0041-1337/01/7109-1308/0 TRANSPLANTATION Vol. 71, 1308–1311, No. 9, May 15, 2001 Copyright © 2001 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. COMPLEMENT ACTIVATION PRODUCTS IN PLASMA AFTER HEART TRANSPLANTATION IN HUMANS 1 HEATHER VALLHONRAT, 2 WINFRED W. WILLIAMS, 3,4 G. WILLIAM DEC, 5 SALLY KECK, 5 DAVID SCHOENFELD, 6 A. BENEDICT COSIMI, 4 AND MANUEL PASCUAL 3,4,7 Renal and Transplantation Units, Heart Failure and Cardiac Transplantation Center, and Center of Biostatistics, Massachusetts General Hospital, Boston, Massachusetts 02114 Background. Complement activation has recently been implicated as a contributing factor to early and late allograft dysfunction in cardiac transplantation. The current study was designed to determine whether measurement of plasma complement fragments C4d and SC5b-9 would be useful in detecting acute rejec- tion or accelerated graft atherosclerosis (AGA) in car- diac allograft recipients. Methods. We measured complement activation prod- ucts, C4d (classical pathway) and SC5b-9 (terminal pathway), at the time of routine endomyocardial bi- opsy in heart transplant recipients. Ten patients in the immediate posttransplantation period (0 –100 days) and 19 patients more than 6 months after transplanta- tion were studied. Results. No correlation was found between plasma levels of complement activation fragments and the presence of biopsy-proven acute allograft rejection or AGA (assessed by coronary angiography). However, plasma C4d and SC5b-9 were significantly elevated in 9 of 10 and 7 of 10 patients, respectively, in the imme- diate posttransplantation period. This was followed by progressive decrease in the levels of C4d and SC5b-9 fragments during the first 4 – 6 weeks after transplantation. Conclusion. We conclude that measuring plasma lev- els of fragments C4d and SC5b-9 is not a useful nonin- vasive method for detecting acute rejection or AGA after heart transplantation. However, this study pro- vides further evidence that early complement activa- tion after heart transplantation may play a pathogenic role in allograft injury. Cardiac transplantation is now recognized as a highly ef- fective treatment for end-stage heart disease with 1-year survival rates of up to 90%. However, acute cardiac allograft rejection occurs in approximately 50 – 60% of recipients and can result in compromised allograft function or even sudden death of the patient (1). In the later posttransplantation period, accelerated graft atherosclerosis (AGA) contributes to significant morbidity and mortality in the cardiac transplant recipient. AGA is a rapidly developing obliterative vascular disease, which is irreversible and refractory to available ther- apies. Currently it is the major cause of death or retrans- plantation in cardiac transplant recipients after the first year (2). Antidonor humoral responses have been shown to play a role in both acute cardiac allograft rejection and in the de- velopment of AGA (3, 4). In particular, evidence of comple- ment activation has been demonstrated in allograft biopsies performed in the first 3 months after transplantation (4). This activation of the complement cascade may contribute to the rejection process itself, and also may result in endothelial cell activation promoting the development of AGA (5). Inter- estingly, capillary deposition of complement fragment C4d in endomyocardial biopsies has been shown to correlate with increased graft loss (6). The current study was designed to determine whether measurement of plasma complement activation fragments in cardiac allograft recipients would be useful in detecting an- tidonor humoral responses, which may manifest clinically as acute rejection or AGA. MATERIALS AND METHODS Patient Population and Immunosuppression Between February and May 1998, 10 adult patients receiving orthotopic heart transplants were prospectively studied in the early posttransplantation period. A second study group included 19 pa- tients who had received a heart transplant in the preceding 2 years but were 6 months after transplantation. Five normal volunteers who received no treatment were used as control subjects. The study was approved by the Massachusetts General Hospital Subcommittee on Human Studies, and informed consent was obtained from all patients. The indications for heart transplantation in the first group (n=10) were dilated cardiomyopathy (n=6), ischemic cardiomyopa- thy (n=3), and rheumatic heart disease (n=1). All cardiac transplant recipients received standard immunosuppression with cyclosporine, azathioprine, and prednisone (7). In patients with preoperative renal dysfunction (n=1) or postoperative acute renal dysfunction (n=1), induction therapy with OKT3 was administered for 7 to 14 days with delayed cyclosporine administration. Routine Endomyocardial Biopsy, Coronary Angiography, and Laboratory Monitoring Surveillance right ventricular endomyocardial biopsies were per- formed weekly for the first 4 weeks after transplantation, biweekly for the next 2 months, and monthly for the next 3 months. Subse- quent biopsies were performed at progressively longer intervals such that by the end of the first year biopsies were performed at 3-month 1 This work was supported in part by the Helen and George Burr endowed research and educational fund in support of transplanta- tion and by the Yates Fund for Transplant Technology. 2 Current affiliation: Washington University School of Medicine, St. Louis, MO. 3 Transplantation Unit. 4 Renal Unit. 5 Heart Failure and Cardiac Transplantation Center. 6 Department of Biostatistics. 7 Address correspondence to: Manuel Pascual, MD, Renal and Transplantation Units, Box MZ70, Massachusetts General Hospital and Harvard Medical School, Fruit Street, Boston, MA 02114. e- mail: mpascual@partners.org 1308