Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

Published on Jun 2, 2021in BMC Nephrology1.913
· DOI :10.1186/S12882-021-02409-8
S E de Boer (UMCG: University Medical Center Groningen), Jan Stephan Sanders22
Estimated H-index: 22
(UMCG: University Medical Center Groningen)
+ 10 AuthorsStefan P. Berger33
Estimated H-index: 33
(UMCG: University Medical Center Groningen)
Source
Abstract
BACKGROUND In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.
References0
Newest
#1Stefan P. BergerH-Index: 33
#2Claudia Sommerer (University Hospital Heidelberg)H-Index: 35
Last. Julio PascualH-Index: 70
view all 21 authors...
: TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-pr...
27 CitationsSource
#1Giselle A. Joseph (Novartis)H-Index: 2
#2Sharon X. Wang (Novartis)H-Index: 4
Last. David J. Glass (Novartis)H-Index: 78
view all 9 authors...
: There is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, partial inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cr...
34 CitationsSource
#1Julio PascualH-Index: 70
#1Julio PascualH-Index: 27
Last. Flavio Vincenti (UCSF: University of California, San Francisco)H-Index: 83
view all 19 authors...
Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation. Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was trea...
80 CitationsSource
#1Flavia Neri (UNIPD: University of Padua)H-Index: 13
#2Lucrezia Furian (UNIPD: University of Padua)H-Index: 17
Last. Paolo Rigotti (UNIPD: University of Padua)H-Index: 36
view all 9 authors...
The aging of the on-dialysis population raises the issue of whether to propose elderly patients for kidney transplantation and how to manage their immunosuppression. This study aims to analyze the outcome of kidney transplantation on an Italian series of elderly recipients. We included in this retrospective study all patients over 60 years, receiving a deceased-donor kidney transplantation from January 2004 to December 2014 in two north Italian Centers. We analyzed the correlation of recipient a...
11 CitationsSource
#1Krishna Karpe (Canberra Hospital)H-Index: 4
#2Girish Talaulikar (Canberra Hospital)H-Index: 13
Last. Giles Walters (Canberra Hospital)H-Index: 15
view all 3 authors...
Background Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI. Objectives This review aimed to look at the benefits and harms of CNI tapering or withdrawal...
30 CitationsSource
#1Y. Qazi (SC: University of Southern California)H-Index: 12
#2David Shaffer (VUMC: Vanderbilt University Medical Center)H-Index: 14
Last. Shamkant MulgaonkarH-Index: 29
view all 12 authors...
In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was mis...
32 CitationsSource
#2Stefan P. Berger (UMCG: University Medical Center Groningen)H-Index: 33
Last. Frederike J. BemelmanH-Index: 29
view all 17 authors...
An increasing number of elderly patients (≥65 years) receive a donor kidney from elderly donors after brain death (DBD) or after circulatory death (DCD). These organs are allocated within the Eurotransplant Senior Program, but outcomes must be evaluated. From the Dutch Organ Transplantation Registry, we selected 3597 recipients (≥18 years) who received a first DBD or DCD kidney during 2002–2012, and categorized them as young or elderly recipients receiving a graft from either a young or elderly ...
31 CitationsSource
#1Burç Dedeoglu (EUR: Erasmus University Rotterdam)H-Index: 5
#2Ruud W. J. Meijers (EUR: Erasmus University Rotterdam)H-Index: 11
Last. Michiel G. H. Betjes (EUR: Erasmus University Rotterdam)H-Index: 60
view all 7 authors...
textabstractBackground End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR). Methods 222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circul...
21 CitationsSource
#1Michiel G. H. Betjes (EUR: Erasmus University Rotterdam)H-Index: 60
CD28 is an important costimulatory molecule expressed on T cells, interacting with CD80 and CD86 on antigen-presenting cells. All naive T cells express CD28, but memory T cells may become CD28 negative (CD28neg) as a result of repetitive cell divisions, the influence of TNF-alpha, and infection with cytomegalovirus. This results in accumulation of CD28neg T cells, which may constitute >50% of the total circulating T-cell population in the elderly. The frequency of CD28neg T cells is associated w...
15 CitationsSource
#1Yunying Shi (Sichuan University)H-Index: 15
#2Dennis A. Hesselink (EUR: Erasmus University Rotterdam)H-Index: 38
Last. Teun van Gelder (EUR: Erasmus University Rotterdam)H-Index: 64
view all 3 authors...
Abstract Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are ...
13 CitationsSource
Cited By0
Newest