Ischemic Heart Disease after Renal Transplantation in Patients on Cyclosporine in Spain
Roberto Marcén*,
José María Morales,
Manuel Arias,
Gema Fernández-Juárez*,
Gema Fernández-Fresnedo,
Amado Andrés,
Emilio Rodrigo,
Julio Pascual*,
Beatriz Domínguez and
Joaquín Ortuño*
Department of Nephrology, * Ramón y Cajal and 12 de Octubre Hospitals, Madrid, and Department of Nephrology, Marqués de Valdecilla Hospital, Santander, Spain
Address correspondence to: Dr. Roberto Marcén, Servicio de Nefrología, Hospital Ramón y Cajal, Ctra Colmenar Viejo km. 9.1, 28034, Madrid, Spain. Phone: +91-336-90-17; Fax: +91-336-80-00; E-mail: rmarcen.hrc{at}salud.madrid.org
Ischemic heart disease (IHD), more common among transplant recipientsthan in the general population, accounts for approximately 50%of cardiovascular deaths. Despite its importance, only a fewpublications have addressed the prevalence of and risk factorsfor this complication. This was a retrospective cohort studyin 2382 cadaver renal transplant recipients who were treatedwith cyclosporine as initial immunosuppression. Two groups wereformed. The first group consisted of 163 patients with IHD,and the second group consisted of 326 patients without IHD.The prevalence of IHD was 6.8%, and the incidence was 15.7/1000patient-years. Cardiac events presented during the first yearin 62 (38%) patients. Multivariate analysis showed that therisk factors for IHD were age at transplant in years (relativerisk [RR] 1.054; 95% confidence interval [CI] 1.033 to 1.075;P = 0.000), male gender (RR 1.940; 95% CI 1.221 to 3.081; P= 0.005), body weight at transplant in kg (RR 1.020; 95% CI1.007 to 1.033; P = 0.002), pretransplantation cardiovasculardisease (RR 2.150; 95% CI 1.733 to 3.359; P = 0.001), and ahistory of pretransplantation hypercholesterolemia (RR 2.032;95% CI 1.378 to 2.998; P = 0.000). When only ischemic eventsthat occurred 12 mo after transplantation were taken into consideration,the risk factors were age, male gender, body weight, smoking,and pretransplantation and posttransplantation hypercholesterolemia,whereas pretransplantation cardiovascular disease disappearedfrom the model. IHD affected nearly 7% of transplant recipients.Smoking, hypertension, and hypercholesterolemia constitutedthe treatable risk factors for IHD in this population. Emphasisshould be placed on the need to stop smoking and to controlhypertension and pre- and posttransplantation levels of serumcholesterol.
Cardiovascular diseases are the most frequent cause of mortalityin both dialysis and transplant patients in Europe (1) and accountfor at least one third of all deaths (2–5). Approximately50% of these deaths in renal transplant recipients are due toischemic heart disease (IHD). This increased mortality can beexplained by the high prevalence of IHD after renal transplantationthat has been reported to be three to four times higher thanin the general population (6). Moreover, several risk factorsfor IHD that have been identified in the general population,such as older age, male gender, diabetes, previous cardiovasculardisease, smoking, and hypercholesterolemia, are very commonin transplant recipients, and they also have been identifiedas risk factors in this population (6–13). The prevalenceof IHD in the general population varies from country to country(14), and this also can be the case in transplant recipients.Despite the importance of IHD as a cause of death, data concerningthe prevalence, incidence, and risk factors are scarce, andmost of them are from North European and American countries(6–12). As a result of these considerations, the presentstudy was performed to (1) analyze the prevalence and the incidenceof IHD in a population of transplant recipients who were oncyclosporine (CsA)-based immunosuppression and (2) to determinethe risk factors that are involved in the development of thiscomplication in Spain.
Patients
We reviewed the records of 2382 cadaver renal transplant recipientsbetween January 1985 and November 1999 in three hospitals, 12de Octubre and Ramón y Cajal hospitals in Madrid andMarqués de Valdecilla hospital in Santander, in the centerand north of Spain, respectively. IHD was identified in 163recipients, and a case-control study was undertaken. Two groupsof recipients were formed: The first group consisted of 163patients with IHD, and the second group consisted of 326 controlpatients without IHD. Control patients were selected from patientswho received a transplant immediately before and immediatelyafter a patient with IHD with a similar follow-up. All patientsreceived CsA and steroids with or without azathioprine as initialtherapy. The dosages of CsA and prednisone were not significantlydifferent in each hospital. Data concerning recipients, donors,and posttransplantation outcome were reviewed retrospectively.
Definitions
The diagnosis of IHD was always made at each hospital by a cardiologist.It was defined as the presence of angina pectoris, a revascularizationprocedure, previous acute myocardial infarction (AMI), or deathattributable to IHD. Angina pectoris was diagnosed from a typicalhistory of chest pain. MI was diagnosed by a history of typicalchest pain and a significant electrocardiographic and acuteenzymatic pattern. Hypertension was diagnosed when BP was >140/90mmHg in the sitting position and/or when the patient was onantihypertensive therapy. Posttransplantation diabetes was definedaccording to the criteria of the American Diabetes Association(15). Hypercholesterolemia was diagnosed according to the NationalCholesterol Education Program guidelines (16) or when the patientswere being treated with statins or fibrates. A patient was definedas being a smoker when he or she smoked at least one cigaretteper day at the time of transplantation (8) or within 5 yr oftransplantation.
Statistical Analyses
Statistical analysis was performed with the t test for normallydistributed continuous variables and with the Mann-Whitney Utest for nonnormal variables. We used the 2 test to comparecategorical data. The Cox proportional hazard analysis was usedto determine the relationship between several known risk factorsand IHD in our population of transplant recipients. We investigatedthe risk factors for early and late (>12 mo after transplantation)posttransplantation IHD. Univariate and multivariate analyseswere performed. The variables that were included in the multivariatemodels were those that were statistically significant in theunivariate analysis and those that were found to be relevantin previous studies. Statistical significance was defined asP < 0.05. All calculations were performed on a personal computerusing the statistical software packages SPSS Base 12.0 (SPSS,Chicago, IL).
Among the 163 patients who received a diagnosis of IHD aftertransplantation and while they had a functioning graft, 62 (38.0%)experienced the cardiac event during the first 12 mo. The prevalenceof IHD was 6.8%, and the incidence was 15.7 cases/1000 patient-years.IHD presented as angina in 79 (48.7%) cases and as AMI in 84(51.7%) cases. Therefore, the prevalence of angina was 3.3%,and the incidence was 7.6 cases/1000 patient-years. AMI was3.5% and 8.1 cases/1000 patient-years, respectively. Among the62 patients who presented with IHD during the first year aftertransplantation, 29 (46%) previously had received a diagnosisof IHD. Revascularization had been performed in 10 patients.All 62 patients were asymptomatic at the time of the transplant.After transplantation, 21 revascularization procedures wereperformed, eight of them during the first year and 13 thereafter.At the time when the study was performed, 137 (28.1%) patientshad lost the graft and 81 (16.5%) patients had died: 55 (33.7%)patients from the IHD group and 31 patients from the controlgroup. Death was related to IHD in 36 (65.5%) of the patientswith IHD.
The demographic characteristics of the patients before transplantationare shown in Table 1. Patients with IHD were older, more oftenwere men with a ratio of 5.3 to 1, and had a higher body weightat the time of transplantation. Nephroangiosclerosis as primaryrenal disease was more prevalent among patients with IHD. Furthermore,they had a history of smoking, hypercholesterolemia, and cardiovasculardisease more frequently than the control patients. Donor agewas higher in the patients with IHD than in the control subjects(40.1 ± 17.1 versus 36.3 ± 17.2 yr; P = 0.023).Both posttransplantation hypercholesterolemia (77.3 versus 62.0%;P < 0.001) and posttransplantation hypertriglyceridemia (29.4versus 21.2%; P = 0.055) also were more frequent in patientswith IHD than in the control subjects. Graft function as measuredby serum creatinine at 12 mo was similar in the two groups (1.7± 0.9 versus 1.6 ± 0.8 mg/dl; P = 0.373). We alsoexamined the use of other medications at 12 mo; 53% of patientswere on calcium channel antagonists, 28.8% were on blockers,7.4% were on angiotensin-converting enzyme inhibitors, 5.8%were on vasodilators, and 8.2% were on diuretics. Furthermore,20.7% patients were on statins. There were not any differencesbetween patients with or without IHD.
Table 1. Characteristics of the patients before transplantationa
Multivariate analysis showed that age at transplantation increasedthe risk for IHD by 5% per year. Men had more than twofold higherrisk for developing IHD than women, and body weight was associatedwith a 2% increased risk for IHD per kg/m2. Hypercholesterolemiabefore transplantation and a previous history of cardiovasculardisease also were independent predictors of IHD (Table 2). Whenwe examined the risk factors for the 101 IHD events that occurred12 mo after transplantation, IHD was associated with some ofthe risk factors that were observed in the previous analysis,but pretransplantation cardiovascular disease disappeared fromthe model and smoking and hypertension before transplantationand hypercholesterolemia after transplantation entered in themodel (Table 3).
This is one of the largest cohort studies published about IHDin renal transplant recipients. The incidence of AMI in ourpatients is lower than that observed in other published series(7–9,12). The differences could be attributed partiallyto the prevalence of pretransplantation diabetes (7,8) or cardiovasculardisease before transplantation (7) and to dietetic, environmental,genetic, or other unknown factors that could reduce the riskfor development of the disease, because age at transplantation,length of follow-up, gender distribution, and immunosuppressionand prevalence of some risk factors before and after transplantationwere similar to the majority of studies. More than one thirdof the events occurred during the first year (10), which couldindicate that the disease was not under proper control at thetime of transplantation; an inadequate pretransplantation evaluationof the recipient; or stress of surgery, immunosuppression, andother factors (17). Although practice guidelines have been publishedfor the evaluation of renal transplant candidates (18,19), thereis not a definitive noninvasive screening test for this population.Moreover, the incidence of AMI was almost threefold that ofcoronary events in the general population aged 35 to 65 (14).This represents a similar increase. These findings are in agreementwith the observations of other authors (6,8).
In the multivariate analysis, the risk factors for early andlate IHD were older age, male gender, body weight, previousvascular disease, and hypercholesterolemia before transplantation.Age was an independent risk factor for IHD in several studies(6,8–12) as well as male gender (8,11,12) and obesity(7). A history of cardiovascular disease before transplantationalso was associated with IHD (11,12), but it disappeared fromthe model when only late events were analyzed. High levels oftotal cholesterol have been related to IHD in some reports (6,8),whereas, in others, HDL cholesterol levels were the factor thatcorrelated with IHD, and total and LDL cholesterol did not predictthe disease (9). Data from several studies, including the presentone, have shown the association between hyperlipidemia and IHD;consequently, it has been recommended that statins be givento graft recipients early after transplantation to reduce thecardiovascular risks (20–22). Furthermore, the use offluvastatin after transplantation was associated with a significantreduction of cardiac death and definitive nonfatal AMI in aprospective study (23).
Despite its association with IHD in the general population,hypertension was identified as a risk factor in only some seriesof transplant patients, in which the cardiovascular risk factorswere studied by multivariate analysis (11,12). This findingcan be attributed to the high percentage of transplant recipientswith hypertension both before and after transplantation, whichmakes this factor have little discriminating capacity, or tothe systematic treatment of hypertension that reduces the adverseeffects in this population. Cigarette smoking has been associatedwith posttransplantation IHD (6,7,10) and with mortality (24,25).Our data confirmed the association between smoking and IHD.Approximately 25% of our transplant patients were active cigarettesmokers at the time of transplantation. This prevalence is similarto that reported in the United States (24) and in France (13)but lower than the 40 to 56% found in other series from Europe(7).
Other risk factors for IHD, such as acute rejection, hypertriglyceridemia,graft function, and diabetes, were not associated with IHD inour series of transplant recipients. Diabetes has been identifiedsystematically as an important predictor of IHD in the generalpopulation, and its impact as a risk factor for IHD is increasedin renal transplant recipients in some studies (10). Only 4%of patients in our study had diabetes, and the relation of pretransplantationdiabetes with IHD could not be demonstrated. The lower incidenceof pretransplantation diabetes in our patients was because themajority of them received a transplant years ago, when the numberof patients who had diabetes and were included on the transplantlist was low. Graft dysfunction as measured by serum creatininewas associated with an increased cardiovascular risk in somestudies (26), but we did not observe this association. Othervariables, such as proteinuria, that have been identified asrisk factors for cardiovascular mortality in other reports (10,27)were not investigated in this study.
Our study has some limitations because it is a retrospectivestudy and the prevalence of IHD could have been underestimated.However, the similar prevalence that was obtained in the threehospitals (data not shown) makes this possibility unlikely.It is a case-control study, and the patients are compared witha reduced number of patients of the whole series, but the selectionof the control subjects took into consideration the variablesthat could influence the presence of IHD.
The prevalence of IHD in our patients is among the lowest reportedin the literature. Because a high percentage of cases manifestedearly after transplantation, it should be emphasized that effortsshould be made to diagnose and treat the disease before transplantation.Our findings confirm that several of the conventional cardiovascularrisk factors in the general population are associated with thepresence of IHD after transplantation and the appropriate treatmentof BP and hypercholesterolemia and the cessation of smokingare mandatory. Because this is a retrospective study, furtherstudies are necessary to confirm and expand our findings.
Acknowledgments
We thank Mary Harper for assistance in preparing the Englishversion of this article and Araceli Gallego for advice on thestatistics. We are grateful to Astellas Spain for scientificsupport and technical assistance.
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Abstract
Introduction
2 test to compare categorical data. The Cox proportional hazard analysis was used to determine the relationship between several known risk factors and IHD in our population of transplant recipients. We investigated the risk factors for early and late (>12 mo after transplantation) posttransplantation IHD. Univariate and multivariate analyses were performed. The variables that were included in the multivariate models were those that were statistically significant in the univariate analysis and those that were found to be relevant in previous studies. Statistical significance was defined as P < 0.05. All calculations were performed on a personal computer using the statistical software packages SPSS Base 12.0 (SPSS, Chicago, IL). 
blockers, 7.4% were on angiotensin-converting enzyme inhibitors, 5.8% were on vasodilators, and 8.2% were on diuretics. Furthermore, 20.7% patients were on statins. There were not any differences between patients with or without IHD. 
