Role of ACE Gene Polymorphism on Cardiovascular Complications After Renal Transplantation D. Herna ´ndez, J. Linares, E. Salido, M. Cobo, A. Rodrı´guez, V. Lorenzo, A. Jime ´ nez, J. Gonza ´ lez-Posada, and A. Torres C ARDIOVASCULAR disease is the major cause of death in renal transplant patients, and an interaction between traditional vascular risk factors and genetic factors may have an important role in this population. 1 On the other hand, the ACE gene (I/D) polymorphism has been associated with cardiovascular complications (CVC), in- cluding left ventricular hypertrophy. 2,3 Subjects with the DD genotype show the highest levels of ACE and angio- tensin II, and these substances play a central role in the pathogenesis of atherosclerosis. 4 However, the influence of this polymorphism on long-term CVC after renal transplan- tation (RT) has been little explored. Thus, this cross-sectional study was performed to inves- tigate the role of ACE gene polymorphisms on CVC after RT, and second to assess the influence of traditional vascular risk factors on CVC after RT. PATIENTS AND METHODS In this retrospective, analysis we included all transplant patients from our clinic who met the following criteria: (1) A functioning graft for at least 1 year; and (2) CsA-based immunossuppression. To analyze the factors inherent to RT, we excluded patients who developed CVC during the first year posttransplant. A total of 207 patients were finally included. Immunossupressive therapy was similar in all patients and consisted of sequential induction therapy with antithymocyte globulin (ATGAM, Upjohn) or OKT3, and CsA, prednisone and azathioprine for maintenance. Episodes of acute rejection were initially treated with three boluses of 500 mg of IV methylprednisolone. Endpoints Assesment of cardiovascular events was performed following RT. Thus, ischemic heart disease (IHD), stroke, and peripheral vascu- lar disease (PVD) were defined by standard criteria. 1 Deaths attributable to CVC were also registered. Predictor Variables Demographic and clinical data recorded at the time of RT included age, gender, cause of end-stage renal disease, body mass index (kg/m 2 ), donor age, prior transplant, previous blood transfusions, panel reactive antibodies, number of ABDR mismatches, delayed graft function, and smoking history. In addition, pretransplant cardiovascular status was evaluated. Following renal transplantion, we recorded biochemical data and major events such as acute rejection and the development of de novo diabetes, dyslipidemia, or hypertension. Genomic Typing of the ACE Deletion/Insertion Polymorphism The ACE genotype (I or D allele) was ascertained by polymerase chain reaction amplification of a fragment of intron 16 of the ACE gene, as previosusly reported. 5 All samples yielding exclusive amplification of the D allele were subjected to a second indepen- dent amplification. 5 Statistical Analysis Categorical variables were analyzed using chi-square test or Fish- er’s exact probability test as appropriate. For univariate compari- sons of numerical variables t test was used. Stepwise logistic regression was performed to identify predictor factor of CVC. Values are expressed as mean  SD, and P  .05 was considered significant. RESULTS No patient suffered CVC before RT, although 50 patients (24%) showed clinical data consistent with artherosclerotic disease (vascular murmurs or arterial calcifications). Seven- ty-seven patients (37%) suffered some symptomatic CVC after RT: 22 IHD (10.6%), 7 stroke (3.4%), and 58 PVD (28%), 10 of whom were associated with IHD or stroke. Moreover, 6 patients died of these events. Not surprins- ingly, patients who developed CVC were older and more likely to be diabetic, hypertensive, and to have dyslipidemic disorders (Table 1). Likewise, male gender and pretrans- plant atherosclerosis were more frequent in these patients (Table 1). Interestingly, DD genotype of the ACE polymor- phism was over-represented in the group with CVC (Table 1). By multivariate analysis, the DD genotype was an independent risk factor for CVC and increased the proba- From the Nephrology Section and Research Unit. Hospital Universitario de Canarias, Tenerife, Spain. Supported by grant (PI 71/98) from Consejerı´a de Sanidad y Consumo; Fundacio ´ n Canaria de Investigacio ´ n y Salud (FUN- CIS); Gobierno de Canarias) and FEDER 1FD97-1781. Address reprint requests to Domingo Herna ´ ndez, Urbaniza- cio ´ n San Diego, 51, 38208 La Laguna. Tenerife. Canary Islands, Spain. E-mail: dhmarrero@hotmail.com. 0041-1345/01/$–see front matter © 2001 by Elsevier Science Inc. PII S0041-1345(01)02503-9 655 Avenue of the Americas, New York, NY 10010 3686 Transplantation Proceedings, 33, 3686–3687 (2001)