Cardiac evaluation of renal transplant candidates with heart failure

Abstract

Patients with advanced kidney disease are at elevated risk of developing heart failure and appropriate risk stratification is important to permit them to receive kidney transplantation. The American Heart Association and American College of Cardiology joint statement provides guidance on risk stratification for the major cause of heart failure for these patients in its recommendations for coronary heart disease. Herein we provide an overview of the available literature on risk stratification for nonischemic heart failure and functional heart disease states such as pulmonary hypertension. Many of these options for optimizing these patients before transplant include optimizing their volume status, often with more aggressive ultrafiltration. Kidney transplantation remains the treatment of choice for patients with advanced kidney disease and cardiac disease, the correction of the azotemic substances with kidney transplantation has been associated with improved survival than remaining on dialysis long-term. The findings in the studies reviewed here are expected to help clinicians refine current strategies for evaluating potential kidney transplant recipients.

Key Words: Kidney transplantation; Preoperative evaluation; Clinical practice guidelines; Heart failure; Pulmonary hypertension

Core Tip: There are several reviews in the literature detailing the risk stratification for patients undergoing kidney transplant evaluation for coronary heart disease. However, there are relatively few reviews that detail the means to optimize patients with heart failure. This review seeks to report on the latest recommendations to permit efficient and appropriate cardiac evaluation and stratification for patients with advanced kidney disease undergoing evaluation for a kidney transplant as well as review the pathophysiology underlying their unique disease state to inform pretransplant therapeutic options.

INTRODUCTION

We define heart failure (HF) as a clinical syndrome resulting from any structural or functional cardiac disorder that impedes the ventricular filling or ejection of blood[1]. Patients with advanced chronic kidney disease (CKD) particularly those with end-stage renal disease (ESRD) requiring dialysis are at particularly increased risk of structural heart disease[2]. This is not surprising given that volume and pressure overload alongside nonhemodynamic factors that are often present in CKD and ESRD are known mechanisms to both cause and worsen cardiovascular disease[2]. Given the specific unmet need for accurate risk stratification of patients with cardiorenal syndrome type IV (advanced CKD and progressive heart disease), the 11th Acute Dialysis Quality Initiative (ADQI) working group proposed the following staging system with the following 3 elements: (1) Echocardiographic evidence of structural and/or functional abnormalities; (2) Dyspnea in the absence of primary lung disease; and (3) Response of congestive symptoms to renal replacement therapies including ultrafiltration[3].

The widely adopted Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines recommend all patients with advanced CKD with a glomerular filtration rate (GFR) less than 30 mL/min/1.73 m² should be informed of and considered for kidney transplant evaluation[4]. This recommendation was based on the well-established findings that patients receiving kidney transplantation will have significantly improved survival and quality of life when compared with those who remain on long-term dialysis[5]. A significant contribution to this is the inherent elevated cardiovascular (CV) risk profile in patients with CKD when compared to the general population[6,7]. Although the risk of CV events is reduced by kidney transplantation, it is still up to 20-50 times higher than the age- and sex-matched cohort members of the general population with mortality from CV disease accounting for close to half of the deaths following the first year post-transplant[8,9]. A large observational cohort study of patients with ESRD requiring dialysis found at baseline approximately 80% of these patients had cardiovascular diseases with 39% having ischemic heart disease[3]. Coronary heart disease (CHD) is an important subset of this source of morbidity and mortality among kidney transplant recipients. CHD has been extensively studied and is a known risk factor for structural and functional heart disease. The risk stratification algorithms based on the presence or absence of specific clinical risk factors and physical performance of candidates have been explored in detail in a recent scientific statement by the American College of Cardiology (ACC) and American Heart Association (AHA) and endorsed by the American Society of Transplantation[10]. The relatively recent International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease (ISCHEMIA-CKD) results informed the ACC/AHA scientific statement[11]. This trial found that initial invasive strategies did not necessarily result in lower incidences of death or otherwise nonfatal myocardial infarctions than conservative strategies[11]. There are several unanswered questions despite a profound investigation in this field. The guidelines advocated by the KDIGO and the AHA focus on using noninvasive CHD testing screening tests in kidney transplant candidates. However, it is not known whether outcomes of revascularization for transplant candidates may differ from others with advanced CKD[12].

That same large observational study of ESRD patients requiring dialysis found that 40% had congestive heart failure[3]. HF is thus another major contributor to cardiac mortality in kidney transplant candidates and recipients and therefore represents an area of further study and consternation in the evaluation of kidney transplants[13].

HEART FAILURE WITH REDUCED EJECTION FRACTION

The presence of left ventricular systolic dysfunction (LVSD), defined as a left ventricular ejection fraction (LVEF) of 40%-45% or less, has significant prognostic implications on mortality in renal transplant candidates independent of the presence of CHD[14]. After renal transplant, the recipients who had pretransplant evidence of LVSD were found to have 5 times the cardiac mortality risk and 2 times the all-cause mortality risk of the general population[15]. Additionally, de novo HF was noted to occur as frequently as de novo CHD in kidney transplant recipients with similar mortality risk, which is 2-5 times greater than the general population[16,17].

Given these adverse risks associated with LVSD, the ACC/AHA recommends that in addition to an electrocardiogram, a resting transthoracic echocardiogram be obtained in kidney transplant candidates referred for transplant regardless of known CHD or symptomatic cardiac disease except those in the very low-risk set of patients under the age of 40, without diabetes, smoking, peripheral artery disease or cerebrovascular accident history, and not on dialysis[10]. Those with echocardiographic evidence highly suggestive of CHD such as LVSD or regional wall motion abnormalities are recommended to be considered for cardiology referral for intensive guideline-directed medical therapy (GDMT) and potential coronary angiography for risk stratification and possible revascularization[10]. These recommendations are tabulated in Table 1.

Table 1 Summary of recommendations for cardiac evaluation in heart failure and pulmonary hypertension.

Cardiovascular disease	Pre-transplant recommendations
Heart failure with reduced ejection fraction	If echocardiographic signs concerning for CHD such as regional wall motion abnormalities, recommend referral to cardiology for intensive GDMT and potential coronary angiography for risk stratification and/or revascularization. If patient requires dialysis, obtain a repeat echocardiography once dry weight has been achieved, usually 1-3 months after the initial echocardiogram
Heart failure with preserved ejection fraction	Optimization of patient's volume status and avoiding hypervolemia
Pulmonary Hypertension	Those patients with severe PH with PAP > 35 mmHg should be referred to a PH specialist for preoperative treatment options
	For patients with group 2 or 5, aggressive volume management pre-transplant is recommended with ultrafiltration as tolerated
	In group 5 PH with AVF flow greater than 30% of their cardiac output, treatment could include ligation of their AVF

CHD: Coronary heart disease; GDMT: Guideline-directed medical therapy; PH: Pulmonary hypertension; PAP: Pulmonary artery pressure; AVF: Arteriovenous fistula.

The KDIGO recommends that patients with end-stage kidney disease (ESKD), defined as GFR less than 15 mL/min/1.73 m² requiring dialysis, obtain a repeat echocardiogram once dry weight has been achieved, usually 1-3 months after the initial echocardiogram revealing LVSD[18]. The adverse prognostic implications that heart failure portends on transplant outcomes are responsible for many patients with significant LVSD being considered ineligible for kidney transplant. The ACC/AHA recommends that patients with persistent LVEF less than 40% receive GDMT with possible revascularization and consideration of referral to a heart failure specialist if dysfunction is deemed nonreversible before reconsideration of transplant candidacy[10]. There is some evidence documented in observational studies of a benefit to LVEF after kidney transplantation. Most patients in these observational studies with nonischemic LVSD before transplant achieved sustained improvement to 40%-50% LVEF or normalized LVEF after transplant. The improvement in LVEF after kidney transplantation may be a result of improvement of the azotemia present in ESRD leading to myocyte injury[19,20] as well as several factors implicated in the development of uremic cardiomyopathy due to prolonged exposure to cardiotoxic uremic toxins like indoxyl sulfate, P-cresyl sulfate, B2-microglobulin, and homocysteine[21]. However, it must be stated that even in this setting, persistent LVEF of less than 50% in the post-transplant setting for these patients was associated with an 8-fold increase in the rate of death[22].

HEART FAILURE WITH PRESERVED EJECTION FRACTION

While much of the discussion thus far has been on systolic dysfunction, it must be said that a significant number of patients with ESKD have HF due to diastolic dysfunction, which can be isolated or in combination with systolic dysfunction[23]. Interestingly, diastolic dysfunction is one of the most common findings on echocardiograms in asymptomatic ESKD patients. This may be related to higher plasma phosphate and calcium-phosphate products in these patients. Of note, these metabolic factors are associated with increased left ventricular mass, cardiovascular damage, and therefore signs of diastolic dysfunction[24,25]. We define heart failure with preserved ejection fraction (HFpEF) as clinical signs and symptoms of HF with LVEF greater than 50% and corroborated by the presence of diastolic dysfunction. It is considered an important prognostic marker for kidney transplantation as it is associated with a higher incidence of post-kidney transplant acute coronary syndrome[26,27]. As in HF with LVSD, several studies have demonstrated improvement in diastolic function after kidney transplantation likely due to the ability of the kidney to maintain sodium and fluid balance[28]. In general, diastolic dysfunction and HfpEF have a tight relationship with hypertension and fluid overload. Therefore, it is not surprising that similar to HF with LVSD fluid balance is of particular importance in kidney transplant evaluation.

PULMONARY HYPERTENSION

The presence of chronic volume overload often goes hand in hand with the diagnosis of pulmonary hypertension (PH) in patients with ESKD[26]. This is apparent given the relative prevalence of echocardiographic PH in the ESKD population with anywhere from 13% and up to 50% of selected pretransplant cohorts[29]. Pretransplant echocardiography is capable of reliably estimating pulmonary pressures. These pressures would need to be confirmed by right heart catheterization (RHC). In patients with elevated pulmonary artery systolic pressures greater than 45 mmHg, RHC should be performed when patients are within 12-24 hours post-dialysis and closest to euvolemia[29,30]. As we discuss PH, we will focus on pulmonary venous hypertension since it is considered a consequence of left heart disease (i.e., World Health Organization group 2)[26]. This group of PH is defined as having a mean pulmonary artery pressure greater than 25 mmHg with a pulmonary artery wedge pressure greater than 15 mmHg and pulmonary vascular resistance less than 3 Wood units[29]. Group 2 PH should be managed per ACC/AHA guidelines for any left heart dysfunction present and/or increased ultrafiltration with dialysis for any volume overload present[29]. In ESKD patients with arteriovenous fistulas (AVF), their respective hemodynamics should ideally be measured both with and without AVF occlusion to permit quantifying the AVF contribution to the elevated pulmonary pressure readings[31]. Patients found to have severe pulmonary hypertension by catheterization with pulmonary arterial pressures greater than 35 mmHg should be referred to a pulmonary hypertension specialist for preoperative treatment options[18].

These treatment options are tailored to the cause of their PH and ESKD patients often have comorbidities from more than one PH etiology or group. For patients with Group 2 or Group 5 PH this management involves improved volume management with aggressive ultrafiltration[32]. For those patients with symptoms of Group 5 PH with AVF flow greater than 30% of their cardiac output, treatment could include ligation of their AVF[29]. Treatment can also include supplemental oxygen for their pulmonary pathology (e.g., obstructive sleep apnea) for Group 3 PH. It can include anticoagulation for chronic thromboembolic disease for Group 4 PH or thrombectomy[33]. Finally, the use of calcium channel blockers for those patients with a positive vasodilator response on testing and/or more targeted therapies such as endothelin receptor antagonists or phosphodiesterase type 5 inhibitors for those with intrinsic pulmonary arterial hypertension or Group 1 PH[29].

Patients with PH undergoing kidney transplant evaluation should have a careful volume assessment in the peri transplant period as the presence of right ventricular systolic pressures greater than 50 mmHg is independently associated with worse transplant outcomes[34] as well as all-cause mortality on follow-up[35]. The presence of PH before kidney transplant has also been associated with early graft dysfunction in the post-transplant period in deceased donor recipients[36]. The potential mechanism for this early graft dysfunction seems inexorably associated with hemodynamic changes and the alterations in vasoactive substances (decreased circulating nitric oxide metabolites) present in PH[37]. Nitric oxide helps maintain vascular relaxation and renal medullary oxygenation so when decreased it can potentiate graft ischemia-reperfusion injury post-transplant[38]. This association of PH with worse post-transplant outcomes remains true for patients undergoing simultaneous heart-kidney transplant given studies establishing PH to be an independent risk factor for delayed graft function for the kidney transplant and with comparatively reduced EGFR at 1-year and 3-year follow-up after transplant[39]. As in ESKD patients with HFrEF and HFpEF, kidney transplantation has been shown to provide benefits in ESKD patients with associated PH with significantly decreased pulmonary artery systolic pressures after kidney transplantation[40].

CONCLUSION

The cardiovascular risk assessment for those ESKD patients undergoing kidney transplant evaluation is complex with significant prognostic implications for the waitlist and post kidney transplant and this is particularly true for the subset of ESKD patients with heart failure and those with associated pulmonary hypertension. Careful assessment of these populations and subsequent management to medically optimize their status by identifying and intervening on reversible causes as well as optimizing their hemodynamics before transplant is important in reducing associated post-transplant morbidity and mortality. Particularly given the findings that the definitive treatment of much of these ESKD-associated heart failure and pulmonary hypertension is with a kidney transplant.