Solid data are available for quadruple therapy in RT candidates with heart failure and reduced ejection fraction (≤ 40%) with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or sacubitril/valsartan, beta-blockers, mineralocorticoid-receptor antagonists (MRAs), and sodium-glucose cotransporter type 2 inhibitors (SGLT2i).12,15–17 Most drug classes are safe and effective in patients with heart failure with reduced ejection fraction and CKD up to stage 3b (estimated glomerular filtration rate [eGFR] minimum 30mL/min/1.73 m2).15 However, data are limited for those with stage 4-5 CKD as most of these patients are excluded from clinical trials.15 In patients with severe CKD (stage 4), there is some evidence of the safety and efficacy15 of SGLT2i, and to a lesser extent of angiotensin-converting enzyme inhibitors, vericiguat, digoxin, and omecamtiv mecarbil, but further clinical research is needed. In dialysis patients with dilated cardiomyopathy, carvedilol has been shown to increase 2-year survival and reduce morbidity and mortality.16 Sacubitril/valsartan has also been shown to improve left ventricular systolic and diastolic function in patients with heart failure with reduced ejection fraction and ESRD.17

Given the significant impact of left ventricular ejection fraction (LVEF) on RT candidacy, the expert panel developed a clinical protocol for up-titration of heart failure medication (figure 3). Adoption of this strategy may lead to better organ distribution due to a lower requirement for combined HT and RT (HRT) and may also increase RT candidacy in patients not eligible for HT if LVEF improvement is achieved.

Figure 3.

Protocol for the management of heart failure in chronic kidney disease at different stages. ACEI, angiotensin-converting enzyme inhibitors; ARAII, angiotensin II receptor antagonists; ARNI, angiotensin receptor-neprilysin inhibitor; BP, blood pressure; GFR, glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; iSGLT2, sodium-glucose transport protein 2 inhibitor; MRA, mineralocorticoid-receptor antagonists.

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In the last 2 decades, there has been a tendency to consider peritoneal dialysis therapy in ESRD patients with ventricular dysfunction and heart failure whenever possible, based on its potential to enhance quality of life for the patient, improve hemodynamic tolerance, and reduce hospital admissions.18 However, there are no randomized studies comparing peritoneal dialysis vs hemodialysis in ESRD patients with heart failure and reduced LVEF. According to the scientific committee, although home dialysis (peritoneal dialysis or home hemodialysis) may be considered as the first-line option,21 conventional hemodialysis may be required for better volumetric depletion or in cases of suboptimal dialysis efficacy with other techniques, as long as sudden changes in blood volume are avoided.

Although the existence of uremic heart disease has not been clearly characterized, there are reports of patients with eccentric left ventricular hypertrophy and significant systolic dysfunction that can be reversible with hemodialysis.18 In this regard, there was consensus among the panelists (82.2%) on the usefulness of intensive hemodialysis for patients with heart failure, reduced LVEF, and advanced CKD (table 2).

After the publication of the KDIGO 2020 guidelines,8 based on the results from the ISCHEMIA-CKD trial,22 in the subgroup of patients with eGFR <30mL/min/1.73 m2 or those on dialysis, an invasive strategy seems to be more favorable than a conservative strategy for severe baseline ischemia.22 There was a consensus (91.1%) among the panelists that revascularization should not be routine but decided on an individualized basis in patients with proven chronic coronary artery disease (table 2).

Several important factors related to blood pressure control in RT recipients were identified (table 4). Currently, no optimal blood pressure targets have been established in the peritransplant or follow-up periods, but chronic hypotension may hinder renal function recovery.33 This clinical issue, in which no pericarditis, pericardial effusion, amyloidosis or other causes of hypotension are detected, is not well understood pathophysiologically. The use of vasoactive drugs to maintain systolic pressure >100mm Hg (and close to 110 or 120mm Hg) may be beneficial in the immediate postoperative period.34 Conversely, high blood pressure may increase surgical RT bleeding and jeopardize long-term patient and graft survival.23 Randomized clinical trials are needed to clarify this concern.

Regarding optimal antihypertensive treatment, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers do not seem to have a prominent role (except in special situations), but there is considerable consensus on the use of calcium antagonists. There was no consensus to recommend any modification of immunosuppression after RT to improve systemic arterial pressure control or reduce cardiovascular events. Nevertheless, in RT recipients with high calcineurin inhibitor levels, dose optimization would be advisable before intensifying antihypertensive therapy (75.6% agreement).

Some studies in RT recipients have reported no change in the risk of cardiovascular events when switching from calcineurin inhibitors to mammalian target of rapamycin inhibitors.35,36 Considering this evidence, there was 90.7% agreement among panelists on the need to balance the potential cardiovascular benefits of modifying immunosuppression against the risks of rejection and the worsening of other cardiovascular risk factors.

There was no consensus to modify the maximum statin dose in RT patients treated with calcineurin inhibitors (cyclosporine and tacrolimus) since the risk of rhabdomyolysis is low. It is important to consider the risk of drug-drug interactions when using statins and to select those that minimally interfere with cytochrome P450 3A4 (CYP3A4).37 While coadministering cyclosporine with specific statins may require a reduction in the statin dose, no adjustment is needed when combined with tacrolimus.38 Several studies have reported a significant decrease in the rate of cardiovascular events and mortality when statins are used in RT recipients.39,40 In HT recipients receiving tacrolimus, high-intensity statins are a safe option for the treatment of refractory hyperlipidemia.41 Thus, there was a 97.6% agreement among the panelists that the choice of statins in both HT and RT should consider patients’ renal function and potential drug-drug interactions.

For patients with RT and atrial fibrillation, there is no evidence on the use of ablation and limited evidence on anticoagulants.42 Although evidence regarding direct-acting oral anticoagulants in RT is limited, the panelists agreed that these treatments are a reasonable alternative to vitamin K antagonists. Cyclosporine has been reported to increase rivaroxaban levels.43 However, a study reported no increase in bleeding events when combining cyclosporine with direct-acting oral anticoagulants in patients with atrial fibrillation.44 All oral anticoagulants have a varying percentage of renal elimination, so they may accumulate and increase the risk of bleeding if taken concomitantly with drugs that decrease their clearance. Therefore, their coadministration with immunosuppressants such as calcineurin inhibitors or mammalian target of rapamycin inhibitors (sirolimus and everolimus) requires careful monitoring.45 Specific dose adjustments of direct-acting oral anticoagulants are not required, although more frequent renal function monitoring should be performed (1-3 months after initiation and every 6-12 months thereafter, or more frequently based on patient-specific characteristics). Drugs that induce lower renal clearance should be avoided (eg, nonsteroidal anti-inflammatory drugs, high doses of diuretics, or immunosuppressants) if there is a degree of renal failure (GFR <50mL/min/1.73 m2).42,46Table 5 shows the possible combinations and interactions between direct-acting oral anticoagulants and anticalcineurinics.

There is a lack of evidence to rule out coronary artery disease in asymptomatic RT recipients.25 Risk factors associated with the occurrence of post-RT myocardial infarction are age, history of angina, peripheral vascular disease, dyslipidemia, pretransplant infarction, posttransplant hemoglobin decline, positive pretransplant noninvasive tests for ischemia, and arrhythmia.27,28 Persistently elevated troponin T levels, without normalization after restoration of renal function, were associated with an elevated risk of death and cardiovascular events at 5 years.51 However, there is no evidence to support the use of markers such as troponin T in the follow-up of RT patients.

There is no specific evidence regarding the treatment of coronary artery disease in RT recipients. The KDIGO guidelines suggest that management should be at least as intensive as in the general population52 and this was supported by the expert panel. Moreover, guidelines focus mainly on medical management and the use of statins and aspirin in cardiovascular disease.52 Primary prevention in diabetes with aspirin is suggested based on individual risk assessment and preferences. Additional well-designed studies are required to clarify this issue.

Natriuretic peptides (brain natriuretic peptide [BNP], NT-proBNP) are important for screening de novo heart failure in RT recipients. Increases in plasma BNP after RT are associated with allograft dysfunction, while both pre- and posttransplant NT-proBNP levels have been linked to diastolic dysfunction and major cardiac adverse events.53,54 However, the predictive role of NT-proBNP in cardiac outcomes is uncertain due to multiple confounding factors (eg, degree of renal function).

There are few studies on the treatment of heart failure in RT recipients. In a small randomized clinical trial of RT recipients with left ventricular hypertrophy, lisinopril reduced left ventricular mass index compared with placebo.55 Randomized clinical studies are urgently needed to establish effective heart failure treatment following RT.

Despite this, all panelists agreed that the treatment of de novo heart failure in RT recipients should be the same as in the general population.56,57 However, the treatment may induce hyperkalemia in RT recipients, especially in those with renal tubular acidosis due to anticalcineurin drugs and with suboptimal graft function. In the absence of clear recommendations, therapies such as patiromer and sodium zirconium cyclosilicate require evaluation in RT recipients due to interference with drug absorption.12 Short reports have indicated that while zirconium cyclosilicate does not modify tacrolimus levels,58 patiromer may require an increase in tacrolimus dosage.59

According to the expert panel, patients requiring short-term mechanical circulatory support due to cardiac instability should receive sequential HRT to mitigate the risk of graft loss. The panel acknowledged the high risk of mortality in HT patients with ESRD who are on long-term dialysis and the need to implement early RT strategies. The Canadian transplant registry indicates that HT recipients with ESRD have longer survival rates when they receive an RT compared with those who remain on the waiting list.66 In addition, UNOS registry data show that patients who received nonrenal transplants and later developed ESRD also have longer survival when they received an RT compared with those who remained on the waiting list. The risk of death or removal from the kidney transplant waiting list was also higher among candidates for RT after HT compared with those who received a RT alone.67 Importantly, it is difficult to predict the length of recovery from acute kidney injury in HT recipients and it may take several months.

However, prioritizing RT in HT recipients on dialysis may reduce opportunities for other patients on the waiting list. Currently, no studies have compared mortality in HT and non-HT recipients on dialysis.

HT recipients receive higher doses of calcineurin inhibitors in the first months after transplant, which can adversely affect renal function. Most panelists (95.2%) agreed that early RT, preferably with a living donor, should be considered in HT recipients with severe renal impairment, even with appropriate use of calcineurin inhibitors and metabolic optimization. However, waiting times for RT and access to living transplant programs vary by center. Thus, in cases of CKD with GFR <20mL/min/1.73 m2, which confer greater mortality risk in HT recipients, it is reasonable to consider early RT if feasible. An American consensus on HRT established a safety net for RT, prioritizing patients on dialysis after HT and those with persistent GFR ≤ 20mL/min/1.73 m2 for 6 weeks from day 30 to 365 after HT.14 Navarro-Manchón et al. reported that survival in patients with a GFR <30mL/min/1.73 m2 1 year after HT was significantly lower than in those with higher GFR.68 Notably, patients who received an RT had longer survival than those who remained on the waiting list,67 as has been demonstrated in patients with advanced CKD following HT.69

The immunologic risk in combined transplant should be based on HT criteria. A virtual crossmatch is required in sensitized patients but should not be performed in the absence of human leukocyte antigen (HLA) antibodies. According to the expert panel, all candidates for HRT should have their HLA antibodies tested periodically.