Ischemic Heart Disease after Renal Transplantation in Patients ... - JASN

Ischemic Heart Disease after Renal Transplantation in Patients on Cyclosporine in Spain Roberto Marceń,* Jose´ Marıá Morales,† Manuel Arias,‡ Gema Fernańdez-Jua´rez,* Gema Fernańdez-Fresnedo,‡ Amado Andre´s,† Emilio Rodrigo,‡ Julio Pascual,* Beatriz Domıńguez,† and Joaquıń Ortunõ* Department of Nephrology, *Ramoń y Cajal and †12 de Octubre Hospitals, Madrid, and ‡Department of Nephrology, Marque´s de Valdecilla Hospital, Santander, Spain Ischemic heart disease (IHD), more common among transplant recipients than in the general population, accounts for approximately 50% of cardiovascular deaths. Despite its importance, only a few publications have addressed the prevalence of and risk factors for this complication. This was a retrospective cohort study in 2382 cadaver renal transplant recipients who were treated with cyclosporine as initial immunosuppression. Two groups were formed. 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 15.7/1000 patient-years. Cardiac events presented during the first year in 62 (38%) patients. Multivariate analysis showed that the risk factors for IHD were age at transplant in years (relative risk [RR] 1.054; 95% confidence interval [CI] 1.033 to 1.075; P ⴝ 0.000), male gender (RR 1.940; 95% CI 1.221 to 3.081; P ⴝ 0.005), body weight at transplant in kg (RR 1.020; 95% CI 1.007 to 1.033; P ⴝ 0.002), pretransplantation cardiovascular disease (RR 2.150; 95% CI 1.733 to 3.359; P ⴝ 0.001), and a history of pretransplantation hypercholesterolemia (RR 2.032; 95% CI 1.378 to 2.998; P ⴝ 0.000). When only ischemic events that 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 disappeared from the model. IHD affected nearly 7% of transplant recipients. Smoking, hypertension, and hypercholesterolemia constituted the treatable risk factors for IHD in this population. Emphasis should be placed on the need to stop smoking and to control hypertension and pre- and posttransplantation levels of serum cholesterol. J Am Soc Nephrol 17: S286 –S290, 2006. doi: 10.1681/ASN.2006080928

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ardiovascular diseases are the most frequent cause of mortality in both dialysis and transplant patients in Europe (1) and account for at least one third of all deaths (2–5). Approximately 50% of these deaths in renal transplant recipients are due to ischemic heart disease (IHD). This increased mortality can be explained by the high prevalence of IHD after renal transplantation that has been reported to be three to four times higher than in the general population (6). Moreover, several risk factors for IHD that have been identified in the general population, such as older age, male gender, diabetes, previous cardiovascular disease, smoking, and hypercholesterolemia, are very common in transplant recipients, and they also have been identified as risk factors in this population (6 –13). The prevalence of 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 concerning the prevalence, incidence, and risk factors are scarce, and most of them are from North European and American countries (6 –12). As a result of these considerations, the present study was performed to (1) analyze the prevalence and the incidence of IHD in a population of trans-

Address correspondence to: Dr. Roberto Marceń, Servicio de Nefrologıá, Hospital Ramoń y Cajal, Ctra Colmenar Viejo km. 9.1, 28034, Madrid, Spain. Phone: ⫹91-336-90-17; Fax: ⫹91-336-80-00; E-mail: [email protected] Copyright © 2006 by the American Society of Nephrology

plant recipients who were on cyclosporine (CsA)-based immunosuppression and (2) to determine the risk factors that are involved in the development of this complication in Spain.

Materials and Methods Patients We reviewed the records of 2382 cadaver renal transplant recipients between January 1985 and November 1999 in three hospitals, 12 de Octubre and Ramoń y Cajal hospitals in Madrid and Marque´s de Valdecilla hospital in Santander, in the center and north of Spain, respectively. IHD was identified in 163 recipients, and a case-control study was undertaken. Two groups of recipients were formed: The first group consisted of 163 patients with IHD, and the second group consisted of 326 control patients without IHD. Control patients were selected from patients who received a transplant immediately before and immediately after a patient with IHD with a similar follow-up. All patients received CsA and steroids with or without azathioprine as initial therapy. The dosages of CsA and prednisone were not significantly different 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 revascularization procedure, previous acute myocardial infarction (AMI), or death attributable to IHD. Angina pectoris was diagnosed from a typical history of chest pain. MI was diagnosed by a history of typical ISSN: 1046-6673/1712-0286

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chest pain and a significant electrocardiographic and acute enzymatic pattern. Hypertension was diagnosed when BP was ⬎140/90 mmHg in the sitting position and/or when the patient was on antihypertensive therapy. Posttransplantation diabetes was defined according to the criteria of the American Diabetes Association (15). Hypercholesterolemia was diagnosed according to the National Cholesterol Education Program guidelines (16) or when the patients were being treated with statins or fibrates. A patient was defined as being a smoker when he or she smoked at least one cigarette per day at the time of transplantation (8) or within 5 yr of transplantation.

Statistical Analyses Statistical analysis was performed with the t test for normally distributed continuous variables and with the Mann-Whitney U test for nonnormal variables. We used the ␹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).

Results Among the 163 patients who received a diagnosis of IHD after transplantation and while they had a functioning graft, 62 (38.0%) experienced the cardiac event during the first 12 mo. The prevalence of 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 was 3.5% and 8.1 cases/1000 patient-years, respectively. Among the 62 patients who presented with IHD during the first year after transplantation, 29 (46%) previously had received a diagnosis of IHD. Revascularization had been performed in 10 patients. All 62 patients were asymptomatic at the time of the transplant. After transplantation, 21 revascularization procedures were performed, eight of

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them during the first year and 13 thereafter. At the time when the study was performed, 137 (28.1%) patients had lost the graft and 81 (16.5%) patients had died: 55 (33.7%) patients from the IHD group and 31 patients from the control group. Death was related to IHD in 36 (65.5%) of the patients with IHD. The demographic characteristics of the patients before transplantation are shown in Table 1. Patients with IHD were older, more often were men with a ratio of 5.3 to 1, and had a higher body weight at the time of transplantation. Nephroangiosclerosis as primary renal disease was more prevalent among patients with IHD. Furthermore, they had a history of smoking, hypercholesterolemia, and cardiovascular disease more frequently than the control patients. Donor age was 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 (29.4 versus 21.2%; P ⫽ 0.055) also were more frequent in patients with IHD than in the control subjects. Graft function as measured by 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 also examined the use of other medications at 12 mo; 53% of patients were 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 differences between patients with or without IHD. Multivariate analysis showed that age at transplantation increased the risk for IHD by 5% per year. Men had more than twofold higher risk for developing IHD than women, and body weight was associated with a 2% increased risk for IHD per kg/m2. Hypercholesterolemia before transplantation and a previous history of cardiovascular disease also were independent predictors of IHD (Table 2). When we examined the risk factors for the 101 IHD events that occurred 12 mo after transplantation, IHD was associated with some of the risk factors that were observed in the previous analysis, but pretransplantation cardiovascular disease disappeared from the model and smoking

Table 1. Characteristics of the patients before transplantationa

a

Characteristic

IHD (n ⫽ 163)

No-IHD (n ⫽ 326)

P

Age of recipient (yr) Gender (M/F) Time on dialysis (mo) Body weight at transplantation (kg) Nephroangiosclerosis (yes/no) Diabetes (yes/no) Hypertension (yes/no) Hypercholesterolemia (yes/no) Smoking at transplantation (yes/no)b Cardiovascular disease (yes/no)

50.7 ⫾ 0.7 137/26 40.8 ⫾ 37.8 67.5 ⫾ 13.5 36/127 10/153 114/49 61/102 52/69 43/120

43.7 ⫾ 13.0 213/113 41.9 ⫾ 39.3 63.6 ⫾ 10.9 28/298 11/315 212/114 65/261 43/222 27/299

0.000 0.000 0.750 0.000 0.000 0.237 0.322 0.000 0.000 0.000

IHD, ischemic heart disease. Data available in 79% of cases.

b

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Table 2. Risk factors for IHD events: Cox proportional hazards modela

a

Risk Factor

RR

Age at transplantation (yr) Male gender (male ⫽ 1) Body weight at transplantation (kg) Cardiovascular diseases before transplantation (yes ⫽ 1) Hypercholesterolemia before transplantation (yes ⫽ 1)

1.054 1.940 1.020 2.150 2.032

95% CI

1.033 1.221 1.007 1.377 1.378

to to to to to

1.075 3.081 1.033 3.359 2.998

P

0.000 0.005 0.002 0.001 0.000

CI, confidence interval; RR, relative risk.

and hypertension before transplantation and hypercholesterolemia after transplantation entered in the model (Table 3).

Discussion This is one of the largest cohort studies published about IHD in renal transplant recipients. The incidence of AMI in our patients is lower than that observed in other published series (7–9,12). The differences could be attributed partially to the prevalence of pretransplantation diabetes (7,8) or cardiovascular disease before transplantation (7) and to dietetic, environmental, genetic, or other unknown factors that could reduce the risk for development of the disease, because age at transplantation, length of follow-up, gender distribution, and immunosuppression and prevalence of some risk factors before and after transplantation were similar to the majority of studies. More than one third of the events occurred during the first year (10), which could indicate that the disease was not under proper control at the time of transplantation; an inadequate pretransplantation evaluation of the recipient; or stress of surgery, immunosuppression, and other factors (17). Although practice guidelines have been published for the evaluation of renal transplant candidates (18,19), there is not a definitive noninvasive screening test for this population. Moreover, the incidence of AMI was almost threefold that of coronary events in the general population aged 35 to 65 (14). This represents a similar increase. These findings are in agreement with the observations of other authors (6,8). In the multivariate analysis, the risk factors for early and late IHD were older age, male gender, body weight, previous vascular 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 transplantation also

was associated with IHD (11,12), but it disappeared from the model when only late events were analyzed. High levels of total cholesterol have been related to IHD in some reports (6,8), whereas, in others, HDL cholesterol levels were the factor that correlated with IHD, and total and LDL cholesterol did not predict the disease (9). Data from several studies, including the present one, have shown the association between hyperlipidemia and IHD; consequently, it has been recommended that statins be given to graft recipients early after transplantation to reduce the cardiovascular risks (20 –22). Furthermore, the use of fluvastatin after transplantation was associated with a significant reduction of cardiac death and definitive nonfatal AMI in a prospective study (23). Despite its association with IHD in the general population, hypertension was identified as a risk factor in only some series of transplant patients, in which the cardiovascular risk factors were studied by multivariate analysis (11,12). This finding can be attributed to the high percentage of transplant recipients with hypertension both before and after transplantation, which makes this factor have little discriminating capacity, or to the systematic treatment of hypertension that reduces the adverse effects in this population. Cigarette smoking has been associated with 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 cigarette smokers at the time of transplantation. This prevalence is similar to 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 in our series of transplant recipients. Diabetes has been identified systematically as an important predictor of IHD

Table 3. Risk factors for IHD events that occurred after 1 yr of renal transplantation Risk Factor

RR

Age at transplantation (yr) Male gender (male ⫽ 1) Body weight at transplantation (kg) Hypertension before transplantation (yes ⫽ 1) Smoking at transplantation (yes ⫽ 1) Hypercholesterolemia before transplantation (yes ⫽ 1) Hypercholesterolemia after transplantation (yes ⫽ 1)

1.050 2.154 1.020 1.765 1.920 1.706 2.132

95% CI

1.026 1.166 1.005 0.998 1.157 1.018 1.155

to to to to to to to

1.075 3.979 1.035 3.124 3.185 2.860 5.105

P

0.000 0.014 0.009 0.051 0.012 0.043 0.049


in the general population, and its impact as a risk factor for IHD is increased in renal transplant recipients in some studies (10). Only 4% of patients in our study had diabetes, and the relation of pretransplantation diabetes with IHD could not be demonstrated. The lower incidence of pretransplantation diabetes in our patients was because the majority of them received a transplant years ago, when the number of patients who had diabetes and were included on the transplant list was low. Graft dysfunction as measured by serum creatinine was associated with an increased cardiovascular risk in some studies (26), but we did not observe this association. Other variables, such as proteinuria, that have been identified as risk factors for cardiovascular mortality in other reports (10,27) were not investigated in this study. Our study has some limitations because it is a retrospective study and the prevalence of IHD could have been underestimated. However, the similar prevalence that was obtained in the three hospitals (data not shown) makes this possibility unlikely. It is a case-control study, and the patients are compared with a reduced number of patients of the whole series, but the selection of the control subjects took into consideration the variables that could influence the presence of IHD.

Conclusion The prevalence of IHD in our patients is among the lowest reported in the literature. Because a high percentage of cases manifested early after transplantation, it should be emphasized that efforts should be made to diagnose and treat the disease before transplantation. Our findings confirm that several of the conventional cardiovascular risk factors in the general population are associated with the presence of IHD after transplantation and the appropriate treatment of BP and hypercholesterolemia and the cessation of smoking are mandatory. Because this is a retrospective study, further studies are necessary to confirm and expand our findings.

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5. 6. 7.

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14.

15.

16.

Acknowledgments We thank Mary Harper for assistance in preparing the English version of this article and Araceli Gallego for advice on the statistics. We are grateful to Astellas Spain for scientific support and technical assistance.

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