- Email: [email protected]
Presence of Cardiovascular Disease in Patients on a Waiting List for Renal Transplantation and in Patients After Kidney Transplantation in a Single Center
Presence of Cardiovascular Disease in Patients on a Waiting List for Renal Transplantation and in Patients After Kidney Transplantation in a Single Center U. Ott, M. Busch, T. Steiner, and G. Wolf ABSTRACT Background. Cardiovascular risk in hemodialysis patients is enhanced, resulting in a higher mortality rate compared with the general population, yet the average wait time for renal transplantation in Germany is 5–7 years. The age of wait-listed patients has risen progressively. The aim of this study was to evaluate the prevalence of cardiovascular disease in patients on the waiting list in our center before and after renal transplantation as well as the extent to which invasive treatment was required in these patients. Methods. The study investigated 2 groups: 350 patients on the renal transplantation waiting list at our center in 2008 and 324 patients who underwent renal transplantation at the same center in the years 2003–2007. Results. In 2008, 141 women and 209 men with a mean age of 48.6 years (range 13–71 years) were on the waiting list. In the years 2003–2007, 98 women and 226 men with a mean age of 54.3 years (range 16 –78 years) received renal transplants. One hundred six patients on the waiting list for renal transplantation had to undergo coronary angiography. There is no upper age limit for donors or recipients in our program. Mean age at admission on the waiting list was 48.6 years (range 13–71 years). Mean age at transplantation was 54.3 years (range 16 –78 years) in our center. Most of these patients were asymptomatic but presented a risk profile that included diabetes mellitus, severe general atherosclerosis, a pathologic ergometric test, or abnormal myocardial scintigraphy. Only in 1 case could coronary heart disease be excluded. Seventy patients (20%) suffered from mild to moderate coronary heart disease without the need for intervention. In 5 patients (1.4%) coronary bypass surgery was necessary due to severe 3-vessel coronary heart disease. In 2 cases (0.6%) replacement of the aortic valve was performed because of aortic valvular stenosis. Coronary angioplasty without implantation of stents was done in 2 patients (0.6%). Twenty-two patients (6.8%) were treated with implantation of bare metal stents and 6 patients (1.7%) with drug-eluting stents. After renal transplantation, 22 patients (6.8%) suffered from peripheral arterial occlusive disease. In 58 patients, coronary heart disease was documented by angiography. 16 patients (4.9%) had 1-vessel disease, 23 patients (7%) 2-vessel disease, and 19 patients (5.8%) 3-vessel disease. Myocardial infarction was documented in 18 patients (5.5%) before and in 5 patients (1.5%) after renal transplantation. Bare metal stent implantation was performed in 6 patients (1.8%) after transplantation. One patient received a drug-eluting stent after renal transplantation. In the years 2003–2007, 22 patients underwent coronary bypass surgery before kidney transplantation.
From the Department of Internal Medicine III (U.O., M.B., G.W.) and Department of Urology (T.S.), Friedrich-Schiller-University, Jena, Germany.
Address reprint requests to Gunter Wolf, MD, Department of Internal Medicine III, University Hospital Jena, Erlanger Allee 101, D-07740 Jena, Germany. E-mail: [email protected]
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.08.047
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3450
Transplantation Proceedings, 42, 3450 –3454 (2010)
CARDIOVASCULAR DISEASE BEFORE AND AFTER KIDNEY TRANSPLANTATION
3451
Conclusion. The prevalence of coronary heart disease is high in patients on the waiting list and after renal transplantation. The majority of these patients are clinically asymptomatic. One-third of the patients with coronary heart disease had to be treated invasively. Nevertheless, many diabetic patients are very sick from multiple complications after the waiting time, making theme unsuitable for transplantation. enal allograft recipients are becoming increasingly older, owing to long wait times, and therefore have a higher prevalence of vascular disease risk factors, including diabetes mellitus, hypertension, and dyslipidemia.1 Time on dialysis before transplantation,2 donor history of hypertension,3 immunosuppressive regimen,4 quality of allograft function,5 and posttransplantation diabetes mellitus6,7 are all also implicated as mediators of cardiovascular risk in this population after renal transplantation. Cardiovascular disease is the major cause of mortality in patients with end-stage renal disease (ESRD).8,9 After renal transplantation one-half of all deaths are cardiac, usually in the first 5 years in the presence of a functional graft.10 On average, 41% of mortality in the transplanted population is a result of cardiovascular diseases. Patients with chronic renal failure and diabetes mellitus have an even higher risk of death, with up to 70% in 7 years.14 –16 The aim of the present study was to assess the number of patients both on the renal transplant waiting list and after transplantation with significant coronary artery disease (CAD) and to predict outcome in renal transplant candidates. The presence of CAD was defined by coronary angiography.
R
PATIENTS AND METHODS A total of 350 patients on the waiting list for renal transplantation at our center in 2008 were investigated. There is no upper age limit for donors recipients in our program. Mean age at admission on the waiting list was 48.6 years (range 13–71 years). Mean age at transplantation was 54.3 years (range 16 –78 years) at our center. Because dialysis is often initiated at other hospital and private practices, we do not have valid information of the mean patient age when starting maintenance dialysis in our population. Diabetic patients are primarily not excluded for coming on the waiting list. However, many diabetic patients are very sick from multiple complications after the waiting time, making theme unsuitable for transplantation Cardiovascular events and coronary artery interventions were registered. In a second study, 324 patients were investigated who underwent renal transplantation in the years 2003–2007 at our center. We performed a retrospective analysis of the renal transplant patients routinely using conventional immunosuppressive treatment with cyclosporine, tacrolimus, rapamycin, prednisolone, mycophenolate, and mofetil and who had to undergo coronary angiography. Patients who underwent coronary angiography or coronary revascularization before renal transplantation were included. Clinical events were registered by assessing medical charts and medical visits. All of the patients had electrocardiograms, echocardiography, ergometric tests, or myocardial scintigraphy. In the presence of high risk for CAD, pathologic ergometric test, or myocardial scintigraphy, coronary angiography was performed. All coronary interventions and diagnostic procedures were counted. Coronary artery interventions, such as coronary bypass operation and percu-
taneous angioplasty with or without coronary stent implantation, and cardiovascular events and outcome were documented. Patients underwent repeated cardiac catheterization when presenting symptoms of CAD, or when presenting a noninvasive test positive for myocardial ischemia.
Coronary Angiography The procedure was performed by the standard Judkins technique via the femoral artery. All predialysis patients received intravenous fluid before and after the procedure. Contrast medium load was kept to a minimum. Angiograms were interpreted blindly by 3 experienced observers. The luminal stenosis severity of each epicardial artery was assessed visually.
Statistical Analysis Spearman rank correlation test was used for estimating correlations between variables. The Kruskal-Wallis test was used to compare differences between ⬎2 independent groups and the Mann-Whitney U test for comparisons between 2 independent groups. If the Kruskal-Wallis test revealed significant differences, each group was compared with each other by using the MannWhitney U test. Distribution of covariates was tested by using the Kolmogorov-Smirnov test with Lilliefors correction. To determine independent predictors of cardiovascular death, multivariate linear regression analysis was done. In addition, chi-square statistics were used. A P value of ⬍.05 or ⬍.01 (as appropriate) was considered to indicate statistical significance. Statistics were done using the software Statistical Package of Social Science (SPSS 13.0, 2004; SPSS, Chicago, IL, USA).
RESULTS Waiting-List Patients
The number, gender, and age of patients on the waiting list in 2008 as well as transplanted patients in the years 2003–2007 are presented in Table 1. Nearly 10% of the patients on the renal transplantation waiting list suffered from diabetes mellitus; 59% had chronic glomerulonephritis, 10% polycystic kidney disease, 14% vascular nephropathy, and 7% interstitial nephritis. A total of 106 out of 350 wait-listed patients (30.3%) underwent coronary angiography (Fig 1). Coronary angiography was performed on patients at high risk for CAD. Most patients do not typically have any clinical symptoms, but risk factors such as diabetes mellitus or severe arteriosclerosis are common in this Table 1. Characteristics of the Studied Population in Our Center
Patients on waiting list Transplanted patients
Men
Women
Mean Age (Range), y
209 226
141 98
48.6 (13–71) 54.3 (16–78)
3452
OTT, BUSCH, STEINER ET AL
period. Diabetes mellitus was significantly correlated with the appearance of severe peripheral arterial occlusive disease (B ⫽ 0.319; r ⫽ 0.111;  ⫽ 0.170; T ⫽ 2.869; P ⫽ .004). No correlation was found between arterial hypertension, hyperlipidemia, or anemia and cardiovascular events. Diabetes mellitus was surprisingly not associated with the prevalence of CAD. Significant association was found between death and arterial hypertension, coronary artery disease, myocardial infarction in the period before renal transplantation, and the implantation of a bare metal stent due to severe coronary artery stenosis after renal transplantation (Table 3). Fig 1. Waiting-list patients, coronary angiography, and patients with coronary artery disease (CAD).
group; pathologic noninvasive ischemic signs in ergometry, stress echocardiography, or myocardial scintigraphy were often present. An ergometric test was performed before patients were listed for renal transplantation. In all diabetic patients or if an ergometric test was pathologic, coronary angiography was performed. There were no significant complications with angiography. Only 1 patient did not suffer from CAD in this group. In 70 patients (20%) no intervention was necessary. In 5 patients (1.4%) coronary bypass surgery was performed owing to severe coronary 3-vessel disease; in 2 patients (0.6%) severe stenosis of aortic valve was treated. Two patients had coronary angioplasty without implantation of stents. In 22 patients (6.3%) coronary angioplasty with implantation of bare metal stent was performed, and in 6 patients (1.7%) a drug-eluting stent was implanted (Table 2). None of the potential recipients resorted to purchased a kidney (which is forbidden by law in Germany) when confronted with the probable long waiting time. However, up to 10% were successful to obtain a living-related donor graft after information of the potential long waiting time. Fewer than 1% of patients accepted the so-called extended donor criteria (grafts from donors with sepsis, cancer not restricted to the brain, hepatitis, meningitis, or a history of drug abuse). Transplanted Patients
Twenty-two renal transplant patients (6.8%) suffered from peripheral arterial occlusive disease. Fifty-eight transplant patients (17.9%) were treated with coronary angioplasty or surgery (Fig 2). Two patients had acute myocardial infarction in the postoperative period despite coronary arterial revascularization. The distribution of involved vessels is shown in Fig 3. One patient was treated with a drug-eluting stent after renal transplantation. In 22 cases (6.3%), coronary bypass surgery was performed before renal transplantation (Fig 4). In the patient population, 25.7% (84 patients) had hyperlipidemia, 90.5% (296 patients) arterial hypertension, 30.3% (99 patients) anemia, and 38.5% diabetes mellitus. Fifteen patients (4.6%) died during the study
DISCUSSION
Cardiovascular disease is a common complication in ESRD.1 At our center, one-third of the waiting-list patients suffered from CAD, and one-third of these patients required invasive cardiac treatment. Not surprisingly, during the wait time cardiovascular risk increased further. The waiting time for patients requiring renal transplantation has continued to lengthen in recent years. Therefore, one may expect that cardiovascular risk has also risen with longer periods on the waiting list. After an average waiting time of 5–7 years, nearly all adult dialysis patients suffer from atherosclerosis. In our center, 17.9% of the patients transplanted required invasive treatment due to CAD in the past 10 years. The lower cardiovascular mortality in transplant patients compared with ESRD patients is related to factors such as selection of patients at a lower risk for transplantation and risk reduction resulting from the transplantation itself. It is important to recognize that despite the lower mortality of transplant patients compared with patients undergoing dialysis, cardiovascular disease remains the main cause of death after renal transplantation.10 –14 High risk for ischemia in untreated critical vascular stenosis exists during renal transplantation. Anemia is another risk factor for ischemia in ESRD. Hypotensive episodes during surgery may induce myocardial infarction or ischemic cerebrovascular insult. Consequently, CAD should be diagnosed and treated before renal transplantation is performed. Diagnostic procedures should be completed before the patient is listed for renal transplantation. An annual follow-up is strongly recommended. Cardiac events are reduced by coronary revascularization before Table 2. Treatment of CAD Among the Patients on the Waiting List
All patients with CAD No invasive treatment PCI without stent PCI with bare metal stent PCI with drug-eluting stent Coronary bypass Aortic valvuloplasty PCI, percutaneous intervention.
n
%
105 70 2 20 6 5 2
100 66.6 1.9 19 5.8 4.8 1.9
CARDIOVASCULAR DISEASE BEFORE AND AFTER KIDNEY TRANSPLANTATION
3453
Fig 2. Results after renal transplantation.
renal transplantation.17 The detection and treatment of CAD is therefore recommended for all renal transplant candidates.18 This is especially important because this disease is characteristically clinically silent. However, the optimal cardiovascular screening technique remains unclear. Typical cardiovascular risk factors, such as hypertension and diabetes mellitus, are not reliable for predicting CAD in this patient population. In the present study, diabetes mellitus was associated with significant risk only for peripheral artery occlusive disease, not for CAD or cardiovascular events. Noninvasive cardiac tests (specifically, thallium scintigraphy or dobutamine echocardiography) have been fairly well studied in patients with ESRD. A meta-analysis found that transplant candidates with positive noninvasive stress tests may have a greater risk for future cardiac events. For prediction of cardiac death, the pooled results revealed a sensitivity of 80% but a specificity of only 59%.19 A study with good evidentiary value was recently reported by de Lima et al.20 Those investigators studied 126 renal transplant candidates, performing coronary angiography as well as both key noninvasive tests. The primary finding was that scintigraphy had sensitivity and specificity of only 58% and 67%, respectively, and dobutamine echocardiography had a sensitivity of only 44% and a better specificity of 87%. Patients were followed for 4 years to determine cardiac outcomes. The noninvasive tests per-
formed with similarly poor accuracy for the prediction of future cardiac events versus stenosis. Only coronary angiography was able to reasonably predict patients at risk. Data on the clinical course, clinical restenosis rates, and progression of CAD in the population of renal transplant patients undergoing coronary angioplasty with stenting are rare in the literature. Chronic renal failure (CRF) patients undergoing stent angioplasty present a 2.2-fold higher need for repeated target vessel revascularization when compared to non-CRF patients (35% vs 16%).21 In two-thirds of our patients, either 2- or 3-vessel disease was diagnosed. In the past, coronary bypass surgery was a common technique for treatment. In recent years, angioplasty with implantation of stent has been more common at our center. In particular, drug-eluting stents have been implanted more often, because interventions are more complex. Significant CAD was seen in 105 patients on the waiting list and 59 transplanted patients. After renal transplantation more than two-thirds of the CAD patients had significant 2- or 3-vessel disease. Only one of the 106 investigated patients from the waiting list had angiographically normal coronary arteries. The optimal cardiovascular screening test for renal transplant candidates remains unclear. Coronary angiography especially contrast-induced nephropathy in predialysis diabetic patients, carries small risks.23 It is probably not cost-effective, because two-thirds of renal transplant candi-
Fig 3. Prevalence of 1 (CAD1), 2 (CAD2), and 3 (CAD3) vessel coronary artery disease in transplanted patients.
Fig 4. Treatment procedures of CAD in transplanted patients. BMS, bare metal stent; DES, drug-eluting stent.
3454
OTT, BUSCH, STEINER ET AL Table 3. Multivariate Stepwise Linear Regression Analysis of Risk Factors Associated with Death
Hypertension Coronary artery disease Myocardial infarction before transplantation PCI with bare metal stent after transplantation
B
r

T
P Value
⫺0.090 0.061 0.196 ⫺0.231
0.041 0.021 0.060 0.098
⫺0.122 0.236 0.209 ⫺0.153
⫺2.187 2.972 3.265 ⫺2.356
.030 .003 .001 .019
dates will not have significant CAD.22 Exercise testing is unreliable, because a significant proportion of patients will not achieve 85% predicted heart rate.24,25 The results of myocardial perfusion imaging are variable, with some suggesting high negative predictive value26 and others low sensitivity.27 Nevertheless, we believe that all patients with risk factors for cardiac disease facing renal transplantation should undergo coronary angiography before transplantation. The fact that only 10% of our recipients had diabetes, which is the likely cause for ⬎40% of all chronic kidney failure, was presumably due to the fact that many diabetic patients are very sick from multiple complications after the waiting time, making them unsuitable for transplantation. REFERENCES 1. Levey AS, Beto JA, Coronado BE, et al: National Kidney Foundation Task Force on Cardiovascular Disease: Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis 32:853, 1998 2. Ponticelli C, Villa M, Cesana B, et al: Risk factors for late kidney allograft failure. Kidney Int 62:1848, 2002 3. Kasiske BL, Guijarro C, Massy ZA, et al: Cardiovascular disease after renal transplantation. J Am Soc Nephrol 7:158, 1996 4. Kramer BK, Zulke C, Kammerl MC, et al: Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation. Am J Transplant 3:982, 2003 5. Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al: Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration. Transplantation 75:1341, 2003 6. Moore R, Boucher A, Carter J, et al: Diabetes mellitus in transplantation: 2002 consensus guidelines. Transplant Proc 35: 1265, 2003 7. Cosio FG, Pesavento TE, Kim S, et al: Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 62:1440, 2002 8. Raine AE, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant 7:7, 1992 9. US Renal Data System. Annual data report; 583, 2000, P 583. http://www.usrds.org/atlas_2000.htm (accessed June 10, 2009) 10. Mota FM, Araujo J, Arruda JA, et al: Clinical outcome of renal transplant patients after coronary stenting. Arq Bras Cardiol 88:521, 2007 11. Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on
Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108:2154, 2003 12. Herzog CA, Ma JZ, Collins AJ: Long-term outcome of renal transplant recipients in the United States after coronary revascularization procedures. Circulation 109:2866, 2004 13. Chuang P, Gibney EM, Chan L, et al: Predictors of cardiovascular events and associated mortality within two years of kidney transplantation. Transplant Proc 36:1387, 2004 14. Braun WE: Long-term complications of renal transplantation. Kidney Int 37:1363, 1990 15. Mahony JF, Caterson RJ, Pollock CA, et al: Coronary artery disease is the major late complication of successful cadaveric renal transplantation. Clin Transplant 4:129, 1990 16. Best PJM, Lennon R, Ting HH, et al: The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 39:1113, 2002 17. Szczech LA, Best PJ, Crowley E, et al: Bypass Angioplasty Revascularization Investigation (BARI) Investigators: Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation. Circulation 105:2253, 2002 18. Ojo AO, Hanson JA, Wolfe RA, et al: Long-term survival in renal transplant recipients with graft function. Kidney Int 57:307– 313, 2000 19. Manske CL, Wang Y, Rector T, et al: Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 340:998, 1992 20. Rabbat CG, Treleaven DJ, Russell JD, et al: Prognostic value of myocardial perfusion studies in patients with end-stage renal disease assessed for kidney or kidney-pancreas transplantation: a meta-analysis. J Am Soc Nephrol 14:431, 2003 21. 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 42:263, 2003 22. Manske CL, Wang Y, Rector T, et al: Coronary revascularization in insulin-dependent diabetic patients with chronic renal failure. Lancet 340:998, 1992 23. Parfrey PS, Griffiths SM, Barrett BJ, et al: Contrast material– induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 320:143, 1989 24. Morrow CE, Schwartz JS, Sutherland DE, et al: Predictive value of thallium stress testing for coronary and cardiovascular events in uremic diabetic patients before renal transplantation. Am J Surg 146:331, 1983 25. Philipson JD, Carpenter BJ, Itzkoff J, et al: Evaluation of cardiovascular risk for renal transplantation in diabetic patients. Am J Med 81:630, 1986 26. Dahan M, Viron BM, Faraggi M, et al: Diagnostic accuracy and prognostic value of combined dipyridamole-exercise thallium imaging in hemodialysis patients. Kidney Int 54:255, 1998 27. Patel AD, Abo Auda WS, Davis JM, et al: Prognostic value of myocardial perfusion imaging in predicting outcome after renal transplantation. Am J Cardiol 92:146, 2003
From the Department of Internal Medicine III (U.O., M.B., G.W.) and Department of Urology (T.S.), Friedrich-Schiller-University, Jena, Germany.
Address reprint requests to Gunter Wolf, MD, Department of Internal Medicine III, University Hospital Jena, Erlanger Allee 101, D-07740 Jena, Germany. E-mail: [email protected]
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.08.047
© 2010 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3450
Transplantation Proceedings, 42, 3450 –3454 (2010)
CARDIOVASCULAR DISEASE BEFORE AND AFTER KIDNEY TRANSPLANTATION
3451
Conclusion. The prevalence of coronary heart disease is high in patients on the waiting list and after renal transplantation. The majority of these patients are clinically asymptomatic. One-third of the patients with coronary heart disease had to be treated invasively. Nevertheless, many diabetic patients are very sick from multiple complications after the waiting time, making theme unsuitable for transplantation. enal allograft recipients are becoming increasingly older, owing to long wait times, and therefore have a higher prevalence of vascular disease risk factors, including diabetes mellitus, hypertension, and dyslipidemia.1 Time on dialysis before transplantation,2 donor history of hypertension,3 immunosuppressive regimen,4 quality of allograft function,5 and posttransplantation diabetes mellitus6,7 are all also implicated as mediators of cardiovascular risk in this population after renal transplantation. Cardiovascular disease is the major cause of mortality in patients with end-stage renal disease (ESRD).8,9 After renal transplantation one-half of all deaths are cardiac, usually in the first 5 years in the presence of a functional graft.10 On average, 41% of mortality in the transplanted population is a result of cardiovascular diseases. Patients with chronic renal failure and diabetes mellitus have an even higher risk of death, with up to 70% in 7 years.14 –16 The aim of the present study was to assess the number of patients both on the renal transplant waiting list and after transplantation with significant coronary artery disease (CAD) and to predict outcome in renal transplant candidates. The presence of CAD was defined by coronary angiography.
R
PATIENTS AND METHODS A total of 350 patients on the waiting list for renal transplantation at our center in 2008 were investigated. There is no upper age limit for donors recipients in our program. Mean age at admission on the waiting list was 48.6 years (range 13–71 years). Mean age at transplantation was 54.3 years (range 16 –78 years) at our center. Because dialysis is often initiated at other hospital and private practices, we do not have valid information of the mean patient age when starting maintenance dialysis in our population. Diabetic patients are primarily not excluded for coming on the waiting list. However, many diabetic patients are very sick from multiple complications after the waiting time, making theme unsuitable for transplantation Cardiovascular events and coronary artery interventions were registered. In a second study, 324 patients were investigated who underwent renal transplantation in the years 2003–2007 at our center. We performed a retrospective analysis of the renal transplant patients routinely using conventional immunosuppressive treatment with cyclosporine, tacrolimus, rapamycin, prednisolone, mycophenolate, and mofetil and who had to undergo coronary angiography. Patients who underwent coronary angiography or coronary revascularization before renal transplantation were included. Clinical events were registered by assessing medical charts and medical visits. All of the patients had electrocardiograms, echocardiography, ergometric tests, or myocardial scintigraphy. In the presence of high risk for CAD, pathologic ergometric test, or myocardial scintigraphy, coronary angiography was performed. All coronary interventions and diagnostic procedures were counted. Coronary artery interventions, such as coronary bypass operation and percu-
taneous angioplasty with or without coronary stent implantation, and cardiovascular events and outcome were documented. Patients underwent repeated cardiac catheterization when presenting symptoms of CAD, or when presenting a noninvasive test positive for myocardial ischemia.
Coronary Angiography The procedure was performed by the standard Judkins technique via the femoral artery. All predialysis patients received intravenous fluid before and after the procedure. Contrast medium load was kept to a minimum. Angiograms were interpreted blindly by 3 experienced observers. The luminal stenosis severity of each epicardial artery was assessed visually.
Statistical Analysis Spearman rank correlation test was used for estimating correlations between variables. The Kruskal-Wallis test was used to compare differences between ⬎2 independent groups and the Mann-Whitney U test for comparisons between 2 independent groups. If the Kruskal-Wallis test revealed significant differences, each group was compared with each other by using the MannWhitney U test. Distribution of covariates was tested by using the Kolmogorov-Smirnov test with Lilliefors correction. To determine independent predictors of cardiovascular death, multivariate linear regression analysis was done. In addition, chi-square statistics were used. A P value of ⬍.05 or ⬍.01 (as appropriate) was considered to indicate statistical significance. Statistics were done using the software Statistical Package of Social Science (SPSS 13.0, 2004; SPSS, Chicago, IL, USA).
RESULTS Waiting-List Patients
The number, gender, and age of patients on the waiting list in 2008 as well as transplanted patients in the years 2003–2007 are presented in Table 1. Nearly 10% of the patients on the renal transplantation waiting list suffered from diabetes mellitus; 59% had chronic glomerulonephritis, 10% polycystic kidney disease, 14% vascular nephropathy, and 7% interstitial nephritis. A total of 106 out of 350 wait-listed patients (30.3%) underwent coronary angiography (Fig 1). Coronary angiography was performed on patients at high risk for CAD. Most patients do not typically have any clinical symptoms, but risk factors such as diabetes mellitus or severe arteriosclerosis are common in this Table 1. Characteristics of the Studied Population in Our Center
Patients on waiting list Transplanted patients
Men
Women
Mean Age (Range), y
209 226
141 98
48.6 (13–71) 54.3 (16–78)
3452
OTT, BUSCH, STEINER ET AL
period. Diabetes mellitus was significantly correlated with the appearance of severe peripheral arterial occlusive disease (B ⫽ 0.319; r ⫽ 0.111;  ⫽ 0.170; T ⫽ 2.869; P ⫽ .004). No correlation was found between arterial hypertension, hyperlipidemia, or anemia and cardiovascular events. Diabetes mellitus was surprisingly not associated with the prevalence of CAD. Significant association was found between death and arterial hypertension, coronary artery disease, myocardial infarction in the period before renal transplantation, and the implantation of a bare metal stent due to severe coronary artery stenosis after renal transplantation (Table 3). Fig 1. Waiting-list patients, coronary angiography, and patients with coronary artery disease (CAD).
group; pathologic noninvasive ischemic signs in ergometry, stress echocardiography, or myocardial scintigraphy were often present. An ergometric test was performed before patients were listed for renal transplantation. In all diabetic patients or if an ergometric test was pathologic, coronary angiography was performed. There were no significant complications with angiography. Only 1 patient did not suffer from CAD in this group. In 70 patients (20%) no intervention was necessary. In 5 patients (1.4%) coronary bypass surgery was performed owing to severe coronary 3-vessel disease; in 2 patients (0.6%) severe stenosis of aortic valve was treated. Two patients had coronary angioplasty without implantation of stents. In 22 patients (6.3%) coronary angioplasty with implantation of bare metal stent was performed, and in 6 patients (1.7%) a drug-eluting stent was implanted (Table 2). None of the potential recipients resorted to purchased a kidney (which is forbidden by law in Germany) when confronted with the probable long waiting time. However, up to 10% were successful to obtain a living-related donor graft after information of the potential long waiting time. Fewer than 1% of patients accepted the so-called extended donor criteria (grafts from donors with sepsis, cancer not restricted to the brain, hepatitis, meningitis, or a history of drug abuse). Transplanted Patients
Twenty-two renal transplant patients (6.8%) suffered from peripheral arterial occlusive disease. Fifty-eight transplant patients (17.9%) were treated with coronary angioplasty or surgery (Fig 2). Two patients had acute myocardial infarction in the postoperative period despite coronary arterial revascularization. The distribution of involved vessels is shown in Fig 3. One patient was treated with a drug-eluting stent after renal transplantation. In 22 cases (6.3%), coronary bypass surgery was performed before renal transplantation (Fig 4). In the patient population, 25.7% (84 patients) had hyperlipidemia, 90.5% (296 patients) arterial hypertension, 30.3% (99 patients) anemia, and 38.5% diabetes mellitus. Fifteen patients (4.6%) died during the study
DISCUSSION
Cardiovascular disease is a common complication in ESRD.1 At our center, one-third of the waiting-list patients suffered from CAD, and one-third of these patients required invasive cardiac treatment. Not surprisingly, during the wait time cardiovascular risk increased further. The waiting time for patients requiring renal transplantation has continued to lengthen in recent years. Therefore, one may expect that cardiovascular risk has also risen with longer periods on the waiting list. After an average waiting time of 5–7 years, nearly all adult dialysis patients suffer from atherosclerosis. In our center, 17.9% of the patients transplanted required invasive treatment due to CAD in the past 10 years. The lower cardiovascular mortality in transplant patients compared with ESRD patients is related to factors such as selection of patients at a lower risk for transplantation and risk reduction resulting from the transplantation itself. It is important to recognize that despite the lower mortality of transplant patients compared with patients undergoing dialysis, cardiovascular disease remains the main cause of death after renal transplantation.10 –14 High risk for ischemia in untreated critical vascular stenosis exists during renal transplantation. Anemia is another risk factor for ischemia in ESRD. Hypotensive episodes during surgery may induce myocardial infarction or ischemic cerebrovascular insult. Consequently, CAD should be diagnosed and treated before renal transplantation is performed. Diagnostic procedures should be completed before the patient is listed for renal transplantation. An annual follow-up is strongly recommended. Cardiac events are reduced by coronary revascularization before Table 2. Treatment of CAD Among the Patients on the Waiting List
All patients with CAD No invasive treatment PCI without stent PCI with bare metal stent PCI with drug-eluting stent Coronary bypass Aortic valvuloplasty PCI, percutaneous intervention.
n
%
105 70 2 20 6 5 2
100 66.6 1.9 19 5.8 4.8 1.9
CARDIOVASCULAR DISEASE BEFORE AND AFTER KIDNEY TRANSPLANTATION
3453
Fig 2. Results after renal transplantation.
renal transplantation.17 The detection and treatment of CAD is therefore recommended for all renal transplant candidates.18 This is especially important because this disease is characteristically clinically silent. However, the optimal cardiovascular screening technique remains unclear. Typical cardiovascular risk factors, such as hypertension and diabetes mellitus, are not reliable for predicting CAD in this patient population. In the present study, diabetes mellitus was associated with significant risk only for peripheral artery occlusive disease, not for CAD or cardiovascular events. Noninvasive cardiac tests (specifically, thallium scintigraphy or dobutamine echocardiography) have been fairly well studied in patients with ESRD. A meta-analysis found that transplant candidates with positive noninvasive stress tests may have a greater risk for future cardiac events. For prediction of cardiac death, the pooled results revealed a sensitivity of 80% but a specificity of only 59%.19 A study with good evidentiary value was recently reported by de Lima et al.20 Those investigators studied 126 renal transplant candidates, performing coronary angiography as well as both key noninvasive tests. The primary finding was that scintigraphy had sensitivity and specificity of only 58% and 67%, respectively, and dobutamine echocardiography had a sensitivity of only 44% and a better specificity of 87%. Patients were followed for 4 years to determine cardiac outcomes. The noninvasive tests per-
formed with similarly poor accuracy for the prediction of future cardiac events versus stenosis. Only coronary angiography was able to reasonably predict patients at risk. Data on the clinical course, clinical restenosis rates, and progression of CAD in the population of renal transplant patients undergoing coronary angioplasty with stenting are rare in the literature. Chronic renal failure (CRF) patients undergoing stent angioplasty present a 2.2-fold higher need for repeated target vessel revascularization when compared to non-CRF patients (35% vs 16%).21 In two-thirds of our patients, either 2- or 3-vessel disease was diagnosed. In the past, coronary bypass surgery was a common technique for treatment. In recent years, angioplasty with implantation of stent has been more common at our center. In particular, drug-eluting stents have been implanted more often, because interventions are more complex. Significant CAD was seen in 105 patients on the waiting list and 59 transplanted patients. After renal transplantation more than two-thirds of the CAD patients had significant 2- or 3-vessel disease. Only one of the 106 investigated patients from the waiting list had angiographically normal coronary arteries. The optimal cardiovascular screening test for renal transplant candidates remains unclear. Coronary angiography especially contrast-induced nephropathy in predialysis diabetic patients, carries small risks.23 It is probably not cost-effective, because two-thirds of renal transplant candi-
Fig 3. Prevalence of 1 (CAD1), 2 (CAD2), and 3 (CAD3) vessel coronary artery disease in transplanted patients.
Fig 4. Treatment procedures of CAD in transplanted patients. BMS, bare metal stent; DES, drug-eluting stent.
3454
OTT, BUSCH, STEINER ET AL Table 3. Multivariate Stepwise Linear Regression Analysis of Risk Factors Associated with Death
Hypertension Coronary artery disease Myocardial infarction before transplantation PCI with bare metal stent after transplantation
B
r

T
P Value
⫺0.090 0.061 0.196 ⫺0.231
0.041 0.021 0.060 0.098
⫺0.122 0.236 0.209 ⫺0.153
⫺2.187 2.972 3.265 ⫺2.356
.030 .003 .001 .019
dates will not have significant CAD.22 Exercise testing is unreliable, because a significant proportion of patients will not achieve 85% predicted heart rate.24,25 The results of myocardial perfusion imaging are variable, with some suggesting high negative predictive value26 and others low sensitivity.27 Nevertheless, we believe that all patients with risk factors for cardiac disease facing renal transplantation should undergo coronary angiography before transplantation. The fact that only 10% of our recipients had diabetes, which is the likely cause for ⬎40% of all chronic kidney failure, was presumably due to the fact that many diabetic patients are very sick from multiple complications after the waiting time, making them unsuitable for transplantation. REFERENCES 1. Levey AS, Beto JA, Coronado BE, et al: National Kidney Foundation Task Force on Cardiovascular Disease: Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis 32:853, 1998 2. Ponticelli C, Villa M, Cesana B, et al: Risk factors for late kidney allograft failure. Kidney Int 62:1848, 2002 3. Kasiske BL, Guijarro C, Massy ZA, et al: Cardiovascular disease after renal transplantation. J Am Soc Nephrol 7:158, 1996 4. Kramer BK, Zulke C, Kammerl MC, et al: Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation. Am J Transplant 3:982, 2003 5. Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al: Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration. Transplantation 75:1341, 2003 6. Moore R, Boucher A, Carter J, et al: Diabetes mellitus in transplantation: 2002 consensus guidelines. Transplant Proc 35: 1265, 2003 7. Cosio FG, Pesavento TE, Kim S, et al: Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 62:1440, 2002 8. Raine AE, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant 7:7, 1992 9. US Renal Data System. Annual data report; 583, 2000, P 583. http://www.usrds.org/atlas_2000.htm (accessed June 10, 2009) 10. Mota FM, Araujo J, Arruda JA, et al: Clinical outcome of renal transplant patients after coronary stenting. Arq Bras Cardiol 88:521, 2007 11. Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on
Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108:2154, 2003 12. Herzog CA, Ma JZ, Collins AJ: Long-term outcome of renal transplant recipients in the United States after coronary revascularization procedures. Circulation 109:2866, 2004 13. Chuang P, Gibney EM, Chan L, et al: Predictors of cardiovascular events and associated mortality within two years of kidney transplantation. Transplant Proc 36:1387, 2004 14. Braun WE: Long-term complications of renal transplantation. Kidney Int 37:1363, 1990 15. Mahony JF, Caterson RJ, Pollock CA, et al: Coronary artery disease is the major late complication of successful cadaveric renal transplantation. Clin Transplant 4:129, 1990 16. Best PJM, Lennon R, Ting HH, et al: The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 39:1113, 2002 17. Szczech LA, Best PJ, Crowley E, et al: Bypass Angioplasty Revascularization Investigation (BARI) Investigators: Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation. Circulation 105:2253, 2002 18. Ojo AO, Hanson JA, Wolfe RA, et al: Long-term survival in renal transplant recipients with graft function. Kidney Int 57:307– 313, 2000 19. Manske CL, Wang Y, Rector T, et al: Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 340:998, 1992 20. Rabbat CG, Treleaven DJ, Russell JD, et al: Prognostic value of myocardial perfusion studies in patients with end-stage renal disease assessed for kidney or kidney-pancreas transplantation: a meta-analysis. J Am Soc Nephrol 14:431, 2003 21. 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 42:263, 2003 22. Manske CL, Wang Y, Rector T, et al: Coronary revascularization in insulin-dependent diabetic patients with chronic renal failure. Lancet 340:998, 1992 23. Parfrey PS, Griffiths SM, Barrett BJ, et al: Contrast material– induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 320:143, 1989 24. Morrow CE, Schwartz JS, Sutherland DE, et al: Predictive value of thallium stress testing for coronary and cardiovascular events in uremic diabetic patients before renal transplantation. Am J Surg 146:331, 1983 25. Philipson JD, Carpenter BJ, Itzkoff J, et al: Evaluation of cardiovascular risk for renal transplantation in diabetic patients. Am J Med 81:630, 1986 26. Dahan M, Viron BM, Faraggi M, et al: Diagnostic accuracy and prognostic value of combined dipyridamole-exercise thallium imaging in hemodialysis patients. Kidney Int 54:255, 1998 27. Patel AD, Abo Auda WS, Davis JM, et al: Prognostic value of myocardial perfusion imaging in predicting outcome after renal transplantation. Am J Cardiol 92:146, 2003