Cardiac death is common in patients with end-stage renal failure. Screening for coronary artery disease prior to renal transplantation is advisable in high-risk patients. The optimal screening test has not been defined; however, myocardial perfusion studies are more sensitive than exercise electrocardiography and are less invasive than coronary angiography, which remains the gold standard. The management of coronary artery disease prior to transplantation is contentious. Revascularization of coronary artery stenoses is associated with high mortality and morbidity in the renal failure population, and there is little data to indicate that most patients with asymptomatic coronary lesions will benefit from prophylactic coronary intervention. In addition, beta-blockers and aspirin are under-utilized in the renal population. This paper reviews the literature and proposes algorithms for the cardiac assessment and management of patients prior to renal transplantation.
Renal transplantation is the treatment of choice for patients with end-stage renal disease. Mortality is significantly reduced in transplant recipients compared to those patients who are listed for transplantation but remain on dialysis in all patient subpopulations examined (1). Cardiovascular disease is the leading cause of mortality in both dialysis and transplant recipients. In order to prevent cardiovascular death after transplantation, cardiac screening of patients has been recommended (2). This review discusses the cardiac evaluation of patients prior to transplantation, the risks and benefits of revascularization of coronary artery lesions and the limitations of current data for management of patients with asymptomatic coronary lesions prior to transplantation.
Cardiovascular Disease in Renal Patients
Renal disease is an important risk factor for all-cause and cardiovascular mortality. The annual mortality rate for all US dialysis patients in 2002 was 210/1000 patient years (3). This increased cardiovascular risk is not confined to dialysis patients. Large observational studies have shown that the risk of death, cardiovascular events and hospitalization increases markedly in association with any reduction in GFR (4,5).
Evaluation of Patients for Transplantation
While there is widespread agreement that a cardiovascular assessment is required for many patients prior to transplantation (2,6,7), there is no consensus regarding the optimal method and frequency of screening. Cardiac screening for all patients listed for transplantation is expensive, time-consuming and impractical in many renal units. There are, however, groups of patients who are at higher risk of coronary events than the general end-stage renal disease population. Diabetics have a markedly elevated risk of cardiovascular disease compared to non-diabetics and have greater mortality after acute coronary syndromes than patients with other causes of end-stage renal disease (8). Similarly, patients with a prior history of ischemic heart disease (IHD) have been shown to be at high risk for the development of coronary events after transplantation. Other clinical parameters linked to ischemic events after transplantation are older age and an abnormal baseline ECG. Risk factors for IHD in the general population include diabetes, smoking, hypertension and hyperlipidemia (9). Increasing age is also an important predictor for cardiac ischemia in the general population with increased risk in males >45 years and females >55 years. While the traditional Framingham risk factors are predictive of IHD after renal transplantation, there is a tendency for the Framingham heart score to underestimate the risk in transplant recipients, especially in diabetics. Other parameters, such as elevations of CRP and homocysteine, have been shown to be additional risk factors for cardiac ischemia in the transplant setting. In dialysis patients, while traditional factors account for some of the increased risk of IHD, the use of Framingham-based equations markedly underestimates the real risk due to the importance of uremic factors such as hyperhomocysteinemia, calcium-phosphate deposition and anemia. Pre-transplant echocardiographic measures of left ventricular structure and function have been shown to be independent predictors of cardiovascular death with increased mortality in those with systolic dysfunction or concentric left ventricular hypertrophy (10). Finally, the duration of dialysis is an important risk factor for cardiovascular death after transplantation (11) with a significantly greater risk associated with increasing time on dialysis compared to patients transplanted pre-emptively.
In order to rationalize cardiac investigations, patients can be stratified according to their likelihood of cardiovascular events, with screening recommended for patients at high risk (Table 1).
Table 1. Patients at high risk for post-transplant cardiovascular events
Males >45 years
Females >55 years
Previous ischemic heart disease
Echocardiographic evidence of LV dysfunction
Duration of dialysis >2 years
Cardiac Screening Tests
There are a number of non-invasive screening tests used to identify patients at high risk for cardiac events. The most commonly used tests include exercise electrocardiogram testing and myocardial perfusion studies (MPS) such as thallium/sestamibi scintigraphy or echocardiography with exercise or dobutamine.
While exercise ECG testing has been shown to identify patients at increased surgical risk in the non-renal population, there are few studies examining this screening modality in patients with renal failure. This is largely due to the markedly reduced exercise capacity of patients with end-stage renal disease. In a recent study of renal transplant candidates, the resting ECG was strongly predictive of coronary artery disease, while the exercise ECG had a sensitivity of only 35% (12).
As exercise testing is not feasible in many patients with renal failure, MPS are commonly used in clinical practice. A recent meta-analysis of 12 studies evaluated the prognostic significance of MPS in patients with end-stage renal disease (13). Patients with a positive MPS had a significantly greater RR of myocardial infarction (MI) (2.73 [95% CI 1.25–5.97], p = 0.01) and cardiac death (2.92 [95% CI 1.66–5.12] p < 0.001) than patients with a negative study. Similar results were seen in the diabetic subpopulation. The sensitivities for a future MI or cardiac death with a positive MPS in this meta-analysis were 70% and 80%, respectively.
Electron beam CT has been shown to correlate with angiographic coronary disease in the general population; however, in diabetics it has poor specificity (45%) and low predictive accuracy (14). In renal failure, where the incidence of coronary artery calcification (CAC) is high, the place for this test in screening has not been adequately evaluated, and thus it cannot currently be recommended.
There is no consensus as to the preferred MPS in the setting of patients with renal failure. In diabetics, the sensitivity of MPS (thallium scintigraphy, dobutamine echocardiography, and persantin thallium scans) appears to be around 85%, while the specificity varies between 85% and 90% (14). This compares favorably to exercise testing. As there is no clear optimal non-invasive screening test for the diagnosis of coronary artery disease in renal failure, the choice of MPS is best determined by the expertise of the individual center.
Coronary angiography remains the gold standard for evaluation of coronary arteries. It is complicated by its invasive nature and the risk of contrast nephropathy. There are few studies specifically examining coronary angiography and cardiac outcomes in patients prior to transplantation. One study, however, has examined potential renal transplant candidates at high risk for coronary artery disease and found that significant coronary artery stenoses (≥70% by visual estimation) occurred in 42% of patients. Coronary stenoses were the strongest predictor of cardiac events at 48 months with a probability of event-free survival at 48 months of 94% in those without significant coronary artery disease and 54% in those patients with stenoses of ≥70% (15).
There is no optimal strategy for ongoing coronary artery surveillance of patients on the renal transplant waiting list. Recent clinical recommendations suggest that patients with diabetes on the waiting list should undergo a cardiac evaluation annually (6). In patients with renal impairment, the cardiac event rate increased from 8% at 24 months to 16% at 40 months after a normal dobutamine stress echocardiography (DSE) (16) while in a prospective study of adults on the renal transplant waiting list, the probability for any cardiovascular event occurring per year in those with diabetes was 12.7% compared to 4.5% for non-diabetics (17). Until there are further studies defining the optimum strategy for cardiac screening, a policy of rescreening all diabetic and high-risk patients at least biannually is a safe recommendation.
While there is no current data proving that screening impacts on peri-operative or long-term survival, screening of high-risk patients is useful to identify patients with coronary artery disease. The algorithm in Figure 1 is proposed for screening of coronary artery disease prior to transplantation.
Coronary Artery Revascularization
Previous reviews have suggested that revascularization of significant coronary artery stenoses should occur prior to transplantation (2,6). In the non-renal population, there are clear guidelines for the revascularization of patients with coronary artery lesions. In early clinical trials, coronary artery bypass grafting (CABG) offered no significant mortality benefits compared to medical therapy; however, there was a survival benefit in subgroups of patients with severe coronary artery disease who were at high risk. These included patients with left main coronary artery stenosis or left main equivalent disease, triple vessel disease with abnormal LV function and two vessel disease with a >75% stenosis in the left anterior descending (LAD) artery. With prolonged follow-up, however, the benefit disappeared in most patients, with the exception of those with left main or equivalent disease who are at increased risk due to the large amount of myocardium supplied (18). Current guidelines for the revascularization of patients with angina in the general population advise medical management in low-risk patients, while revascularization is recommended in those with left main disease, severe triple vessel disease and for those with symptoms refractory to medical therapy.
As those with end-stage renal disease are at high risk for ischemic events, revascularization of coronary stenoses has been recommended prior to transplantation. Manske et al. (19) conducted a randomized controlled trial of 26 patients with asymptomatic coronary artery disease and diabetes mellitus. Patients were randomized to medical therapy or revascularization prior to renal transplantation. The outcome for those managed medically was markedly inferior to that of those who were revascularized, with only 2 of 13 of the revascularized patients reaching a cardiovascular endpoint in 8.4 months of follow-up compared to 10 of 13 of the patients managed medically. This trial, however, was limited by the use of short-acting calcium channel blockers in the medically managed group, the suboptimal use of aspirin, the small sample size and short follow-up.
There are no other randomized controlled studies examining revascularization compared to medical management prior to non-cardiac surgery in dialysis patients. There are, however, a number of studies in patients with vascular disease who have a high risk of cardiac events associated with non-cardiac surgery (20). The Coronary Artery Revascularization Prophylaxis trial examined the impact of prophylactic coronary revascularization in patients requiring major vascular surgery (21). A total of 510 patients were randomized to either revascularization (N = 258) or medical management (N = 252). Ninety-three percent of those randomized to revascularization underwent CABG (N = 99) or percutaneous coronary angioplasty (PTCA) (N = 141). Revascularization was not associated with any benefit in patient survival, with a 22% incidence of mortality in the revascularization group and 23% in the group who were medically managed. In addition, there was no difference in survival in any high-risk group examined. The results of this study concur with the guidelines from the American College of Physicians, which do not recommend revascularization prophylactically, in patients undergoing non-cardiac surgery, stating that there are clear potential risks and no evidence of either a short- or long-term benefit from revascularization.
Coronary revascularization in patients with renal disease is associated with an in-hospital mortality 3.1 times greater for dialysis patients compared to patients not requiring renal replacement therapy. Similarly, the survival rates at 24 months after coronary revascularization are markedly lower in the dialysis population compared to the general population for both CABG and angioplasty with a 24-month survival of only 54.8% after CABG (22). The optimal method for coronary revascularization in renal patients has been controversial. Percutaneous coronary intervention has been shown to have superior in-hospital and 30-day post-procedural survival compared with CABG in dialysis patients. However, the long-term survival of dialysis patients is better after CABG than after PTCA (23). In an analysis of dialysis patients undergoing coronary revascularization using the US Renal Data System (22), while the in-hospital mortality was greatest for those undergoing CABG (8.6%) compared to patients having stents (4.1%) or PTCA (6.4%), the 2-year patient all-cause survival was significantly superior in those after CABG (56.4%) than after stenting (48.4%) or PTCA (48.2%).
The restenosis rate of revascularized vessels is also an important endpoint. While some have indicated that the restenosis rate in the renal population was similar to that of non-renal patients, there does appear to be a higher rate of both restenosis and death in dialysis patients compared to those without renal failure (24). In the general population, coronary artery stenting has been associated with lower rates of restenosis than occurs after PTCA. In patients with renal failure, there is some evidence that the use of stents reduces the risk of restenosis in patients on hemodialysis. While there have been no published studies specifically examining the use of drug-eluting stents in patients with renal failure, the use of sirolimus-eluting stents has been shown to reduce restenosis rates in the general population. Early data suggest that this may be true even in diabetic patients.
Until recently, there has been little data on the outcome of patients requiring coronary revascularization after renal transplantation. A recent analysis using the USRDS showed that in 5349 renal transplant recipients, patient survival at 2 years after revascularization was similar in patients undergoing coronary stenting (82.5%), PTCA (82.1%) and CABG using internal mammary grafts (82.7%) (25). The risk of a cardiac death or acute MI was lowest in the group treated with internal mammary grafts; RR 0.57 (95% CI 0.42–0.76) compared to PTCA. These results are consistent with other smaller series and show a significantly better survival after revascularization in patients after renal transplantation than in dialysis patients. While this may in part be due to population bias, there is evidence that supports a survival benefit associated with transplantation. This is presumably due to the restoration of renal function and correction of uremic factors. Indeed the incidence of both cardiovascular and non-cardiovascular mortality is strongly associated with renal function after transplantation, with a greater risk of CVS events in those with an elevated creatinine (11). In addition to lower mortality rates in transplanted patients compared to transplant waiting list patients, the survival after MI is also significantly greater in patients who have been transplanted compared to those waiting for kidney transplantation. A number of entities are favorably affected by renal transplantation. CAC has been shown to stabilize in patients after renal transplantation compared to patients remaining on dialysis in whom there is progression of CAC. While there is little compelling evidence that renal transplantation prevents progression of pre-existing atheroma, an improvement in endothelial function has been shown to occur after renal transplantation. Renal transplantation has also been shown to be associated with a regression of left ventricular hypertrophy and an improvement in left ventricular dilatation. These beneficial changes occur within the first 2 years after transplant and appear to persist. Likewise, successful transplantation has been shown to be associated with an improvement in systolic function and symptoms of heart failure in patients with uremic cardiomyopathy.
Thus, while dialysis patients with coronary stenoses of greater than 70% are at higher risk for cardiac events and death than those without significant coronary lesions, the benefits of revascularization in patients with end-stage renal disease are uncertain. CABG offers superior survival benefits compared to PTCA and coronary artery stenting in both diabetic and non-diabetic patients with renal failure, although in-hospital and long-term patient survival after both CABG and PTCA is significantly inferior in those on dialysis compared to the non-renal population. In the absence of a survival benefit associated with the revascularization of asymptomatic patients with renal disease prior to surgery, there is no evidence that coronary intervention prior to transplantation should be mandated. However, optimal medical treatment with agents known to improve cardiac survival both in the general and renal populations should be offered to all patients with coronary artery disease and renal failure. An algorithm for the management of patients with coronary disease is presented in Figure 2. This proposal suggests that patients with only mild coronary artery lesions do not require revascularization, while only those with left main stem or equivalent stenoses of >70% require revascularization prior to transplantation. There is no good evidence that the group with stenoses >70% not affecting the left main stem or equivalent will benefit from revascularization. However, if the patient has angina or a strongly positive MPS, the opinion of a cardiologist should be sought to determine whether that particular individual will benefit from intervention. All patients with coronary stenoses should have medical management optimized.
Alternatives to Revascularization
Studies in patients with chronic kidney disease and MI have shown that the likelihood of receiving therapies proven to reduce mortality in the general population appears to be inversely proportional to the severity of renal failure. The use of beta-blockers has been shown to be reduce peri-operative ischemia in patients with vascular disease. A recent retrospective analysis examined 782 969 patients who had undergone surgery and compared the in-hospital mortality of patients receiving beta-blockers with those who did not receive this treatment (26). Patients with a cardiac risk index score of 2, 3 or 4 (1 point each for high-risk surgery, IHD, cerebrovascular disease, renal insufficiency and diabetes mellitus) had a significantly lower odds ratio for in-hospital death if they were treated with peri-operative beta-blockers. There are few observational studies and no randomized controlled trials specifically examining the use of beta-blockers in patients with renal failure. There are, however, several studies indicating that the survival benefit found in the general population with IHD also occurs in those with renal failure. Dialysis patients with dilated cardiomyopathy and heart failure who were treated with carvedilol had a 49% reduction in death and a marked improvement in cardiac function. Another study examined over 6000 patients with renal impairment who had congestive heart failure and coronary artery disease and found a survival benefit in patients treated with aspirin (OR for death 0.69 (0.57–0.85)), statins (OR 0.79 (0.64–0.97)) and beta-blockade (OR 0.75 (0.62–0.90)) (27).
While the use of statins remains contentious in patients with renal failure, with no survival benefit seen in diabetic hemodialysis patients, statins are associated with a significant reduction in cardiovascular events and mortality in the general population with vascular disease. After renal transplantation, the use of fluvastatin was associated with a non-significant reduction in the composite endpoint of cardiac death, definite or probable MI and coronary revascularization (28). However, a post hoc analysis using the more defined endpoints of cardiac death and definite non-fatal MI showed a significant reduction in these endpoints (RR 0.65; 95% CI 0.48, 0.88; p = 0.005) with the use of fluvastatin (29). Currently, while the results of ongoing studies are pending, it is reasonable to treat patients with significant coronary artery disease with statins.
There are no randomized controlled trials examining the use of aspirin in patients with coronary artery disease and renal failure. In the general population, there is excellent evidence that aspirin confers a survival benefit in patients with coronary artery disease. As MI in both the general population and renal patients is due to a thrombotic event, we can extrapolate from existing data and should treat all patients with renal disease and coronary artery disease with aspirin in the absence of a specific contraindication.
Finally, the use of angiotensin converting enzyme inhibitors has been shown to be beneficial in patients with left ventricular dysfunction after acute MI (30). Patients randomized to captopril had a reduction in cardiac death and recurrent MI compared to the group given placebo with patients who had the most renal impairment appearing to reap the greatest survival benefit.
Limitations of Data and Future Research
While it is clear that those with end-stage renal disease are at high risk for cardiac events, there are few trials examining the optimal modality for cardiac screening, and no large trials examining the risks and benefits of revascularization of coronary lesions in the renal population. In addition, there are few trials of optimal medical management of coronary disease in the renal population. The schema for the management of coronary artery lesions proposed in this paper is derived from the current literature and in the absence of clinical trial data, there may be unanticipated risks. Randomized controlled trials examining medical management compared with revascularization in renal failure patients with coronary artery disease are required before recommendations for revascularization of those with significant coronary stenoses can be made.
Guidelines for assessment and management of patients with CAD
Patients with chronic renal disease who are at high risk for coronary artery disease should undergo a cardiac assessment. However, there is no consensus as to the best method of screening, nor the optimal treatment for coronary stenoses prior to transplantation. This paper presents a review of the literature with algorithms formulated by the author for the assessment and management of patients with coronary disease based on current data. Clearly, verification of these proposed algorithms in appropriate clinical trials is required. In order to prevent nephrotoxicity induced by contrast agents, a MPS offers screening that is reasonably sensitive and specific in asymptomatic patients. In those with symptomatic angina or a positive MPS, coronary angiography should be undertaken. Treatment after coronary angiography should be determined by the extent of the underlying coronary artery disease. Currently, there is no data to suggest that the revascularization of coronary artery lesions in the absence of symptoms of ischemia is beneficial in the current era of beta-blockade, aspirin, ACE inhibitors and statins. Renal transplantation itself appears to be associated with a survival benefit and a reduction in cardiac morbidity. As pre-emptive renal transplantation is associated with a reduction in cardiovascular events, all efforts should be made to encourage renal transplantation prior to the requirement for initiation of dialysis.