Current practices in coronary artery disease evaluation of renal transplant candidates prior to renal transplantation

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in renal transplant recipients and candidates awaiting transplant. Pre-transplant coronary artery disease evaluation can aid in determining transplant candidacy, identifying patients who may benefit from pre-operative cardiac intervention, and implementing measures to reduce perioperative and post-transplant cardiovascular events. However, the choice of investigations and approach in evaluation has yet to be well defined. This article aims to review the evidence for the use of non-invasive investigations and coronary angiography in prognostication, as well as the evidence for revascularization in reducing future cardiac events. The article will also summarize international recommendations and describe the local practice in coronary artery disease evaluation prior to transplant.

Keywords

Renal transplant cardiovascular evaluation

Introduction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in renal transplant recipients and candidates awaiting transplant.^1–5 In suitable end-stage renal failure (ESRF) patients, a transplant provides better long-term survival outcomes and improved quality of life when compared with dialysis.^6–11 Despite receiving a transplant, renal transplant recipients still have higher mortality rates when compared with the general population, and cardiovascular events (CVE) remain the leading cause of death.¹²

The wait for a cadaveric renal transplant is long, and the median waiting time in Singapore is 9.44 years.¹³ Some suitable candidates may develop a CVE during the wait, and as a result become ineligible for a transplant. In a retrospective study of all patients registered under the cadaveric renal transplant wait list in Singapore General Hospital (SGH) from 16 April 1987 to 31 October 2010, CVE was the leading cause for patients to exit the wait list, accounting for 38.8% of those that dropped out due to medical reasons or death.¹⁴ Other studies, such as studies by Gill et al. and König et al.,^5,15 also demonstrated high CVE rates among patients waiting for a renal transplant.

However, the high prevalence of coronary artery disease (CAD) among patients with chronic kidney disease (CKD) is incompletely explained. Although traditional cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, and older age, are prevalent among patients with CKD,^16,17 their role in the development of CAD among this group of patients is not entirely clear. The benefits of statin therapy on clinical outcomes still remain controversial among patients on dialysis after the 4D, AURORA, and SHARP studies.^18–20 The lack of benefit of statins on clinical outcomes in the 4D and AURORA studies may suggest that the development of CAD in patients undergoing hemodialysis may differ from that in another patient. The contributions of non-traditional risk factors that are unique to patients with CKD, such as inflammation, uremia, anemia, coronary calcification, and hyperhomocysteinemia, could play a part, but how these factors lead to CAD remains unclear.^21–25

A renal transplant would also introduce unique CAD risks. The use of immunosuppressants, such as corticosteroids and cyclosporine, increases the risk of hypertension, hyperlipidemia, and diabetes mellitus.^26–33 Tacrolimus is associated with a higher risk of post-transplant diabetes mellitus as compared to cyclosporine.^34,35 Physicians may also be hesitant to prescribe statins to transplant recipients due to its interaction with cyclosporine.³⁶

There are hence strong indications to screen patients for CAD prior to renal transplantation, to determine transplant candidacy, to identify patients who may benefit from pre-operative cardiac intervention, and to implement measures to reduce perioperative and post-transplant CVE.

Coronary artery disease screening and revascularization prior to renal transplant

Dobutamine stress echocardiography (DSE) and myocardial perfusion studies (MPS) are non-invasive stress tests commonly used for pre-transplant cardiovascular evaluation. Studies have shown a wide range of sensitivities and specificities for these tests in the detection of CAD among renal transplant candidates. In different studies, DSE’s sensitivity ranges from 37% to 95% and its specificity ranges from 74% to 95%,^37–40 while MPS has a sensitivity of 37–80% and specificity of 37–73%.^41,42 When comparing DSE and MPS, Wang et al. demonstrated in a meta-analysis that there was no difference in diagnostic accuracy in renal transplant candidates.^43,44 It should however be noted that DSE provides not only proof of myocardial ischemia, but also additional valuable structural and hemodynamic information of the heart.

When evaluating the prognostic value of these non-invasive tests in predicting future CVE, studies had mixed conclusions:

Rabbat et al. performed a meta-analysis of 12 studies and demonstrated that a positive non-invasive test for ischemia was associated with an increased risk of myocardial infarction and cardiac death.⁴⁵

Studies by Patel et al. and Wong et al. also demonstrated the usefulness of MPS in prognostication of future cardiac events.^46,47

However, in a study done by Lima et al.,⁴⁸ where 126 moderate to high risk renal transplant candidates underwent MPS, DSE, or coronary angiography (CA), only CA was found to reasonably predict future cardiac events while both non-invasive tests failed to do so.

Welsh et al. described similar conclusions as Lima et al:⁴⁹ only angiographic CAD, and not positive MPS results, was predictive of major adverse cardiac events (MACE) in diabetic patients undergoing assessment for renal transplantation.

It is known that the ability of a test to exclude a disease (negative predictive value) depends not only on the accuracy of the test (sensitivity and specificity), but also on the patient’s risk profile (pre-test probability). In a population with a higher disease prevalence, and hence a higher pre-test probability, the chance of a false negative test is greater.⁵⁰ The patient profile in the studies done by Lima et al and Welsh et al had high baseline cardiac risk, and this could explain the failure of non-invasive tests in accurately predicting future cardiac events.

Since cardiac risk in CKD patients is generally high, should CA be routinely included in pre-transplant cardiac screening? CA is however invasive with potential serious complications and may be difficult to be justified as a screening tool for patients without clinical evidence of CAD. As for pre-transplant revascularization in reducing future cardiac events, the evidence so far is mixed:

Manske et al. conducted a randomized controlled trial on 26 renal transplant candidates who had insulin-dependent diabetes mellitus and greater than 75% stenosis in one or more coronary arteries.⁵¹ These patients were randomized into two groups that underwent medical management or revascularization. 10 of 13 medically managed patients and 2 of 13 revascularized patients experienced a cardiac event, demonstrating that revascularization improved cardiovascular outcomes. However, there were several limitations in this study. Firstly, medical management of CAD in this study included only calcium-channel blockers and aspirin. Medical therapy of CAD has since been improved, and it is hence difficult to extrapolate these results to our current clinical practice. Secondly, in this study, coronary artery bypass grafting (CABG) and angioplasty were considered equivalent methods of revascularization and we know that with current evidence, they have different long term outcomes with different patient profiles. Thirdly, the small sample size may have affected the power of the study.⁵²

Kahn et al. conducted a retrospective review of patients who underwent renal transplantation and found that patients with medically managed obstructive CAD had significantly higher rates of death at 5 years post-transplant as compared to those who had undergone revascularization either via percutaneous coronary intervention (PCI) or CABG.⁵³

Hage et al. differed in conclusion regarding the benefits of pre-transplant revascularization.⁵⁴ In their retrospective analysis of 260 patients who underwent CA as part of evaluation for renal transplantation, 94 underwent revascularization and this did not impact survival except in patients with triple vessel disease.

Similarly, in a prospective observational cohort study of 300 patients screened for CVD in Glasgow prior to listing for renal transplantation, there was no significant difference in survival between patients who underwent revascularization compared to those who underwent angiography without intervention or no angiography at all.⁵⁵

Our current understanding on the pathophysiology of acute coronary syndromes is the disruption of vulnerable, non-obstructive coronary artery plaque that leads to coronary artery thrombosis. Therefore a pre-emptive strategy of revascularization prior to non-cardiac surgery may seem incongruent. Large clinical trials such as the CARP and DECREASE-V studies did not demonstrate improved clinical outcomes with preoperative coronary revascularization in the general population.^56,57 Essentially, plaque character and not just plaque burden play a part in determining the risk of CVE. Computerized tomography coronary angiography (CTCA) allows for a non-invasive assessment of both luminal stenosis as well as plaque morphology. The severity of stenosis as well as identification of high-risk plaques by CTCA have been shown to be predictive of future CVE.^58,59 Studies on the use of CTCA, coronary artery calcium scoring (CACS), as well as a hybrid approach combining CTCA and MPS are in progress,^60,61 but more evidence for their use in renal transplant candidates is needed.

International recommendations for coronary artery disease evaluation prior to renal transplant

What is the recommended strategy for cardiovascular evaluation and intervention prior to renal transplantation?

The 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines provide specific recommendations for cardiac evaluation for patients undergoing non-cardiac surgery.⁶² A stepwise approach to perioperative cardiac assessment for CAD is recommended, which takes into account the combined clinical and surgical risk, the functional capacity of the patient, as well as the decision if further CAD testing would impact patient’s willingness for surgery or the perioperative care. However, this algorithm was developed for the general population, and is not specific for renal transplant candidates who have a higher baseline cardiovascular risk.

Over the past decade, various regulatory bodies have developed guidelines and recommendations on CAD evaluation prior to renal transplantation, and these are summarized in Table 1.^54,63–66 They recommend non-invasive stress testing in high-risk patients (usually defined as those with diabetes, prior CAD, or two or more cardiac risk factors), and coronary angiogram and revascularization before transplant in those with evidence of ischemia. In 2012, the American Heart Association/American College of Cardiology Foundation (AHA/ACCF) issued a scientific statement on cardiac disease evaluation and management in renal and liver transplant candidates, and this statement was endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation. It recommends that non-invasive stress testing may be considered in renal transplant candidates with no active cardiac conditions, based on the presence of multiple CAD risk factors, and regardless of functional status. Relevant risk factors include diabetes mellitus, prior CVD, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The specific number of risk factors to be used as the criteria for testing remains to be determined, but the committee considered three risk factors or more as a reasonable guide. This recommendation was given a Class IIb grade. Coronary revascularization prior to transplantation should also be considered in patients who meet the guideline’s criteria for revascularization. However, the risks and benefits of coronary revascularization may need to be discussed by a multi-disciplinary transplant team on a case-by-case basis.

Table 1.

Recommendations for coronary artery disease evaluation in renal transplant candidates.

Guideline	Recommendations
2012 AHA/ACCF Scientific Statement⁶³	Non-invasive stress testing may be considered in kidney transplantation candidates with no active cardiac conditions based on the presence of multiple CAD risk factors regardless of functional status.
	Relevant risk factors among transplantation candidates include diabetes mellitus, prior CVD, more than 1 year on dialysis, LVH, age greater than
	60 years, smoking, hypertension, and dyslipidemia. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers 3 or more as reasonable (Class IIb; Level of Evidence C).
	Coronary revascularization before transplantation surgery should be considered in patients who meet the criteria outlined in the “2011 ACCF/AHA Guidelines for Coronary Artery Bypass Graft Surgery” (Class I; Level of Evidence B). It is recognized that in some asymptomatic transplantation candidates, the risk of coronary revascularization may outweigh the risk of transplantation and these risks must be weighed by the multidisciplinary transplantation team on a case-by-case basis until further studies are performed in this population.
2007 Lisbon Conference⁶⁴	Evaluation of asymptomatic patients at highest risk for CVD events may include non-invasive and/or invasive testing such as a coronary angiography, depending on local expertise and availability.
	However, there are no data establishing that screening of asymptomatic patients in itself prevents CVD events.
	Highest-risk patients are those with the following conditions: diabetes mellitus, prior CVD and multiple CVD risk factors (such as more than 1 year on dialysis, LVH, age greater than 60 years old, smoking, hypertension and dyslipidaemia).
2005 NKF/KDOQI Guidelines⁶⁵	Non-invasive testing is recommend for➢ Patients with diabetes mellitus: every 12 months➢ Patients with CAD • Not revascularized: every 12 months • History of PCI: every 12 months • History of CABG: 3 years after CABG, then every 12 months➢ Patients classified as “high risk” and are not diabetic: every 24 months • “High risk” defined as more than 20% per 10 years cardiovascular event rate risk according to Framingham data. It includes those with 2 or more ‘traditional’ risk factors, a known history of CAD, left ventricular ejection fractions 40%,or peripheral vascular disease.➢ Patients not classified as “high risk”: every 36 months
2001 AST Guidelines⁵²	Patients at high risk, defined as renal disease from diabetes, prior history of ischemic heart disease, or two risk factors, should have a cardiac stress test.
	Patients with a positive cardiac stress test should undergo coronary angiography for possible revascularization prior to transplantation. Patients with critical coronary lesions should undergo revascularization prior to transplantation.
2000 European Best Practice Guidelines⁶⁶	In patients with history of myocardial ischemia or at high risk for myocardial ischemia, thallium scintigraphy is recommended. Coronary angiography is recommended if thallium scan is positive for myocardial ischemia.
	Revascularization is recommended if lesions are suitable.

AHA, American Heart Association; ACCF, American College of Cardiology Foundation; CAD, coronary artery disease; CVD, cardiovascular disease; LVH, left ventricular hypertrophy; NKF, National Kidney Foundation; KDOQI, Kidney Disease Outcomes Quality Initiative; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; AST, American Society of Transplantation.

Singapore General Hospital’s guidelines for cardiac evaluation prior to renal transplant

Deceased donor kidney transplant recipients

All patients will have an electrocardiogram, chest radiograph, and transthoracic echocardiogram. Patients aged 60 years and older or patients with diabetes mellitus will also undergo a MPS. Patients with diabetes mellitus who have a left ventricular ejection fraction (LVEF) of more than 50% would be required to undergo a CA. Patients with LVEF of less than 50% or coronary artery stenosis of greater than 50% in at least one epicardial coronary artery on angiography will be excluded.

Living donor kidney transplant recipients

In the past, living donor transplant recipients were reviewed by a cardiologist and subsequently sent for cardiac investigations as necessary. Since March 2015, a new workflow has been implemented. All patients with diabetes mellitus now undergo a DSE and CA as part of pre-transplant cardiovascular evaluation. Patients without diabetes mellitus undergo a DSE, and may be sent for further investigations depending on the results. If DSE demonstrates ischemia or significant structural or hemodynamic abnormalities, a cardiologist would determine the next course of action. If results are inconclusive, the patient will proceed with MPS before a cardiology review. If DSE is negative for ischemia, the patient will proceed for the renal transplant without further cardiac evaluation.

In our center, the criteria for eligibility of deceased or living kidney donor transplantation determines the nature of the evaluation protocol. For deceased donor kidney transplantation, the objective of evaluation is to exclude patients with clinical or subclinical cardiac disease that is likely to progress over the long wait (and hence places them at risk during emergency transplant surgery) or is associated with a poorer prognosis after transplantation. This is partly based on the allocation policy and philosophy of allocating a scarce resource to the selected few who are likely to survive the long wait as well as survive long enough to accrue the benefit of a transplant. It is also partly based on evidence to suggest that patients with cardiac disease do not benefit as well as those without cardiac disease after transplantation.⁶⁷ Even if the cardiac disease can be optimized via revascularization prior to deceased donor kidney transplantation, it cannot be assured that CAD will not recur during the decade long wait for a kidney transplant. It is also not possible for CAD to be immediately rectified when a donor is available. Therefore, even patients with subclinical CAD will be excluded from the waiting list. The objective of living donor kidney transplant is different. The aim is to optimize the patient for transplantation even if there is detectable cardiac disease. Since there is an identifiable donor, if all other evaluation parameters are acceptable, the transplant can proceed in a definite time period after optimization of CAD through intervention like revascularization. In summary, evaluation for deceased donor kidney transplantation is to exclude patients with clinical or subclinical CVD regardless of whether they can be improved for transplantation. As for living donor kidney transplantation, the objective is to include patients with CVD provided they can be optimized for transplantation to proceed safely. Finally, there is no difference in evaluation approach for patients on dialysis (regardless of modality) and patients not on dialysis.

Conclusion

Cardiovascular disease is a major cause of morbidity and mortality in renal transplant candidates and recipients. However, the optimal strategy for CAD evaluation and intervention has not been developed, as the accuracy of non-invasive tests and the benefit of CA and revascularization among renal transplant candidates have yet to be determined. There is hence a need for more studies and randomized controlled trials, before definite guidelines can be developed to determine a patient’s suitability for transplant, need for pre-transplant cardiac intervention and long term cardiovascular prognosis.

Footnotes

Conflict of interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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