Preoperative Noncoronary Cardiovascular Assessment and Management of Kidney Transplant Candidates

Abstract

The pretransplant risk assessment for patients with ESKD who are undergoing evaluation for kidney transplant is complex and multifaceted. When considering cardiovascular disease in particular, many factors should be considered. Given the increasing incidence of kidney transplantation and the growing body of evidence addressing ESKD-specific cardiovascular risk profiles, there is an important need for a consolidated, evidence-based model that considers the unique cardiovascular challenges that these patients face. Cardiovascular physiology is altered in these patients by abrupt shifts in volume status, altered calcium-phosphate metabolism, high-output states (in the setting of arteriovenous fistulization), and adverse geometric and electrical remodeling, to name a few. Here, we present a contemporary review by addressing cardiomyopathy/heart failure, pulmonary hypertension, valvular dysfunction, and arrhythmia/sudden cardiac death within the ESKD population.

Kidney Transplantation

ESKD is a state of advanced CKD or kidney failure, objectively quantified as GFR<15 ml/min per 1.73 m². Nearly all patients require a kidney replacement strategy, which can include hemodialysis (HD), peritoneal dialysis (PD), and/or kidney transplantation. Given the numerous functions performed by the kidneys, disruption of normal kidney physiology has marked downstream effects, particularly in the cardiovascular system. ESKD is associated with dysregulations in lipid and glucose metabolism, electrolyte management (particularly calcium, phosphate, and urea), and the renin-angiotensin-aldosterone system, as well as more commonly recognized phenomena such as hypertension and vascular remodeling. The risk of hospitalization for coronary artery disease, heart failure, stroke, and peripheral artery disease is approximately three times greater in the ESKD population compared with patients with preserved GFR, and the incidence of all-cause mortality is six times greater in the ESKD population (¹). Kidney transplantation helps to mitigate cardiovascular risk compared with those who remain on long-term dialysis; however, the risk of cardiovascular events remains elevated above that of the general population (²). The American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) have previously published a scientific statement for the cardiovascular risk assessment of kidney and liver transplant candidates. In this report, four major conditions are identified that carry major clinical risk: marked coronary artery disease, heart failure and cardiomyopathy, severe valvular disease, and clinically significant arrhythmias (³). We have previously published a review article on the coronary evaluation of this patient population, so we have elected to omit that particular topic from this article (⁴). Below, we present a contemporary review of noncoronary cardiovascular assessment in the ESKD population.

Heart Failure and Cardiomyopathy

Congestive heart failure is common in patients with ESKD and the two disease entities share many risk factors (⁵). Patients with ESKD can have heart failure due to systolic dysfunction, diastolic dysfunction, or both. According to one series, 36% of patients with ESKD carry a diagnosis of heart failure at the time dialysis is initiated, and an additional 7% develop de novo heart failure during maintenance dialysis (⁶). The prevalence of heart failure reaches over 50% for patients with ESKD on a transplant waiting list for 3 years (⁷). The risk factors for developing heart failure in patients with ESKD include left ventricular systolic dysfunction, diabetes mellitus, older age, and coronary artery disease (⁸).

Patients with ESKD and heart failure have a shorter life expectancy than patients with ESKD without heart failure (36 months versus 62 months). In one single-center, retrospective review of over 3000 patients with ESKD evaluated for kidney transplant with 4 years of follow-up, mortality was found to be most strongly associated with systolic dysfunction (2.7% mortality per each 1% drop in ejection fraction) (⁹). The most recent ACCF/AHA statement describes a Class IIA recommendation for routine preoperative resting echocardiogram in transplant candidates (Level of Evidence B) (³).

Kidney transplantation in patients with systolic heart failure is associated with an increase in left ventricular ejection fraction, functional status improvement, and improved survival (¹⁰). These beneficial effects on heart failure diminish the longer a patient with ESKD receives dialysis before transplantation, likely because of irreversible remodeling changes. For these reasons, it is critical to identify patients with ESKD who are at risk for heart failure as early as possible (¹⁰). The Kidney Disease Outcomes Quality Initiative guidelines recommend echocardiography at the initiation of HD, once dry weight is achieved (usually 1–3 months later) and every 3 years thereafter (¹¹).

Several baseline echocardiographic characteristics have been found to have prognostic significance in patients with ESKD: abnormal left ventricular geometry, wall motion abnormalities (¹²), systolic dysfunction (¹³), diastolic dysfunction (¹⁴), left atrial enlargement (¹³), mitral annular calcification, and aortic valve calcification (¹⁵,¹⁶). These abnormalities can be broadly categorized into markers of either adverse left ventricular remodeling or coronary artery disease. In fact, the combined assessment of left ventricular dysfunction and coronary atherosclerosis has been shown to provide powerful prognostic information in ESKD (¹⁷).

There is no clear “cut-off” for kidney transplant eligibility in the setting of advanced heart failure. This decision should be made on a case-by-case basis, on the basis of the presence and extent of shock parameters and associated multiorgan dysfunction, ability to stabilize patient with medical and/or mechanical support before graft availability, likelihood of surviving planned surgical anesthesia, and likelihood of long-term cardiac survival and/or long-term advanced cardiac treatment eligibility. In addition, it must be noted that there is a growing body of evidence for combined heart-kidney transplant, with continued efforts to identify appropriate candidates for this approach (¹⁸,¹⁹).

Pericardial Disease

Pericardial disease is common in the setting of ESKD, and given the advent of, and improvements in dialysis, short-term mortality from uremic pericarditis and tamponade has markedly declined (²⁰). However, this results in patients with ESKD experiencing long-term exposure to recurring nonfatal dialysis-associated pericarditis with inflammatory, exudative, and often serosanguinous effusions (occurring any time after 8 weeks of dialysis initiation). This is the likely pathophysiologic basis of the observed slow progression to subacute fibrosis, pericardial adhesions/loculations, and ultimately, chronic constrictive pericarditis in present-day kidney transplant candidates (²¹). “Intensive” dialysis, usually performed 5–7 days per week until clinical improvement, is traditionally used as initial therapy for moderate uremic pericarditis, although care must be taken to monitor for hemodynamic instability with early aggressive fluid shifts. In contrast, surgical drainage via pericardiotomy or pericardiectomy has proven effective and well tolerated for dialysis-associated pericarditis, or for uremic pericarditis refractory to intensive dialysis (²²). The incidence of pericardial disease appears reduced post-transplant, and suspicion for an infectious cause must remain high in the post-transplant setting in light of required transplant immunosuppression.

Pulmonary Hypertension

Pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg with a pulmonary artery wedge pressure ≤15 mm Hg and a pulmonary vascular resistance >3 Wood units) is common in patients with ESKD. Pulmonary hypertension associated with ESKD is often seen in the setting of more global illnesses, including autoimmune diseases, thromboembolic disease, chronic left-sided heart failure, and chronic lung disease (²³). Dialysis itself can contribute directly to pulmonary hypertension, particularly in patients with a surgically created arteriovenous conduit; the degree of pulmonary hypertension correlates with the size of the shunt, patient age, and the duration of dialysis dependence (^24–26). Many studies of pulmonary hypertension in ESKD rely on echocardiographic parameters to calculate systolic pulmonary artery pressure, and give us estimates of pulmonary hypertension incidence of 17%–56% in this population when defining pulmonary hypertension as systolic pulmonary artery pressure of >30 mm Hg (²⁴). Preoperative echocardiography should be performed in kidney transplant candidates to estimate pulmonary pressures, followed by confirmation by right heart catheterization in patients with evidence of elevated right-sided pressures (³). Measurements are recommended to be made on interdialytic days, when patients are closest to euvolemia (¹¹). Rates of pulmonary hypertension among patients on HD or PD (pretransplant) and no dialysis (post-transplant) are estimated at 18%–47% (HD), 6%–23% (PD), and 5%–18% (post-transplant), respectively (²⁷,²⁸). Choice of dialysis is likely a covariate rather than strong cause of pulmonary hypertension. Pulmonary hypertension (especially when pulmonary artery systolic pressure is >35 mm Hg) is associated with lower survival in ESKD, including lower patient and graft survival among those who undergo successful kidney transplantation (²⁵,²⁹). It is likely mediated by the high-output state of ESKD and exacerbated by a background of anemia and arteriovenous fistulization, which contributes to pulmonary artery calcification, endothelial dysfunction, and impaired nitric oxide production. Although treatment strategies for significant pulmonary hypertension in patients with ESKD could include shunt reduction surgery or transition to nonshunt dialysis, such as PD or catheter-based HD, the National Kidney Foundation’s “Fistula First” strategy remains the general rule for preferred access, with individual access decisions to be made in concert with each patient’s nephrologist (³⁰). Kidney transplantation is considered the definitive treatment for ESKD-associated pulmonary hypertension (³¹). The evaluation of pulmonary hypertension in this population is illustrated in Figure 1.

Figure 1.: Evaluation of pulmonary hypertension in kidney transplantation candidates. Modified from references ⁵⁴ and ⁵⁵, with permission.

Valvular Heart Disease

Degenerative valvular calcification, specifically aortic stenosis, is more prevalent and progresses faster in patients with ESKD than in individuals with preserved kidney function (³²,³³). This is likely related to aberrant calcium and phosphate metabolism. Mitral annular calcification can be found in up to 50% of patients with ESKD and can lead to varying degrees of leaflet restriction, systemic embolization, infective endocarditis, conduction abnormalities, and/or ventricular dysfunction (³⁴). The incidence of aortic valve calcification in ESKD nearly doubles that in the general population, and it usually tracks with duration of dialysis (¹⁵). Outcomes with severe aortic stenosis in patients on dialysis are worse than those in the general population (³⁵).

Although severe valvular disease can be a contraindication to kidney transplantation, successful valve surgery can facilitate transplantation. In a retrospective analysis of 35,000 patients in the US Renal Data System, patients with valvular disease were significantly less likely to undergo kidney transplantation, whereas those who had successful valve surgery were transplanted at a rate similar to patients without valve disease (³³). Furthermore, kidney transplantation was associated with a halting of valvular disease progression, particularly aortic stenosis (³³).

Mortality after cardiac surgery is high in the kidney failure population. An earlier analysis of the Society of Thoracic Surgeons National Cardiac Surgery Database suggests that ESKD is associated with a four-fold higher operative mortality after aortic valve replacement when compared with patients without ESKD (operative mortality 17.1% versus 4.0%, respectively) (³⁶). More contemporary analyses of this robust database report an odds ratio of 2.8 for mortality after aortic valve replacement in patients on dialysis relative to those not on dialysis (95% confidence interval, 2.3 to 3.4) (³⁷).

Nevertheless, it is important to remember that morbidity and mortality from advanced untreated valvular disease can be quite high as well, and that progression of valvular disease may be accelerated in ESKD (³²). The ACCF/AHA scientific statement remarks on the role of annual echocardiograms in patients with moderate aortic stenosis, given the high risk for progression of disease (Class IIB, Level of Evidence C) (³). We know that symptomatic severe aortic stenosis carries 50% 5-year mortality in all-comers (³⁸). Therefore, when valve surgery would traditionally be indicated in patients with ESKD, careful risk–benefit analysis must also take into account expected event rates if left untreated, which parallel (or may exceed) those observed in the general population.

Mechanical and tissue valves have yielded similar outcomes in patients with ESKD (¹¹,³⁹). Competing risks include accelerated degeneration from exposure to cardiovascular comorbidities and high shear stress with tissue valves versus increased bleeding and cardioembolic complications with mechanical valves.

Transcatheter aortic valve replacement is becoming an increasingly viable option among patients with favorable anatomy who are deemed unsuitable for aortic valve surgery and who might otherwise be denied kidney transplantation on the basis of severe aortic stenosis. Not surprisingly, patients felt to have prohibitive surgical risks have elevated long-term mortality; however, improvements in aortic valve parameters with transcatheter aortic valve replacement have been durable among long-term survivors over a 4-year follow-up period (⁴⁰).

Arrhythmia and Sudden Cardiac Death

Sudden cardiac death is the leading cause of death in patients with ESKD, accounting for approximately 25% of all deaths and 60% of cardiac deaths (⁴¹). The risk of sudden cardiac death is successively greater with increasing kidney dysfunction; current risk stratification algorithms markedly underestimate the rate of sudden cardiac death in this population (⁴²).

Mechanisms of sudden cardiac death in ESKD are being actively investigated. Adverse left ventricular and coronary artery remodeling via apoptosis, fibrosis, and calcium-phosphate deposition have all been implicated. Such structural changes are known to alter electrical conduction pathways and influence plaque stability, thereby promoting re-entrant and/or ischemic arrhythmias (⁴³). Mechanical disruptions in normal myocardial depolarization, moreover, lead to delayed ventricular activation and prolonged action potentials. In fact, prolonged corrected QT interval is independently associated with all-cause mortality in ESKD, and this interval may correct significantly after transplantation (⁴⁴). Finally, the risk of sudden cardiac death in patients with ESKD may, in part, be related to metabolic fluctuations associated with dialysis timetables, as incidence of sudden cardiac death rises during longer intervals between dialysis sessions (⁴⁵). There is a significant decline in sudden cardiac death rates after kidney transplantation (⁴¹).

The utility of implantable cardioverter defibrillators (ICDs) in patients with ESKD is not well known because these patients have historically been excluded from the pivotal trials demonstrating their benefit postcardiac arrest and in systolic heart failure. In a study of Medicare patients with ESKD and cardiac arrest, those who had ICD placed for secondary prevention certainly had a lower risk for death over those who did not; however, rates of recurrent ventricular arrhythmia and overall mortality remain elevated in ESKD even after ICD implantation, raising concern that competing risks with progressive kidney dysfunction may blunt the benefit gained with ICD implantation in the general population (^46–48).

Atrial fibrillation is another common arrhythmia in the ESKD population. Kidney dysfunction is independently associated with atrial fibrillation in CKD even after adjustment for potential covariates (⁴⁹). In one large, retrospective study of >250,000 Medicare patients initiating dialysis, 30% carried a diagnosis of atrial fibrillation at the time of initiating kidney replacement therapy, and another 30% went on to develop atrial fibrillation before death or kidney transplantation (⁵⁰). Another retrospective Medicare study found that only 6% of transplant candidates held a pretransplant diagnosis of atrial fibrillation. The presence of atrial fibrillation portended a 46% higher risk of post-transplant death at 4.9 years follow-up (⁵¹).

A decreased GFR is associated with higher mortality and ischemic stroke rates even after adjustment for CHADS2 score ≥2 (scoring system includes congestive heart failure, hypertension, age ≥75 years old, diabetes history and history of prior stroke or transient ischemic attack) (⁵²). This may be associated with abnormal natural anticoagulant homeostasis (for example, loss of proteins C and S) and may suggest heightened need for therapeutic anticoagulation in patients with atrial fibrillation and kidney dysfunction; however, care must be taken because kidney dysfunction also carries increased risk of bleeding (through platelet dysfunction such as uremic thrombocytopathy) and complicates dosing with certain agents. The decision for anticoagulation and choice of agent and dose must be tailored after a careful discussion of risks, benefits, and alternatives with each patient. The large initial trials that studied novel anticoagulants versus warfarin typically excluded with patients with ESKD. However, apixaban is currently approved by the US Food and Drug Administration for prevention of ischemic stroke in patients with nonvalvular atrial fibrillation on dialysis (⁵³).

Recommendations

We propose a model for the preoperative cardiovascular assessment of kidney transplant candidates (Figure 1, Table 1). These recommendations should be considered in the context of a patient’s overall health and functional status, which can affect the intensity of diagnostic and therapeutic efforts before transplant. All patients should undergo preoperative echocardiography (Table 1). This will help identify the presence and severity of left ventricular hypertrophy, dilatation, and dysfunction, which are all associated with cardiovascular mortality. Patients with left ventricular systolic dysfunction should be started on medical therapy, including β-blockers; however, regardless of systolic function, volume status should be optimized with appropriate ultrafiltration. Currently, there is insufficient evidence to strongly recommend the routine use of implantable cardiac defibrillators in patients with ESKD and a low ejection fraction; these patients were excluded from the primary ICD trials, but ICD placement should not necessarily be withheld in this population and warrants careful case-by-case consideration of the risks and benefits. Accordingly, these decisions should be individualized. Patients with severe aortic stenosis should be referred to a center with expertise in high-risk cardiac surgery and transcatheter aortic valve replacement. Significant pulmonary hypertension (pulmonary artery systolic pressure >40 mm Hg) identified by echocardiography, especially in the presence of changes to right ventricular size and function, should be further evaluated for common etiologies, and if persistent despite standard management, should be confirmed by right heart catheterization during a postdialytic period, while at dry weight. Patients with severe pulmonary hypertension by catheterization (mean >35 mm Hg) should be referred to a pulmonary hypertension specialist for preoperative treatment options. At the current time, professional society guidelines do not define absolute cardiovascular contraindications to kidney transplantation; these decisions are made on a case-by-case basis. Common relative contraindications—that differ by institution—include recent myocardial infarction in the preceding months, severe coronary artery disease, severe aortic stenosis, severe pulmonary hypertension, and poor functional status. In many cases, cardiologists work alongside transplant nephrologists in the pretransplantation evaluation. If this is not the case, then any abnormalities noted on routine screening echocardiogram, concerns on the basis of surface electrocardiogram or concerns about cardiorespiratory functional status should prompt referral to cardiology.

Table 1. - Perioperative noncoronary cardiovascular assessment and management

Cardiovascular Pathophysiology	Diagnostic Test of Choice	Recommendations
Cardiomyopathy/heart failure	Echocardiography
Volume overload
Arteriovenous fistulization		Echocardiography at HD initiation, once dry weight is achieved (usually 1–3 mo later) and every 1–3 yr thereafter
High cardiac output
Angiotensin-mediated LVH
Pulmonary hypertension
Arteriovenous fistulization	Echocardiography	Echocardiography to assess pulmonary pressures
Medial artery calcification endothelial dysfunction	Right heart catheterization	Consider right heart catheterization if there is evidence of elevated right-sided pressures on echocardiography
Impaired NO production		Consider referral for treatment for advanced pulmonary hypertension as indicated
Valvular disease
High calcium/phosphate	Echocardiography	Annual echocardiography for moderate aortic stenosis
Inflammatory mediators		Consider referral for surgery or TAVR for severe aortic stenosis
Arrhythmia	Limited testing for prediction of sudden cardiac death	Baseline electrocardiography at time of initial evaluation
Micro or macro scar		Insufficient evidence for continued screening or ambulatory rhythm monitor
Sudden cardiac death risk

LVH, left ventricular hypertrophy; HD, hemodialysis; NO, nitric oxide; TAVR, transcatheter aortic valve replacement.

Conclusions

The pretransplant cardiovascular risk evaluation of patients with ESKD who are undergoing workup for kidney transplant is complex. There are a number of factors at play that directly relate to the altered physiology common in this patient population. Patients with ESKD are subject to risk of cardiomyopathy/heart failure, valvular disease, pulmonary hypertension, and arrhythmia. Here, we include evidence-based recommendations for the risk stratification and management of these major noncoronary cardiovascular sequelae. As with any patient, medical decision making should be personalized to the individual patient, but the included analysis provides a thorough, evidence-based framework for those discussions.

Disclosures

Dr. Ali reports grants from Abbott Vascular and Cardiovascular Systems Inc.; personal fees from Acist Medical, AstraZeneca, Boston Scientific, Cardinal Health, and Opsens Medical; and personal and other fees such as stock from Shockwave Medical, outside the submitted work. Dr. Cuttica reports grants for clinical trials, personal fees from speaker bureaus and advisory board consulting, and nonfinancial support from Actelion and United Therapeutics; grants for clinical trials, personal fees from speaker bureaus and advisory board consulting, and nonfinancial support from Bayer and Gilead; and a clinical trial grant from Reata Pharmaceuticals, outside of the submitted work. Dr. Friedewald reports grants and personal fees from AbbVie; personal fees from American Society of Nephrology; personal fees from Novartis; personal fees from Sanofi; grants from Shire; grants, personal fees, and other fees including equity interest from Transplant Genomics, Inc.; grants from Vaiteris; and personal fees from Viela Bio, outside the submitted work. Dr. Abecassis, Dr. Baman, Dr. Flaherty, Dr. Harinstein, Dr. Knapper, Dr. Maganti, and Dr. Raval have nothing to disclose.