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Cardiovascular Risk Assessment and Management in Prerenal Transplantation Candidates
Cardiovascular Risk Assessment and Management in Prerenal Transplantation Candidates Eric M. Lindley, MDa,*, Amanda K. Hall, DOb, Jordan Hess, MDc, Jo Abraham, MDb, Brigham Smith, MDa, Paul N. Hopkins, MDa, Fuad Shihab, MDb, Frederick Welt, MDa, Theophilus Owan, MDa, and James C. Fang, MDa Cardiovascular (CV) assessment in prerenal transplant patients varies by center. Current guidelines recommend stress testing for candidates if ‡3 CV risk factors exist. We evaluated the CV assessment and management in 685 patients referred for kidney transplant over a 7-year period. All patients had CV risk factors, and the most common cause of end-stage renal disease was diabetes. Thirty-three percent (n [ 229) underwent coronary angiography. The sensitivity of stress testing to detect obstructive coronary artery disease (CAD) was poor (0.26). Patients who had no CAD, nonobstructive CAD, or CAD with intervention had significantly higher event-free survival compared with patients with obstructive CAD without intervention. There were no adverse clinical events (death, myocardial infarction, stroke, revascularization, and graft failure) within 30 days post-transplant in patients who had preoperative angiography (n [ 77). Of the transplanted patients who did not have an angiogram (n [ 289), there were 8 clinical events (6 myocardial infarctions) in the first 30 days. In conclusion, our results indicate that stress testing and usual risk factors were poor predictors of obstructive CAD and that revascularization may prove beneficial in these patients. Ó 2015 Published by Elsevier Inc. (Am J Cardiol 2015;-:-e-) Chronic kidney disease is a potent risk factor for cardiovascular disease (CVD) and a significant harbinger of morbidity and mortality.1,2 The risk of CV complications and death is particularly high for patients with end-stage renal disease (ESRD).3,4 Although kidney transplantation improves morbidity and mortality in ESRD, CVD remains the primary cause of death.2 There exists a need to ensure that recipients are optimized from a CV standpoint before transplantation. Past and current guidelines and position statements are limited by a lack of randomized data as these data do not exist, which results in considerable variability in assessments that are performed.5e8 The 2012 American Heart Association/American College of Cardiology (AHA/ACC) consensus statement regarding CV evaluation before kidney and liver transplantation recommends preoperative stress testing only if at least 3 CV risk factors are present but only as a IIb recommendation.5 In contrast, some transplant centers use a more aggressive angiographic and revascularization strategy, which may improve survival in these patients.9 Here, we report our experience with the CV
Divisions of aCardiovascular Medicine, bNephrology, and cInternal Medicine, University of Utah Hospitals and Clinics, Salt Lake City, Utah. Manuscript received June 18, 2015; revised manuscript received and accepted October 9, 2015. Statistical analyses and the project described were supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant 8UL1TR000105 (formerly UL1RR025764). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. See page 4 for disclosure information. *Corresponding author: Tel: (801) 585-1686; fax: (801) 581-7735. E-mail address: [email protected] (E.M. Lindley). 0002-9149/15/$ - see front matter Ó 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2015.10.016
assessment and management in patients with ESRD being evaluated for renal transplantation. Methods The study was approved by the University of Utah Institutional Review Board (IRB project #00069927). All consecutive patient records who were referred for kidney transplantation from January 2007 to December 2013 were reviewed. These patients were presented at the Kidney Transplant Selection Committee (KTSC) at the University of Utah, a large, tertiary academic referral center for a 6 state region. The KTSC comprised a multidisciplinary team of transplant nephrologists, transplant surgeons, and other specialized support staff. During the study period, a cardiologist was not part of the KTSC. Data were gathered prospectively by support staff and recorded in the minutes of the KTSC meeting. These minutes and the patients’ electronic health records were then systematically reviewed and entered into a database. Patients were excluded if they were <18 years or if they had not been evaluated in the prerenal transplant clinic before being presented at the KTSC. The database comprises demographic information and the 8 risk factors according to the AHA/ACC consensus statement (age >65 years, history of CVD, left ventricular hypertrophy, diabetes mellitus, hypertension, hyperlipidemia, smoking, and dialysis >1 year).5 The patient’s preoperative CV assessment (i.e., stress testing, angiography, echo, etc.) was also recorded. At the conclusion of the KTSC, a patient was either felt to be at acceptable risk for listing/transplantation or excluded from listing/transplantation. Exclusion reasons were also recorded in the database. Clinical end points were defined as death, nonfatal myocardial infarction (MI), stroke, revascularization, and www.ajconline.org
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Table 1 Demographic and clinical characteristics of all subjects evaluated by the KTSC at baseline. Shown are mean SD for continuous variables and number (%) for categorical variables (n ¼ 685) Age (years) Male Female Body mass index (kg/m2) Age >60 Prior diagnosis of CVD Hypertension Hyperlipidemia Diabetes Mellitus Smoker Dialysis >1 year Left ventricular hypertrophy ESRD etiology Diabetes mellitus Hypertension Graft failure Other Angiogram performed Transplanted Awaiting transplant Denied transplant Received renal transplant Stress test Angiogram No stress test nor angiogram Living donor Denied transplant
48 15 386 (56%) 299 (44%) 28 5 195 (28%) 109 (16%) 574 (84%) 280 (41%) 252 (37%) 43 (6%) 268 (39%) 85 (12%) 216 65 108 296 229 77 126 26 366 247 77 42 123 88
(32%) (9%) (16%) (43%) (33%) (43%) (55%) (11%) (53%) (67%) (21%) (11%) (34%) (13%)
graft failure defined as the need for permanent (>3 months) renal replacement therapy after transplant. The KTSC reviewed the baseline CV assessment in all patients that included a detailed history and examination and any testing that had been done by the referring provider. There were no set protocols used by referring providers or transplant nephrologists/surgeons for CV assessment. It was typical for the KTSC to recommend or require that at least some CV assessment be done in all patients, at a minimum an electrocardiogram and echocardiogram at rest if not done before. Most patients underwent some form of stress testing and/or angiography before or at the recommendation of the KTSC. Some of the patients were referred for angiography even in the setting of a negative stress test based on high pretest suspicion. The decision to revascularize obstructive coronary artery disease (CAD) found at the time of angiography was left to the discretion of the interventional cardiologist and transplant nephrologist. Obstructive CAD was typically defined as a major epicardial coronary artery stenosis of >70% and/or a fractional flow reserve value of 0.8. All statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc., Cary, North Carolina). Descriptive summaries were generated for pertinent and clinically relevant variables and examined to ensure complete and reasonable ranges. An a ¼ 0.05 was considered statistically significant. All hypothesis tests were 2 sided, all p values are nominal, and no adjustments were made for multiple comparisons. Survival analyses were performed with PROC LIFETEST using the Kaplan-Meier method and differences
Figure 1. Number of patients evaluated in the KTSC and preoperative angiograms performed by year.
Table 2 Reason for denying wait listing/renal transplant for 88 patients Reason for Denial
Number Denied
Cardiovascular Psychosocial Co-morbidity Oncology Pulmonary Patient refusal Gastroenterology Obesity Urologic Infectious disease
25 19 18 10 7 3 2 2 1 1
compared with log-rank test. Logistic regression was performed with PROC LOGISTIC without stepping. Results A total of 685 consecutive patients over a 7-year time period were included in the analysis. The majority were men (56%) with a mean age (SD) of 48 15 years at the time of evaluation. At least one of the 8 risk factors was present in all patients. The most common risk factor was hypertension. Most patients (n ¼ 480, 70%) underwent some form of stress testing as part of their workup (Table 1). The number of new patients presented at the KTSC meeting increased annually during the study period as did the number and percentage of patients who had a coronary angiogram as part of their pretransplant assessment (Figure 1). There were 64 patients who were initially considered unsuitable for transplantation and were, therefore, denied waitlisting/transplantation. In addition, 24 patients were later deemed unsuitable for transplantation for a total of 88 patients denied waitlisting/transplantation. Although there were a variety of reasons to not proceed with transplantation, the most common reason was because of CV disease (Table 2). There were 15 clinically significant end points during the follow-up period of those 88 patients
Miscellaneous/CV Assessment in Renal Transplant
Figure 2. Event-free survival of the angiogram cohort presented at the KTSC by angiographic result.
Table 3 Association of risk factors with angiographically defined obstructive coronary artery disease among 229 end-stage renal disease patients with data available from angiography Risk factor Age (per year) Male History of CVD* Diabetes Hypertension Hyperlipidemia Smoking LVH Dialysis >1year
Odds ratio
95% CI
p-value
1.02 1.27 2.42 1.56 1.18 1.41 1.01 2.00 1.02
0.99-1.04 0.68-2.3 1.20-4.9 0.81-3.0 0.46-3.0 0.66-3.0 0.36-2.9 0.81-4.90 0.56-1.9
0.27 0.46 0.014 0.19 0.73 0.37 0.98 0.13 0.94
* Defined as previous myocardial infarction, cerebral vascular accident, transient ischemic attack, peripheral vascular disease, or revascularization.
including 13 deaths. Twelve of the 13 deaths (92%) were attributed to CVD. Of the 685 patients, 229 (33%) underwent coronary angiography. Of those who underwent coronary angiography, 31% had obstructive CAD, 46% had nonobstructive CAD, whereas only 23% had normal angiographic coronary arteries. Of the 72 patients with obstructive CAD, 60 (83%) underwent some revascularization procedure (16 ¼ coronary artery bypass grafting [CABG] and 44 ¼ percutaneous coronary intervention). Of the 229 patients, 28 (12%) were considered to be unsuitable for transplant and 16 of 28 deemed unsuitable because of CVD. Of those 16 patients who were deemed unsuitable because of CVD, 6 went on to a revascularization procedure (3 PCI and 3 CABG) as recommended during their transplant workup; however, they were subsequently deemed unsuitable regardless. Four of those 28 patients died during the follow-up period. Event-free survival was no different between those with angiographically normal coronary arteries, those with nonobstructive CAD, and those with revascularized CAD. Those 3 groups all had a significantly higher event-free survival compared with the patients who had obstructive CAD but were not revascularized (log-rank p <0.001 comparing all 4 groups, p <0.0001 comparing those with
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obstructive CAD without revascularization to all others with angiography) (Figure 2). Most of the angiographic cohort (174 of the 229, 76%) underwent some form of stress testing before coronary angiography. Stress testing sensitivity to detect obstructive CAD was poor (0.26). In a multivariable regression analysis, the only risk factor that predicted the presence of obstructive CAD with statistical significance was a history of known CVD. The other risk factors failed to predict the presence of obstructive CAD (Table 3). Indeed, even age of those with obstructive CAD (ages 24 to 77) entirely overlapped with patients who had normal coronary arteries (ages 24 to 74). There were 366 patients transplanted during the study period (53% of original 685). Of those patients transplanted, 77 (21%) underwent preoperative angiography; 22 of 77 (29%) had obstructive CAD. All but 3 of those patients (n ¼ 19) underwent revascularization (3 CABG and 16 PCI). Of the 19 patients who were revascularized and transplanted, none had an adverse CV event or graft failure at either 30 days or 1-year post-transplant. Of the 3 patients who had obstructive CAD but still underwent transplant despite not being revascularized, 1 experienced CV death 6 months post-transplant and 1 patient had an MI 4 months post-transplant. Importantly, although 16 of the 22 patients with obstructive CAD underwent some form of stress test before their angiogram, only 2 of those 16 patients had a positive stress test (sensitivity of 0.13). Of the 289 patients (79% of the transplant cohort) who did not have an angiogram before transplant, there were 8 clinically significant adverse events including 6 MIs in the first 30 days post-transplant. All 6 postoperative patients with MI had negative stress testing before transplant. There were no clinically significant events in the first 30 days after transplant in the angiography group. At 1 year, there were a total of 4 events in the angiogram group (including 3 deaths); 2 of those events were in patients with obstructive but nonrevascularized CAD as detailed earlier. Discussion Our observational, retrospective study explored the CV risk assessment and management over a 7-year period in 685 patients evaluated at a large academic transplant center. Two important findings came from our analysis: (1) stress testing and usual risk factors were very poor predictors of obstructive CAD and (2) patients who underwent coronary angiography and revascularization before transplant had no adverse CV events or evidence of graft failure at 30 days or 1-year post-transplant, and their event-free survival was equivalent to patients with normal angiographic coronary arteries. The most appropriate CV risk stratification approach remains debatable. Stress testing (as currently recommended by the AHA/ACC guidelines) as part of a prerenal transplant strategy has been reported before in multiple studies using a variety of stress imaging techniques.10e17 Sensitivities of such testing vary widely from 0.29 to 0.92. Moreover, sensitivity is generally poor in patients with ESRD compared with the general population.18 Our study supports these findings, with a sensitivity of only 0.26 in the overall
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cohort and only 0.13 in the transplanted cohort. Importantly, in our angiographic cohort, only previously known CVD predicted the presence of obstructive CAD, whereas the other risk factors, including age, did not. Of particular note, all 6 patients who had an MI within 30 days post-transplant had negative stress tests (and did not undergo preoperative coronary angiography). During the index transplant hospitalization, 3 of these 6 patients underwent post-transplant, post-infarction, coronary angiography. Obstructive CAD was found in all 3 patients. Two patients underwent CABG and 1 underwent multivessel PCI. The optimal management, not just diagnosis, of pretransplant obstructive CAD also remains uncertain. Most recommendations have been extrapolated from nontransplant, non-ESRD surgical cohort. The largest of these experiences was the Veteran Administration’s Coronary Artery Revascularization Prophylaxis (CARP) trial.19 CARP was a study of 510 patients who underwent major vascular surgery and were randomized to medical therapy versus revascularization. The primary end point of all-cause mortality did not differ between the groups. However, as in most trials, patients with chronic kidney disease were excluded. Nearly 4,500 of screened but excluded patients from CARP were followed long term, and patients with a creatinine of >3.5 mg/dl had the highest risk of mortality with a hazard ratio of 4 (confidence interval 2.19 to 7.32; p <0.01).20 The only randomized trial of CAD management in prerenal transplant patients was performed >2 decades ago in 1992, by Manske et al.21 In that study, the investigators performed consecutive coronary angiograms on 151 asymptomatic diabetic prerenal transplant patients and found obstructive CAD in 31, 26 of whom agreed to randomization. At the end of 8 months, 10 patient in the medical arm and 2 patients in the revascularization arm had a CV event. There were 4 deaths alone in the medical management group. More recently, Kumar et al9 reported their experience with routine coronary angiography over a 3-year period at a single center in the United Kingdom in 657 pretransplant patients with ESRD who were selected from a larger cohort for angiography based on symptoms, age, presence of diabetes, or abnormal electrocardiographic findings. They found that 28% of those patients had obstructive CAD and were offered revascularization; 16 of those patients refused revascularization and were not transplanted nor wait listed. Survival at 3 years was only 37%. Patients who underwent revascularization followed by transplantation (n ¼ 51) had a 98% and 88% cardiac eventefree survival at 1 and 3 years, respectively. Cardiac eventefree survival for patients revascularized and awaiting deceased donor transplantation was similar: 94% and 90% at 1 and 3 years, respectively. These findings suggest that it was not just transplantation that affected these patients’ event-free survival but revascularization as well. In our study, we also found a high prevalence (30%) of obstructive CAD. Like Kumar et al,9 we found that CV eventefree survival was no different between groups with normal coronary arteries, nonobstructive CAD, or obstructive CAD with intervention, whereas all 3 groups had
significantly higher event-free survival compared with patients with obstructive CAD without intervention. The overall event-free survival by those who were transplanted compared with those who were not was also nearly identical to their experience. There are several limitations to our study. There was no set protocol as to who should or should not get coronary angiography and/or stress testing. The University of Utah has one of the largest geographical referral bases in the United States, and this large referral base leads to a large variation in preoperative assessment even before coming to pretransplant clinic and being presented at the KTSC. This lack of standardization can, therefore, lead to bias but may also represent a more “real-world” experience in how patients arrive at transplant centers for evaluation. Our study is a single-center, retrospective cohort and, therefore, is limited by the lack of prospective outcomes data collection. The demographic and CV assessment was gathered prospectively at the time of KTSC. Poor outcomes in patients who were not revascularized may be driven by multiple factors and not just nonrevascularized CAD. In the absence of randomized data, our data would suggest that coronary angiography may be the optimal approach to CV risk stratification in patients with ESRD being evaluated for kidney transplant and that selective revascularization in this high-risk cohort may improve post-transplant outcomes. Disclosures The authors have no conflicts of interest to disclose. 1. United States Renal Data System. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013. 2. Stoumpos S, Jardine AG, Mark PB. Cardiovascular morbidity and mortality after kidney transplantation. Transpl Int 2015;28:10e21. 3. 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;49:409e416. 4. Gill JS, Ma I, Landsberg D, Johnson N, Levin A. Cardiovascular events and investigation in patients who are awaiting cadaveric kidney transplantation. J Am Soc Nephrol 2005;16:808e816. 5. Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, Carithers RL, Ragosta M, Bolton K, Auerbach AD, Eagle KA; American Heart Association Council on the Kidney in Cardiovascular Disease, Council on Peripheral Vascular Disease, American Heart Association, American College of Cardiology Foundation. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation 2012;126:617e663. 6. EBPG (European Expert Group on Renal Transplantation); European Renal Association (ERA-EDTA); European Society for Organ Transplantation (ESOT). European best practice guidelines for renal transplantation (part 1). Nephrol Dial Transplant 2000;15(Suppl 7): 1e85. 7. Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, Rush DN, Vazquez MA, Weir MR. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;1(Suppl 2):3e95. 8. Abbud-Filho M, Adams PL, Alberu J, Cardella C, Chapman J, Cochat P, Cosio F, Danovitch G, Davis C, Gaston RS, Humar A, Hunsicker LG, Josephson MA, Kasiske B, Kirste G, Leichtman A, Munn S,
Miscellaneous/CV Assessment in Renal Transplant
9.
10.
11. 12.
13.
14.
15.
Obrador GT, Tibell A, Wadstrom J, Zeier M, Delmonico FL. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation 2007;83:S1e22. Kumar N, Baker CS, Chan K, Duncan N, Malik I, Frankel A, Ashby DR, McLean A, Palmer A, Cairns TD, Taube D. Cardiac survival after pre-emptive coronary angiography in transplant patients and those awaiting transplantation. Clin J Am Soc Nephrol 2011;6: 1912e1919. Marwick TH, Steinmuller DR, Underwood DA, Hobbs RE, Go RT, Swift C, Braun WE. Ineffectiveness of dipyridamole SPECT thallium imaging as a screening technique for coronary artery disease in patients with end-stage renal failure. Transplantation 1990;49: 100e103. Boudreau R. Perfusion thallium imaging of type I diabetes patients with end stage renal disease: comparison of oral and intravenous dipyridamole administration. Card Radiol 1990;175:103e105. Vandenberg BF, Rossen JD, Grover-McKay M, Shammas NW, Burns TL, Rezai K. Evaluation of diabetic patients for renal and pancreas transplantation: noninvasive screening for coronary artery disease using radionuclide methods. Transplantation 1996;62: 1230e1235. Herzog CA, Marwick TH, Pheley AM, White CW, Rao VK, Dick CD. Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. Am J Kidney Dis 1999;33:1080e1090. Worthley MI, Unger SA, Mathew TH, Russ GR, Horowitz JD. Usefulness of tachycardic-stress perfusion imaging to predict coronary artery disease in high-risk patients with chronic renal failure. Am J Cardiol 2003;92: 1318e1320. De Lima JJ, Gowdak LH, de Paula FJ, Arantes RL, de Oliveira AL, Ramires JA, Cesar LA, Krieger EM. Treatment of coronary artery disease in hemodialysis patients evaluated for transplant-a registry study. Transplantation 2010;89:845e850.
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16. Sharma R, Chemla E, Tome M, Mehta RL, Gregson H, Brecker SJ, Chang R, Pellerin D. Echocardiography-based score to predict outcome after renal transplantation. Heart 2007;93:464e469. 17. Ferreira PA, de Lima VC, Campos Filho O, Gil MA, Cordovil A, Machado CV, Pestana JO, Carvalho AC. Feasibility, safety and accuracy of dobutamine/atropine stress echocardiography for the detection of coronary artery disease in renal transplant candidates. Arq Bras Cardiol 2007;88:45e51. 18. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL, King SB III, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR Jr, Smith SC Jr, Spertus JA, Williams SV. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44ee164. 19. McFalls EO, Ward HB, Moritz TE, Goldman S, Krupski WC, Littooy F, Pierpont G, Santilli S, Rapp J, Hattler B, Shunk K, Jaenicke C, Thottapurathu L, Ellis N, Reda DJ, Henderson WG. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351:2795e2804. 20. McFalls EO, Ward HB, Moritz TE, Littooy F, Santilli S, Rapp J, Larsen G, Reda DJ. Clinical factors associated with long-term mortality following vascular surgery: outcomes from the Coronary Artery Revascularization Prophylaxis (CARP) Trial. J Vasc Surg 2007;46:694e700. 21. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992;340:998e1002.
Divisions of aCardiovascular Medicine, bNephrology, and cInternal Medicine, University of Utah Hospitals and Clinics, Salt Lake City, Utah. Manuscript received June 18, 2015; revised manuscript received and accepted October 9, 2015. Statistical analyses and the project described were supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant 8UL1TR000105 (formerly UL1RR025764). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. See page 4 for disclosure information. *Corresponding author: Tel: (801) 585-1686; fax: (801) 581-7735. E-mail address: [email protected] (E.M. Lindley). 0002-9149/15/$ - see front matter Ó 2015 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2015.10.016
assessment and management in patients with ESRD being evaluated for renal transplantation. Methods The study was approved by the University of Utah Institutional Review Board (IRB project #00069927). All consecutive patient records who were referred for kidney transplantation from January 2007 to December 2013 were reviewed. These patients were presented at the Kidney Transplant Selection Committee (KTSC) at the University of Utah, a large, tertiary academic referral center for a 6 state region. The KTSC comprised a multidisciplinary team of transplant nephrologists, transplant surgeons, and other specialized support staff. During the study period, a cardiologist was not part of the KTSC. Data were gathered prospectively by support staff and recorded in the minutes of the KTSC meeting. These minutes and the patients’ electronic health records were then systematically reviewed and entered into a database. Patients were excluded if they were <18 years or if they had not been evaluated in the prerenal transplant clinic before being presented at the KTSC. The database comprises demographic information and the 8 risk factors according to the AHA/ACC consensus statement (age >65 years, history of CVD, left ventricular hypertrophy, diabetes mellitus, hypertension, hyperlipidemia, smoking, and dialysis >1 year).5 The patient’s preoperative CV assessment (i.e., stress testing, angiography, echo, etc.) was also recorded. At the conclusion of the KTSC, a patient was either felt to be at acceptable risk for listing/transplantation or excluded from listing/transplantation. Exclusion reasons were also recorded in the database. Clinical end points were defined as death, nonfatal myocardial infarction (MI), stroke, revascularization, and www.ajconline.org
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Table 1 Demographic and clinical characteristics of all subjects evaluated by the KTSC at baseline. Shown are mean SD for continuous variables and number (%) for categorical variables (n ¼ 685) Age (years) Male Female Body mass index (kg/m2) Age >60 Prior diagnosis of CVD Hypertension Hyperlipidemia Diabetes Mellitus Smoker Dialysis >1 year Left ventricular hypertrophy ESRD etiology Diabetes mellitus Hypertension Graft failure Other Angiogram performed Transplanted Awaiting transplant Denied transplant Received renal transplant Stress test Angiogram No stress test nor angiogram Living donor Denied transplant
48 15 386 (56%) 299 (44%) 28 5 195 (28%) 109 (16%) 574 (84%) 280 (41%) 252 (37%) 43 (6%) 268 (39%) 85 (12%) 216 65 108 296 229 77 126 26 366 247 77 42 123 88
(32%) (9%) (16%) (43%) (33%) (43%) (55%) (11%) (53%) (67%) (21%) (11%) (34%) (13%)
graft failure defined as the need for permanent (>3 months) renal replacement therapy after transplant. The KTSC reviewed the baseline CV assessment in all patients that included a detailed history and examination and any testing that had been done by the referring provider. There were no set protocols used by referring providers or transplant nephrologists/surgeons for CV assessment. It was typical for the KTSC to recommend or require that at least some CV assessment be done in all patients, at a minimum an electrocardiogram and echocardiogram at rest if not done before. Most patients underwent some form of stress testing and/or angiography before or at the recommendation of the KTSC. Some of the patients were referred for angiography even in the setting of a negative stress test based on high pretest suspicion. The decision to revascularize obstructive coronary artery disease (CAD) found at the time of angiography was left to the discretion of the interventional cardiologist and transplant nephrologist. Obstructive CAD was typically defined as a major epicardial coronary artery stenosis of >70% and/or a fractional flow reserve value of 0.8. All statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc., Cary, North Carolina). Descriptive summaries were generated for pertinent and clinically relevant variables and examined to ensure complete and reasonable ranges. An a ¼ 0.05 was considered statistically significant. All hypothesis tests were 2 sided, all p values are nominal, and no adjustments were made for multiple comparisons. Survival analyses were performed with PROC LIFETEST using the Kaplan-Meier method and differences
Figure 1. Number of patients evaluated in the KTSC and preoperative angiograms performed by year.
Table 2 Reason for denying wait listing/renal transplant for 88 patients Reason for Denial
Number Denied
Cardiovascular Psychosocial Co-morbidity Oncology Pulmonary Patient refusal Gastroenterology Obesity Urologic Infectious disease
25 19 18 10 7 3 2 2 1 1
compared with log-rank test. Logistic regression was performed with PROC LOGISTIC without stepping. Results A total of 685 consecutive patients over a 7-year time period were included in the analysis. The majority were men (56%) with a mean age (SD) of 48 15 years at the time of evaluation. At least one of the 8 risk factors was present in all patients. The most common risk factor was hypertension. Most patients (n ¼ 480, 70%) underwent some form of stress testing as part of their workup (Table 1). The number of new patients presented at the KTSC meeting increased annually during the study period as did the number and percentage of patients who had a coronary angiogram as part of their pretransplant assessment (Figure 1). There were 64 patients who were initially considered unsuitable for transplantation and were, therefore, denied waitlisting/transplantation. In addition, 24 patients were later deemed unsuitable for transplantation for a total of 88 patients denied waitlisting/transplantation. Although there were a variety of reasons to not proceed with transplantation, the most common reason was because of CV disease (Table 2). There were 15 clinically significant end points during the follow-up period of those 88 patients
Miscellaneous/CV Assessment in Renal Transplant
Figure 2. Event-free survival of the angiogram cohort presented at the KTSC by angiographic result.
Table 3 Association of risk factors with angiographically defined obstructive coronary artery disease among 229 end-stage renal disease patients with data available from angiography Risk factor Age (per year) Male History of CVD* Diabetes Hypertension Hyperlipidemia Smoking LVH Dialysis >1year
Odds ratio
95% CI
p-value
1.02 1.27 2.42 1.56 1.18 1.41 1.01 2.00 1.02
0.99-1.04 0.68-2.3 1.20-4.9 0.81-3.0 0.46-3.0 0.66-3.0 0.36-2.9 0.81-4.90 0.56-1.9
0.27 0.46 0.014 0.19 0.73 0.37 0.98 0.13 0.94
* Defined as previous myocardial infarction, cerebral vascular accident, transient ischemic attack, peripheral vascular disease, or revascularization.
including 13 deaths. Twelve of the 13 deaths (92%) were attributed to CVD. Of the 685 patients, 229 (33%) underwent coronary angiography. Of those who underwent coronary angiography, 31% had obstructive CAD, 46% had nonobstructive CAD, whereas only 23% had normal angiographic coronary arteries. Of the 72 patients with obstructive CAD, 60 (83%) underwent some revascularization procedure (16 ¼ coronary artery bypass grafting [CABG] and 44 ¼ percutaneous coronary intervention). Of the 229 patients, 28 (12%) were considered to be unsuitable for transplant and 16 of 28 deemed unsuitable because of CVD. Of those 16 patients who were deemed unsuitable because of CVD, 6 went on to a revascularization procedure (3 PCI and 3 CABG) as recommended during their transplant workup; however, they were subsequently deemed unsuitable regardless. Four of those 28 patients died during the follow-up period. Event-free survival was no different between those with angiographically normal coronary arteries, those with nonobstructive CAD, and those with revascularized CAD. Those 3 groups all had a significantly higher event-free survival compared with the patients who had obstructive CAD but were not revascularized (log-rank p <0.001 comparing all 4 groups, p <0.0001 comparing those with
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obstructive CAD without revascularization to all others with angiography) (Figure 2). Most of the angiographic cohort (174 of the 229, 76%) underwent some form of stress testing before coronary angiography. Stress testing sensitivity to detect obstructive CAD was poor (0.26). In a multivariable regression analysis, the only risk factor that predicted the presence of obstructive CAD with statistical significance was a history of known CVD. The other risk factors failed to predict the presence of obstructive CAD (Table 3). Indeed, even age of those with obstructive CAD (ages 24 to 77) entirely overlapped with patients who had normal coronary arteries (ages 24 to 74). There were 366 patients transplanted during the study period (53% of original 685). Of those patients transplanted, 77 (21%) underwent preoperative angiography; 22 of 77 (29%) had obstructive CAD. All but 3 of those patients (n ¼ 19) underwent revascularization (3 CABG and 16 PCI). Of the 19 patients who were revascularized and transplanted, none had an adverse CV event or graft failure at either 30 days or 1-year post-transplant. Of the 3 patients who had obstructive CAD but still underwent transplant despite not being revascularized, 1 experienced CV death 6 months post-transplant and 1 patient had an MI 4 months post-transplant. Importantly, although 16 of the 22 patients with obstructive CAD underwent some form of stress test before their angiogram, only 2 of those 16 patients had a positive stress test (sensitivity of 0.13). Of the 289 patients (79% of the transplant cohort) who did not have an angiogram before transplant, there were 8 clinically significant adverse events including 6 MIs in the first 30 days post-transplant. All 6 postoperative patients with MI had negative stress testing before transplant. There were no clinically significant events in the first 30 days after transplant in the angiography group. At 1 year, there were a total of 4 events in the angiogram group (including 3 deaths); 2 of those events were in patients with obstructive but nonrevascularized CAD as detailed earlier. Discussion Our observational, retrospective study explored the CV risk assessment and management over a 7-year period in 685 patients evaluated at a large academic transplant center. Two important findings came from our analysis: (1) stress testing and usual risk factors were very poor predictors of obstructive CAD and (2) patients who underwent coronary angiography and revascularization before transplant had no adverse CV events or evidence of graft failure at 30 days or 1-year post-transplant, and their event-free survival was equivalent to patients with normal angiographic coronary arteries. The most appropriate CV risk stratification approach remains debatable. Stress testing (as currently recommended by the AHA/ACC guidelines) as part of a prerenal transplant strategy has been reported before in multiple studies using a variety of stress imaging techniques.10e17 Sensitivities of such testing vary widely from 0.29 to 0.92. Moreover, sensitivity is generally poor in patients with ESRD compared with the general population.18 Our study supports these findings, with a sensitivity of only 0.26 in the overall
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cohort and only 0.13 in the transplanted cohort. Importantly, in our angiographic cohort, only previously known CVD predicted the presence of obstructive CAD, whereas the other risk factors, including age, did not. Of particular note, all 6 patients who had an MI within 30 days post-transplant had negative stress tests (and did not undergo preoperative coronary angiography). During the index transplant hospitalization, 3 of these 6 patients underwent post-transplant, post-infarction, coronary angiography. Obstructive CAD was found in all 3 patients. Two patients underwent CABG and 1 underwent multivessel PCI. The optimal management, not just diagnosis, of pretransplant obstructive CAD also remains uncertain. Most recommendations have been extrapolated from nontransplant, non-ESRD surgical cohort. The largest of these experiences was the Veteran Administration’s Coronary Artery Revascularization Prophylaxis (CARP) trial.19 CARP was a study of 510 patients who underwent major vascular surgery and were randomized to medical therapy versus revascularization. The primary end point of all-cause mortality did not differ between the groups. However, as in most trials, patients with chronic kidney disease were excluded. Nearly 4,500 of screened but excluded patients from CARP were followed long term, and patients with a creatinine of >3.5 mg/dl had the highest risk of mortality with a hazard ratio of 4 (confidence interval 2.19 to 7.32; p <0.01).20 The only randomized trial of CAD management in prerenal transplant patients was performed >2 decades ago in 1992, by Manske et al.21 In that study, the investigators performed consecutive coronary angiograms on 151 asymptomatic diabetic prerenal transplant patients and found obstructive CAD in 31, 26 of whom agreed to randomization. At the end of 8 months, 10 patient in the medical arm and 2 patients in the revascularization arm had a CV event. There were 4 deaths alone in the medical management group. More recently, Kumar et al9 reported their experience with routine coronary angiography over a 3-year period at a single center in the United Kingdom in 657 pretransplant patients with ESRD who were selected from a larger cohort for angiography based on symptoms, age, presence of diabetes, or abnormal electrocardiographic findings. They found that 28% of those patients had obstructive CAD and were offered revascularization; 16 of those patients refused revascularization and were not transplanted nor wait listed. Survival at 3 years was only 37%. Patients who underwent revascularization followed by transplantation (n ¼ 51) had a 98% and 88% cardiac eventefree survival at 1 and 3 years, respectively. Cardiac eventefree survival for patients revascularized and awaiting deceased donor transplantation was similar: 94% and 90% at 1 and 3 years, respectively. These findings suggest that it was not just transplantation that affected these patients’ event-free survival but revascularization as well. In our study, we also found a high prevalence (30%) of obstructive CAD. Like Kumar et al,9 we found that CV eventefree survival was no different between groups with normal coronary arteries, nonobstructive CAD, or obstructive CAD with intervention, whereas all 3 groups had
significantly higher event-free survival compared with patients with obstructive CAD without intervention. The overall event-free survival by those who were transplanted compared with those who were not was also nearly identical to their experience. There are several limitations to our study. There was no set protocol as to who should or should not get coronary angiography and/or stress testing. The University of Utah has one of the largest geographical referral bases in the United States, and this large referral base leads to a large variation in preoperative assessment even before coming to pretransplant clinic and being presented at the KTSC. This lack of standardization can, therefore, lead to bias but may also represent a more “real-world” experience in how patients arrive at transplant centers for evaluation. Our study is a single-center, retrospective cohort and, therefore, is limited by the lack of prospective outcomes data collection. The demographic and CV assessment was gathered prospectively at the time of KTSC. Poor outcomes in patients who were not revascularized may be driven by multiple factors and not just nonrevascularized CAD. In the absence of randomized data, our data would suggest that coronary angiography may be the optimal approach to CV risk stratification in patients with ESRD being evaluated for kidney transplant and that selective revascularization in this high-risk cohort may improve post-transplant outcomes. Disclosures The authors have no conflicts of interest to disclose. 1. United States Renal Data System. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013. 2. Stoumpos S, Jardine AG, Mark PB. Cardiovascular morbidity and mortality after kidney transplantation. Transpl Int 2015;28:10e21. 3. 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;49:409e416. 4. Gill JS, Ma I, Landsberg D, Johnson N, Levin A. Cardiovascular events and investigation in patients who are awaiting cadaveric kidney transplantation. J Am Soc Nephrol 2005;16:808e816. 5. Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, Carithers RL, Ragosta M, Bolton K, Auerbach AD, Eagle KA; American Heart Association Council on the Kidney in Cardiovascular Disease, Council on Peripheral Vascular Disease, American Heart Association, American College of Cardiology Foundation. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. Circulation 2012;126:617e663. 6. EBPG (European Expert Group on Renal Transplantation); European Renal Association (ERA-EDTA); European Society for Organ Transplantation (ESOT). European best practice guidelines for renal transplantation (part 1). Nephrol Dial Transplant 2000;15(Suppl 7): 1e85. 7. Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, Rush DN, Vazquez MA, Weir MR. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;1(Suppl 2):3e95. 8. Abbud-Filho M, Adams PL, Alberu J, Cardella C, Chapman J, Cochat P, Cosio F, Danovitch G, Davis C, Gaston RS, Humar A, Hunsicker LG, Josephson MA, Kasiske B, Kirste G, Leichtman A, Munn S,
Miscellaneous/CV Assessment in Renal Transplant
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Obrador GT, Tibell A, Wadstrom J, Zeier M, Delmonico FL. A report of the Lisbon Conference on the care of the kidney transplant recipient. Transplantation 2007;83:S1e22. Kumar N, Baker CS, Chan K, Duncan N, Malik I, Frankel A, Ashby DR, McLean A, Palmer A, Cairns TD, Taube D. Cardiac survival after pre-emptive coronary angiography in transplant patients and those awaiting transplantation. Clin J Am Soc Nephrol 2011;6: 1912e1919. Marwick TH, Steinmuller DR, Underwood DA, Hobbs RE, Go RT, Swift C, Braun WE. Ineffectiveness of dipyridamole SPECT thallium imaging as a screening technique for coronary artery disease in patients with end-stage renal failure. Transplantation 1990;49: 100e103. Boudreau R. Perfusion thallium imaging of type I diabetes patients with end stage renal disease: comparison of oral and intravenous dipyridamole administration. Card Radiol 1990;175:103e105. Vandenberg BF, Rossen JD, Grover-McKay M, Shammas NW, Burns TL, Rezai K. Evaluation of diabetic patients for renal and pancreas transplantation: noninvasive screening for coronary artery disease using radionuclide methods. Transplantation 1996;62: 1230e1235. Herzog CA, Marwick TH, Pheley AM, White CW, Rao VK, Dick CD. Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. Am J Kidney Dis 1999;33:1080e1090. Worthley MI, Unger SA, Mathew TH, Russ GR, Horowitz JD. Usefulness of tachycardic-stress perfusion imaging to predict coronary artery disease in high-risk patients with chronic renal failure. Am J Cardiol 2003;92: 1318e1320. De Lima JJ, Gowdak LH, de Paula FJ, Arantes RL, de Oliveira AL, Ramires JA, Cesar LA, Krieger EM. Treatment of coronary artery disease in hemodialysis patients evaluated for transplant-a registry study. Transplantation 2010;89:845e850.
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16. Sharma R, Chemla E, Tome M, Mehta RL, Gregson H, Brecker SJ, Chang R, Pellerin D. Echocardiography-based score to predict outcome after renal transplantation. Heart 2007;93:464e469. 17. Ferreira PA, de Lima VC, Campos Filho O, Gil MA, Cordovil A, Machado CV, Pestana JO, Carvalho AC. Feasibility, safety and accuracy of dobutamine/atropine stress echocardiography for the detection of coronary artery disease in renal transplant candidates. Arq Bras Cardiol 2007;88:45e51. 18. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL, King SB III, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR Jr, Smith SC Jr, Spertus JA, Williams SV. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44ee164. 19. McFalls EO, Ward HB, Moritz TE, Goldman S, Krupski WC, Littooy F, Pierpont G, Santilli S, Rapp J, Hattler B, Shunk K, Jaenicke C, Thottapurathu L, Ellis N, Reda DJ, Henderson WG. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004;351:2795e2804. 20. McFalls EO, Ward HB, Moritz TE, Littooy F, Santilli S, Rapp J, Larsen G, Reda DJ. Clinical factors associated with long-term mortality following vascular surgery: outcomes from the Coronary Artery Revascularization Prophylaxis (CARP) Trial. J Vasc Surg 2007;46:694e700. 21. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992;340:998e1002.