American Journal of Transplantation 2011; 11: 26652674 Wiley Periodicals Inc.

Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/j.1600-6143.2011.03734.x

Coronary Artery Disease in a Large Renal Transplant Population: Implications for Management
M. R. Kahn , A. Fallahi, M. C. Kim, R. Esquitin and M. J. Robbins
Mount Sinai School of Medicine, New York, NY *Corresponding author: Mark R. Kahn, Mark.Kahn@mssm.edu Coronary artery disease (CAD) accounts for approximately one-half of the sizable mortality in patients with end-stage renal disease who have undergone transplantation. The study was a retrospective review of 1460 patients who underwent renal transplantation at the Mount Sinai Medical Center from January 1, 2000 to October 31, 2009. Noninvasive stress testing was performed in 848 patients (88.1%) with 278 patients (32.8%) having abnormal results. Cardiac catheterization was performed in 357 patients (37.1%) and of these, 212 patients had obstructive disease (59.4%). At 5 years posttransplant, there was no statistically signicant difference between those with nonobstructive CAD and those who required percutaneous or surgical interventions (adjusted hazard ratio [aHR], 1.243; CI 95%, 0.5133.010; p = 0.630). Those with medically managed obstructive CAD had signicantly higher rates of death at the 5-year period when compared to those who received percutaneous intervention (aHR, 3.792; CI 95%, 1.32010.895; p = 0.013) or those who received coronary artery bypass grafting (aHR, 6.691; CI 95%, 1.20037.323). Because noninvasive imaging is poorly predictive of coronary disease in this high-risk population, an anatomic diagnosis is recommended. Revascularization may result in improved long-term outcomes. Key words: Cardiovascular evaluation, cardiovascular mortality, cardiovascular risk factors, renal transplantation, survival analysis Abbreviations: CABG, coronary artery bypass grafting; CAD, coronary artery disease; ESRD, end-stage renal disease; OTTR, Organ Transplant Tracking Record; PCI, percutaneous intervention. Received 10 May 2011, revised 07 July 2011 and accepted for publication 9 July 2011

Introduction
The high incidence of coronary disease in patients with chronic kidney disease presents a signicant challenge in the management of patients being considered for renal transplant. In fact, 50% of all deaths in patients with endstage renal disease (ESRD) are due to cardiovascular disease and 36% of those patients who die after transplantation with a functioning graft do so due to cardiac disease (13). Given the scarcity of donor organs, it is critical to develop protocols that assure the greatest safety for the recipients and put the available donor organs to best use. Although the transplant evaluation is often perceived as a preoperative clearance the fact remains that many pa, tients wait on the transplant list for many years so that continued reevaluation may be required. In addition, there is a signicant mortality observed in patients awaiting transplant, much of which is cardiovascular. Consequently, although the pretransplant cardiac evaluation is useful in determining those patients who are not transplant candidates, it is even more valuable as a tool to optimize the cardiac care of these very vulnerable patients. There is signicant controversy regarding the appropriate cardiovascular pretransplant screening methodology due to the variability in the reported and perceived sensitivities and specicities of available noninvasive imaging modalities. In addition, the signicance of the results of these tests is unknown because the population has such a high pretest probability of disease. The sensitivities and specicities of noninvasive modalities for detecting angiographic coronary artery disease (CAD) in patients with ESRD range from 3790% and 4090% for myocardial perfusion studies, respectively (25), and 3795% and 7195% for dobutamine stress echocardiography, respectively. Given this data, it remains unclear which testing modality should be used to provide an assessment of the coronary artery anatomy. One approach is to risk stratify the patients on the basis of a careful history as well as a stress test. In the absence of symptoms suggestive of high-risk coronary disease, the decision to proceed with angiography is then based on the nding of abnormalities on the stress test. Other institutions risk-stratify according to individual institutional guidelinessuch as performing stress testing on patients with low pretest probability while proceeding directly to 2665

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Figure 1: Listing criteria for renal transplantation.

coronary angiography on patients with high pretest probability (6,7). Although the use of myocardial perfusion studies to guide therapy has been shown to decrease myocardial infarction and cardiac death in the ESRD population awaiting renal transplantation (8), mortality rates remain unacceptably high when dealing with a high-risk patient population. This is compounded by the loss of a viable organ to another potential recipient given the scarcity of donor kidneys. Reports of angiographic studies in patients undergoing transplant evaluation show a prevalence rate of CAD ranging from 42% to 81% but are largely based on small sample populations (814). In the absence of prospective trials addressing the optimal strategies for managing these patients, we have performed a retrospective analysis of patients who underwent renal transplantation at the Mount Sinai Medical Center in New York City. Evaluation and therapeutic strategies were determined by the patients physicians and this allowed us, in a retrospective manner, to assess the different approaches taken. In this paper we describe the prevalence and extent of coronary disease in patients with ESRD using both noninvasive imaging and coronary angiography and explore the usefulness of clinical markers in the assessment of these patients. Further, in an effort to formulate a rational approach to their management, we examine the long-term outcomes of these patients beyond transplantation in the context of the coronary disease detected during their pretransplant evaluations and in view of any cardiac interventions that resulted from that evaluation.

stitutional criteria to remain on the transplant list. These are summarized in Figure 1. The only specied cardiac exclusion criterion for transplantation was severe congestive heart failure with an ejection fraction of less than 20%. Otherwise, patients needed cardiac clearance from an attending cardiologist every 18 months to remain on the list.

Screening methodology
The charts of all patients who were presented to the renal transplant group at the Mount Sinai Hospital were reviewed to identify those who completed an initial cardiovascular screening process including a 12-lead electrocardiogram, echocardiogram and a stress test or coronary angiography. The identication of risk factors and history of CAD were either patient-reported or physician-diagnosed by standard screening modalities. In addition, the records were reviewed for patient-reported symptoms of chest pain or typical anginal equivalents. The approach to pretransplant cardiac evaluation and management was determined by the attending cardiologist, as there were no standardized institutional guidelines in place at the time of this study. The decision as to whether to send the patient for angiography, either initially or after an abnormal nuclear study, as well as the decision to proceed with revascularization either by percutaneous intervention (PCI) or by coronary artery bypass grafting (CABG) was also made by the attending cardiologist. These decisions were based on the clinical judgment of the consulting cardiologist and likely reect practice patterns in the community. In addition, it was at the cardiologists discretion to not send a given patient with an abnormal stress test to angiography; and this generally occurred if, despite being abnormal, the study was felt to impart a low-risk, such as one demonstrating mild ischemia in one territory only.

Data collection
Patient encounters, cardiac test and procedural results and laboratory results were recorded via electronic medical records in the Organ Transplant Tracking Record (OTTR) system. Patient charts were analyzed according to testing modality for pretransplant screening and disease prevalence. Coronary angiography results were included only if performed before transplant. Noninvasive imaging was considered abnormal if there was evidence of ischemia, scar or cardiomyopathy on the scintigram or wall motion abnormalities on the echocardiogram. Angiographically signicant coronary

Methods
Patient population
Our study targeted renal transplant patients who had an initial pretransplant evaluation at our institution. Patients were required to meet our in-

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Figure 2: ACC/AHA guidelines showing high-risk noninvasive imaging results.

disease was obtained from the coronary angiography report, and obstructive disease was dened as a visually estimated stenosis of greater than 70% of the vessels diameter. Mortality was assessed through the OTTR system and conrmed by Social Security Death Index (25). Because many patients received multiple stress tests and/or coronary angiographies before transplant, the following criteria were used to determine how studies were recorded. For calculation of sensitivity, specicity, positive predictive value and negative predictive value, the patients rst coronary angiography and the most recent stress test before that coronary angiography were selected for analysis. For overall disease burden, if a patient had multiple coronary angiography results before transplant, these results were combined to reveal the true disease burden in each vessel. This was done to account for worsening of disease while on the transplant list and prevent loss of data after PCIs in which vessels would be subsequently reported as patent even though they were severely diseased beforehand. For example, a 70% occluded left anterior descending artery that was intervened on and reported as only a 10% lesion in a following angiography would still be considered a 70% lesion when combining results so as to not lose the overall arterial disease burden.

tients had complete charts available for review. The remaining 498 patients were excluded because their evaluations had been performed elsewhere and their noninvasive and invasive test results were not available for review. Baseline clinical and demographic information are shown in Table 1. Of the 962 patients in the cohort, 89.3% were asymptomatic at the time of initial evaluation. Patient chart information was recorded for a maximum of 5 years posttransplant. The median duration of follow-up was 2.9 years. Prevalence of CAD in patients who have undergone renal transplant Tables 2 and 3 summarize the noninvasive and invasive test results with their corresponding prevalence of CAD in this population. Noninvasive stress testing was performed in 88.1% of patients. Patients who were asymptomatic had a 30.7% likelihood of having an abnormal noninvasive test, whereas 53.2% of symptomatic patients had abnormal results. Of the 357 patients who had coronary angiography performed at any stage in evaluation, 59.4% were found to have signicant disease in at least one vessel; this represents 14.5% of the entire transplant cohort. In addition, of those who had received coronary angiography, 22.1% had conrmed triple vessel disease, which reects 5.4% of the entire transplant cohort. Frequency of interventions The use of PCI and CABG is summarized in Table 4. PCI was performed more frequently than CABG in our study. Of the asymptomatic patients who underwent coronary angiography, 44.8% received an intervention; this is contrasted with symptomatic patients, in whom 72.7% of those who underwent coronary angiography subsequently underwent an intervention. Noninvasive and invasive test correlations There were 133 patients who underwent initial screening with noninvasive imaging and subsequent coronary angiography; the remainder of patients had only noninvasive imaging done or coronary angiography as the initial screening modality. Sensitivity, specicity, positive predictive value and negative predictive value are shown in Table 5 for the two analyzed correlations.
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Statistical analysis
Continuous variables are reported as median and quartiles. The p values for comparisons of percentages are based on the chi-square test. Sensitivity, specicity, positive predictive value and negative predictive value of noninvasive imaging were calculated using coronary angiography as the gold standard. Data for this were analyzed in two waysone correlating any perfusion defect on noninvasive imaging with signicant CAD on coronary angiography and the second correlating high-risk abnormalities on noninvasive imaging as outlined in the relevant American College of Cardiology (ACC)/American Heart Association (AHA) guidelines (15) with signicant CAD on coronary angiography. The relevant ACC/AHA indications for coronary angiography that were used are summarized in Figure 2. KaplanMeier analysis was used to determine postoperative patient survival over a 5-year period using the log-rank test to compare differences between groups. A Cox proportional hazards model was used to calculate hazard ratios (HRs) between groups and was adjusted for age, gender, hypertension, diabetes, hypercholesterolemia, past tobacco use and previous history of CAD.

Results
Patient population From January 1, 2000 to October 31, 2009, 1460 patients received a renal transplant (Figure 3). Of these, 962 paAmerican Journal of Transplantation 2011; 11: 26652674

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Figure 3: Pretransplant evaluation of patients and results of imaging and coronary angiography.

Survival analysis There was a statistically nonsignicant trend toward better 5-year posttransplant survival rates in patients with normal noninvasive imaging study results as compared with those with abnormal results after adjusting for age, gen2668

der, hypertension, diabetes, hypercholesterolemia, past tobacco use and previous history of CAD (adjusted hazard ratio [aHR], 0.626; CI 95%, 0.3691.062; p = 0.082). The presence of inducible myocardial ischemia (aHR, 1.478; CI 95%, 0.8112.695; p = 0.202) and the presence of
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Table 1: Baseline characteristics of patients awaiting renal transplant No known obstructive disease (N = 749) Medically managed obstructive disease (N = 31) Revascularized obstructive disease (N = 182) 64 (57, 69) 139 (76.4%) 178 (97.8%) 121 (66.5%) 120 (65.9%) 57 (31.3%) 158 (86.8%) 75 (41.2%) 130 (71.4%) 106 (58.2%) 132 (72.5%) 82 (45.1%)

Characteristic

Asymptomatic (N = 859)

Symptomatic (N = 103)

p-Value

p-Value <0.001 <0.001 0.004 <0.001 <0.001 0.001 <0.001 0.071 <0.001 <0.001 <0.001 <0.001 <0.001

Age Median (25th, 75th 56 (47, 65) 61 (52, 68) 0.001 55 (45, 63) 62 (50, 72) percentile) Male 535 (62.3%) 64 (62.1%) 0.977 438 (58.5%) 22 (71.0%) Hypertension 786 (91.5%) 98 (95.1%) 0.200 679 (90.7%) 27 (87.1%) Diabetes mellitus 336 (39.1%) 56 (54.4%) 0.003 249 (33.2%) 22 (71.0%) Hypercholesterolemia 333 (38.8%) 56 (54.4%) 0.002 251 (33.5%) 18 (58.1%) Prior tobacco use 182 (21.2%) 29 (28.2%) 0.106 145 (19.4%) 9 (29.0%) Prior CAD 146 (17.0%) 58 (56.3%) <0.001 29 (3.9%) 17 (54.8%) Medications at initial evaluation ACEI or ARB1 303 (35.3%) 36 (35.0%) 0.948 257 (34.3%) 7 (22.6%) Beta blocker 434 (50.5%) 60 (58.3%) 0.138 349 (46.6%) 15 (48.4%) Statin 301 (35.0%) 45 (43.7%) 0.084 230 (30.7%) 10 (32.3%) Antiplatelet agent 242 (28.2%) 58 (56.3%) <0.001 155 (20.7%) 18 (58.1%) Insulin 187 (21.8%) 34 (33.0%) 0.001 126 (16.8%) 13 (41.9%) Initial laboratory and imaging values LDL (mg/dL) Median (25th, 75th 84 (63, 103) 78 (62, 101) 0.606 85 (65, 105) 80 (51, 108) percentile) Median hematocrit (%) Median (25th, 75th 37.0 (33.3, 40.7) 35.7 (32.0, 40.6) 0.304 36.9 (33.2, 40.5) 35.0 (28.0, 38.4) percentile) Ejection fraction Severe 7 (0.8%) 1 (1.0%) 0.277 4 (0.5%) 0 (0%) dysfunction (< 30%) Mild to moderate 94 (10.9%) 14 (13.6%) 74 (9.9%) 2 (6.5%) dysfunction (3050%) Normal (>50%) 528 (61.5%) 53 (51.5%) 482 (64.4%) 14 (45.2%) Unknown 230 (26.8%) 35 (34.0%) 189 (25.2%) 15 (48.4%) Dialysis information Dialysis type Hemodialysis 579 (67.4%) 72 (69.9%) 0.869 500 (66.8%) 25 (80.6%) Peritoneal dialysis 48 (5.6%) 5 (4.9%) 47 (6.3%) 0 (0%) Unknown 232 (27.0%) 26 (25.2%) 202 (27.0%) 6 (19.4%) Time on dialysis Median (25th, 75th 1125 (499, 2189) 1349 (780, 1937) 0.600 1112 (496, 2191) 1388 (739, 2288) percentile)
1 ACEI

75 (54, 96)

37.0 (33.5, 41.2)

0.150

4 (2.2%) 32 (17.6%) 85 (46.7%) 61 (33.5%)

<0.001

126 (69.2%) 6 (3.3%) 50 (27.5%) 1306 (507, 1937)

0.220

0.727

= angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker.

scar without inducible ischemia (aHR, 1.471; CI 95%, 0.5563.890; p = 0.437) did not signicantly alter mortality rates at the 5-year mark. The presence of cardiomyopathy on noninvasive imaging predicted a statistically nonsignicant trend towards impaired survival when compared to patients with normal results (aHR, 2.189; 95% CI, 0.9085.276; p = 0.081). Survival in patients who underwent invasive imaging with possible revascularization is shown in Figures 4 and 5. The presence of an angiographically signicant and subsequently revascularized lesion did not portend worse 5year posttransplant survival rates when compared to those with nonobstructive angiograms (aHR, 1.243; CI 95%, 0.5133.010; p = 0.630).

When specically comparing different treatment options in those with signicant vessel CAD, there was no statistical difference in survival between those who underwent PCI and those who underwent CABG (HR, 1.885; CI 95%, 0.4078.734; p = 0.418). Those with medically managed obstructive disease (dened as patients receiving medical management only for CAD with lesions >70%), however, had signicantly higher mortality rates at 5 years when compared to those who received PCI only (aHR, 3.792; CI 95%, 1.32010.895; p = 0.013). This was seen to an even greater extent when comparing those who were medically managed to those who received CABG only (aHR, 6.691; CI 95%, 1.20037.323). When compared to patients with any revascularization procedure (PCI, CABG or combined interventions), those who were medically

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Table 2: Noninvasive results based upon symptomatology Results Normal Abnormal Ischemia Scar only Other Total (N = 848) 570 (67.2%) 278 (32.8%) 205 (24.2%) 39 (4.6%) 34 (4.0%) No symptoms (N = 769) 533 (69.3%) 236 (30.7%) 173 (22.5%) 33 (4.3%) 30 (3.9%) Symptoms (N = 79) 37 (46.9%) 42 (53.2%) 32 (40.5%) 6 (7.6%) 4 (5.1%) p-Value <0.001

managed had poorer outcomes overall (aHR, 4.537; CI 95%, 1.77711.581; p = 0.002). We attempted to determine if pretransplant symptomatology had any effect on 5-year posttransplant survival rates. In the overall cohort, the patients who had anginal symptoms did not have worse outcomes than those without (aHR, 1.248; CI 95%, 0.6562.376; p = 0.499). In patients with abnormal noninvasive imaging results, those with anginal symptoms also did not have worse outcomes than those without anginal symptoms but with abnormal noninvasive imaging (aHR, 1.304; CI 95%, 0.5043.375; p = 0.585). Similarly, in patients with signicant disease by angiography, those with anginal symptoms did not have worse outcomes than those without (aHR, 1.470; CI 95%, 0.6353.403; p = 0.368).

disease. Interestingly, in our study there were 23 asymptomatic patients who had a normal nuclear stress test but who were nonetheless sent for coronary angiography by their cardiologists. Of these, 13 of them had nonobstructive or normal coronaries. However, 10 (44%) of them had obstructive disease, of which 8 received PCI, 1 received CABG and 1 received both PCI and CABGa large burden of disease in patients with no symptoms and a negative stress test. The reason for the absence of symptoms in these patients is unclear. It has long been suggested that diabetics have a diminished sensitivity to anginal pain, and in our study, 40.7% had diabetes. This issue, however, is controversial and more recent ndings suggest that abnormal thresholds for the detection of anginal pain do not indeed occur in diabetes (17). Further, it may be that patients with ESRD on hemodialysis are likely to be less active and thus not hit their ischemic thresholds or alternatively may attribute their less-than-classic symptoms, that is exertional fatigue, to anemia from their kidney disease rather than to see them as coronary symptoms. Given the high incidence of signicant CAD in the absence of symptoms, it is clear that history is of little value in assessing these patients before transplant. In formulating a strategy of care, one needs to consider the risks and benets of further studies. Stress testing is commonly performed, often using radionuclide imaging. However, using coronary angiography as a benchmark, De Lima et al. (9) found that nuclear stress testing offered a sensitivity and specicity of 58% and 67%, respectively, for the detection of coronary disease in a pretransplant population and a multivariate analysis showed that the sole predictor of cardiac events was the presence of signicant coronary lesions. Given the relatively low sensitivity and specicity for the detection of CAD, it was not unexpected that radionuclide imaging was also poorly predictive of cardiac outcomes over a 4-year follow-up period. Ohtake et al. (18), performing angiography on an asymptomatic group

Discussion
In our review of 962 patients with ESRD who received a renal transplant at our institution, one nding stood out. Specically, that the absence of symptoms in this population does not imply the absence of signicant coronary disease. In fact, although scintigraphic evidence of disease (specically xed defects, reversible perfusion defects or cardiomyopathy on a nuclear study) was found in 32.8% of all potential transplant recipients, 30.7% of those without symptoms had the same ndings In contrast, in patients without ESRD, abnormal nuclear studies are found in only 215% of asymptomatic individuals, depending upon decade of life (16). Admittedly, some patients were sent directly to angiography by their cardiologist and this could have introduced a bias into the analysis. However, in clinical practice, there will always be those for whom stress testing is considered inappropriate or hazardous. Nonetheless, in our patients who underwent stress testing, its sensitivity for the detection of CAD was quite modest. Also of signicance is the fact that the absence of symptoms did not confer a better prognosis in the presence of coronary
Table 3: Coronary anatomy based upon symptomatology Results No obstruction Obstruction 1 Vessel 2 Vessel 3 Vessel Total (N = 357) 145 (40.6%) 212 (59.4%) 79 (22.1%) 54 (15.1%) 79 (22.1%)

No symptoms (N = 281) 129 (45.9%) 152 (54.1%) 63 (22.4%) 39 (13.9%) 50 (17.8%)

Symptoms (N = 76) 16 (21.1%) 60 (78.9%) 16 (21.1%) 15 (19.7%) 29 (38.2%)

p-Value <0.001

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Table 4: Prevalence of interventions Results None PCI only CABG only Both Any Total (N = 357) 176 (49.3%) 117 (32.8%) 38 (10.6%) 26 (7.3%) 181 (50.7%) No symptoms (N = 281) 155 (55.2%) 82 (29.2%) 30 (10.7%) 14 (5.0%) 126 (44.8%) Symptoms (N = 76) 21 (27.6%) 35 (46.1%) 8 (10.5%) 12 (15.8%) 55 (72.4%) p-Value <0.001

of ESRD patients, found a 58% prevalence of CAD. This is similar to the 54.1% of our asymptomatic patients who were found to have CAD. The literature has been unclear as to the impact of detectable coronary disease on the event rates and long-term survival of these patients. Most studies have been of small cohorts of patients and have offered conicting data (814). Gowdak et al. describe 301 patients referred for transplant evaluation who were deemed at high coronary risk and found that major adverse cardiovascular events (dened as myocardial infarction, unstable angina, sudden death, unplanned coronary or peripheral arterial revascularization, stroke or heart failure) were signicantly greater in those with CAD during the 1.8-year observation period (45% vs. 18%; p < 0.001) (11). However, Hage et al. looked at the results of coronary angiography in a cohort of 260 patients who were referred for transplant evaluation and had a positive stress test or who had known CAD and found that the presence and severity of CAD was not associated with crude survival in those who underwent angiography after two years (12). Our study also demonstrated that posttransplant survival was not affected as much by the presence of obstructive disease as by its management. Ultimately, however, the rational for preoperative evaluation lies not merely in the detection of disease but in our ability to use that knowledge to improve outcomes. Risk reduction must be considered in terms of both perioperative and long-term survival (19). In a population of patients at high-risk for coronary disease undergoing major vascular surgery, McFalls et al. (20) failed to demonstrate any perioperative survival benet to presurgical revascularization. Although this was not a study of ESRD patients, they too were at high risk of CAD and underwent surgical interventions presumably as stressful as a transplant. Thus, it

would be reasonable to assume that it is not necessary to subject ESRD patients to revascularization merely to get them through the peritransplant period. One caveat is the study by Ojo et al. (1), who evaluated 18 482 renal transplantation and found that 47% of those who died within 30 days of transplant with a functioning graft died of a cardiac event, most likely a myocardial infarction. The paper does not detail how many patients this involved; however our study shows the all-cause mortality at 30 days after transplant to be exceedingly low. Of 962 posttransplant patients, there were only nine deaths (0.92%) within the rst 30 days. Further, Hemmelgarn et al. (17) have demonstrated a signicant improvement in long-term survival for ESRD patients who underwent revascularization with CABG or PCI compared to those with no revascularization. Their study further suggested a greater benet to CABG than with PCI. In addition, Herzog et al. (21) demonstrated similar outcomes for CABG and PCI survival posttransplant and suggested a possible benet to CABG recipients. Although clinicians are often concerned with getting the patient through the peritransplant period, the real benets may actually lie in long-term mortality and morbidity. Despite a small sample size, we compared posttransplant patients who had received no revascularization to those who received PCI or CABG and looked at long-term survival. Our study suggested a trend towards improved longterm posttransplant survival with revascularization compared with no revascularization. The survival curves of the two groups appear to deviate sharply 1 year after transplant. This would appear to suggest a long-term benet of revascularization, although larger randomized studies with optimal medical management and updated revascularization techniques are needed. Interestingly, in our study, there is a trend towards improved outcome with CABG compared to PCI, consistent with the ndings of Hemmelgarn et al. as well as those of Herzog et al., but further studies would be required before recommendations can be made with regard to the optimal mode of revascularization. Given the observational nature of this study, the results have to be considered cautiously. The decisions as to the extent and approach to each patients pretransplant cardiac assessment were made by the patients own cardiologist and so there was no uniform protocol that was followed. Further, the medical record was often unclear as to why a given approach was taken in a specic patient, which could potentially introduce some degree of bias into the
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Table 5: Sensitivity, specicity, positive predictive value and negative predictive value of noninvasive imaging of 133 patients Result1 Sensitivity Specicity PPV NPV
1 Values

ACC/AHA analysis 0.34 (0.230.46) 0.80 (0.680.89) 0.67 (0.490.81) 0.51 (0.410.61)

Perfusion defect analysis 0.76 (0.640.85) 0.41 (0.290.54) 0.60 (0.490.70) 0.60 (0.430.74)

are reported as estimated values with a 95% condence interval. PPV = positive predictive value; NPV = negative predictive value.

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Figure 4: Survival analysis between nonobstructive CAD, revascularized obstructive CAD and medically managed signicant CAD.

Figure 5: Subgroup analysis between PCI only, CABG only and medically managed obstructive CAD.

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interpretation. Nonetheless this is also one of the strengths of our study in that it reects the way such pretransplant evaluations are performed in many centers. Thus, it suggests concerns with the approach currently taken in many institutions, including our own. Although there is clearly much work needed to clarify the optimal approach to these patients, the following considerations seem reasonable at the present time and have informed our own practice: (1) Patients with ESRD are at especially high risk for coronary disease and given that history is not helpful in identifying those with signicant CAD, it is important to obtain some estimate of the extent and severity of their coronary disease. Studies have suggested that critical coronary lesions may be the only statistically signicant predictor of cardiac events, the leading cause of death in this patient population (9). (2) Nuclear imaging is of marginal utility in this population and thus for those already on hemodialysis and angiography, either via cardiac catheterization or computed tomography (CT) angiography should be considered. (3) Those patients with severe chronic kidney disease (CKD) who have yet to require dialysis present a management challenge for they are also at risk of accelerating their need for dialysis if intravenous contrast is administered. Given the long wait for a suitable organ, it is conceivable that angiography could make the patient dialysis dependent for several years. Accordingly, an alternate strategy needs to be determined. As nuclear imaging and dobutamine stress echocardiography are neither sensitive nor specic in this population, they are of minimal utility for these patients. Although speculative, it is possible that an adequate exercise capacity as demonstrated on stress testing may offer some reassurance, but again, there is no data in the CKD population to support this as yet. (4) Although it is not clear that pretransplant revascularization improves peritransplant mortality, our data suggest that it does improve posttransplant survival and thus it seems prudent to use this opportunity to identify those with severe CAD. Because of the exceedingly high burden of coronary disease in this population, prospective randomized trials should be pursued to help guide the optimal management of these high-risk patients.

quisition of data: Kahn, Fallahi and Esquitin. Analysis and interpretation of data: Kahn, Fallahi, Robbins, Esquitin and Kim. Drafting of the manuscript: Kahn, Fallahi, Robbins, Esquitin and Kim. Statistical analysis: Kahn, Fallahi and Esquitin. Administrative, technical, or material support: Kahn, Fallahi, Robbins, Esquitin and Kim. Study supervision: Kim and Robbins.

Disclosure
The authors of this manuscript have no conicts of interest to disclose as described by the American Journal of Transplantation.

References
1. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307313. 2. Koistinen MJ, Huikuri HV, Pirttiaho H, Linnaluoto MK, Takkunen JT. Evaluation of exercise electrocardiography and thallium tomographic imaging in detecting asymptomatic coronary artery disease in diabetic patients. Br Heart J 1990; 63: 711. 3. Marwick TH, Steinmuller DR, Underwood DA, et al. Ineffectiveness of dipyridamole SPECT thallium imaging as a screening technique for coronary artery disease in patients with end-stage renal failure. Transplantation 1990; 49: 100103. 4. Dahan M, Viron BM, Faraggi M, et al. Diagnostic accuracy and prognostic value of combined dipyridamole-exercise thallium imaging in hemodialysis patients. Kidney Int 1998; 54: 255262. 5. Schmidt A, Stefenelli T, Schuster E, Mayer G. Informational contribution of noninvasive screening tests for coronary artery disease in patients on chronic renal replacement therapy. Am J Kidney Dis 2001; 37: 5663. 6. Jones DG, Taylor AM, Enkiri SA, et al. Extent and severity of coronary disease and mortality in patients with end-stage renal failure evaluated for renal transplantation. Am J Transplant 2009; 9: 1846 1852. 7. Kasiske BL, Malik MA, Herzog CA. Risk-stratied screening for ischemic heart disease in kidney transplant candidates. Transplantation 2005; 80: 815820. 8. Sharma R, Pellerin D, Gaze DC, et al. Dobutamine stress echocardiography and the resting but not exercise electrocardiograph predict severe coronary artery disease in renal transplant candidates. Nephrol Dial Transplant 2005; 20: 22072214. 9. De Lima JJ, Sabbaga E, Vieira ML, et al. Coronary angiography is the best predictor of events in renal transplant candidates compared with noninvasive testing. Hypertension 2003; 42: 263268. 10. Charytan D, Kuntz RE, Mauri L, DeFilippi C. Distribution of coronary artery disease and relation to mortality in asymptomatic hemodialysis patients. Am J Kidney Dis 2007; 49: 409416. 11. Gowdak LH, de Paula FJ, Cesar LA, et al. Screening for signicant coronary artery disease in high-risk renal transplant candidates. Coron Artery Dis 2007; 18: 553558. 12. Hage FG, Smalheiser S, Zoghbi GJ, et al. Predictors of survival in patients with end-stage renal disease evaluated for kidney transplantation. Am J Cardiol 2007; 100: 10201025. 13. Patel RK, Mark PB, Johnston N, et al. Prognostic value of cardiovascular screening in potential renal transplant recipients: A singlecenter prospective observational study. Am J Transplant 2008; 8: 16731683.

Acknowledgments
The authors thank Drs. Roxana Mehran and George Dangas for their thoughtful review of the manuscript and Dr. Susan Lerner for access to the renal transplant database.

Authors Contributions
Drs. Kahn and Fallahi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kahn, Fallahi, Robbins, Esquitin and Kim. AcAmerican Journal of Transplantation 2011; 11: 26652674

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