The Prevention and Treatment of Coronary Artery Disease in Kidney Transplant Recipients

Rahul Koushik

Bertram L. Kasiske

Department of Medicine, University of Minnesota School of Medicine, Fairview University Medical Center, Minneapolis, Minnesota 55455

INTRODUCTION

The morbidity and mortality from cardiovascular disease (CVD) is high in patients with end-stage kidney disease (ESKD). Death from CVD is 20 to 40 times more common in ESKD patients than in the general population, and 72% of ESKD patients with an acute myocardial infarction (AMI) die within 2 years (1). This high mortality rate has not changed in the past several years; indeed, in a recent study the adjusted mortality rate was unchanged between 1977 to 1994 and 1995 to 1999 (2). Sixty percent of deaths reported in the US Renal Data System are attributed to unexpected, sudden death or dysrhythmia, and cardiac arrest is often caused or predisposed by coronary artery disease (CAD) (2). Even children and young adults are not exempted, as CVD accounts for 23% of mortality among children and young adults with ESKD in the United States (3).

The incidence of CVD is also high after kidney transplantation (Table 17.1). Although the risk of CAD events has been decreasing in the transplant population over the past 3 decades, it continues to have a major effect on the outcome (Fig. 17.1) (8).

In a study from the precyclosporine era, the incidence of all CAD complications was found to be 5 times higher in the transplant population, than that predicted by the Framingham Heart Study for age and gender matched patients (4). Even in transplant recipients without clinical evidence of CAD at the time of transplantation, the incidence of posttransplant CAD was 3 times what would be expected in the general population (4). It is not surprising, therefore, that CVD is the most common cause of death after kidney transplantation (9). In the United States, one half of the late kidney allograft failures are attributable to death with a functioning graft, and half of these deaths are due to CVD
(10). This has also been observed in Europe, where 53% of graft failures at 5 years after transplantation were attributable to CAD death with functioning allografts (7).

TABLE 17.1. The incidence of coronary artery disease after kidney transplantation

Study	Population	Incidence	Method of detection	Number	Definition
Kasiske BL, 1988(4)	4 years posttransplant	11%	History	464	Angina or MI
Kasiske BL et al, 1996(5)	7 years posttransplant	26%	History	706	Event (excluding angina)
Aakhus S et al, 1999(6)	4 years posttransplant	14%	History	406	Angina or MI
Lindholm A et al, 1995(7)	5 years posttransplant	40%	Registry	1,347	CAD deaths
MI myocardial infarction; CAD, coronary artery disease.

FIG. 17.1. Adjusted risk of coronary artery disease events over three eras of transplantation. (From Kasiske BL, Chakkera H, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000;11:1735-1743, with permission.)

Cardiac arrests, most of which are likely caused or predisposed by CAD, are also more common after kidney transplantation than in the general Medicare population. Specifically, the cardiac arrest rate is 11 per 1,000 patient-years in kidney transplant recipients compared to 8 per 1,000-patient-years in the general Medicare population (2). The increased risk of CAD persists even after the graft has failed. Indeed, graft loss was identified as an independent risk factor for acute coronary syndromes in the United States (11). The incidence of acute CAD syndromes was 12.1/1,000 patient-years in patients with graft loss compared to 6.6/1,000 patient-years among patients with functioning transplants (11).

TABLE 17.2. The prevalence of coronary artery disease in transplant candidates

Study	Population	Prevalence	Method of detection	N	Definition
Landray MJ et al, 2001(12)	Pre-ESKD (mean creatinine 2.99 mg/dL)	21%	History or angiogram	127	Angina, MI, revascularization, > or = 50% stenosis of one vessel
Kasiske BL, 1988(4)	Pretransplant	9.5%	History	464	Angina, MI, CABG, PTCA
Manske CL et al, 1992(13)	Pretransplant, DM1	47%	Angiogram	110	> or = 50% stenosis of one vessel
Herzog CA et al, 1999(14)	Pretransplant (80% DM)	54%	Angiogram	50	> or = 50% stenosis of one vessel
Varghese K et al, 2001(15)	Pretransplant	60%	Angiogram	116	> or = 50% stenosis of one vessel
Foley RN et al, 1995(16)	All ESKD	33%	History	433	Angina, MI, revascularization
USRDS, 2003(2)	All ESKD	40%	History^*	295,913	Variable
^*From the Medical Evidence Form, number 2728.
ESKD, end-stage kidney disease; MI, myocardial infarction; CABG, coronary artery bypass graft; PTCA, percutaneous coronary artery angioplasty; DM1, type 1 diabetes mellitus; USRDS, United States Renal Data System.

In summary, available evidence suggests that CVD is very common in ESKD, before and after kidney transplantation. The high prevalence and incidence of CVD suggest that intensive screening and risk factor management strategies may be warranted in this population. However, it is also clear that additional, prospective data are needed to better define the role of screening and intervention in ESKD and kidney transplantation.

PREVALENCE OF CARDIOVASCULAR DISEASE IN KIDNEY TRANSPLANT CANDIDATES

Understanding the prevalence of CAD at the time of evaluation for kidney transplantation has important implications for screening and risk assessment. The prevalence of pretransplant CAD varies with the definition of CAD, the population studied, and the method used to detect CAD (Table 17.2). In patients with stages 1 to 4 chronic kidney disease (CKD), the prevalence of clinically evident CAD has been reported to be 21% (12). Forty percent of patients initiating
renal replacement therapy have clinically apparent CAD (2). Of course, not all such patients are candidates for transplantation. In another study, about 10% of patients who underwent kidney transplantation had a clinical history of pretransplant CAD (4). The prevalence of angiographic CAD at the time of transplant evaluation of high-risk patients (e.g., patients with diabetes) has been reported to be 50% to 60% (Table 17.2). Emerging data from electron beam computed tomography (EBCT) suggest that there may be more extensive CAD disease in the ESKD population than is revealed by angiography (17). However, whether EBCT-detected coronary calcifications predict CAD events in patients with ESKD has not been clearly established.

RISK FACTORS FOR CARDIOVASCULAR DISEASE IN KIDNEY TRANSPLANT RECIPIENTS

In a retrospective analysis, risk factors for CVD after transplantation included the presence of pretransplant CVD, age, diabetes, male gender, pretransplant splenectomy, the number of acute rejection episodes and a low level of high-density lipoprotein (HDL) cholesterol (4). Many of these are no different from the risk factors for CAD in the general population (Table 17.3). In a subsequent analysis by the same group, the risk predicted by the Framingham Heart Study tended to underestimate the CAD risk in transplant recipients (8). This would suggest that factors unique to the posttransplant state, including immunosuppressive agents, infections and rejections, might contribute to CAD in this population.

MANAGEMENT OF CORONARY ARTERY DISEASE IN KIDNEY TRANSPLANT RECIPIENTS

Methods for managing the risk of CAD, considered to be standard in the general population, appear to be under-utilized in ESKD and kidney transplant recipients. An analysis of USRDS data indicated that 58% of dialysis and 64% of transplant patients did not have plasma lipids measured during the first year of renal replacement therapy. Of those tested, only 33% of dialysis and 27% of transplant patients had two or more tests performed within the first year (1). The USRDS data also suggest an underutilization of coronary revascularization in the ESKD population. For example, the revascularization rate within the first year after AMI was found to be 39% (26/66 per 1,000 patient-years) in the ESKD population compared to 80% (12/14.5 per 1,000 patient-years) in the general Medicare population (2). Altogether, these data suggest that there may be more that can be done to maximize the management of cardiovascular risk in patients with ESKD, and by inference, kidney transplant recipients.

TABLE 17.3. Risk factors for coronary artery disease after kidney transplantation

Study	N	CAD	Risk factor	Relative risk
Kasiske BL et al, 2000(8)	1,124	10.9%	Age	Men 1.05/women 1.40
			Cholesterol	Men 2.13/women 2.24
			Blood pressure	Men 1.47/women 0.31
			Diabetes	Men 2.78/women 5.40
			Smoking	Men 1.95/women 1.82
Kasiske BL et al, 1996(5)	706	26%	Age	1.88
			Male gender	2.68
			LDL	No effect
			Blood Pressure	No effect
			Diabetes	3.25
			Acute rejection	1.40
			Splenectomy	2.07
Aakhus S et al, 1999(6)	406	14%	Age	NA
			Male gender	NA
			Cholesterol	NA
Lindholm A et al, 1995(7)	1,347	40%	Age	1.06
			Diabetes	3.94
			Acute rejection	2.02
CAD, coronary artery disease; LDL, low-density lipoprotein cholesterol.

Preemptive Kidney Transplantation

Mortality is higher among dialysis patients on the waiting list compared to kidney transplant recipients (18). An increasing amount of data also suggests that the longer the transplant is delayed, the poorer the outcomes after kidney transplantation. Indeed, the best outcomes are achieved by pre-emptive transplantation, i.e., transplantation before the initiation of dialysis. Therefore, early referral and evaluation for transplantation is likely to reduce the risk of CVD among ESKD patients and improve outcomes after kidney transplantation.

Pretransplant Screening for Coronary Artery Disease

The presence of pretransplant CVD is an important risk factor for CAD after kidney transplantation (4,5). The adjusted risk for posttransplant CAD (AMI, revascularization or cardiac death) was threefold higher for patients with pretransplant CAD compared to patients without pretransplant CAD
among 706 transplants. This increase in risk was greater than the risk attributable to age, gender, diabetes and dyslipidemia (5). Herzog et al. found, at 36 months after transplantation, that patients with at least one coronary artery occluded >50% had a 22% chance of cardiac death or MI compared to 0% in those with no coronary occluded >50% (Fig. 17.2) (14). These data suggest that patients with angiographic evidence of CAD have an increased risk of cardiac events after transplantation.

Nearly half (47%) of deaths with a functioning kidney transplant that occurred within 30 days after transplantation were due to CVD, predominantly CAD (19). Although it is common practice, pretransplant screening for CAD has not been shown to improve outcomes after kidney transplantation in large, prospective trials. The rationale for screening is to detect clinically silent CAD lesions, to intervene with revascularization and to thereby prevent early posttransplant CAD, AMI and death. In ESKD patients CAD is often silent, and this is especially true in ESKD patients with diabetes. Manske et al screened 90 asymptomatic type 1 diabetic ESKD patients with coronary angiography and found significant (>50% occlusion in at least one coronary vessel) CAD in 42% of patients (20). Koch et al. found that only 24% of diabetics with >50% CAD lesions had angina (21). Resting EKG had a sensitivity of only 43% for detecting CAD.

Proof that pretransplant screening effectively reduces the incidence of posttransplant CAD can only come from randomized, controlled trials. The only randomized trial assessing the effects of pretransplant screening and revascularization on outcomes was stopped prematurely due to worse outcomes in the control, medical treatment group (22). However, the very small number of patients enrolled in this trial (N = 26) makes it doubtful that there was adequate statistical power to determine whether the observed results were due to chance. In addition, in this trial conducted more than a decade ago not all patients assigned to medical management received prophylactic beta-blockers. Thus, this trial does not answer the important question of whether screening and coronary revascularization in asymptomatic patients reduces CAD events after transplantation compared to standard medical management that includes perioperative beta-blockade.

FIG. 17.2. Effect of pretransplant coronary artery disease on posttransplant coronary artery events. (From Herzog CA, Marwick TH, Pheley AM, et al. Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. Am J Kidney Dis 1999;33:1080-1090, with permission.

The American Heart Association (AHA) and American College of Cardiology (ACC) guidelines do not recommend routine screening for asymptomatic patients prior to elective, noncardiac surgery (23). Nevertheless, most transplant centers in the United States screen high-risk patients. Which patients are high-risk and should be screened is not clear. Patients with diabetes are often selected for screening (20). However, Kasiske et al. found that 58% of cardiac events (AMI, revascularization, cardiac death) occurred in patients who did not have diabetes (5). Thus, restricting screening to patients with diabetes would miss a large number of preventable adverse outcomes. Others have used retrospective data to show that an effective strategy would screen individuals who had diabetes, age >50 years, resting EKG changes, angina and perhaps congestive heart failure (24). This clinical risk stratification system had an 82% sensitivity for cardiac events over a 4-year follow-up period (25). The American Society of Transplantation (AST) Guidelines recommend screening individuals at high risk with nuclear or dobutamine stress testing (26). In these guidelines, high risk is defined as ESKD due to diabetes, prior history of CAD, or two or more risk factors, where risk factors include: (a) men >45 years, women >55 years, (b) CAD in a first degree relative, (c) current smoker, (d) diabetes, (e) hypertension, (f) fasting cholesterol >200 mg/dL, (g) fasting HDL cholesterol <35 mg/dL, or (h) left ventricular hypertrophy. These guidelines suggest that individuals with a positive stress test should be considered for revascularization before elective transplant surgery (26).

What tests should be used to screen is also uncertain. Some centers screen all high-risk individuals with coronary angiography. However, most centers use a noninvasive cardiac stress test. Several studies in the ESKD population (Table 17.4) have documented that noninvasive, preoperative screening is a poor predictor of perioperative cardiac events. Vandenberg et al found that the perioperative rate of adverse cardiac outcomes was identical in patients with normal and abnormal pharmacologic nuclear stress tests in diabetic kidney transplant recipients (28). Bates et al found that dobutamine stress echocardiography predicted adverse cardiac events over a mean follow-up of 418 days in diabetic kidney or pancreas transplant recipients (30). In a study of 97 ESKD patients evaluated for kidney transplantation, a normal dobutamine stress echocardiography identified a very low risk population, with a 97% probability of being free of cardiac complications or death during a 6-month follow-up period (27). All of these studies have been relatively small, and none have compared nuclear scans with echocardiographic stress testing.

Once significant CAD has been detected, it is also unclear what revascularization technique should be used. In ESKD
patients, coronary artery bypass graft (CABG) reduced the relative risk of mortality 0.39 when compared to percutaneous coronary intervention (31). However, this effect was not seen in the pre-ESKD population (31). The treatment of CAD by percutaneous transluminal coronary angioplasty (PTCA) (without stents) and CABG in ESKD patients has met with limited success with high restenosis rates (Fig. 17.3) (32). Although the 2-year survival rate after CABG (66%) did not differ from the PTCA group (51%), 47% of PTCA patients had to be reevaluated for angina within 6 months compared to 6% of the CABG group. The 18-month incidence of MI was no different in the two groups (32). In diabetic ESKD patients, perioperative mortality after CABG was 3% and the complication rate was 60%. Twenty-one of 30 patients underwent successful kidney transplantation after the bypass operation. Despite a high complication rate, the long-term outcome after CABG was good with a 80% and 66% survival at 1 and 4 years, respectively (33).

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