Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation

Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.

Wound Healing Complications and the Use of Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation: A Critical Review of the Literature

Wound Healing Complications and the Use of Mammalian Target of Rapamycin Inhibitors in Kidney Transplantation: A Critical Review of the Literature

Surgical complications, including events such as lymphocele and urological complications that affect wound healing, are reported with an incidence of 15% to 32% after kidney transplantation. The experience of the surgeon and comorbidities play an important role in determining the risk of such complications occurring. Since the introduction of the inosine 5′-monophosphate dehydrogenase inhibitors (mycophenolate mofetil) to the immunosuppressive armamentarium, replacing the antimetabolite prodrug azathioprine, reports have associated certain forms of wound healing complications (wound dehiscence, impaired healing, lymphocele, and incisional hernia) with the use of these agents. When mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) became available, these findings were observed increasingly, particularly in direct comparisons with inosine 5′-monophosphate dehydrogenase inhibitors. The purpose of this article was to review the reported incidence of wound healing complications from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo kidney transplantation and the information available from the U.S. Food and Drug Administration database. The clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors’ discretion. This review summarizes these studies to consider whether modern mTOR inhibitor–based immunosuppressive regimens exert and affect wound healing after kidney transplantation.

A Comprehensive Review of Everolimus Clinical Reports: A New Mammalian Target of Rapamycin Inhibitor

A Comprehensive Review of Everolimus Clinical Reports: A New Mammalian Target of Rapamycin Inhibitor

As new immunosuppressive agents are introduced to the market, clinicians are faced with the daunting task of sifting through the published literature to decide the value that the agent will add to their own practice. We often must extrapolate information provided through study in other solid-organ transplantation populations than our specific area of interest as we interpret the results and outcomes. With these challenges in mind, this compilation of published work for the newest mammalian target of rapamycin inhibitor everolimus (Certican; Novartis Pharmaceuticals, Hanover, NJ) (Zortress; Novartis Pharmaceuticals, Basel, Switzerland) is intended to provide a concise but thorough presentation of available literature so that the reader who may be unfamiliar with the agent can make their own judgment. Both Ovid and PubMed search engines were queried with a particular focus on high-impact articles noted in the Web of Science or Citation Index. Work described solely in abstract or case report form was excluded, as well as meta-analyses or those that were editorial or commentary in nature. Included were publications presented using the English language that described adult human subjects who received a heart, lung, kidney, or liver allograft. The goal of this strategy was to allow for the inclusion of pertinent literature in an unbiased fashion. Tables are provided that outline trial specific information, leaving a discussion of major outcomes to the text of the review. (C) 2012 Lippincott Williams & Wilkins, Inc.

Review of Cytomegalovirus Infection Findings With Mammalian Target of Rapamycin Inhibitor-Based Immunosuppressive Therapy in De Novo Renal Transplant Recipients

Review of Cytomegalovirus Infection Findings With Mammalian Target of Rapamycin Inhibitor-Based Immunosuppressive Therapy in De Novo Renal Transplant Recipients: Cytomegalovirus (CMV) infection and disease are major complications in the renal transplant recipient. The occurrence of CMV is associated with acute rejection, allograft dysfunction, significant end-organ disease, and mortality. Several clinical studies have indicated that the use of certain immunosuppressive drugs can delay the reconstitution of CMV-specific cell-mediated immune responses, thereby leading to uncontrolled CMV replication. Accumulating evidence indicates, however, that the use of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, may decrease the incidence and severity of CMV infection in renal transplant recipients. The purpose of this article is to review CMV infection data from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo renal transplantation. The mTOR inhibitor clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors’ discretion. This review will summarize these studies to discuss whether mTOR inhibitor-based immunosuppressive therapy can reduce the magnitude of CMV-related complications in the de novo renal transplantation setting.

Conversion From Cyclosporine to Everolimus at 4.5 Months Posttransplant: 3-Year Results From the Randomized ZEUS Study

Conversion From Cyclosporine to Everolimus at 4.5 Months Posttransplant: 3-Year Results From the Randomized ZEUS Study

Everolimus as Primary Immunosuppression in Kidney Transplantation: Experience in Conversion From Calcineurin Inhibitors

Everolimus as Primary Immunosuppression in Kidney Transplantation: Experience in Conversion From Calcineurin Inhibitors: Background: We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion.
Methods: 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.
Results: 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).

Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials

Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials:

Summary

mTOR inhibitors have been associated with wound complications and lymphoceles. We systematically reviewed randomized controlled trials (RCTs) to compare these outcomes for solid organ transplant recipients. Relevant medical databases were searched to identify RCTs in solid organ transplantation comparing mTOR inhibitors with an alternative therapy reporting on wound complications and/or lymphoceles. Methodological quality of RCTs was assessed. Pooled analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Thirty-seven RCTs in kidney, heart, simultaneous pancreas-kidney and liver transplantation were included.

Pregnancy under everolimus-based immunosuppression

Pregnancy under everolimus-based immunosuppression:

Summary

The ability to give birth to a live child is one of the best success of kidney transplantation. While there are an increasing number of pregnancies reported in kidney transplant recipients treated with cyclosporine or tacrolimus, there is little evidence of pregnancy among kidney transplant recipients exposed to sirolimus or everolimus. We present the first successful delivery in an organ transplant recipient exposed to everolimus during the whole gestation. The absence of congenital anomalies in the child as well as the recipient’s successful renal outcome are promising, although pregnancy in renal transplant recipients exposed to everolimus should be considered at higher risk.

Cytomegalovirus Incidence Between Everolimus Versus Mycophenolate in De Novo Renal Transplants: Pooled Analysis of Three Clinical Trials

Cytomegalovirus Incidence Between Everolimus Versus Mycophenolate in De Novo Renal Transplants: Pooled Analysis of Three Clinical Trials: "

Everolimus (EVR) in heart and renal transplant (RTx) recipients may be associated with a decreased incidence of cytomegalovirus (CMV). A detailed analysis of the association between EVR versus mycophenolic acid (MPA) and CMV events has not been reported.

Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus: A Randomized, Multicenter, 24-Month Study

Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus: A Randomized, Multicenter, 24-Month Study: "Background. Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain.
Methods. ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m2) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization.