Predictor

Predictors of Cardiovascular Events and Associated Mortality of Kidney Transplant Recipients A. Fazelzadeh, A.R. Mehdizadeh, M.A. Ostovan, and G.A. Raiss-Jalali ABSTRACT Background. Cardiovascular disease is the most common cause of death after renal transplantation. Furthermore, acute coronary syndrome (ACS) attributable to coronary artery disease (CAD) accounts for the majority of deaths due to cardiovascular disease posttransplant. Although renal transplantation is the treatment of choice for end-stage renal disease, understanding the causes of graft and patient loss is exceedingly important to improve outcomes. Methods. This observational study included 1200 patients who underwent a kidney transplant between 1988 and 2003. The outcome was the occurrence of an ACS event within a maximum of 15 years after renal transplantation. Results. Of all 215 deaths, 28.3% were caused by complications of CAD, the most common cause of death at our center. On multivariate analysis, diabetes (P ⫽ .005), prior transplant (P ⫽ .047), body mass index (BMI) at the time of transplant (P ⫽ .01), cholesterol level (P ⫽ .012), and low-density lipoprotein (LDL) level (P ⫽ .007) during 3 years after transplant were associated with early ACS. In conclusion, diabetes, prior transplant, BMI, cholesterol, and LDL were significantly associated with early ACS highlighting the importance of improved screening and perioperative management.

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ENAL TRANSPLANTATION is the treatment of choice for most patients with end-stage renal disease. The survival of patients who undergo renal transplantation has improved considerably over the past three decades. At present one can expect a survival rate of 95% at 1 year and around 90% at 3 to 5 years.1 Thus, in the short term, renal transplantation offers a good prospect of survival for patients who are free of major comorbid illness. There has been an encouraging decrease in mortality following renal transplantation during the past 25 years, particularly during the early posttransplant period. However, life expectancy beyond 10 years is still considerably lower than in the general population.2 Patient death continues to be a leading cause of renal transplant failure. This mortality is mainly due to cardiovascular events.3 Although renal transplantation is the treatment of choice for end-stage renal disease, understanding the causes of graft and patient loss is exceedingly important to improve outcomes. MATERIALS AND METHODS We retrospectively analyzed outcomes in 1200 renal transplant recipients who underwent transplant from January 1988 to Decem© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 509 –511 (2006)

ber 2003. Patients were included if they had a functioning graft and were free of clinical heart disease at 1 year after transplantation. Patients with known pretransplant cardiac disease were excluded because cardiac disease at the time of transplantation was due to risk exposures before transplantation, which might confound the relationship between posttransplant risk factors and subsequent outcomes. We reviewed all inpatient and outpatient records, abstracting data on baseline demographic, clinical, and outcome variables. The baseline variables included age, gender, presence or absence of diabetes and hypertension, body mass index (BMI) at the time of transplant, living or cadaver donor status, history of prior transplant, underlying kidney disease, and smoking status. Systolic and diastolic, blood pressure (BP), hemoglobin, albumin, and serum creatinine (Cr) were measured at least monthly, From the Shiraz Transplant Research Center, (A.F.); Shiraz Transplant Center Nemazee Hospital (A.R.M., G.A.R.-J.); and the Cardiology Department (M.A.O.), Shiraz University of Medical Sciences, Shiraz, Iran. Supported by a grant from the Shiraz Medical University and Namazi Hospital Transplantation Center. Address reprint requests to Afsoon Fazelzadeh, P.O. Box 71847-37513, Shiraz, Iran. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.02.004 509

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and lipid profile (total cholesterol, triglycerides, high-density lipoprotein [HDL], and low-density lipoprotein [LDL]) was measured yearly. Outcome variables included occurrence of any acute coronary syndrome event within maximum of 15 years after renal transplantation, was defined as hospitalization for acute myocardial infarction namely chest pain accompanied by characteristic electrocardiogram changes of infarction or a threefold elevation in creatine kinase levels or revascularization, namely coronary artery bypass grafting or percutaneous transluminal angioplasty. Outcomes are described using event-free Kaplan-Meier survival curves. Cox proportional hazards regression was used for both univariate and multivariate analyses.

RESULTS

Among the 1200 patients, who have been followed from inception in 1988 to 2003, namely a mean follow-up of 68.1 ⫾ 29.2 (range 12 to 200) months, 30% of patients developed cardiovascular events including 215 (17.9%) patients who were dead, with 28.3% caused by complications of coronary artery disease (CAD) the most common cause of death in our center. The male/female ratio was 2.1 (808 male, 392 female); the mean age was 33.6 ⫾ 12.5 years (4.5 to 68). Of the patients, 40% were diabetic and 55% were smokers; 14% received a cadaveric donor organ, mean systolic BP was 138 ⫾ 16 mm Hg and mean diastolic BP was 85 ⫾ 8 mm Hg; mean Cr was 160 ⫾ 61 ␮mol/L; mean hemoglobin was 126 ⫾ 19 g/L; mean total cholesterol was 6.4 ⫾ 1.3; mean albumin was 39 ⫾ 4 g/L; and mean BMI was 22.2 ⫾ 4.6 kg/m2 (50.7, 12.3) (Table 1). On multivariate analysis, diabetes (P ⫽ .005), prior transplant (P ⫽ .047), BMI at the time of transplant (P ⫽ .01), cholesterol level (P ⫽ .012), and LDL (P ⫽ .007) over 3 years after transplant were associated with early ACS (Table 2). DISCUSSION

Cardiovascular disease is the leading cause of death following renal transplantation, accounting for 40% to 55% of all deaths. Although it is much commoner among transplant patients, its contribution to posttransplant mortality to some extent reflects the incidence of cardiac disease in the Table 1. Clinical and Laboratory Data of the Patient Population Patients (n) Sex (M/F) Mean age (ys) Diabetes mellitus Smoking Cardiovascular disease Systolic BP (mm Hg) Diastolic BP (mm Hg) Creatinine (mg/dL) Hemoglobin (g/L) BMI (kg/m2) Total cholesterol (mg/dL) Albumin (g/L) Data are presented as means ⫾ SD unless otherwise noted.

1200 808/392 33.6 ⫾ 12.5 40% 55% 14% 138 ⫾ 16 85 ⫾ 8 160 ⫾ 61 126 ⫾ 19 22.2 ⫾ 4.6 6.4 ⫾ 1.3 39 ⫾ 4

Table 2. Results of Multivariate Analysis for Cardiovascular Risk Factors Variable

Odds Ratio

95% CI

P Value

Diabetes mellitus Prior transplants BMI Cholesterol LDL Smoking

7.2 5.5 6.11 6.3 6.9 4

1.88, 27.6 1.65, 19.4 1.70, 20.2 1.73, 22.5 1.79, 24.3 1.2, 11.7

.005 .047 .01 .012 .007 .049

general population and, as a consequence, the incidence varies widely between countries.3 An analysis in one center showed that the death rate from ischemic heart disease in patients on renal replacement therapy was around five times higher than that in the general population.4 Our investigations reported a 15% mortality among a cohort of renal transplant recipients followed for an average of 68.1 ⫾ 29.2 months. Of 215 deaths that occurred during the period of observation, 28.3% were caused by complications of atherosclerosis, the most common cause of death in our center. There are, however significant regional differences; Iranian renal transplant patients show a lower cardiovascular mortality than those in the United States or Northern Europe.5 This observation may be related to a different incidence and prevalence of associated risk factors especially the Iranian diet, which needs more investigation. Although cardiovascular disease is a major cause of death after renal transplantation, predictors for cardiovascular events have not been well defined.5 There are numerous reports documenting hyperlipidemia following renal transplantation. Correlations between increased serum lipoprotein(a) concentration, hypertriglyceridemia, or low HDL and ischemic heart disease have been confirmed.6 Lossey et al7 reported a relationship between obesity and hyperlipidemia,7 results confirmed by our findings that BMI, cholectrol, and LDL were significantly associated with the development of cardiovascular events. Diabetes as an underlying cause of renal failure or as a complication of transplantation is known to be a significant risk factor for posttransplant cardiovascular disease.4 Our data show that the 40% of our patients who were diabetic had more ACS. So, efforts should be made to reduce the risk of diabetes and to treat the condition appropriately. The high incidence of cardiovascular events in this study warrants consideration for aggressive managements of risk factors, to prevent or minimize serious cardiovascular complications and improve recipient survival.

REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation and recipients of a first cadaver transplant. New Engl J Med 341:1725, 1999

CARDIOVASCULAR EVENT PREDICTORS 2. Ojo AO, Hanson JA, Wolfe RA, et al: Long-term survival in renal transplant recipients with graft function. Kidney Int 57:307, 2000 3. Raine AEG, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII 1991. Nephrol Dial Transplant 7(Suppl 2):7, 1992 4. Kasiske BL, Guijarro C, Massy ZA, et al: Cardiovascular disease after renal transplantation. J Am Soc Nephrol 7:158, 1996

511 5. McGregor E, Stewart G, Rodger RSC, et al: Early echocardiographic changes and survival following renal transplantation. Nephrol Dial Transplant 15:93, 2000 6. Steinberg D, Parthasarathy S, Carew TE, et al: Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915, 1989 7. Lossey L, Asztlos L, Kinceses Z, et al: The importance of obesity and hyperlipidemia in patients with renal transplants. Int Urol Nephrol 30:767, 1998