International Urology and Nephrology (2019) 51:2063–2072 https://doi.org/10.1007/s11255-019-02251-w NEPHROLOGY - ORIGINAL PAPER Outcomes of sirolimus regimens in 65‑year‑old and older kidney transplant recipients: a registry‑based observational study Alfonso H. Santos Jr.1 · Chao Chen2 · Kawther Alquadan1 · Xuerong Wen3 Received: 28 April 2019 / Accepted: 29 July 2019 / Published online: 5 August 2019 © Springer Nature B.V. 2019 Abstract Purpose In large observational studies of adult kidney transplant recipients (KTRs) where older adults (65 years old and older) were not well represented, the mammalian target of rapamycin inhibitors (mTOR inhibitors) has poorer outcomes than the standard tacrolimus–mycophenolate–steroids (TAC–MPA–S) regimen. We conducted this study to compare the outcomes of regimens containing the common mTOR inhibitor, sirolimus (SRL) against TAC–MPA–S in older adult KTRs. Methods Using the 2000–2016 Scientifc Registry of Transplant Recipients, Cox multivariable regression models were conducted to analyze the patient and graft outcomes associated with regimens containing SRL, steroids (S) and cyclosporine (CSA), tacrolimus (TAC), or mycophenolate (MPA) vs. the standard (TAC–MPA–S) regimen in older adult KTRs. Results Included in the analysis were 15,008 (95.19%) older adult KTRs on standard (TAC–MPA–S) regimen, 242 (1.53%) on SRL–MPA–S, 300 (1.90%) on SRL–TAC–S, and 217 (1.38%) on SRL–CSA–S. Compared with the standard regimen, the adjusted risks of all-cause death and overall graft loss over a maximum 5-year follow-up were highest with SRL–MPA–S, intermediate with SRL–TAC–S and not signifcantly diferent with SRL–CSA–S. The adjusted risks of all-cause death and overall graft loss were modifed by a pre-transplant history of malignancy in older adult KTRs on SRL–TAC–S, not in those on SRL–MPA–S or SRL–CSA–S. Conclusions In older adult kidney transplant recipients, SRL–TAC–S or SRL–MPA–S, but not SRL–CSA–S is associated with higher risks of death and allograft loss than standard TAC–MPA–S regimen and a pre-transplant malignancy history worsens these risks in patients on SRL–TAC–S. Confrmation of our fndings by a prospective randomized trial is needed before translation into clinical practice can be recommended. Keywords Sirolimus · Outcomes · Older adult kidney transplants Introduction transplantation over dialysis seen in younger KTRs have also been demonstrated in older adult KTRs [2]. However, Over the past decade, kidney transplantation in older adults except for a few studies, the outcomes of specifc immuno- (65 years old and older) has steadily increased. In 2017, suppression regimens have not been well studied in older 18.5% of KTRs were 65 years old and older [1]. The sur- adult KTRs who were either under-represented or excluded vival, quality of life, and economic advantages of kidney in clinical trials of rejection prophylaxis drugs [3–6]. With the lack of evidence to support optimal immunosuppression regimen in older adult KTRs, it has been customary to use * Alfonso H. Santos Jr. the standard immunosuppression regimen for patients in this [email protected] age category [6, 7]. While the standard immunosuppression 1 Division of Nephrology, Hypertension and Renal regimen (consisting of a calcineurin inhibitor, mycopheno- Transplantation, Department of Medicine, College late, and prednisone) is deemed efcacious and safe in pre- of Medicine, University of Florida, 1600 SW Archer Road, venting allograft rejection, in a minority of KTRs, compel- Medical Science Bldg, NG-4, Gainesville, FL 32610, USA ling medical indications constrain the use of an alternative 2 Department of Pharmaceutical Outcomes and Policy, College regimen such as an mTOR inhibitor [7–9]. of Pharmacy, University of Florida, Gainesville, FL, USA mTOR inhibitor drugs have been used to reduce the risk 3 Department of Pharmacy Practice, College of Pharmacy, of or adjunctly manage malignancies, viral infections, and University of Rhode Island, Kingston, RI, USA Vol.:(0123456789)1 3 2064 International Urology and Nephrology (2019) 51:2063–2072 calcineurin-induced nephrotoxicity in transplant recipients Rhode Island Institutional Review Board. The SRTR sys- [9–12]. By their pleiotropic anti-atherosclerotic properties, tem includes data on all donors, waitlisted candidates, and the mTOR inhibitors prevent or delay the progression of transplant recipients in the United States, submitted by the vasculopathy after kidney transplantation [13–19]. Siroli- members of the Organ Procurement and Transplantation mus (SRL) is the most common mTOR inhibitor given to Network and has been described elsewhere. The Health KTRs in the US [8]. Despite its putative benefts mentioned Resources and Services Administration provides oversight above, large non-randomized studies have shown that SRL into the activities of the Organ Procurement and Transplan- is associated with inferior graft and (or) patient outcomes in tation Network and SRTR contractors. kidney transplantation [20–23]. The caveat though is those Collected data on clinically relevant covariates chosen studies have not included enough 65-year-old and older a priori [24] are enumerated in Table 1 including mainte- KTRs, so that the patient and allograft survival outcomes nance immunosuppression regimen, history of coronary of SRL regimens in older adult KTRs remains unclear [6]. It artery disease or equivalent risk [25, 26]; era of transplan- is crucial to determine the outcomes of SRLs in older adult tation 2000–2009 or 2010–2015; history of any type of KTRs who are predisposed to infections, malignancies, and malignancy pre-transplant; history of delayed graft function progression of atherosclerotic diseases: complications of (DGF) defned as the need for dialysis within the 1st week immunosuppression that could be attenuated by an mTOR following transplant; immunosuppression induction agent inhibitor [10–12]. We hypothesized that by its anti-neoplas- classifed as anti-thymocyte globulin (ATG), alemtuzumab, tic, -atherosclerotic, and -viral properties, SRL provides interleukin-2-receptor blocker, none, or others; peak panel greater patient and allograft survival benefts than the stand- reactive antibody (PRA) percent before transplant stratifed ard tacrolimus, mycophenolate and steroids (TAC–MPA–S) as < 50% or >/=50%; number of human leukocyte antigen regimen in older adult KTRs. Therefore, we conducted this (HLA) mismatches between donor and recipient, stratifed study to compare the outcomes of SRL regimens against as </=3, > 3, or unknown; primary native renal diagnosis standard TAC–MPA–S in older adult KTRs. We secondarily classifed as diabetes mellitus, glomerulonephritis, hyperten- aimed to determine the modifying infuence, if any, of a pre- sion or other; duration of pre-transplant maintenance dialy- transplant history of malignancy on the outcomes of SRL sis stratifed into </=2 years, > 2 years, or none; and donor regimens in older adult KTRs. The fndings of this research type classifed as: (1) expanded criteria donor (ECD) if the when confrmed by further studies could be useful in guiding deceased donor met the following criteria: age >/= 60 years the use of SRL-containing immunosuppression regimens in or 50–59 years of age with any two of the following: ter- older adult KTRs with compelling indications for avoidance minal creatinine > 1.5 mg/dl, history of hypertension, or of the standard regimen. cardiovascular accident as the cause of death; (2) standard deceased donor, if the deceased donor does not meet the criteria for an ECD above; and (3) living donor [27]. Method Exposure and outcomes Study population Patients who received their kidney transplant between This study included 15,767 patients aged 65 years old and January 1, 2000 and May 31, 2015 and qualified for the older that received a kidney-only transplant (KT) in the study based on the inclusion and exclusion criteria were United States between January 1, 2000 and May 31, 2015 included in the analysis and followed after the 12th month and survived with a functioning allograft in the frst trans- of transplant until the first of the following events: death, plant year. Patients were included if they were on one of the end of 5-year maximum follow-up, end of SRTR follow- study (sirolimus, tacrolimus and prednisone, SRL–TAC–S; up, or 1 June 2016. The primary exposure was the use of sirolimus, cyclosporine, and steroids, SRL–CSA–S; or a sirolimus regimen: (A) SRL–MPA–S, (B) SRL–TAC–S, sirolimus, mycophenolate and steroids, SRL–MPA–S) or or (C) SR–CSA–S consistently for at least 6 months reference (TAC–MPA–S) maintenance immunosuppression immediately before and through the 12th month of trans- regimens continuously for at least 6 months immediately plant based on the SRTR immunosuppression records. preceding and including the 12th month of kidney transplant TAC–MPA–S was the reference regimen. The primary as previously described [23]. study outcomes were: (1) overall graft loss, defined as death from all causes or non-death graft loss defined as Data collection the return to dialysis or re-transplantation; and (2) all- cause death. Secondary outcomes were overall graft loss This study used data from the Scientifc Registry of Trans- and all-cause death in the subgroups with and without a plant Recipients (SRTR) as approved by the University of pre-transplant history of malignancy. The methodology 1 3 International Urology and Nephrology (2019) 51:2063–2072 2065 Table 1 Demographic and transplant-related characteristics