Article Mammalian Target of Rapamycin Inhibitors and Clinical Outcomes in Adult Kidney Transplant Recipients | Sunil V. Badve,*†‡ Elaine M. Pascoe,* Michael Burke,§ Philip A. Clayton, ¶ Scott B. Campbell,§ Carmel M. Hawley,*§ | Wai H. Lim,** Stephen P. McDonald, ¶ Germaine Wong,†† and David W. Johnson*§ Abstract Background and objectives Emerging evidence from recently published observational studies and an individual – *Australasian Kidney patient data meta analysis shows that mammalian target of rapamycin inhibitor use in kidney transplantation Trials Network, School is associated with increased mortality. Therefore, all-cause mortality and allograft loss were compared of Medicine, between use and nonuse of mammalian target of rapamycin inhibitors in patients from Australia and New University of Zealand, where mammalian target of rapamycin inhibitor use has been greater because of heightened skin Queensland, cancer risk. Brisbane, Australia; †Department of Nephrology, Design, setting, participants, & measurements Our longitudinal cohort study included 9353 adult patients who St. George Hospital, underwent 9558 kidney transplants between January 1, 1996 and December 31, 2012 and had allograft survival Sydney, Australia; ‡ $1 year. Risk factors for all-cause death and all–cause and death–censored allograft loss were analyzed by Renal and Metabolic Division, The George multivariable Cox regression using mammalian target of rapamycin inhibitor as a time-varying covariate. fi Institute for Global Additional analyses evaluated mammalian target of rapamycin inhibitor use at xed time points of baseline and Health, Sydney, 1year. Australia; §Department of Results Patients using mammalian target of rapamycin inhibitors were more likely to be white and have a history Nephrology, Princess Alexandra Hospital, of pretransplant cancer. Over a median follow-up of 7 years, 1416 (15%) patients died, and 2268 (24%) allografts Brisbane, Australia; | were lost. There was a higher risk of all-cause mortality with time–varying mammalian target of rapamycin The Australia and inhibitor use (hazard ratio, 1.47; 95% confidence interval, 1.23 to 1.76) as well as in the fixed time model analyses New Zealand Dialysis comparing mammalian target of rapamycin inhibitor use at baseline (hazard ratio, 1.54; 95% confidence interval, and Transplant fi – Registry, Adelaide, 1.22 to 1.93) and 1 year (hazard ratio, 1.63; 95% con dence interval, 1.32 to 2.01). Time varying mammalian target Australia; ¶Central of rapamycin inhibitor use was associated with higher risk of death because of malignancy (hazard ratio, 1.37; Northern Adelaide 95% confidence interval, 1.09 to 1.71). There were no statistically significant differences in the risk of all–cause Renal and (hazard ratio, 0.98; 95% confidence interval, 0.85 to 1.12) and death–censored (hazard ratio, 0.85; 95% confidence Transplantation interval, 0.69 to 1.03) allograft loss between the mammalian target of rapamycin inhibitor use and nonuse groups Service, School of fi Medicine, University in the time-varying model as well as the xed time models. of Adelaide, Adelaide, Australia; Conclusions Mammalian target of rapamycin inhibitor use was associated with a higher risk of all-cause mortality **Department of but not allograft loss. Renal Medicine, Sir Clin J Am Soc Nephrol – Charles Gairdner 11: 1845 1855, 2016. doi: 10.2215/CJN.00190116 Hospital, Perth, Australia; and ††Center for Kidney Research, The Introduction nonskin cancer malignancies after kidney transplanta- Children’s Hospital at Mammalian target of rapamycin (mTOR) inhibitors tion (1,6,7). A Scientific Registry of Renal Transplant Westmead, Sydney, sirolimus and everolimus are commonly prescribed Recipients (SRTR) study reported significantly higher Australia maintenance immunosuppressive agents in kidney risks of death and graft loss with sirolimus versus transplantation. Randomized trials with short–term tacrolimus use (8). Subsequently, a Hungarian study Correspondence: follow-up have shown that de novo or delayed intro- Dr. Sunil V. Badve, reported a higher mortality risk with mTOR inhibitor Department of duction of mTOR inhibitors with and without calci- use (9). A United Network for Organ Sharing (UNOS) Nephrology, The neurin inhibitors is associated with increased risks of study also reported higher risks of death and graft St. George Hospital, rejection, hyperlipidemia, proteinuria, and delayed loss with mTOR inhibitor versus calcineurin inhibitor Suite 1, 50 wound healing. Compared with calcineurin inhibi- use (10). More recently, an individual patient data Montgomery Street, – Kogarah, New South tors, mTOR inhibitors have been shown to achieve meta analysis using data from 21 randomized trials Wales 2217, Australia. superior allograft function up to 5 years after trans- showed that sirolimus was associated with a 43% Email: sbadve@ plantation and are associated with reduced risks of higher risk of all-cause death compared with in con- georgeinstitute.org.au cytomegalovirusandBKvirusinfections(1–5). trols (7). mTOR inhibitors have been shown to reduce the Because of heightened skin cancer risk, the use of risk of nonmelanoma skin cancers (NMSCs) and mTOR inhibitors is greater in Australia than in the www.cjasn.org Vol 11 October, 2016 Copyright © 2016 by the American Society of Nephrology 1845 1846 Clinical Journal of the American Society of Nephrology United States (11,12). Therefore, the aim of this study was validation are described in detail on the ANZDATA Reg- to compare all–cause patient mortality and all–cause and istry website (http://www.anzdata.org.au). The data col- death–censored allograft loss in kidney transplant recipi- lected include demographic details; comorbidities; history ents treated with or without mTOR inhibitors using data of pretransplant cancer; donor- and transplant-related from the Australia and New Zealand Dialysis and Trans- characteristics; the number, type, and treatment of rejec- plant (ANZDATA) Registry. tion episodes; nonskin tumors; melanomas; and skin tu- mors. The information about immunosuppressive Materials and Methods medications and serum creatinine is collected at 1, 2, 3, and6months;1,2,3,5,7,and10yearsaftertransplant Study Population The study included a total of 9353 adult patients with surgery; and every 5 years thereafter. Exact start and end ESRD who underwent 9558 living and deceased donor dates of immunosuppressive medications and blood drug kidney transplants in Australia and New Zealand between concentrations are not collected. Information on how the January 1, 1996 and December 31, 2012 whose allograft causes of death and graft loss are categorized by the ANZ- survived at least 1 year. Patients were excluded if they were DATA Registry is described in Supplemental Table 1. younger than 18 years old at transplantation, were multi- organ transplant recipients, or had received their first Study Outcomes kidney transplant before January 1, 1996. The primary study outcomes were all-cause mortality and all–cause allograft loss. Secondary study outcomes Data Collection were death with functioning graft, death after graft loss, – fi The ANZDATA Registry collects data in accordance with death censored allograft loss, cause-speci c mortality, and – fi the Australian Commonwealth Privacy Act and associated cause speci c allograft loss. All analyses, except death state legislation governing health data collection, and with functioning graft and death after graft loss, included fi individual opt–in patient consent is not required for the rst as well as repeat kidney transplants. registry data. This analysis was performed on an anonymized extract released by the registry to researchers. The clinical Statistical Analyses and research activities being reported are consistent with For the purpose of describing the baseline characteristics, the Principles of the Declaration of Istanbul as outlined in the study population was divided into four groups: (1) the Declaration of Istanbul on Organ Trafficking and never treated with mTOR inhibitor (never used group), Transplant Tourism. The methods of data collection and (2) treated with mTOR inhibitor–based immunosuppressive Table 1. Baseline patient characteristics by mammalian target of rapamycin inhibitor use Early Late Variable Never Used Baseline Use Total P Value Conversion Conversion N 7801 481 504 567 9353 Men 4820 (62) 315 (65) 315 (63) 379 (67) 5829 (62) 0.05 Age, yr, mean6SD 47.1613.2 44.9612.4 48.6612.8 45.9613.1 47613.1 ,0.001 Ethnicity ,0.001 White 6295 (81) 437 (91) 429 (85) 486 (86) 7647 (82) ATSI 234 (3) 5 (1) 18 (4) 15 (3) 272 (3) Maori/PI 403 (5) 1 (,1) 8 (2) 9 (2) 421 (5) Asian 451 (6) 22 (5) 31 (6) 33 (6) 537 (6) Other 418 (5) 16 (3) 18 (4) 24 (4) 476 (5) Primary cause of ESRDa 0.004 Chronic glomerulopathy 3741 (48) 247 (51) 265 (53) 271 (48) 4524 (48) Diabetic nephropathy 758 (10) 29 (6) 31 (6) 34 (6) 852 (9) Renovascular disease 456 (6) 29 (6) 25 (5) 31 (5) 541 (6) Polycystic kidney disease 1203 (15) 88 (18) 88 (17) 89 (16) 1468 (16) Reflux or obstructive 863 (11) 55 (11) 47 (9) 74 (13) 1039 (11) nephropathy Other 441 (6) 21 (4) 29 (6) 41 (7) 532 (6) Unknown 333 (4) 12 (2) 19 (4) 27 (5) 391 (4) Comorbid conditiona Current or former smoker 3379 (44) 211 (44) 229 (46) 234 (41) 4053 (44) 0.50 Chronic lung disease 355 (5) 24 (5) 23 (5) 24 (4) 426 (5) 0.90 Cardiovascular disease 1148 (15) 50 (10) 64 (13) 62 (11) 1324 (14) 0.004 Diabetes mellitus 1026 (13) 46 (10) 58 (12) 46 (8) 1176 (13) 0.001 Cancer 2298 (29) 185 (38) 147 (29) 261 (46) 2891 (31) ,0.001 All