Stress Echocardiography for Risk Stratification in Patients with End-Stage Renal Disease Undergoing Renal Transplantation

Stress Echocardiography for Risk Stratification in Patients with End-Stage Renal Disease Undergoing Renal Transplantation Cristina Tita, MD, Vanji Karthikeyan, MD, Alice Stroe, MD, Gordon Jacobsen, MS, and Karthik Ananthasubramaniam, MD, FACC, FASE, FASNC, Detroit, Michigan

Background: The predictive accuracy of stress echocardiography (SE) for adverse cardiac events has been variable in the population with end-stage renal disease undergoing renal transplantation (RT). Methods: We performed a retrospective study of 149 patients who had pretransplant SE before RT between 1997 and 2003. Patients were followed up for a mean of 2.85 years for major adverse cardiovascular events (MACE). Results: Of 149 patients studied, 139 had a negative SE, 65% were African American; 12 underwent cardiac catheterization. Only 1 patient required pre-RT revascularization. Sixteen MACE occurred over the follow-up period. SE had 37.5% sensitivity, 95.3% specificity, 33.3% positive predictive value, and 96.1% negative predictive value for MACE in the first year post-RT. First-year posttransplant event rates were 4.0% versus 30% (P ⬍ .001) for patients with a negative SE and positive SE, respectively. Multivariate predictors of MACE were positive SE (hazard ratio [HR] 7.64), hemoglobin less than 11 g/dL post-RT (HR 4.44), and calcium channel blocker use posttransplant (HR 2.90). Conclusions: A negative SE has low incidence of MACE in this intermediate- to high-risk patient subset. A positive SE predicts a sevenfold higher risk of cardiovascular events regardless of the need for revascularization before the transplant.

The number of patients active on the waiting list for renal transplantation (RT) continues to increase: 25,509 at the end of 1995, 45,676 at the end of 2004, and more than 64,000 currently.1,2 Because cardiovascular disease is the leading cause of death after RT, accounting for 40% to 55% of all deaths,3,4 it also becomes one of the leading causes of renal allograft failure4 and renders preoperative cardiovascular risk assessment and aggressive risk modification crucial in RT candidates. The role of stress testing, including that of stress echocardiography (SE), has been extensively validated in preoperative risk evaluation.4-8 Some studies have shown that SE is a reliable technique for evaluation of significant coronary artery disease (CAD) in patients with end-stage renal disease (ESRD).9-12 Others have suggested that SE is an imperfect screening tool in patients with ESRD who are being evaluated for RT.11,13 Furthermore, angiographic studies have also shown a high prevalence of asymptomatic CAD in patients with

From the Heart and Vascular Institute, Division of Nephrology, Department of Medicine, and Department of Biostatistics and Epidemiology, Henry Ford Hospital, Detroit, Michigan. This study was presented as a moderated poster session at the American Society of Echocardiography Scientific Sessions, Baltimore, June 2006. Reprint requests: Karthik Ananthasubramaniam, MD, FACC, FASE, FASNC, Henry Ford Hospital, Heart and Vascular Institute, K-14, 2799 West Grand Blvd, Detroit MI 48202 (E-mail: [email protected]). 0894-7317/$34.00 Copyright 2008 by the American Society of Echocardiography. doi:10.1016/j.echo.2007.06.004

ESRD.14 De Lima et al.13 suggested that coronary angiography (CA) may be the best predictor of events in RT candidates. A review of prior studies showed that African Americans formed mostly a minority in all published studies.15,16 Because renal disease is a source of major morbidity in this subgroup, we studied whether SE maintained its predictive accuracy in our inner-city patient population at Henry Ford Hospital, Detroit, Michigan, where more than 60% of renal transplant candidates and recipients were African Americans. METHODS Population A total of 555 consecutive patients undergoing RT at Henry Ford Hospital, Detroit, between January 1997 and December 2003 were retrospectively studied. Of these 555 patients, 266 were screened for CAD by echocardiographic or nuclear stress noninvasive modalities. The patients screened were considered to be at high risk for perioperative cardiovascular complications on the basis of prior studies that have tested and validated a clinical risk factor profile (age ⬎ 50 years, diabetes, abnormal electrocardiogram, and history of angina or congestive heart failure).17,18 Patients with one or more of these factors were considered high risk and subjected to noninvasive risk stratification. A total of 175 patients (of 266) underwent SE (139 dobutamine and 36 exercise). Complete follow-up data were not available in 26 patients who were followed up in medical systems outside our city after transplant. Our final study group was composed of 149 patients (out of which 114 underwent dobutamine and 35 underwent exercise SE). 321

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Stress Echocardiography Protocol Dobutamine. Images were obtained in the parasternal long- and short-axis, apical four-, two-, and long-axis at baseline and after each incremental dose of dobutamine in 3-minute intervals. Heart rate, blood pressure, and 12-lead electrocardiograms were recorded at baseline and monitored through each stage. Dobutamine was initiated at a dose of 10 ␮g/kg/min and increased at 3-minute intervals to 20, 30, and a maximum of 40 ␮g/kg/min. After the 3-minute infusion at the 20 ␮g/kg/min stage, if 85% or greater age-predicted maximum heart rate (maximum age-predicted heart rate ⫽ 220 ⫺ age) or an absolute heart rate of 100 or greater had not been reached, atropine was injected at a 0.2-mg dose increment every minute up to a total dose of 2 mg. The test was terminated at the completion of the protocol or with the development of significant ischemic ST segment shifts, intolerable symptoms, ventricular tachycardia, symptomatic hypotension (or systolic blood pressure ⬍ 90 mm Hg), or severe hypertension (⬎220/110 mm Hg). Digital quad screen interpretation was performed by an American Society of Echocardiography Level 2 or Level 3 echocardiographer. In case of suboptimal digital quality of capture, tape review was done for interpretation. Visual assessment of wall motion was done using the standard format: 0 ⫽ normal, 1 ⫽ mildly hypokinetic, 2 ⫽ moderately hypokinetic, 3 ⫽ severely hypokinetic, 4 ⫽ akinetic, and 5 ⫽ dyskinetic. Ejection fraction estimation was based on visual assessment, and ejection fraction of 50% or greater was defined as normal. A positive stress echocardiography (PSE) was defined as new echocardiographic evidence of ischemia in patients with normal or abnormal baseline wall motion. All studies showing normal segmental and global augmentation with dobutamine were designated negative stress echocardiographic (NSE) studies, regardless of the presence or absence of resting wall motion abnormalities. Electrocardiograms were designated as ischemic with the presence of ⱖ 1 mm or horizontal or downsloping ST-segments 80 ms after the J-point, or if there were ⱖ 1 mm ST-segment elevations in leads without significant Q waves at baseline. Patients with a positive stress electrocardiogram but negative dobutamine stress echocardiography (DSE) were considered overall to have negative DSE. Exercise. All patients underwent symptom-limited treadmill exercise testing according to the Bruce protocol. Standard indications for exercise termination were followed, and interpretation protocols were the same as indicated for DSE above. End Points The patients were followed up for major adverse cardiovascular events (MACE: nonfatal myocardial infarction, coronary revascularization, new-onset congestive heart failure, and cardiac death) from the date of transplant to September of 2005. Data were also collected on cerebrovascular events, which included stroke (cardiovascular accident) and transient ischemic attacks. Data Collection Data were collected on demographics, comorbidities, pretransplant medications, cause of renal failure, duration/modality of dialysis, and type of kidney donor. SE data and posttransplant variables, including medications, blood pressure, cholesterol, hemoglobin, and creatinine, were recorded. Cardiac catheterization data were collected in the subset who underwent catheterization as necessitated by their physicians. The patients were screened for MACE occurring from the date of transplantation to September of 2005, when data collection ended.

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Table 1 Baseline characteristics in renal transplant candidates Demographics

No. (%)

Age Male sex African-Americans Diabetes Hypertension Prior CAD EF ⬍ 50% Hypercholesterolemia

53.4 ⫾ 11 79 (53%) 97 (65%) 97 (65%) 143 (96%) 16 (10.7%) 15 (10%) 89 (59.7%)

EF, Ejection fraction; CAD, coronary artery disease.

Statistical Analysis Sensitivity, specificity, positive predictive value, and negative predictive value for MACE were calculated for SE post-RT. If one patient had more than one MACE during the follow up period, he or she was treated as an “event patient” and accounted for as one event. The time to event in these patients was the time from RT to the first qualifying MACE. Patients who experienced transplant failure were censored from analysis at the failure date (including the two patients who had cardiovascular events after transplant failure). The reason for these patients’ exclusion was the fact that after graft failure they belong to the dialysis population, and the purpose of the study was to evaluate the prognostic value of SE in patients undergoing RT with functioning grafts. Univariate analysis of all variables was performed using the chisquare and Student t tests. Cox proportional hazards regression analysis was performed to identify multivariate predictors of MACE posttransplant. All of the variables on the univariate analysis rendering a log-rank P value of .10 or less were included in the multivariate analysis. RESULTS The baseline characteristics of the study patients are shown in Table 1. Of the 149 patients studied, DSE was performed in 114 patients and exercise stress echocardiography was performed in 35 patients. Of the 149 patients studied, 139 (93.3%) had a negative stress test result (109 negative DSE, 30 negative exercise stress echocardiography). Twelve patients underwent cardiac catheterization: all of the 10 patients with PSE and 2 patients who had NDSE but who achieved a markedly suboptimal heart rate. Seventy percent of the patients (90/149) did not achieve greater than 85% of the predicted maximal heart rate despite the use of atropine as indicated. Among those who had MACE versus no MACE, 62.5% and 60%, respectively, did not achieve 85% or greater of the predicted maximum heart rate (P ⫽ not significant [NS]). Table 2 highlights the coronary anatomy by catheterization, percutaneous coronary intervention performed, and MACE events. As shown, only 1 of 12 patients undergoing cardiac catheterization required revascularization, and the rest had no significant epicardial CAD (n ⫽ 2) or disease not warranting revascularization (n ⫽ 9). The mean follow-up in this study was 2.85 years. Sixteen patients had MACE during follow-up: four nonfatal myocardial infarctions, nine cardiac deaths, two had coronary revascularization, and one developed new congestive heart failure. SE had a 37.5% sensitivity, 95.3% specificity, 33.3% positive predictive value, and 96.1% negative predictive value for MACE occurring in the first year posttrans-

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Table 2 Characteristics of patients undergoing cardiac catheterization Patient

SE

Catheterization

Previous CABG

PCI done

1 2 3 4 5 6 7 8 9 10 11 12

Positive Positive Positive Positive Positive Positive Positive Positive Positive Positive Negative Negative

3-vessel CAD Diffuse branch disease Mild 1-vessel CAD Mild 1-vessel CAD Negative Severe diffuse branch disease (D2,3; OM2, RPDA) 60% distal LAD 70% OM3; 95% dRCA and pRPDA 70% dLAD (small), 60% mid-Cx Severe 2-vessel disease Negative 50% mid-LAD, 40% mid-RCA

Yes No No No No No No No No Yes No No

No No No No No No No Yes RCA No No No No

Event type

NFMI, CD

NFMI NFMI, CVA CD PCI CABG

CABG, Coronary artery bypass grafting; PCI, percutaneous intervention; SE, stress echo; CAD, coronary artery disease; NFMI, nonfatal myocardial infarction; LAD, left anterior descending; RCA, right coronary artery; OM, obtuse marginal; Cx, circumflex, CD, cardiac death; RPDA, right posterior descending artery; CVA, cerebrovascular accident.

Figure 1 NSE, Negative stress echocardiography; PSE, positive stress echocardiography. plantation. Kaplan-Meier freedom from events curves for NSE and PSE are shown in Figure 1, demonstrating significant difference in outcomes between the two groups (P ⬍ .001). In the first year post-RT, the MACE rate for patients with NSE was 4% compared with 31% for those with PSE. At the end of 2 years, the MACE rates were 5% and 43% for patients with NSE and PSE, respectively. For patients with MACE, the mean time interval between the SE and transplantation was not different for negative versus positive SE results (NSE 452 days vs. PSE 404 days, P ⫽ NS). However, there was a trend to MACE occurring closer to transplantation in PSE, although this was not statistically significant as shown in Figure 2). There was no difference in the mean SE to MACE and RT to MACE intervals in patients with NSE (962 and 608 days, respectively, P ⫽ NS). The only statistically significant variable in predicting MACE after the univariate analysis was the presence of ischemia on the SE. Other variables with trends toward statistical significance were history of pulmonary vascular disease; history of CAD before the transplantation; living donor; LVH on baseline echocardiography; baseline wall

Figure 2 Mean time interval (in days) between completion of SE to MACE and transplant to MACE. There was a nonstatistical significant trend toward earlier occurrence of MACE in patients with PSE. NSE, negative stress echocardiography; PSE, positive stress echocardiography; SE, stress echocardiography. Color figure online.

motion abnormality; use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or calcium channel blockers (CCBs); and hemoglobin less than 11 g/dL in the posttransplantation period. Logistic regression modeling for multivariable predictors of MACE identified positive SE (hazard ratio [HR] 7.64), post-RT hemoglobin level less than 11 g/dL (HR 4.44), and use of CCBs post-RT (HR 2.90) as the most significant variables (Table 3). DISCUSSION Patients with ESRD awaiting RT are a population at much higher risk for cardiac events when compared with the general population.19,20 Most centers such as ours do not use CA as the initial screening modality for these patients because it is not only invasive but may accelerate the need for initiation of dialysis in patients with chronic kidney disease21 but not on dialysis. Various algorithms have been

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Table 3 Multivariate predictors of major adverse cardiovascular events Variable

P value

Hazard ratio (95% CI)

Post-RT Hb ⬍ 11 Positive stress echo Post-RT CCB use

⬍.001 ⬍.001 .026

4.56 (2.00-10.37) 6.86 (2.41-19.56) 2.78 (1.13-6.83)

Hb, Hemoglobin; RT, renal transplant; CI, confidence interval; CCB, calcium channel blocker.

proposed to enable identification of a “low-risk “group and a “highrisk” group among patients with ESRD being evaluated for RT. Age 50 years or more, diabetes mellitus, history of angina, history of congestive heart failure, and an abnormal electrocardiogram (excluding left ventricular hypertrophy) have been shown to reliably separate patients into these two groups and are useful for an initial risk assessment strategy.17,18 Patients with none of these parameters had a low risk for cardiac events compared with those with one or more risk factors when placed on the transplant list;17,18 thus, no screening tests are generally performed in the “low-risk” group before listing. In moderate or higher-risk renal transplant candidates, one study suggests that CA might be a better predictor of cardiac events.13 In this study, 126 moderate- to high-risk renal transplant candidates underwent dobutamine echocardiogram, myocardial perfusion imaging, and CA. The sensitivities and negative predictive values for both stress imaging modalities were less than 75%. Only clinical risk stratification (P ⫽ .007) and CA (P ⫽ .0002) best predicted freedom from cardiac events. Multivariate analysis showed that the sole predictor of cardiac events was critical coronary lesions (defined as ⬎ 70% stenosis on CA, P ⫽ .003). Our study shows that SE had a good specificity (95.3%) and negative predictive value (96.1%) with a 4% event rate at 1 year and a 5% event rate at 2 years for MACE. A PSE was associated with a significantly worse outcome for cardiac death and nonfatal myocardial infarction, as shown in the Kaplan-Meier curves in Figure 1. A NSE had excellent predictive value for freedom from such events over the follow-up period shown. Baseline wall motion abnormalities were also predictive of cardiac events in our study (P ⫽ .036), but not as strongly as a PSE. Although the literature on NSE in the general population with known or suspected CAD suggests a low annual hard cardiac event rate of 1.2%,22 the event rate in our study population with an NSE was higher, reflecting the higher cardiac risk of the population with ESRD (diabetes 65%, hypertension 96%, hyperlipidemia 59.7%, in our study). Furthermore, in the posttransplant period, subnormal renal function and commonly used immunosuppressive medications, such as steroids, cyclosporine, tacrolimus and sirolimus, result in new onset of (more commonly) worsening of preexisting hypertension, diabetes mellitus, dyslipidemia, and atherosclerosis.23 Thus, MACE after a NSE in patients with ESRD undergoing RT tend to be slightly worse than in the general population but still significantly less than after a PSE in this high-risk group. There was a significant number of cardiovascular accidents and transient ischemic attacks (n ⫽ 8) during the follow-up. This is consistent with prior reports highlighting the fact that cerebrovascular complications are a major source of morbidity and mortality in the post-RT period.24,25 Studies have highlighted the importance of uncontrolled hypertension, diabetes, and atherosclerosis as being important risk factors for stroke before and after RT.26,27 Most of the cerebrovascular accidents and transient ischemic attacks in our study

occurred in patients with NSE and reflects the importance of the need for aggressive control of cardiac risk factors in patients with ESRD who are on the waiting list and after RT despite no evidence of cardiac ischemia. The majority of the patients in our study did not achieve 85% or more of predicted maximal heart rate (90/149, 70%) despite the use of atropine as indicated. This percentage of chronotropic incompetence is much higher than previously reported in patients with ESRD.11 This is likely due to a combination of many factors, such as high use of beta-blockers (46%) and nondihydropyridine calcium blockers (54%) at the time of DSE. Nevertheless, 120 of 149 (80%) of our patients achieved a 70% or greater age-predicted maximum heart rate. This may explain why a NSE retained its predictive value for low MACE compared with a PSE in our patients (most achieved a reasonable level of stress). Whether the higher incidence of chronotropic incompetence is reflective of the predominantly African American population (65%) in our study needs to be evaluated because there are no previous studies with which to compare. Data from our group in 801 patients (African Americans ⫽ 421) showed that African Americans less often achieved the target heart rate than their white counterparts despite a comparable use of beta/calcium blockers.28 It is important to note that none of the 175 patients in the original study population (before exclusion of 26 lost to follow-up) had any MACE before hospital discharge regardless of heart rate achieved on their stress test. These observations are similar to those of Labib et al.,29 who showed that despite a submaximal negative DSE, a favorable perioperative outcomes were observed in those undergoing noncardiac surgery. Our group previously showed that as long as the contractile response to dobutamine is normal and resting left ventricular function is preserved, chronotropic incompetence in the presence of beta/calcium blockade is still associated with a low hard cardiac event rate of 1% per year.30 Nevertheless, a lack of achievement of heart rate is a major problem in patients with ESRD, which may compromise the sensitivity of SE for CAD. Thus, aggressive efforts to hold beta/calcium blockers before testing are warranted. Patients in our study with PSE had a high event rate postoperatively irrespective of the need for revascularization before transplantation. To our knowledge, only one randomized trial has specifically looked at a small group of asymptomatic diabetic patients with ESRD undergoing CA (n ⫽ 26) who were randomized to medical versus revascularization (percutaneous coronary intervention or coronary artery bypass grafting) strategies.31 This was done in the era of calcium blockers with no preoperative beta-blocker, statins, or stents in the revascularization group. This study showed that medical therapy in diabetic patients with ESRD with significant (⬎70%) stenosis on angiography was associated with a higher event rate compared with prophylactic revascularization. These results contrast with the Coronary Artery Revascularization Prophylaxis trial performed in patients undergoing major vascular surgery, which showed no benefit of prophylactic revascularization versus medical therapy in stable patients with significant angiographic disease.32 There is no data regarding the management and outcomes of patients with positive stress test results who do not need or are ineligible for revascularization before surgery. Although the number of patients with a PSE in our study was small, precluding firm conclusions, it seems that these patients remain at a high risk for MACE long term post-RT and that aggressive medical management may be required in this group of patients if listed for RT. Our study is unique in that 65% of patients were African Americans. To our knowledge, this is the first study looking at the predictive value of SE in a predominantly African American population with

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ESRD undergoing RT. Previous studies have not specified ethnicity or have had less than 30% African American representation.15,16 We showed that SE retains its powerful predictive value in African Americans just as it has been in the predominantly white population in previous studies. Furthermore, the high prevalence of cerebrovascular events in this study also highlights the high prevalence and morbidity of hypertension (present in 96% of study group) on preand post-RT vascular complications in African Americans. Anemia has been linked to increased cardiovascular morbidity in patients with chronic kidney disease and renal transplant recipients. In our study, anemia was found to be an independent predictor of cardiovascular outcomes, and this is entirely in keeping with other published studies on the population undergoing RT. In a study of 626 kidney recipients, the prevalence of anemia (defined as hemoglobin ⬍ 12 g/dL) was 72%, 40%, and 20.3% at 1, 3, and 12 months, respectively. The patients with anemia had inferior survival and a higher proportion of cardiovascular deaths (6.3% vs. 2.2%) than non-anemic patients.33 The prevalence of anemia in patients undergoing RT is often high because of the myelosuppressive effect of the immunosuppressive medications. Also, the glomerular filtration rate is often subnormal in these patients and results in decreased erythropoietin production and, consequently, anemia. Judicial use of erythropoietin-stimulating agents can result in correction of anemia and might improve cardiovascular outcomes in these patients. CCBs were used in 47% of patients post-RT and were found to adversely impact cardiac events and survival. They are often used as second- or third-line agents after ACEI/ARB and beta-blockers for severe hypertension post-RT. Thus, the adverse association between CCBs and increased MACE may be reflective of complications of severe hypertension. Although there are some data that CCBs decrease the rate of graft failure after transplantation,34 there is also evidence that they are inferior to ACEI/ARBs in preventing graft failure if there is proteinuria34 and even evidence that they reduce patient and graft survival altogether.35 None of these studies were randomized, so it may be premature to exclude CCBs from the antihypertensive regimen of patients posttransplant. This association needs to be studied prospectively in randomized trials of larger patient populations. LIMITATIONS This was a retrospective study with its inherent limitations and bias. Treatment strategies were left to the individual physicians and thus may have been biased. Only a limited number of PSEs were present, and, similarly, a low number of cardiac catheterizations were performed before RT. No conclusions can be drawn regarding the incidence of asymptomatic CAD in these patients, and no definite statement can be made about the appropriate medical management in patients with PSE but no revascularizable targets. Follow-up was limited to our health system patients, and no MACE data were available on the 26 excluded patients, which may have biased the results. However, because the baseline characteristics of the study group and those excluded for lack of follow-up were the same, our results seem still valid. CONCLUSIONS SE remains a powerful diagnostic tool for pre-RT risk stratification. The incidence of cardiovascular and cerebrovascular events contin-

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ues to be a major limiting factor in long-term survival after RT, as shown previously. The fact that a PSE predicts a high adverse event regardless of whether revascularization is performed underscores the importance of aggressive risk factor modification before and after RT. This may include the use of aspirin, beta-blockers, and statins, along with strict control of diabetes and hypertension. Although our study was not powered to specifically answer this question, on the basis of our study and the existing literature, we believe that patients with ischemia and revascularizable targets should be offered percutaneous coronary intervention or coronary artery bypass grafting before RT. This may reduce ischemic burden in the perioperative and long-term period and avoid exposing the transplanted kidney to angiography after RT (if significant ischemia is not addressed before RT). Posttransplant anemia less than 11 g/dL seems to predict adverse outcomes, and attempts to maintain hemoglobin at 11 g/dL or more may help in decreasing MACE. Our study raises the interesting issue of adverse outcomes related to post-RT CCB use. The use of ACEIs and ARBs as first-line agents, beta-blockers (particularly in those with prior CAD) as second-line agents, and reserving calcium blockers as third-line agents for hypertensive therapy should be considered. Whether any or all of these above strategies will reduce MACE rates in the population with ESRD deserves study in prospective randomized trials. REFERENCES 1. Organ Procurement and Transplantation Network. (2006). Waiting list candidates. Available at: http://www.optn.org. Accessed October 19, 2006. 2. The U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. (2005). 2005 OPTN/SRTR Annual Report. Available at: http://www.ustransplant.org/annual_reports/ current/. Accessed October 19, 2006. 3. Briggs JD. Cardiovascular complications in renal transplantation. Nephrol Dial Transplant 2001;16(Suppl 6):156-8. 4. Lindholm A, Albrechtsen D, Frodin L, Tufveson G, Persson NH, Lundgren G. Ischemic heart disease—major cause of death and graft loss after renal transplantation in Scandinavia. Transplantation 1995;60:451-7. 5. Das MK, Pellikka PA, Mahoney DW, Roger VL, Oh JK, McCully RB, et al. Assessment of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients. J Am Coll Cardiol 2000;35:1647-53. 6. Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery— executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 2002;39:542-53. 7. Eagle KA, Brundage BH, Chaitman BR, Ewy GA, Fleisher LA, Hertzer NR, et al. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 1996;27:910-48. 8. Poldermans D, Arnese M, Fioretti PM, Salustri A, Boersma E, Thomson IR, et al. Improved cardiac risk stratification in major vascular surgery with dobutamine-atropine stress echocardiography. J Am Coll Cardiol 1995; 26:648-53. 9. Bates JR, Sawada SG, Segar DS, Spaedy AJ, Petrovic O, Fineberg NS, et al. Evaluation using dobutamine stress echocardiography in patients with insulin-dependent diabetes mellitus before kidney and/or pancreas transplantation. Am J Cardiol 1996;77:175-9. 10. Dahan M, Viron BM, Poiseau E, Kolta AM, Aubry N, Paillole C, et al. Combined dipyridamole-exercise stress echocardiography for detection

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23. Fazelzadeh A, Mehdizadeh A, Ostovan MA, Raiss-Jalali GA. Incidence of cardiovascular risk factors and complications before and after kidney transplantation. Transplant Proc 2006;38:506-8. 24. Howard RJ, Patton PR, Reed AI, Hemming AW, Van der Werf WJ, Pfaff WW, et al. The changing causes of graft loss and death after kidney transplantation. Transplantation 2002;73:1923-8. 25. Oliveras A, Roquer J, Puig JM, Rodriguez A, Mir M, Orfila MA, et al. Stroke in renal transplant recipients: epidemiology, predictive risk factors and outcome. Clin Transplant 2003;17:1-8. 26. Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg 2004;107:1-16. 27. Iseki K, Fukiyama K. Predictors of stroke in patients receiving chronic hemodialysis. Kidney Int 1996;50:1672-5. 28. Srivastava AV, Patel SJ, Lingam N, Kancherla S, Jacobsen G, Anathasubramaniam K. Long Term Outcomes Following Negative Dobutamine Stress Echocardiography in African Americans compared to Caucasians. J Am Soc Echocardiogr 2007;20:563 [P1-21]. 29. Labib SB, Goldstein M, Kinnunen PM, Schick EC. Cardiac events in patients with negative maximal versus negative submaximal dobutamine echocardiograms undergoing noncardiac surgery: importance of resting wall motion abnormalities. J Am Coll Cardiol 2004;44:82-7. 30. Patel SJ, Lingam N, Srivastava A, Jacobsen G, Ananthasubramaniam K. Favorable prognostic value of submaximal negative dobutamine echocardiography in patients with preserved ejection fraction regardless of percentage predicted maximal heart rate or double product achieved. J Am Soc Echocardiogr 2006;19:647 [P4-24]. 31. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992;340:998-1002. 32. McFalls EO, Ward HB, Moritz TE, Goldman S, Krupski WC, Littooy F, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351:2795-804. 33. Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD. Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: risk factors and implications for mortality. J Am Soc Nephrol 2006;17:3240-7. 34. Premasathian NC, Muehrer R, Brazy PC, Pirsch JD, Becker BN. Blood pressure control in kidney transplantation: therapeutic implications. J Hum Hypertens 2004;18:871-7. 35. Tutone VK, Mark PB, Stewart GA, Tan CC, Rodger RS, Geddes CC, et al. Hypertension, antihypertensive agents and outcomes following renal transplantation. Clin Transplant 2005;19:181-92.