Calcineurin Inhibitor Elimination Research Articles

Everolimus Based Immunosuppression Strategies in Adult Lung Transplant Recipients: Calcineurin Inhibitor Minimization Versus Calcineurin Inhibitor Elimination.

Everolimus (EVE) provides an alternative to maintenance immunosuppression when conventional immunosuppression cannot be tolerated. EVE can be utilized with a calcineurin inhibitor (CNI) minimization or elimination strategy. To date, clinical studies investigating EVE after lung transplant (LTx) have primarily focused on the minimization strategy to preserve renal function. The primary aim was to determine the preferred method of EVE utilization for lung transplant recipients (LTR). To undertake this aim, we compared the safety and efficacy outcomes of EVE as part of minimization and elimination immunosuppressant regimens. Single center retrospective study of 217 LTR initiated on EVE (120 CNI minimization and 97 CNI elimination). Survival outcomes were calculated from the date of EVE commencement. On multivariate analysis, LTR who received EVE as part of the CNI elimination strategy had poorer survival outcomes compared to the CNI minimization strategy [HR 1.61, 95% CI: 1.11-2.32, p=0.010]. Utilization of EVE for renal preservation was associated with improved survival compared to other indications [HR 0.64, 95% CI: 0.42-0.97, p=0.032]. EVE can be successfully utilized for maintenance immunosuppression post LTx, particularly for renal preservation. However, immunosuppressive regimens containing low dose CNI had superior survival outcomes, highlighting the importance of retaining a CNI wherever possible.

Acute Kidney Injury After Liver Transplantation.

Since the implementation of the Model of End-stage Liver Disease score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of postliver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post-LT AKI which then predisposes to posttransplant chronic kidney disease. Prevention of posttransplant AKI is essential in the improvement of long-term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate. New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post-LT in patients with early posttransplant AKI may improve glomerular filtration rate in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late chronic kidney disease.

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.

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial.

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

Conversion to mTOR-inhibitors with calcineurin inhibitor elimination or minimization reduces urinary polyomavirus BK load in kidney transplant recipients.

Polyomavirus BK (BKV) reactivation causes allograft dysfunction in some kidney transplant recipients. The use of mammalian target of rapamycin (mTOR) inhibitor-based immunotherapy is associated with a lower incidence of polyomavirus-associated nephropathy compared with other immunosuppressants. This retrospective study assessed whether conversion to mTOR inhibitor-based immunotherapy directly reduced urinary BKV load. A total of 63 kidney recipients were divided into mTOR inhibitor-conversion (21 patients) and nonconversion (42 patients) groups. Urinary BKV loads were determined before and at least 6months after the conversion. The results demonstrated that urinary BKV titer was significantly reduced in the conversion group (3.94±0.43 copies (log)/mL to 2.49±0.19 copies (log)/mL) and remained unaltered in the nonconversion group (3.19±0.20 copies (log)/mL to 2.90±0.20 copies (log)/mL). In addition, the percentage of patients with reduced urinary BKV load was significantly higher in the conversion group (76.2% vs. 42.9%). The estimated glomerular filtration rate after 24months mTOR inhibitor conversion was significantly increased compared with that in the nonconversion group. Conversion to mTOR-inhibitor-based immunotherapy was the only factor associated with an increase in estimated glomerular filtration rate. This study reveals an association of conversion to mTOR-inhibitor-based immunotherapy with the reduction of urinary BKV load.

Reviewing 15years of experience with sirolimus.

Here, we review 15 years of clinical use of sirolimus in our transplant center, in context with the developing immunosuppressive strategies use worldwide. The majority of studies were conducted in de novo kidney transplant recipients, using sirolimus (SRL) in combination with calcineurin inhibitors (CNIs). We also explored steroid (ST) or CNI-sparing therapies, including CNI minimization, elimination, or conversion strategies in combination with mycophenolate (MMF/MPS). Pooled long-term outcomes were comparable with those obtained with CNI and antimetabolite combination. Surprisingly, there are still several areas that need further investigation to improve the risk/benefit profile of SRL in kidney transplantation, including pharmacokinetic/pharmacodynamic drug-to-drug interaction with cyclosporine (CsA) or tacrolimus (TAC), mechanisms of SRL-associated adverse reactions and combinations with other drugs such as belatacept and once-daily TAC, possibly leading to improved long-term adherence. These studies, along with others investigating the benefits of SRL associated lower viral infections and malignancies, are essential as we do not expect the introduction of new immunosuppressive drugs in the near future.

Everolimus in de novo liver transplant recipients: a systematic review

Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients. Randomized controlled trials comparing everolimus for de novo liver transplant in PubMed, the Cochrane Library, and ScienceDirect published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval (95% CI) for renal function, relative risk (RR) and 95% CI for treated biopsy-proven acute rejection (tBPAR), graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with RevMan version 5.10. A total of four randomized controlled trials covering 1119 cases were included. The meta-analyses revealed that compared with standard exposure of calcineurin inhibitors (CNIs), everolimus combined with reduced CNIs improved creatinine clearance (calculated with the Cockcroft-Gault formula) by 5.13 mL/min at one year (95% CI: 0.42-9.84; P=0.03), and decreased tBPAR (RR: 0.56; 95% CI: 0.35-0.90; P=0.02). Everolimus initiation with CNIs elimination improved glomerular filtration rate (GFR, measured with the modification of diet in renal disease formula) of 10.42 mL/min/1.73 m2 (95% CI: 3.44-17.41; P<0.01) one year after treatment, but increased tBPAR (RR: 1.71; 95% CI: 1.15-2.53; P<0.01). Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant (RR: 0.60; 95% CI: 0.34-1.03; P=0.06), but was associated with greater risk of adverse events which resulted in drug discontinuation (RR: 1.98; 95% CI: 1.49-2.64; P<0.01). Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of tBPAR one year after liver transplant, but everolimus administered without CNIs increases tBPAR.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis.

Calcineurin inhibitors (CNI) associated nephrotoxicity remains a risk factor for long-term graft dysfunction after renal transplantation. Everolimus is a mammalian target of rapamycin inhibitor and exhibits synergistic immunosuppressive activity with CNI to permit CNI-reduction. We conducted a systematic review to compare the efficacy of everolimus-based CNI sparing and standard CNI regimens in renal transplantation recipients. We searched PubMed and Web of Science databases to identify relevant randomized controlled trials. Glomerular filtration rate (GFR), biopsy-proven acute rejection (BPAR), death or graft loss and incidence of adverse events were the major estimates of renal function, efficacy, and tolerability of the two regimens. Seven studies providing data for 2,067 patients were included. Six of the seven studies used cyclosporine as the CNI. The patients were divided into two groups: everolimus-based CNI sparing (elimination and minimization) group and standard CNI group. Everolimus-based regimen was associated with increased GFR [P = 0.02; weighted mean difference (WMD) 4.83 mL/min], decreased serum creatinine (P = 0.004; WMD -9.94 μmol/L) and no more death or graft loss [P = 0.72; relative risk (RR) 1.07]. CNI-minimization was not associated with increased BPAR (P = 0.25; RR 0.85) while CNI-elimination was associated with more BPAR Grade 1 (P < 0.00001; RR 4.20). Use of everolimus reduced the risk of CMV infection (P = 0.0002; RR 0.47). There was a higher risk of discontinuation of everolimus (P < 0.00001; RR 1.69) and non-fatal adverse events (P < 0.00001; RR 1.73) in patients on the everolimus based CNI sparing regimens. Everolimus-based CNI sparing regimen could optimize long-term graft function without leading to more death or graft loss. Although CNI elimination was associated with higher risk of BPAR, everolimus use with CNI minimization did not increase the risk of acute rejections. Use of everolimus was associated with reduction in the incidence of CMV infection, but there was a higher risk of discontinuation of this drug and other non-fatal adverse events.

Early use of renal-sparing agents in liver transplantation: A closer look

Renal dysfunction is a critical issue for liver transplant candidates and recipients. Acute nephrotoxicity and chronic nephrotoxicity, however, are the compromises for the potent immunosuppression provided by calcineurin inhibitors (CNIs). To maintain the graft and patient survival afforded by CNIs while minimizing renal dysfunction in liver transplant patients, the reduction, delay, or elimination of CNIs in immunosuppression regimens is being implemented more frequently by clinicians. The void left by standard-dose CNIs is being filled by nonnephrotoxic immunosuppressants such as mycophenolates and mammalian target of rapamycin inhibitors. The results of studies of renal-sparing regimens in liver transplant recipients have been inconsistent, and this may be explained upon a closer examination of several study-related factors, including the study design and the duration of follow-up.

Management of Calcineurin Inhibitors-Related Chronic Kidney Disease in Cardiac Transplantation

Background: The use of calcineurin inhibitors revolutionized transplantation by prolonging patients’ survival. However, their utility is limited by the development of significant chronic kidney disease. Methods: We reviewed the English literature looking for recent publications regarding the management of chronic kidney disease in cardiac transplant patients. We chose relevant papers based on design, number of patients and clinical utility. Results: Most publications on the subject involve small populations with few prospective, randomized studies. Early use of tacrolimus appears to be associated with better kidney function after one year compared to cyclosporine. Once chronic kidney disease is established, successful strategies include reduction or elimination of calcineurin inhibitors while relying on mycophenolate mofetil, proliferation signal inhibitors or anti-CD 25 antibodies to prevent rejection. There is no follow up longer than two years with these approaches. Kidney transplantation might offer improved long-term survival compared to dialysis in end-stage disease. Conclusions: Prospective studies with long-term follow-up are needed to decide about the timing and to confirm the utility of replacing calcineurin inhibitors with other agents in cardiac transplant patients with chronic kidney disease.

Donor-Derived Mesenchymal Stem Cells Facilitate Minimization of Calcineurin Inhibitors in Kidney Transplant Patients and the Immune Profile Monitoring: A Clinical Pilot Study

Background: The deleterious side effects of calcineurin inhibitors (CNIs) such as nephrotoxicity, cardiovascular events, infection and malignancy, have impaired patients long-term survival. New immunotherapy regimens with minimization or elimination of CNIs are required to improve transplant outcome. Mesenchymal stem cells (MSCs) represent a unique cell population with potent immunosuppressive function, and can prolong allograft survival in experimental organ transplant models. In this present study, MSCs combined with sparing tacrolimus (TAC) were administered to de novo living related kidney transplant (KTx) recipients to prevent acute rejection, and post-transplant immune profile was monitored. Patients and methods: Twelve patients were enrolled in this prospective study. Six patients received donor-derived MSCs combined with minimized TAC, and the other six without MSCs were assigned as control. MSCs were infused into renal allograft via renal artery prior to vessel anastomosis (5×106 cells), and were subsequently given intravenously one month later (2×106 cells/kg). Safety of MSCs infusion, renal function and complications were observed. Donor-specific mixed lymphocyte reaction (MLR) was performed prior to KTx (day 0) and three (mon 3) or six months (mon 6) post-transplant. Chimerism was examined. Immune cells including CD4+ and CD8+ T cell, CD4+CD25+CD127lowFoxp3+ regulatory T cell (Tregs), NK cell, and CD19+CD27+ memory B cell were monitored by flow cytometry. Intracellular cytokines including IFN-γ, TNF-α, IL-4 and IL-10 were examined. Results: Tacrolimus dose in MSCs group was significantly reduced compared to control group (0.047 ± 0.005 vs 0.073 ± 0.013 mg/kg). One acute rejection occurred in control group, and was reversed by antithymocyte globulin and methylprednisolone therapy. None acute rejection was observed in MSCs group. All patients survived with stable renal function at mon 6. There was no significant different in MLR proliferation analysis at mon 3 and mon 6 between two groups. The proportion and absolute count of peripheral blood lymphocyte was not significantly different between two groups. Total T cells, CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio were significantly different neither. Tregs proportion in MSCs group increased at mon 3 and returned at mon 6, compared to Tregs at day 0. However, Tregs significantly decreased at mon 3 in control group. B cells proportion in MSCs group increased from 9.5% (day 0) to 16.7% at mon 3, and returned at mon 6. While in control group, B cells constantly decreased within six months (3.8% vs 7.9%). The proportion of memory B cells increased by 27.9% at mon 3 in MSCs group, in contrast to 23% of decrease in control group. NK cells proportion in control group continually increased post KTx, while it showed transient decrease at mon 3 in MSCs group. No chimerism was detected in both groups. The proportion of IL-10 producing cells showed constant increase tendency within six months after KTx in MSCs group, while it transiently decreased at mon 3 in control group. Conclusions: Donor-derived MSCs may guarantee efficient hypo-responsiveness to allograft while minimizing calcineurin inhibitors in living related kidney transplantation. The long-term therapeutic effect and its mechanism of action need to be further investigated.

Calcineurin Inhibitor Sparing with Mycophenolate Mofetil in Liver Transplant Recipients: A Systematic Review and Meta-Analysis

Liver transplant recipients are at high risk to develop acute and chronic renal failure. Sparing calcineurin inhibitors (CNI) with the use of mycophenolate mofetil (MMF) may improve renal function without increasing the risk of acute rejection, graft loss, or death. We therefore conducted a systematic review and meta-analysis of randomized, controlled trials. Eight trials could be identified according to predefined selection criteria: two trials in which MMF was used directly after liver transplantation in combination with reduced dose CNI compared to normal dose CNI without MMF; and six trials in which patients were converted to MMF in combination with reduction or elimination of CNI. In conversion trials estimated glomerular filtration rate was higher in patients that received MMF in combination with low-dose CNI compared to patients that continued CNI (mean difference 8.27, 95%-confidence interval [CI] 3.65 to 12.90), but patients in the experimental group also had a significantly higher risk of acute rejection (risk ratio [RR] 4.96, CI 1.75 to 14.07). In de-novo trials the risks of acute rejection, graft loss, and death were not statistically different, but patients had a lower risk of post-operative renal dysfunction (RR 0.57, CI 0.41 to 0.78).

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.

Randomized Trial Comparing Late Concentration-Controlled Calcineurin Inhibitor or Mycophenolate Mofetil Withdrawal

Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn. This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng·hr/mL or tacrolimus: 120 ng·hr/mL) or CNI-withdrawal (target area under the time-concentration curve-mycophenolic acid: 75 μg·hr/mL). The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5±2.1 mL/min vs. 51.1±2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated. These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low.

Everolimus: preventing organ rejection in adult kidney transplant recipients

Introduction: Kidney transplantation is the treatment of choice for patients with end-stage renal failure, and their survival after transplantation is gradually improving. Everolimus (EVL) is a mammalian target of rapamycin inhibitor, providing a safe and effective immunosuppressive regime after kidney transplantation.Areas covered: The objective of this review is to summarize the clinical efficacy and safety of the EVL-based immunosuppressive regimen by analyzing peer-review reports and ongoing trials of its use after kidney transplantation in adult patients.Expert opinion: Judging by the more recent trials, it seems that EVL, in association with calcineurin inhibitor (CNI) minimization, provides a well-tolerated regimen with a low risk of rejection and good graft function. Such regimens have been investigated intensively and should be preferable to complete elimination of CNI. In addition, future clinical studies should explore whether the pleiotropic effects of EVL are beneficial in the long term, leading to a reduction of cardiovascular diseases and de-novo malignancies.

Everolimus as Primary Immunosuppression in Kidney Transplantation

We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion. Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival. Baseline creatinine clearance was 52.4±17.8 mL/min vs. 53.4±20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160-507) to 458 mg/day (interquartile range 238-892; P<0.001). Risk factors for development of proteinuria ≥900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15-9.89), serum triglycerides ≥150 mg/day (OR 4.35; 95% CI: 1.70-11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22-7.59), baseline proteinuria ≥550 mg/day (OR 10.37; 95% CI: 3.99-26.99), and conversion ≥3 years after transplant (OR 5.77; 95% CI: 1.89-17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria ≥550 mg/day, the risk of developing proteinuria ≥900 mg/day was 77.1% if they were converted after ≥3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria ≥550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion. Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria.

Conversion from everolimus with low-exposure cyclosporine to everolimus with mycophenolate sodium maintenance therapy in kidney transplant recipients: A randomized, open-label multicenter study

Data in kidney transplant recipients regarding elimination of calcineurin inhibitor (CNI) therapy from a de novo regimen based on low CNI exposure and an mTOR inhibitor are sparse, and restricted to CNI elimination within the first six months post-transplant. In a 12-month, randomized, multicenter, open-label study, kidney transplant patients who had received everolimus, low-exposure cyclosporine and corticosteroids from transplantation to month 12 (with proteinuria <1 g/24 h at month 12) were randomized to convert from cyclosporine to mycophenolate sodium 720 mg/day with increased everolimus exposure (6-10 ng/mL [CNI-free group], n=15) or continue unchanged (everolimus 3-8 ng/mL [CNI group], n=15). Median (range) baseline mGFR was 54 (21-87) mL/min and 37 (range 18-69) mL/min (p=0.053) in the CNI-free and CNI groups, respectively, compared to 56 (18-126) mL/min and 32 (12-63) mL/min at month 12 (p=0.007). The between-group difference in change in mGFR from baseline to month 12 post-conversion (the primary endpoint) was -14.4 mL/min (95% CI -29.3 to 0.6 mL/min, p=0.059 [least squares mean]). Changes in serum creatinine and estimated GFR to month 12 were significantly in favor of CNI-free patients. One CNI patient experienced biopsy-proven acute rejection. Study drug was discontinued due to adverse events in one CNI-free patient (7%) and three CNI-treated patients (20.0%). Elimination of CNI from a de novo regimen of everolimus with low-exposure CNI at one year post-transplant maintained efficacy and led to a non-significant but clinically relevant improvement in renal function, although patients numbers were low (n=30). Findings from this small study require confirmation in a larger controlled trial.

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal

The use of calcineurin inhibitors is associated with chronic nephrotoxicity and lower glomerular filtration rate (GFR). As a result, one strategy of transplant immunosuppression is calcineurin inhibitor elimination. The aim of this study was to determine the outcome of a prospective randomized trial of kidney transplant recipients receiving rapid corticosteroid withdrawal, tacrolimus and mycophenolate mofetil (MMF) for 1 month followed by randomization to switch to sirolimus-MMF or to stay on tacrolimus-MMF. The primary outcome was the difference in measured GFR at 1 year using intention-to-treat analysis. Sixty patients were randomized to stay on tacrolimus-MMF and 62 to sirolimus-MMF. Actual graft survival (including death) at 2 years was 98.4% in the sirolimus group, 96.7% in the tacrolimus group. Sixty-three percentage of the patients in the sirolimus group withdrew during the 2-year period of the study compared with 18% of the tacrolimus group (P<0.0001), primarily related to rejection or medication side effects. Rejection during the first year occurred in 5% of the tacrolimus group and 13% of the sirolimus group (P=0.15). Measured GFR at 1 year (mean±SD) was 57.4±20.7 mL/min/1.73 m in the sirolimus group and 62.7±26.5 mL/min/1.73 m in the tacrolimus group (95% CI of difference -3.7-14.4). We conclude that conversion from tacrolimus-MMF to sirolimus-MMF at 1 month posttransplant in kidney recipients on rapid steroid withdrawal is poorly tolerated and does not improve GFR at 1 year.

Steroid or tacrolimus withdrawal in renal transplant recipients using sirolimus

Calcineurin inhibitor (CNI) and steroid (ST) withdrawal are strategies under investigation to reduce long-term toxicities associated with current immunosuppressive regimens. We conducted a single center, prospective trial comparing the efficacy and safety of CNI or ST withdrawal in kidney transplant recipients receiving sirolimus-based immunosuppressive regimen. Forty-seven recipients of first renal transplant with non-HLA-identical living donors received sirolimus (SRL), tacrolimus (TAC), and ST without induction therapy and were randomized to undergo ST (TAC/SRL group, n = 24) or TAC (SRL/ST group, n = 21) withdrawal 3 months after transplantation. Primary efficacy and safety endpoints were the incidence of biopsy-confirmed acute rejection (BCAR) and renal function at 12 months. No differences were observed in the incidence of BCAR (4.2% vs. 9.5%), graft (95.8% vs. 95.6%), and patient (95.8% vs. 95.6%) survivals or in renal function (60 ± 11.5 vs. 63.4 ± 10.5 ml/min, P = 0.361). Higher mean cholesterol concentration was observed in the SRL/ST group (191.9 ± 63.3 vs. 241.6 ± 61.5 mg/dl, P = 0.019). Treatment discontinuation due to adverse events occurred in 12.5% of patients in TAC/SRL group and 21.7% in SRL/ST group. Within this short period of observation, our study was unable to detect any significant difference in major transplant outcomes comparing CNI and ST elimination strategies.