Extent and Severity of Coronary Disease and Mortality in Patients with End-Stage Renal Failure Evaluated for Renal Transplantation

Abstract

The purpose of this study is to explore the relationship between coronary artery disease (CAD), transplantation status and subsequent mortality in end-stage renal disease (ESRD) patients undergoing evaluation for renal transplantation. Two hundred fifty-three ESRD patients at high risk for CAD underwent coronary angiography as part of a renal transplant evaluation. The cohort was divided into three groups: Group 1 (n = 127) had no vessels with ≥50% stenosis, Group 2 (n = 56) had one vessel with ≥50% stenosis and Group 3 (n = 70) had two or more vessels with ≥50% stenosis. Long-term survival was determined; median follow-up was 3.3 years. The baseline characteristics were similar except for older age and higher proportion of diabetes mellitus, dyslipidemia and peripheral vascular disease in Groups 2 and 3 patients as compared to Group 1. Survival was worse in Group 3 compared to Group 1 (p < 0.0001). Each of the three subgroups had better survival with renal transplantation than those who did not undergo transplantation (p < 0.0001). Although the degree of CAD is related to subsequent mortality, transplantation is associated with better survival regardless of the extent and severity of CAD. Thus, the presence of CAD should not exclude ESRD patients from consideration for this therapy.

Abbreviations 

ESRD

end-stage renal disease

CAD

coronary artery disease

Introduction

Renal transplantation liberates patients with end-stage renal disease (ESRD) from dialysis and is associated with improved long-term survival (1–3). However, renal failure is associated with an increased risk of developing a serious cardiac event such as death and myocardial infarction. These events are often attributed to accelerated coronary atherosclerosis that, in turn, may be caused by the high prevalence of atherosclerotic risk factors such as diabetes and hypertension, as well as the existence of proatherogenic factors associated with dialysis and renal failure (4). Thus, there is great concern that significant morbidity and mortality may occur during the perioperative or long-term maintenance phases after renal transplantation, potentially eliminating the benefit of renal transplantation (5).

The optimal way to screen for and manage coronary artery disease (CAD) prior to and following renal transplantation is a topic of substantial debate (6–9). Multiple studies evaluating both noninvasive tests and coronary angiography in patients with ESRD under evaluation for renal transplantation consistently report a high frequency of obstructive CAD (10–14). For this reason, as part of the pretransplant evaluation, the American Society of Transplantation recommends noninvasive testing of individuals with atherosclerosis risk factors while coronary angiography is generally reserved for those with abnormal tests or for patients with certain high-risk features (7). Once significant obstructive CAD has been identified, however, it is entirely unclear how best to manage these patients. It is not clear whether significant CAD is associated with outcomes poor enough to obviate the benefits of renal transplantation thus, potentially eliminating such patients from consideration for transplant. Furthermore, it is not clear whether revascularization, often encouraged in these patients based on studies suggesting benefit, influences outcome relative to transplantation status (15–18). Accordingly, we studied the relationships between extent and severity of CAD, performance of revascularization, transplantation status and long-term survival in consecutive patients with ESRD undergoing coronary angiography as a pretransplantation evaluation.

Methods

Patient population

Based on the American Society of Transplantation's guidelines, the Cardiovascular Division and Renal Transplantation Team at the University of Virginia Health System have developed an algorithm for the evaluation of patients prior to renal transplantation (Table 1) (7). In general, coronary angiography is recommended in ‘high-risk’ patients and in ‘intermediate’ risk patients with significant ischemia on a noninvasive test.

Table 1.  University of Virginia algorithm for the cardiac evaluation of patients with end-stage renal disease undergoing evaluation for renal transplantation

Risk Status	Criteria	Recommendation
Low	Age <50 years and a normal ECG and no diabetes and no past history or symptoms of coronary artery, peripheral artery or cerebrovascular disease	No further cardiac work-up before transplantation
Intermediate	Nondiabetic patients age >50 years with no major coronary disease risk factors (dyslipidemia, family history, tobacco abuse) or no prior history of myocardial infarction or revascularization event, stroke or peripheral vascular disease Diabetic patient <50 years but with duration of diabetes >20 years and no other evidence of atherosclerosis	Exercise or pharmacological stress test. If normal, no further work-up. If significant ischemia or reduced left ventricular function, then coronary angiography
High	Any patient with symptoms of angina, heart failure or prior cardiac event (myocardial infarction or revascularization), prior stroke or documented extracardiac atherosclerosis Diabetes and any one of the following: age >50 years, >20 years duration of diabetes, history of smoking or dyslipidemia or an abnormal electrocardiogram suggesting prior, silent infarction	Coronary angiography

Between January 1, 1999 and December 31, 2006, 1158 consecutive ESRD patients underwent evaluation for renal transplantation, and coronary angiography was performed on 253 (22%) patients at the University of Virginia as part of the pretransplant evaluation. Of these 253 patients, 224 (88%) met criteria for ‘high risk’ and the remaining 29 were deemed ‘intermediate’ risk based on the presence of ischemia on a stress test. Clinical variables including patient demographics, medical history, cardiac symptoms, procedural indications and laboratory results were prospectively collected according to definitions established by the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR) guidelines prior to catheterization and entered into point-of-care databases (CAOS [IBS Inc., Winston-Salem, NC] from January 1999 through December 2005, and Encompass™[Agfa Heartlab Inc., Greenville, SC] from January 2006 through December 2006). Similarly, the attending cardiologist performing the procedure entered the angiographic and procedural findings from the catheterization procedure into the database at the time of the procedure using the rigorous data definitions provided by the ACC-NCDR.

Patients were divided into three groups based on the extent and severity of coronary disease. Group 1 (n = 127) consisted of patients with minimal angiographic disease, defined as the absence of a ≥50% stenosis in a major epicardial artery or important branch of a major epicardial coronary artery. Group 2 (n = 56) consisted of patients with single-vessel disease, defined as a ≥50% stenosis in only one major epicardial artery or an important branch of a major epicardial coronary artery. Group 3 (n = 70) consisted of patients with multivessel coronary disease defined as the presence of a >50% stenosis in two or more major epicardial arteries or their major branches; in this group, patients were required to have a ≥50% stenosis in at least two different vascular territories (i.e., not multiple stenoses involving a single-vessel and its branches).

Decisions regarding coronary revascularization either via percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were made on a clinical basis at the discretion of the attending cardiologist. Revascularization procedures performed within 1 month of the coronary angiogram catheterization were considered as an index procedure related to the initial coronary angiogram; revascularization events occurring more than 1 month after the index catheterization were considered to have occurred during follow-up. All patients remained on the transplant list following cardiac catheterization and no patient was excluded from consideration based on the results of coronary angiography.

Follow-up and study end points

Patients were followed for a median of 3.3 years (mean 3.5 years). The primary end point was all-cause mortality. Death was determined by review of the Renal Transplant Database, the University of Virginia's clinical database and the Social Security Death Index (19). Causes of death were determined by review of the death certificates or hospital records when available. The need for subsequent revascularization and transplantation status were determined from review of the Renal Transplant Database and the University of Virginia's clinical database.

Statistical analysis

Continuous variables were presented as mean ± standard deviation or median with interquartile range as appropriate. Differences in means were compared using the student t-test. Differences in medians were compared using the Wilcoxon–Mann–Whitney U test. Categorical variables were compared using chi-square or Fisher's exact test where sample sizes were small. Kaplan–Meier curves were used for survival data to analyze the effects of CAD and transplant on mortality. Cox proportional hazards modeling was used to examine the association between CAD, transplant, and clinical outcomes. Clinical characteristics accounted for in Cox proportional hazards modeling include extent of CAD, transplantation, time on dialysis, gender, age, race, diabetes, body mass index and revascularization. Post hoc power calculations for transplant versus no transplant were performed with an α of 0.05, n (experimental) of 116, m1 of 927 (median survival for control), m2 of 1618.5 (median survival for experimental), A (accrual time) of 2190, F (follow-up time) of 3000 and experimental to control ratio of 1.18. These calculations yield a power of 0.986. All statistical analysis was performed with SAS version 9.1 (SAS Institute, Cary, NC).

Results

Baseline characteristics

The baseline characteristics of the 253 consecutive patients are shown in Table 2. When compared to patients with minimal angiographic coronary disease (Group 1), patients with single-vessel (Group 2) and multivessel (Group 3) coronary disease were older and had a higher frequency of diabetes, prior coronary artery disease and peripheral vascular disease. There was no significant difference between the three groups in terms of time on dialysis, type of dialysis or prior heart failure. Importantly, the proportion of patients with depressed left ventricular function (ejection fraction <40%) was similar between the three groups. More than 80% of patients in each group were without angina pectoris with no differences observed in the occurrence of angina between groups. The median time to follow-up for the three groups was statistically different with Group 3 consisting of significantly fewer days of follow-up (938 days) as compared to Group 1 (1246 days) and Group 2 (1218 days) [p = 0.036].

Table 2.  Patient characteristics based on extent of coronary artery disease

	All patients (N = 253)	Group 1 Minimal CAD (n = 127)	Group 2 Single-vessel CAD (n = 56)	Group 3 Multivessel CAD (n = 70)	p-Value
CAD = coronary artery disease; CHF = congestive heart failure; PVD = peripheral vascular disease; CVD = cerebrovascular disease; PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting.
Age, years (median; 25th, 75th percentile)	55 (48, 62)	54 (45, 62)	55 (48, 61)	57 (50, 63)	0.03
Male	154 (60%)	70 (55%)	40 (71%)	44 (62%)	0.13
Caucasian	175 (69%)	81 (64%)	43 (77%)	51 (73%)	0.36
Diabetes mellitus	165 (65%)	71 (56%)	39 (70%)	55 (79%)	<0.01
Hypertension	238 (94%)	119 (94%)	52 (93%)	67 (96%)	0.83
Dyslipidemia	156 (62%)	71 (56%)	40 (71%)	46 (66%)	0.10
Prior CAD	101 (40%)	37 (29%)	25 (45%)	39 (56%)	<0.01
Prior PCI or CABG	53 (21%)	20 (16%)	14 (25%)	19 (27%)	0.13
Prior CHF	40 (16%)	17 (13%)	11 (20%)	12 (17%)	0.53
Prior PVD	62 (25%)	21 (17%)	21 (38%)	20 (29%)	0.01
Prior CVD	53 (21%)	29 (23%)	9 (16%)	15 (21%)	0.58
Body-mass Index (median; 25th, 75th percentile)	28 (25, 33)	28 (24, 33)	29 (24, 35)	28 (25, 32)	0.65
Smoker
Never	105 (42%)	58 (46%)	25 (45%)	22 (31%)	0.28
Former	97 (38%)	48 (38%)	19 (34%)	30 (43%)
Current	51 (20%)	21 (17%)	12 (21%)	18 (26%)
Ejection fraction
< 0.40	15 (6%)	8 (6%)	4 (7%)	3 (4%)	0.90
> 0.40	156 (62%)	78 (61%)	36 (64%)	42 (60%)
Unmeasured	82 (32%)	41 (32%)	16 (29%)	25 (36%)
Ischemia on stress test	29 (11%)	17 (13%)	2 (4%)	10 (14%)	0.30
Angina type
No angina	223 (88%)	113 (89%)	51 (91%)	59 (84%)	0.28
Angina	30 (12%)	14 (11%)	5 (9%)	11 (16%)
Dialysis type
No dialysis	19 (8%)	7 (6%)	7 (13%)	5 (7%)	0.41
Hemodialysis	186 (74%)	99 (78%)	41 (73%)	46 (66%)
Peritoneal	16 (6%)	16 (13%)	4 (7%)	7 (10%)
Unknown	21 (8%)	5 (4%)	4 (7%)	12 (17%)
Time on Dialysis, days (median; 25th, 75th percentile)	1317 (635, 1980)	1410 (646, 2053)	1106 (671, 1728)	1172	0.26

Survival

Of the 253 patients, 96 patients (38%) died during follow-up. The causes of death were as follows: 76 (79%) died either of cardiovascular causes (n = 45) or of unknown causes (n = 31). Of the remaining 20 deaths, 17 (18%) died of sepsis, 1 (1%) died of metastatic cancer, 1 (1%) died of calciphylaxis, and 1 (1%) died from thrombotic thrombocytopenic purpura. The Kaplan–Meier survival curves for the three groups are shown in Figure 1. Patients with minimal angiographic coronary disease (Group 1) had the best survival and patients with multivessel disease (Group 3) exhibited the worst survival (p < 0.0001, Group 1 vs. Group 3). Table 3 shows the hazards ratio for predicting survival in the entire cohort using Cox proportional hazards. After multivariate regression analysis, the presence of multivessel coronary disease was associated with an increased risk of death with a hazards ratio of 2.951 (p < 0.001) while renal transplantation afforded marked protection from death with a hazards ratio of 0.191 (p < 0.001). Revascularization was not associated with mortality.

Figure 1. Survival according to the extent and severity of coronary artery disease. Probability of death based on the extent of coronary artery disease (Group 1 = patients with minimal angiographic disease, defined as the absence of a >50% stenosis; Group 2 = patients with single-vessel disease, defined as a ≥50% stenosis in one major epicardial artery and Group 3 = patients with multivessel coronary disease defined as the presence of a >50% stenosis in two or more major epicardial arteries. (p < 0.0001 for Group 1 vs. Group 3.)

Table 3.  Hazard ratios predicting death for the entire cohort

Variable	Entire cohort	p-Value
CAD = coronary artery disease.
Age	1.019	0.11
Male	1.402	0.19
Caucasian	1.409	0.16
Diabetes mellitus	0.951	0.85
Revascularization	0.944	0.60
Single-vessel CAD	1.637	0.11
Multivessel CAD	2.951	<0.001
Renal transplantation	0.191	<0.001

Transplantation

Of the entire cohort of 253 patients, 116 (46%) underwent renal transplantation during a mean follow-up of 471 days after cardiac catheterization. In this cohort, the rate of death for patients while on the transplant list was 10.9 deaths per 100 patient-years. Long-term survival was significantly better for patients undergoing renal transplantation compared to patients who did not undergo transplantation (Figure 2, p<0.0001). By chi-square analysis, patients undergoing renal transplantation did not differ from patients remaining on dialysis in terms of gender, age, presence of angina or heart failure, ejection fraction, diabetes, hypertension, dyslipidemia, cerebrovascular disease, prior coronary disease or revascularization and current or past tobacco abuse history. The two groups differed in terms of prior peripheral vascular disease (15.5% in the transplant group vs. 32.1% in the patients remaining on dialysis, p = 0.002) and proportion of patients with significant coronary disease in one or more vessels (46% in the transplant group vs. 53% in the patients remaining on dialysis, p = 0.03).

Figure 2. Survival according to transplantation status. Probability of death in patients who underwent transplantation compared to patients who remained on dialysis (p < 0.0001).

The relationship between long-term survival, extent and severity of coronary artery disease and transplantation status is further explored in Figure 3. Patients undergoing renal transplantation have better survival rates than individuals remaining on dialysis for each subgroup based on the degree of coronary artery disease (Figure 3A, minimal angiographic CAD or Group 1; Figure 3B, patients with single-vessel CAD or Group 2; and Figure 3C, multivessel CAD or Group 3). Among patients undergoing renal transplantation, age and the presence of either single-vessel CAD or multivessel CAD were predictive of death by multivariate analysis (Table 4). In comparison, by multivariate analysis, the only variable that significantly affected survival in patients remaining on dialysis was the presence of multivessel coronary artery disease.

Figure 3. Survival according to extent and severity of coronary artery disease and transplantation status. Probability of death based on transplantation status for patients with minimal angiographic coronary disease (Group 1 patients, Panel A; p = 0.0001), single-vessel disease (Group 2 patients, Panel B; p = 0.03) and multivessel xdisease (Group 3 patients, Panel C; p < 0.0001).

Table 4.  Hazard ratios predicting death according to transplantation status

Variable	Transplant	p-Value	No transplant	p-Value
CAD = coronary artery disease.
Age	1.056	0.04	1.006	0.68
Male	2.831	0.06	1.093	0.74
Caucasian	1.844	0.26	1.102	0.71
Diabetes mellitus	0.980	0.97	1.293	0.38
Revascularization	0.660	0.21	0.893	0.35
Single-vessel CAD	4.014	0.02	1.588	0.19
Multivessel CAD	5.124	0.01	3.663	<0.001

Coronary revascularization

Of the entire cohort of 253 patients, 54 (21%) underwent coronary revascularization at the time of catheterization (n = 31) or during follow-up (n = 23). At the time of initial catheterization, revascularization was accomplished percutaneously in 24 and by coronary bypass surgery in 7. For the entire cohort and when stratified by transplantation status, revascularization did not convey a survival benefit in patients with coronary artery disease (p = 0.35).

Discussion

Clinicians involved in the management of patients with ESRD are faced with the challenge of determining if renal transplantation is an appropriate therapy for their patient. This important therapy improves quality of life and offers enhanced survival but is extremely resource intensive and depends on availability of scarce donor organs. In addition, clinicians are concerned about these patients risk of a cardiac event because of the high degree of coexisting heart disease in this population. Several retrospective studies note that patients with significant coronary disease are often denied renal transplantation because of the concern about expending these valuable and limited resources in a patient with a potentially shortened long-term survival (9). However, the relationship between degree of coronary disease, transplantation status and survival has not been elucidated. It was the purpose of the present study to explore this relationship and develop a more clear understanding of the influence of coronary disease on long-term survival in this complex population.

The present study observed several important findings. First, coronary disease is highly prevalent in this population. Fifty percent of patients with ESRD determined to be ‘high risk’ by readily available, predefined clinical characteristics have >50% stenosis in at least one coronary artery on coronary angiography; more than one-fourth of the cohort had significant multivessel disease. Second, the rate of death for the population at high risk while on the list awaiting transplantation is 10.9 deaths per 100 patient-years. This is in comparison to the 6.3 deaths per 100 patient-years observed in a general population of dialysis patients awaiting transplantation (1). Third, as shown in other studies, patients undergoing transplantation survive longer than individuals with similar clinical characteristics remaining on dialysis and the extent and severity of CAD in patients with ESRD is directly related to their survival. Patients with ESRD and minimal CAD live significantly longer than those with multivessel disease. Finally, and perhaps most importantly, this study suggests that transplantation conveys a survival benefit regardless of the extent or severity of coronary disease. Although survival did relate to the extent and severity of coronary disease, each group enjoyed improved survival with transplantation and, as shown in Figure 3C, the 3-year survival after transplantation even in patients with multivessel CAD was 90%. Multivariate analysis determined that transplantation status is more important than extent of CAD in predicting survival. These data suggest that the degree of coronary disease should not necessarily exclude a patient from consideration for renal transplantation.

The present study also attempted to explore the relationship between revascularization and survival in those with severe coronary disease. In this cohort, revascularization did not appear to offer a mortality benefit. While the number of patients undergoing revascularization was relatively small, this result is not surprising given the lack of survival benefit seen in much larger cohorts of stable patients without ESRD undergoing elective revascularization (20). However, any conclusion regarding the role of revascularization in these complex patients can only arise from carefully performed, randomized controlled trials.

The mechanism of improved survival in patients with ESRD, undergoing renal transplantation regardless of the extent of coronary disease is multifactorial. Although our analysis focused on all-cause mortality, cardiac causes were the most common cause of death. Even when deaths are attributed to a noncardiac etiology such as sepsis, it is often the case that underlying cardiac disease exacerbates their condition and plays a major role in their demise. Renal transplantation can diminish the proatherosclerotic mechanisms that decimate the ESRD population over time. This effect likely benefits all patients including those with more severe degrees of coronary disease. In addition, transplantation reduces the likelihood of noncardiac causes of death in this population such as sepsis from dialysis access sites, electrolyte imbalances and complications of uremia. These benefits would also be independent of the extent and severity of coronary disease. Finally, it is possible that the heavy investment in valuable resources provided to patients undergoing renal transplantation translates to improved survival because these patients receive more rigorous follow-up, more aggressive risk factor modification and better overall medical care compared to patients remaining on dialysis.

This study has several limitations. As already noted, we did not know the precise cause of death or discriminate cardiac from noncardiac etiologies. In addition, although all patients remained candidates for renal transplantation despite the findings on coronary angiography, selection bias and numerous complex factors other than extent of coronary disease may have played a role in determining which patients ultimately received a renal transplant. While the easily obtainable, baseline clinical characteristics of the various groups were similar, there is a chance that we failed to identify a key factor influencing a patient's referral for renal transplantation, which may have impacted survival. Finally, this study evaluated a consecutive cohort of ESRD patients deemed to be ‘high risk’ by well-accepted criteria. This population represents only a subset of the ESRD patient population, and the conclusions may not apply to the general ESRD population or other definitions used to describe patients at increased risk.

In conclusion, high-risk patients with ESRD have a high prevalence of significant coronary artery disease. Long-term survival is related to the extent and severity of coronary artery disease, and renal transplantation is associated with better survival regardless of the degree of coronary disease. This data suggests that ESRD patients with single- or multivessel disease should not necessarily be excluded from consideration for renal transplantation based solely on their burden of coronary disease. Further prospective studies are necessary to define this relationship so that, in the future, these patients are not unnecessarily excluded from receiving this potentially life-saving therapy.