Everolimus In Renal Transplant Recipients Research Articles

Population pharmacokinetics of everolimus in renal transplant recipients receiving long-term multiple immunosuppressive therapy

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3–8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3–4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30–61 μg/L) and at Cpeak (143–449 μg/L), with limited variability in the 25th–75th percentile range. Tacrolimus (Ctrough 3–13 μg/L; Cpeak 3–16 μg/L), everolimus (Ctrough 3–11 μg/L; Cpeak 5–17 μg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9–28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.

A Limited Sampling Strategy to Estimate Whole Blood and Intra-lymphocyte Exposure of Everolimus in Renal Transplant Recipients using Population Pharmacokinetic Modeling and Bayesian Estimators

Introduction Intra-lymphocyte exposure of everolimus may be a better marker of therapeutic effect compared to trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of whole blood and intra-lymphocyte dose interval exposures of everolimus in renal transplants. Methods Full whole-blood and intra-lymphocyte concentration-time profiles of everolimus were obtained from 12 stable renal transplants on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n=20) and a validation dataset (n=4). The pharmacokinetic model was developed using non-parametric modeling (Pmetrics) and its performances and those of the derived Bayesian estimator were evaluated in the validation set. Results A structural two compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, gender, CYP3A5-genotype, hematocrit, fat-free mass) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 hours and one intra-lymphocyte sample at 1.5 hours post dose provided accurate estimates of the area under the curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± SD = -3.9 ±10.6% and 4.1 ±12.3% for whole blood and intra-lymphocyte concentrations, respectively). Conclusion The developed model allows a simultaneous and accurate prediction of whole blood and intra-lymphocyte everolimus exposure based on two sample times and one intracellular concentrations determination. The model supplies a base for a feasible exploration of the relationships between intra-lymphocyte exposure and therapeutic effects in prospective trials.

Pharmacokinetics and Long-Term Safety and Tolerability of Everolimus in Renal Transplant Recipients Converted From Cyclosporine.

Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail. Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up. The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 ± 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 ± 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 ± 1.4 ng/mL. Whereas mean maximum concentration (13.4 ± 2.8 versus 22.9 ± 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 ± 79 versus 366 ± 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 ± 22.1 versus 102.5 ± 38.5 ng.h/mL, P = 0.067) and mean C0 (3.7 ± 1.3 versus 4.1 ± 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients. The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.

Cardiac response to early conversion from calcineurin inhibitor to everolimus in renal transplant recipients--a three-yr serial echocardiographic substudy of the randomized controlled CENTRAL trial.

In transplant recipients, calcineurin inhibitors (CNIs) are associated with adverse cardiac effects while mTOR inhibitors have been reported to be beneficial. We performed a randomized controlled trial (RCT) in de novo renal transplant recipients examining cardiac responses of everolimus vs. CNI. This was a substudy of the three-yr CENTRAL study, an RCT on safety and efficacy of early (week 7 post-engraftment) conversion from cyclosporine A (CsA) to everolimus vs. continued CsA. Thirty-nine recipients [median age 64 yr, (range 31-81)] completed echocardiographic evaluations at baseline, one, and three yr. After three yr, there was no difference between groups in left ventricle (LV) diastolic function, LV systolic function, LV morphology, and blood pressure response. We observed a relevant decrease in LV mass (CsA; 9.6%, p = 0.008, vs. everolimus; 7.0% reduction, p = 0.15), stabilized LV diastolic function, and a trend toward lower systolic blood pressure with 6 mmHg decrease in both arms (CsA, p = 0.08; everolimus, p = 0.14). Diastolic blood pressure was significantly reduced (8 mmHg decrease, p = 0.002) only in everolimus patients. After three-yr follow-up, no clinically relevant effect on cardiac function of an early conversion from CsA to an everolimus-based immunosuppressive regimen was detected in de novo renal transplant recipients.

Use of Everolimus in Renal Transplant Recipients: Data From a National Registry

Proliferation signal inhibitors, such as everolimus, offer immunosuppression without the toxicity of calcineurin inhibitors. This descriptive and prospective study reports outcomes at 1 year and predictors of improved estimated glomerular filtration rate (eGFR) in 174 renal transplant recipients from a national registry of the use of everolimus. At 1 year after conversion, 48.85% of patients had improved eGFR compared with baseline. The mean time from transplantation to initiation of treatment with everolimus was 47.97 months, the median 22 (range, 0–312) months. The kidneys were from deceased donors in 120 patients (68.79%) and from living donors in 54 (31.21%); 35 (20.83%) were expanded-criteria donors. When comparing the baseline versus 12-month values of laboratory results, total cholesterol levels and platelet counts differed significantly—191.55 ± 43.92 mg/dL versus 204.52 ± 41.29 mg/dL (P < .05) and 213,411 ± 63,231/mm3 vs 255,571 ± 59,153/mm3, respectively (P < .05)—but remained within clinically controllable ranges. Glycemia, triglycerides, hematocrit, hemoglobin, and leukocytes remained stable. Logistic regression analysis of baseline variables showed that the only independent prognostic factor for improved eGFR at 1 year was the conversion of patients to everolimus within the first 12 months after transplantation (odds ratio, 2.17; 95% confidence interval, 1.15–4.10). In conclusion, regarding the effectiveness of everolimus in our subjects, the only predictor of improved eGFR identified at 1 year was conversion within 12 months after transplantation.

Everolimus Based Calcineurin Inhibitors Minimization Regimens in Renal Transplantation Recipients: A Meta-Analysis.

Background Calcineurin inhibitors (CNIs) are widely-used immunosuppressants in renal transplantation, although it has been proved that CNIs can cause nephrotoxicity. Minimization of CNIs seems a better immunosuppression protocol after renal transplantation. Here we conduct a meta-analysis on the outcomes of CNI minimization by Everolimus in renal transplant recipients. Methods We included randomized trials with no year and language restriction. All data were analyzed using fix or random effect model. The primary endpoints were estimated glomerular filtration rate (eGFR), biopsy proven acute rejection (BPAR) and patient survival at month 12. The secondary endpoints were incidence of infection, blood creatinine level, allograft dysfunction, and other side effects such as hypertriglyceridemia. ResultseGFR was significantly improved in Everolimus group (MD=5.41, 95% CI 0.63 to 10.19, Z=2.22, P=0.03). There was no significant difference in BPAR episodes (RR=1.29, 95% CI=0.82 to 2.04, Z=1.10, P=0.27), patient survival (RR=0.88, 95% CI=0.45 to 1.75, Z=0.35, P=0.73), overall infection rate (RR=0.99, 95%CI=0.93 to 1.06, Z=0.28, P=0.78) and incidence of hypertriglyceridemia (RR=0.94, 95%CI=0.56 to 1.57, Z=0.24, P=0.81).Table: No Caption available.Conclusion The findings of this meta-analysis suggest that CNI minimization regimen with Everolimus elicits benefits in renal function, while not comprising immunosuppressive effects.

Analytical Performance of QMS Everolimus Assay on Ortho Vitros 5,1 FS Fusion Analyzer

Everolimus has recently been approved by Food and Drug Administration for graft maintenance in liver transplant recipients. This drug has a narrow therapeutic index and benefits from close blood level monitoring. Currently, in the United States, the Thermo Fisher Scientific Quantitative Microsphere System (QMS) Everolimus Immunoassay is the only Food and Drug Administration-cleared immunoassay for monitoring everolimus in renal transplant recipients. However, studies on this assay adapted to the Ortho Vitros 5,1 FS chemistry analyzer have not been published, and data of this assay applied to monitoring drug levels in liver transplant recipients are limited. Here, the authors evaluated and validated the QMS everolimus assay on the Vitros analyzer and its application to supporting the immunosuppressant management of mainly liver transplant recipients. The analysis was performed according to the QMS assay package insert. The method was compared with a liquid chromatography-tandem mass spectrometry method from a reference laboratory using a total of 34 samples from 1 double lung and liver, 8 liver, and 3 kidney recipients. The method comparison was assessed by Deming regression. Proficiency test materials issued by Everolimus TDM Proficiency Support Program were tested and compared with the peer group results of using the QMS kits. The assay was linear in the range of 0.75-20.0 ng/mL. Limit of detection was 0.70 ng/mL and lower limit of quantitation was 0.75 ng/mL. Within-day and between-day (20 days) coefficients of variation were between 3.1% and 16.5% at mean levels of 5.3, 12.0, and 17.2 ng/mL, respectively. We obtained a Deming regression of y = 1.271 - 0.666 (r = 0.880) when comparing with the liquid chromatography-tandem mass spectrometry method. The authors concluded that the analytical performance of the QMS everolimus immunoassay by the Vitros 5,1 FS analyzer was satisfactory for monitoring drug levels of solid organ transplant patients.

Cardiac Response to Early Conversion from Calcineurin Inhibitor to Everolimus in Renal Transplant Recipients

Calcineurin inhibitors are associated with adverse cardiac effects. Mammalian target of rapamycin inhibitors have been reported to have beneficial effects on cardiac function. We used advanced echocardiographic techniques in a randomized controlled trial to examine cardiac responses to an everolimus-based arm versus a calcineurin inhibitor-based arm in de novo kidney transplant recipients. This was a substudy of the Certican Nordic Trial in Renal Transplantation study, a randomized controlled trial on safety and efficacy of early (week 7 after renal transplantation) conversion from cyclosporine A (CsA) to everolimus versus continued CsA during 1-year follow-up. A total of 44 patients (66% men; median [range] age, 61 [28-78] years) were included. All participants had a complete echocardiographic evaluation at baseline and at 1-year follow-up. Left ventricular (LV) systolic function, LV mass, left atrial volumes, and blood pressure response did not differ between groups during 1-year follow-up. There was, however, a difference between the groups in change in peak early mitral velocity after 1 year (P=0.02), and E/e' ratio trended higher in the everolimus group (P=0.09). Early conversion from CsA-based to everolimus-based immunosuppressive treatment in de novo renal transplant recipients caused marginal changes in LV diastolic function but no effect on LV systolic function or LV mass.

Safety and efficacy of everolimus in chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is a major cause of late kidney allograft loss. Everolimus, a novel proliferation signal inhibitor, ameliorates CAN by its antiproliferative or apoptosis-enhancing effects. This study aims to evaluate the safety and efficacy of everolimus in renal transplant recipients with calcineurin inhibitor (CNI) withdrawal either due to CAN or cal-cineurin inhibitor toxicity (CNIT). A total 21 patients with CAN or CNIT converted from CNI to everolimus were prospectively studied from 2006 to 2009. There were 19 males and two females, with a mean age of 32.9 ± 10.7 years. Eight patients had chronic interstitial nephritis, three had diabetes mellitus, nine had end-stage renal disease and one had focal segmental glomerulosclerosis as native kidney disease. The mean duration of dialysis was 10.7 ± 7 months. 57.2% of the patients had CAN and 42.8% had CNIT. Everolimus was started within six months of post-transplantation in six patients, within 6-12 months in two patients, within 1-2 years in four patients and after more than 2 years in nine patients. The mean dose at first month was 1.25 mg/day, at six month was 1.028 ± 0.3 mg/day and at 12 th month was 0.97 ± 0.2 mg/day, with a mean trough level of 6.35 ± 3 ng/dL, 5.18 ± 3 ng/dL and 6.43 ± 1.7 ng/dL, respectively. At the 12 th month, serum creatinine declined from 2.07 ± 0.58 mg/dL to 1.65 ± 0.81 mg/dL. The mean calculated glomerular filtration rate improved from 40.85 ± 8.8 mL/min to 56.84 ± 11.4 mL/min. No major side-effects were observed. Everolimus along with mycophenolate mofetil or azathioprine and prednisolone as a maintenance immunosuppressive therapy was found to be effective and safe in patients with CNIs withdrawal either due to CAN or CNIT.

Early Conversion to Everolimus in Renal Transplant Recipients

Background: Despite being an effective immunosuppressive agent, the calcineurin inhibitors (ciclosporin and tacrolimus) are associated with nephrotoxicity, chronic allograft nephropathy and long term graft loss. The authors proposed that the early replacement of calcineurin inhibitors with everolimus (a mammalian-target-of-rapamycin inhibitor) may be an effective strategy of immunosuppression following renal transplantation, and may improve renal function without compromising efficacy. We present our experience of early conversion to everolimus after 6 months of renal transplantation. Material and methods: Patients who underwent renal transplantation from 2009 to 2011 were enrolled in the study. In is prospective open label study. Patients received triple maintenance immunosuppression; prenisolone 20mg/day, tacrolimus 0.1mg/kg/day, Mycophenolate mofitil 2.0g/day. Basiliximab induction (20 mg, intravenously, on day 0 and on day 4) was given to patients with spousal donors. After 6 months of renal transplantation tacrolimus was replaced by everolimus. (trough concentrations of 6-10 ng/mL] Results: Totally 33 renal transplant recipients were converted to everolimus during this period. Female to male ratio was 1: 5.6. The mean age was 35.8 years. In 3 patients (9.09%), tacrolimus was changed to everolimus at 3 months due to tacrolimus toxicity, another 3 patients (9.09%), mycophenolate mofitil was convered to everolimus due to drug induces bone marrow depression and in 27 patients (81.81%) everolimus was started after 6 months of renal transplantation as a protocol. Ten patients (30.3%) received basileximab, nine (27.27%) were spousal transplantation and one (3.03%) was deseased donor transplantation. Kidney donor was mother in 10 patients (30.3%), father in 3 (9.09%), brother in 5(15.15%) and sister in 4 patients (12.12%). Mean serum creatinine before start of everlimus was 1.34mg/Dl, and GFR was 54ml/min. At 6 months and 1 year follow-up, patient and graft survivals were 100%. None of the 33 patients suffered rejection. Mean serum creatinine and GFR at 6 months and 1 year were 1. 26 mg/dl, 59 ml/min and 1.21mg/dl, 61/min respectively. Mean 24 hours urinary proteiuria before conversion to everolimus, at 6 months and at 1 year after conversion to everlimus were 342 mg, 397mg and 413 mg. Five patients (15.15%) suffered CMV infection after convertion to everolimus and one (3.03%) patient suffered B K Virus nephropathy. Eighteen patients (54.54%) developed hyperlipidemia after conversion to everolimus. Conclusion: Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients.

Sotrastaurin, a Novel Protein Kinase C- Inhibitor: Evaluation of a CNI-Free Combination with Everolimus in Renal Transplant Recipients

Sotrastaurin, a Novel Protein Kinase C- Inhibitor: Evaluation of a CNI-Free Combination with Everolimus in Renal Transplant Recipients

Early Conversion to Everolimus in Renal Transplant Recipients

Early Conversion to Everolimus in Renal 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.

Results of the Conversion to Everolimus in Renal Transplant Recipients With Posttransplantation Malignancies

Management of posttransplantation malignancies should include control of the neoplasia and preservation of renal function. Conversion to everolimus (EVL) would potentially have both effects. Twenty-one patients were converted to EVL due to posttransplantation neoplasms. We have presented herein descriptive data and postconversion (PC) outcomes among subjects of mean age 53.6 ± 10.1 years (range, 36–69), 57.1% were males, undergoing conversion at 108.2 ± 74.7 (range, 5–316) months after transplantation. All patients received standard immunosuppressive therapy and 9.5% had been induced with thymoglobulin. Malignant neoplasms were as follows: skin (n = 7), gynecological (n = 3), gastrointestinal (n = 3), PTLD (n = 2), renal (n = 2), CNS (n = 1), seminoma (n = 1), Kaposi's sarcoma (n = 1), and prostate cancer (n = 1). PC to EVL, calcineurin inhibitors (CNIs) were discontinued in 18 of 19 patients, mycophenolate in 9/12, and azathioprine in 5/7; all patients continued to receive steroids. In 16 patients (79%) tumors were removed. Chemotherapy was performed in 2 patients with PTLD and radiotherapy was performed in 1 patient with prostate cancer. Mean follow-up was 505 days (range, 59–1151); baseline glomerular filtration rate (GFR) was 53.5 ± 21.6 mL/min versus 48.5 ± 25.7 mL/min ( P = not significant [NS]) at the last control. One patient experienced graft loss at day 744 after conversion due to chronic rejection. Adverse events were observed in 57% of patients and 28% displayed infections; no patient discontinued EVL. There were 2 deaths: 1 due to an infection and the other due to postsurgical complication. No deaths due to cancer progression were observed. The results observed in this series suggested that conversion to EVL for a posttransplantation neoplasm is a valid therapeutic alternative to preserve graft function and control disease progression.

The use of everolimus in renal-transplant patients

Despite advances in immunosuppressive therapy, long-term renal-transplantation outcomes have not significantly improved over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is an important cause of chronic allograft nephropathy (CAN), the major driver of long-term graft loss. Everolimus is a proliferation signal inhibitor with a mechanism of action that is distinct from CNIs. The efficacy and tolerability of everolimus in renal-transplant recipients have been established in a wide range of clinical trials. Importantly, synergism between everolimus and the CNI cyclosporine (CsA) permits CsA dose reduction, enabling nephrotoxicity to be minimized without compromising efficacy. Currently, everolimus is being investigated in regimens where reduced exposure CNIs are used from the initial post-transplant period to improve renal function and prevent CAN. By inhibiting the proliferation of smooth muscle cells, everolimus may itself delay the progression or development of CAN. Although everolimus is associated with specific side effects, these can generally be managed. By targeting the main causes of short- and long-term graft loss, everolimus has a key role to play in renal transplantation, which is being explored further in a number of ongoing Phase III-IV trials.

Conversion Therapy to Everolimus in Renal Transplant Recipients: Results After One Year

Background Two new diagnoses have been causing graft loss during long-term follow-up, namely, chronic nephropathy and anticalcineurinic toxicity. The advent of the mammalian target of rapamycin (m-TOR) obviates anticalcineurine toxicity and reduces posttransplant malignancy incidence with good inmunosuppressive potential. We examinated the renal and metabolic behavior in renal transplant recipients who required conversion from an anticalcineurinic (cyclosporine or tacrolimus) to an m-TOR inhibitor (everolimus) as part of their immunosuppressive maintenance therapy. Materials and Methods Twenty-one first renal transplant recipients had everolimus added to their inmunosuppressive therapy combined with an antimetabolite (mycophenolate mofetil or sodium mycophenolate). The mean age of the patients was 35 ± 17 years (range, 6 to 65). The prevalence of male recipients was 57%; the overall mean weight, 64 kg (range, 48 to 95). All patients were hispanic with 15 transplants from cadaveric donors (71%). The mean follow-up posttransplant was 18 months (range, 3 to 40) and the mean follow-up on everolimus, 10 months (range, 2 to 22). Results There was no mortality or graft loss, but there were 3 (17%) biopsy-confirmed acute rejection episodes. There were no significant changes in metabolic function pre- or postconversion. Regarding renal function, the mean creatinine serum showed a trend to decline: preconversion 1.7 mg/dL; postconversion 1.5 mg/dL. In 10 patients, it was possible to discontinue at least one antihypertensive medication (48%). Conclusions Everolimus was an effective medication to manage renal transplant patients. It produced metabolic stability and low myelotoxicity, despite combination with an antimetabolite (mycophenolic acid). Also, reduction of antihypertensive medications was an additional benefits for many patients.

Conversion From a Calcineurin Inhibitor-Based Immunosuppressive Regimen to Everolimus in Renal Transplant Recipients: Effect on Renal Function and Proteinuria

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.

Evaluation of a fluorescent polarization immunoassay for whole blood everolimus determination using samples from renal transplant recipients

Objectives: This study compared the performance of a fluorescent polarization immunoassay (FPIA) against HPLC-tandem mass spectrometry (HPLC-MS) for the measurement of everolimus in renal transplant recipients. Design and methods: A total of 333 pre-dose samples from 45 renal transplant patients were analyzed by FPIA and HPLC-MS. Results: The inter-batch inaccuracy and precision of the FPIA for control samples were ≤6% and ≤13.0%, respectively ( n = 17). The comparison of patient results yielded the Deming regression equation FPIA = 1.19 × HPLC-MS + 0.51. The mean bias was 24.4% (95% CI: −3.0 to 54.2%, range: −30.1% to 79.4%). Conclusions: The FPIA had acceptable analytical performance during the study but compared to HPLC-MS overestimated everolimus in patient samples. This overestimation is probably due to calibration differences between the methods and cross-reactivity of the FPIA antibody with everolimus metabolites. The clinical importance of the observed overestimation by FPIA requires further investigation.