Acute Rejection, T-CellYDepleting Antibodies, and Cancer After Transplantation Wai H. Lim, 1,6 Robin M. Turner, 2 Jeremy R. Chapman, 3 Maggie K.M. Ma, 4 Angela C. Webster, 2,3,5 Jonathan C. Craig, 2,5 and Germaine Wong 2,3,5 Background. Systemic inflammatory response has been shown to play a vital role in carcinogenesis and tumor progression. Acute rejection is a systemic inflammatory state and may share a common casual pathway for cancer development after transplantation. The increased burden of immunosuppression used in the treatment of acute re- jection, particularly the use of T-cellYdepleting antibody may further heighten the risk of cancer development. We aimed to determine the association between acute rejection, T-cellYdepleting antibody use and cancer risk after kidney transplantation. Methods. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the risk of incident cancer among those who had experienced rejection stratified by the use of T-cellYdepleting antibody using adjusted Cox proportional hazard and competing risk models. Results. A total of 7153 kidney transplant recipients between 1997 and 2009 were included. A total of 467 (6.5%) recipients developed cancers. Recipients who experienced acute rejection and treated with T-cellYdepleting antibody were at a 1.4-fold increased risk of cancer (adjusted hazard ratio [HR] 1.42, 95% CI 1.02Y1.99, P =0.039) compared with those who did not experience acute rejection. There was an excess risk of genitourinary tract cancers among recipients who had experienced rejection requiring T-cellYdepleting antibody compared with recipients who did not experience acute rejection (HR 2.20, 95% CI 1.33 Y3.66, P=0.007). Conclusion. Acute rejection requiring T-cellYdepleting antibody is a significant risk factor for cancer development in kidney transplant recipients independent of competing events such as age and cardiovascular deaths. Keywords: Cancer, Kidney Transplantation, Rejection, T-cellYdepleting antibody, Epidemiology, ANZDATA. (Transplantation 2014;00: 00Y00) C ancer is a well-established complication after kidney transplantation, but the causal pathway is incompletely understood. The risk of cancer after kidney transplantation is at least 1.5-fold higher than an age- and sex-matched popu- lation (1Y3). Analogous to other immunodeficient conditions, immunosuppression contributes to the development of cancers, particularly for virus-related neoplasms such as posttrans- plant lymphoproliferative disease (PTLD), Kaposi’s sarcoma, and cervical cancers (4 Y6). Several pretransplant patient- related factors, such as increasing time on dialysis and age, have been identified as risk factors (7). Previous studies have also shown that induction with T-cellYdepleting antibodies, such as antithymocyte and antilymphocyte globulins are asso- ciated with a higher risk of cancer after transplantation com- pared with recipients who received interleukin-2 receptor antibody (IL-2Ra) (8). T cells are critical in immune surveil- lance against foreign antigens and therefore have a critical role in the development of malignancies. Systemic inflammation including inflammatory che- mokines is a risk factor of carcinogenesis because it may lead to proliferation, angiogenesis, and metastasis in the in vitro and preclinical cancer models (9, 10). Markers of inflam- mation may also reliably predict survival in patients with advanced cancers (11). Given the proinflammatory state associated with rejection, coupled with the burden of im- munosuppression for treating rejection, it is potentially CLINICAL AND TRANSLATIONAL RESEARCH Transplantation & Volume 00, Number 00, Month 00, 2014 www.transplantjournal.com 1 The authors declare no funding or conflicts of interest. The results presented in this paper have not been published previously in whole or part, except in abstract format. 1 Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. 2 Sydney School of Public Health, University of Sydney, New South Wales, Australia. 3 Centre for Transplant and Renal Research, Westmead Hospital, New South Wales, Australia. 4 Department of Medicine, Queen Mary Hospital, Hong Kong. 5 Centre for Kidney Research, The Children’s Hospital at Westmead, New South Wales, Australia. 6 Address correspondence to: Wai H. Lim, MBBS, PhD, FRACP, Depart- ment of Renal Medicine, Sir Charles Gairdner Hospital, Hospital Avenue, Perth, Australia 6009. E-mail: wai.lim@health.wa.gov.au All authors participated in designing the research/study, analyzing data, and writing the paper. Received 30 September 2013. Revision requested 15 October 2013. Accepted 12 December 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/0000-00 DOI: 10.1097/01.TP.0000442773.38510.32 Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.