients After Conversion to Everolimus-Based Immunosuppression Regimen with CNI Reduction or Elimination

Background Chronic allograft nephropathy (CAN) is a major cause of progressive renal failure in kidney transplant recipients. Its etiology is multifactorial and can be due to immunologic or nonimmunologic conditions including calcineurin inhibitor (CNI) toxicity. Objective To evaluate the effect of conversion from CNIs to everolimus in kidney transplant recipients with CAN. Patients and Methods In this 12-month pilot study in renal transplant recipients with biopsy-proved CAN, therapy was changed to an everolimus-based immunosuppression regimen. Cyclosporine or tacrolimus dosage was reduced by 80% (group 1, n = 10) or discontinued (group 2, n = 10). Mycophenolate mofetil or azathioprine were withdrawn in group 1, whereas both agents were maintained in group 2. All patients received prednisone. Results Twenty renal allograft recipients switched to an everolimus-based regimen, and patients were followed up for a mean (SD) of 12 (0.1) months. Baseline and end-of-study data were as follows: serum creatinine concentration, 1.27 (0.35) mg/dL vs 1.24 (0.4) mg/dL in group 1, and 1.27 mg/dL (0.36) vs 1.25 (0.3) mg/dL in group 2 (difference not significant); and estimated glomerular filtration rate, 72.4 (19.86) mL/min vs 76.26 (22.69) mL/min in group 1 (not significant), and 66.2 (12.95) mL/min vs 66.2 (13.73) mL/min in group 2 (not significant). One patient in group 1 experienced an acute rejection episode (Banff grade Ib), and 2 patients in group 1 and 1 patient in group 2 demonstrated borderline changes, all associated with everolimus blood concentration less than 3 ng/mL. Conclusions Reduction or withdrawal of CNI and introduction of everolimus may be useful to slow the rate of loss of renal function in patients with CAN.

Conversion to Everolimus in Kidney Transplant Recipients With Decreased Renal Function

Whenever graft function is good and proteinuria is under control, many reports describe the efficacy and safety of the conversion to Everolimus (EVL) among stable kidney recepients, simultaneously withdrawing the calcineurin inhibitor (CNI). However, there are few publications that evaluate the role of EVL in patients with decreased renal function. We describe our experience with 22 stable renal transplant recipients whose serum creatinine concentrations were >2 mg/dL and proteinuria <1000 mg/24 h who underwent an abrupt switch from a CNI to EVL. Conversion was simple, well-tolerated, and safe using an initial dose of 1-3 mg/d that was sufficient to achieve the recommended levels of 3-8 ng/dL. The adverse events were expected; most of them were of medium intensity. Globally, over the 24 months follow-up, there was improved renal function despite the initial creatinine. The improvement was greater when the switch was performed during the first year after transplantation. Two patients lost their grafts after a dramatic evolution with development of nephrotic syndrome and increasing creatinine. In our experience, conversion to EVL is a safe alternative among patients with chronic allograft nephropathy or nephrotoxicity due to CNI, even in patients with significantly decreased renal function at the time of the switch.

Conversion to Everolimus in Kidney Transplant Recipients: A Safe and Simple Procedure

To date there is a substantial experience with rapamycin conversion in stable renal transplant recipients with respect to the procedure of conversion, initial doses, and target blood levels as well as adverse events, but in the case of Everolimus there is almost no experience with conversion and calcineurin inhibitor (CNI) withdrawal. We describe an initial experience among 32 renal transplant recipients who were converted to Everolimus with complete suspension of CNI in two Spanish transplant centers. Our results emphasised the procedure for conversion, the target levels, the adverse events, and the initial efficacy, over the first month after conversion. Our conclusions were that conversion from CNI to Everolimus was a simple, safe procedure with a predictable profile of adverse events, which were, in general, of mild intensity. There was a good correlation between initial dose and blood level. Initial doses of about 3 mg/d combined with rapid reduction in CNI exposure seemed to be adequate. The target range levels between 5 and 10 ng/mL seemed to be sufficient for complete CNI elimination, especially in patients also receiving antiproliferative drugs (such as mycophenolate mofetil or azathioprine) in whom levels near the lower end of the range might be adequate.