Heart Failure in Kidney Transplant Recipients: Narrative Review of Risk Factors, Therapy, and Current Gaps in Management

Abstract

Among kidney transplant recipients (KTR), cardiovascular disease remains the leading cause of mortality, with heart failure (HF) being especially common in this population. Risk factors for HF in KTR can be categorized as traditional (risks relevant to the general population) versus nontraditional (unique to kidney disease and transplantation). Despite the substantial burden of cardiovascular disease, KTR have been excluded from large clinical trials in cardiovascular medicine and from landmark studies looking at the kidney-protective effects of novel cardiorenal metabolic agents, including sodium–glucose cotransporter 2 inhibitors (SGLT2i). Thus, there is uncertainty about the safety and efficacy of the use of guideline directed medical therapy (GDMT) for HF in this population. Long-term optimal use of GDMT in KTR is limited by various barriers, including the risk of hyperkalemia from concomitant use of renin–angiotensin inhibitors and mineralocorticoid receptor antagonists, fears about genitourinary infections from SGLT2i, and lack of evidence for kidney-protective effects from GDMT agents among KTR. Overcoming these barriers will require a multifaceted approach that involves evidence generation to understand the efficacy and safety of GDMT among KTR, implementation-based strategies to increase uptake of GDMT, and development of multispecialty combined clinical care approaches to care for KTR with HF.

Key Summary Points

Kidney transplant recipients (KTR) have both traditional and nontraditional risk factors for developing heart failure.

To date, large randomized control trials assessing guideline directed medical therapy (GDMT) for heart failure have excluded KTR.

Potential barriers to utilization of GDMT for heart failure in KTR include hyperkalemia with renin–angiotensin–aldosterone blocking agents, and fear of urogenital infections with sodium–glucose cotransporter 2 inhibitors.

Strategic use of pharmacotherapy to manage hyperkalemia can facilitate utilization of GDMT.

Evidence generation, implementation-based strategies, and multispecialty clinical approaches all have the potential to increase uptake of GDMT among KTR.

Introduction

By 2030, it is estimated that the global prevalence of kidney failure will reach 5.4 million [1]. This will lead to an increasing need for dialysis and transplantation services to provide life-sustaining kidney replacement therapy. Given the improved quality of life and survival associated with kidney transplant over dialysis [2], as well as the associated cost savings [3], there has been emphasis on increasing access to kidney transplantation globally in a safe and ethical manner [4].

Despite nominal advances over time, cardiovascular disease (CVD) remains the leading cause of death among kidney transplant recipients (KTR) [5–8]. Although the risk of cardiovascular events is reduced among KTR versus patients with kidney failure treated with dialysis [2], it is still notably higher than in the general population [7]. KTR are at an increased risk of developing ischemic heart disease [9, 10], fatal and nonfatal arrhythmias [11, 12], and heart failure (HF) [10, 13]. Further, there has been a trend towards transplanting older, more comorbid patients with greater CVD risk in the recent eras [14]. Thus, given the growing prevalence of kidney failure and increasing transplantation of higher-risk candidates, there will be a need for new strategies to manage CVD and mitigate corresponding risk in this population.

Among different CVD phenotypes, HF is a major cause of morbidity and hospitalizations [6], and is often the first CVD event experienced post-transplant [15]. Although recent data characterizing contemporary epidemiology of HF among KTR are limited, heart failure with preserved ejection fraction (HFpEF) has been found to be the most common HF phenotype among patients with chronic kidney disease in the nontransplant population [16]. Among KTR, HFpEF is an even more common phenotype as relatively fewer patients with severe left ventricular dysfunction are transplanted (given the significant perioperative cardiovascular risk) [17]. Previous work has estimated the incidence of “de novo” HF (HF identified after transplantation, but not pre-transplantation) to be 18% by 12 months post-transplant [13]. However, this study and other available evidence [18] are outdated and do not account for the temporal changes in the burden and prognosis of CVD over time [8], coupled with changes in the medical complexity of nephrology patients [14, 19, 20]. Thus, there are limited data about the prevalence and incidence of specific HF phenotypes (e.g., HFpEF vs. HF with reduced ejection fraction vs. de novo HF) in the contemporary kidney transplant population. Further, in light of the emerging pharmacologic therapies for HF [21], there is a paucity of knowledge about the optimal management of KTR with HF.

This review evaluates the existing literature and highlights both the understanding and gaps in knowledge surrounding the use of guideline directed medical therapy (GDMT) for HF among KTR. Our specific objectives in this review are to (1) highlight the nontraditional risk factors for CVD and HF among KTR, (2) review barriers to uptake of GDMT in KTR including special considerations in this population, (3) propose strategies to overcome these barriers, and (4) highlight areas for future work in this area.

Methods

Given the nature of this work (narrative review) we did not develop a formal search strategy with specific inclusion or exclusion criteria. In our original search, we reviewed PubMed for studies published from inception to December 2025 and included the following search items: “heart failure,” “kidney transplant,” and “kidney failure.” This review highlights work from previous studies and do not contain any original or unpublished data.

Risk Factors

CV risk factors that contribute to developing HF among patients with kidney disease can be broadly categorized as “traditional” and “nontraditional.” Traditional CV risk factors are those that are also relevant in the broader population of patients. In addition to these traditional risk factors, there are specific phenotypic traits unique to kidney disease and transplantation (“nontraditional”) that are important to consider when risk-stratifying CVD among KTR. The presence of nontraditional risk factors may explain why conventional risk stratification tools such as the Framingham risk score tend to underestimate CV risk in KTR [9].

Traditional Risk Factors

Many traditional CV risk factors are present in the pre-transplant phase and may contribute to the development of kidney failure. For example, kidney disease from diabetes is the result of significant upregulation of pro-inflammatory pathways that result in endothelial dysfunction, vascular injury, and end-organ fibrosis, all of which are also implicated in the development of CVD [22, 23]. Established traditional risk factors for CVD include diabetic nephropathy, history of claudication (a known marker of vascular disease), previous cardiac event, previous cerebrovascular accident, increased age, and body mass index, which are each independently associated with risk for developing a post-transplant CV event [8, 9, 24, 25]. These traditional risk factors may be present in the pre-transplant phase, or may also develop after transplantation.

Nontraditional Risk Factors

In addition to traditional risk factors, there are also important nontraditional CV risk factors that contribute to the development of HF, many of which may be associated with having kidney disease. For example, in the nontransplant population, reduced kidney function and severe albuminuria have been established as independent risk factors for developing CVD across multiple studies [26–32]. The mechanism is generally felt to be related to increased inflammation and oxidative injury resulting in endothelial dysfunction and atherosclerosis [33, 34]. Severe chronic kidney disease and kidney failure are also associated with inadequate clearance of uremic molecules, which in turn has been implicated in the development of non-ischemic cardiomyopathy [35–37]. Both intensified hemodialysis (6 times per week vs. 3 times per week) and KT have been shown to reduce left ventricular (LV) mass/hypertrophy and partially reverse deleterious LV remodelling [25, 38–41]. In addition to the adequacy of dialysis, the type of vascular access used can also influence CVD. Arteriovenous fistulas (AVF) have generally been the preferred type of vascular access for hemodialysis; however, they have been shown to increase cardiopulmonary circulation and result in high-output HF [42]. Even without overt HF, a persistent AVF may lead to cardiac remodelling and LV hypertrophy over time [43], and elective ligation of AVFs post-transplant has been shown to result in significant reductions in LV geometry including end-diastolic and end-systolic volumes [44].

There are also factors specific to the post-transplantation phase that heighten the risk of developing CVD, such as the use of immunosuppressive agents. For example, mammalian target of rapamycin inhibitors (mTORi), calcineurin inhibitors (CNI), and steroids can all worsen dyslipidemia, and both CNI (especially tacrolimus) and steroids are associated with sodium retention, hypertension, and hyperglycemia [45]. CNI and steroids are also both risk factors for developing post-transplant diabetes, which is a specific form of type 2 diabetes that is associated with increased insulin resistance and decreased insulin secretion in the post-transplant phase [45, 46], and is associated with the development of CVD [47]. Steroids also contribute to weight gain and increase the risk of obesity, with associated metabolic consequences [45]. While antimetabolites such as azathioprine and mycophenolate mofetil have not been implicated in the progression of CVD, they are rarely used in isolation and are often prescribed alongside a CNI, mTORi, and/or steroids.

There are also specific markers of allograft injury that contribute to the development of CVD, independent of kidney function. In the immediate post-transplant phase, patients may experience delayed graft function (DGF) which is often defined as needing dialysis within the first week of transplantation. Recent work from a French cohort highlighted that DGF predicts the risk of post-transplant major adverse cardiovascular events (aHR 1.24, 95% CI 1.10–1.40), driven by increased HF events, and that this association is independent of eGFR at 3 months (suggesting that impaired kidney function is not a mediator of the association between DGF and CV events) [15]. DGF is associated with allograft rejection [48], which is an immune-mediated phenomenon resulting in graft injury, and also an independent predictor of post-transplant CVD [49]. Rejection often necessitates the use of high-dose steroids which may further contribute to this risk. Further, rejection can lead to the development of chronic allograft nephropathy, which is a histopathological diagnosis and is characterized by progressive, nonreversible lesions of the allograft [50], and has been associated with CVD likely due to the activation of pro-inflammatory pathways that result in myocardial fibrosis and endothelial dysfunction [51, 52]. Chronic allograft nephropathy is also associated with the development of hypertension and proteinuria which may further compound the risk for developing ischemic cardiomyopathy [53, 54]. In summary, there are various nontraditional CV risk factors to consider in KTR, including reduced kidney function, albuminuria, dialysis adequacy, AVF, DGF, specific immunosuppressive therapy, allograft rejection, and chronic allograft nephropathy. Figure 1 summarizes nontraditional risk factors for developing HF and non-ischemic cardiomyopathy in KTR.

Fig. 1.

Nontraditional cardiovascular risk factors among kidney transplant recipients. CV cardiovascular, mTORi mammalian target of rapamycin inhibitors

Utilization of Guideline Directed Medical Therapy in KTR

Despite the lack of interventional studies for HF therapy specifically targeting KTR, it is generally recommended to treat HF the same as would be indicated in the general population [18, 21]. This involves stratifying patients based on baseline and subsequent left ventricular ejection fraction (LVEF), looking for secondary and reversible causes, and utilizing four drug-combination therapy including (1) either angiotensin receptor–neprilysin inhibitor (ARNI), angiotensin-converting enzyme inhibitor (ACEi), or angiotensin receptor blocker (ARB), (2) one of three beta-blockers: bisoprolol, sustained-release metoprolol (succinate), or carvedilol, (3) mineralocorticoid receptor antagonists (MRA), and (4) sodium–glucose cotransporter 2 inhibitors (SGLT2i) [21]. Although device therapies and heart transplantation are also options for managing HF, the focus of this current review is on pharmacotherapy.

Unfortunately, the uptake of GDMT among KTR with diagnosed HF is low. Previous work characterizing the uptake of GDMT in KTR with systolic dysfunction and kidney failure highlighted that 1 year post-transplant, the proportion of patients on beta-blockers, ACEi, or ARB, and MRA was only 16% [41]. A more recent study of patients with LVEF < 40% who received a kidney transplant between 2015 and 2020 found that beta-blocker utilization decreased from 92% pre-transplant to 76% at 24 months post-transplant, while renin–angiotensin–aldosterone inhibitor utilization decreased from 49% to 27% [55]. Studies examining the use of RASi, SGLT2i, MRA, and beta-blockers in KTRs as discussed throughout the remainder of the paper are summarized in Table 1. Of note, the specific kidney transplant populations being examined in these studies have been variable (e.g., KTR with diabetes, KTR with LV hypertrophy, etc.) as shown in Table 1. Special considerations for GDMT in KTR are demonstrated in Fig. 2 and discussed in more detail below.

Table 1.

Summary of GDMT agents used in KTR

GDMT	References	Examined HF population or outcome?	Population	Study design	Number of participants	Specific adverse events associated with GDMT	Summary of evidence
RASi	Paoletti [62]	No	KTR with LV hypertrophy	RCT	70		Lisinopril associated with greater LV mass index reduction vs. placebo (between-group difference, 10.1 ± 16.3 g/m2; 95% CI 4.2–16.1; P < 0.01)
	Knoll [61]	No	KTR with proteinuria	RCT	213	Nonsignificant increased risk of hyperkalemia with ramipril	No significant reduction in doubling of serum creatinine, kidney failure, or death with ramipril (vs. placebo)
	Hiremath [65]	No	KTR	Systematic review and meta-analysis	1502	Significantly increased risk of hyperkalemia with RASi	RASi did not significantly reduce all-cause mortality, transplant failure, or doubling of creatinine
MRA	Mortensen [72]	No	KTR	RCT	188		Spironolactone did not improve kidney function, proteinuria, or interstitial fibrosis on allograft biopsies
	Dibo [73]	No	KTR	Systematic review and meta-analysis	293	Steroidal MRA increased risk of hyperkalemia by fourfold	Steroidal MRA did not significantly alter kidney function, blood pressure, or histological features on kidney biopsy compared to placebo
SGLT2i	Lim [77]	Yes	KTR with diabetes	Observational	750	No difference in the incidence of UTI between participants being treated with SLT2i vs. not	SGLT2i associated with lower risks of MACE (aHR 0.30, 95% CI 0.10–0.88) and MI (aHR 0.04, 95% CI 0.004–0.4), but not incidence of hospitalizations for HF
	Sridhar [85]	No	KTR	RCT	52	No episodes of genitourinary tract infections reported	Dapagliflozin had various effects on physiological outcomes (blood pressure, mGFR, proximal sodium handling, etc.)
	Maigret [86]	No	KTR	Observational	374	UTI in 6.6% and genital mycosis infection in 0.6% of participants on SGLT2i	SGLT2i associated with reduction in proteinuria in KTR with and without diabetes
Beta-blockers	Aftab [92]	No	KTR	Observational	321		Adjusted 10-year survival of patients on combined beta-blockers + RASi (95%, 95% CI 87–100%) superior to those taking either (72%, 95% CI 63–81%)
GDMT uptake	Hill [55]	Yes	KTR with LVEF < 40%	Observational	750		RASi used in 27%, and beta-blockers used in 76% of KTR 24 months post transplant. No participants on MRA or SGLT2i at 24 months
	Hawwa [41]	Yes	KTR with LV dysfunction	Observational	232		RASi used in 16%, beta-blockers used in 64%, and MRA used in 1% of participants post transplant

aHR adjusted hazard ratio, GDMT guideline directed medical therapy, KTR kidney transplant recipients, LVEF left ventricular ejection fraction, MACE major adverse cardiovascular events, MI myocardial infraction, mGFR measured glomerular filtration rate, MRA mineralocorticoid receptor antagonist, RASi renin–angiotensin system inhibition, SGLT2i sodium–glucose cotransporter 2 inhibitors, UTI urinary tract infection

Fig. 2.

Special considerations for use of guideline directed medical therapy in kidney transplant recipients. CV cardiovascular, GDMT guideline directed medical therapy, KTR kidney transplant recipients, MRA mineralocorticoid receptor antagonist, RASi renin–angiotensin system inhibition, SGLT2i sodium–glucose cotransporter 2 inhibitors

Barriers to Implementing Treatment

There are many reasons for the low uptake of GDMT use among KTR. Importantly, despite being a high-risk patient population, there is a lack of dedicated interventional trials in KTR to assess CV outcomes [18]. Many of the large landmark cardiology trials that have demonstrated benefit of cardiorenal metabolic therapies in the general population have excluded patients with advanced kidney disease and kidney failure, and/or do not provide information on whether KTR were included, making it challenging to extrapolate the benefits from these trials to KTR [56–60]. This evidence gap is important as interventions showing benefit in the non-transplant kidney population do not always translate to KTR. For example, ACEi have established benefit in the general population for reducing the progression of CKD and CVD. However, a large multicenter randomized control trial (RCT) examining the use of ACEi in KTR with proteinuria failed to demonstrate slowing of the progression of CKD or the prevention of kidney failure, though it did show a significant increase in the incidence of acute kidney injury and a non-significant increase in hyperkalemia [61]. Similarly, despite widely touted benefits of statin therapy, they have not consistently been borne out in KTR populations [60], with potential for important drug–drug interactions between statins and CNI. In addition to a lack of proven benefit in KTR populations, these medications may further be limited by clinically relevant adverse effects in KTR, as described below. Thus, the lack of high-quality evidence and risk of relevant side effects from these medications serve as barriers for uptake of GDMT.

Renin–Angiotensin Inhibition

ACEi and ARB are commonly used for hypertension management but there are limited data to suggest their cardioprotective potential among KTR. A randomized clinical trial involving 70 KTR assigned to lisinopril or placebo found a significant improvement in LV mass parameters (between-group difference, 10.1 ± 16.3 g/m²; 95% CI 4.2–16.1; P < 0.01) for those assigned to lisinopril; however, this study did not assess patients with HF specifically [62]. Further, while there is emerging data supporting the efficacy of ARNI among patients undergoing dialysis [63] and those with advanced non-dialysis CKD [64], this drug class has not been studied in the kidney transplant population to date. RASi are also associated with hyperkalemia, and KTR are particularly susceptible to potassium abnormalities on account of two medications commonly used post-transplant that impair renal potassium secretion: CNI, which are a main stay of immunosuppression, and trimethoprim–sulfamethoxazole (TMP-SMX), which is commonly used as prophylaxis for Pneumocystis jirovecii pneumonia. In fact, RCTs examining ACEi in KTR have shown an increased risk of hyperkalemia [61, 65]. The use of RASi in KTR may compound the hyperkalemic effects of these standard medications, and have yet to demonstrate proven cardioprotective effects for KTR with HF. Further, kidney transplants are denervated and thus have impaired sympathetic nervous system regulation [66]. Consequently, KTR may have less plasma renin activity and reduced neurohormonal hyperactivity [67], which may attenuate the impact of renin–angiotensin blockade.

Mineralocorticoid Receptor Antagonists

There is a lack evidence supporting MRA use for cardioprotection among patients with kidney failure. Despite the benefits of MRA for treating HF in the general population [68, 69], the ACHIEVE study randomized 2538 participants with HF being treated with hemodialysis to spironolactone versus placebo and did not find a difference between the two groups for the composite outcome of cardiovascular mortality and hospitalization due to HF [70]. KTR were not included. A recent systematic review of 19 trials found that MRA had no significant effect in reducing cardiovascular mortality among patients being treated with dialysis [71]. In addition to the paucity of evidence regarding the cardioprotective benefits from MRA in KTR, the few studies examining renal protection with MRA in KTR have been negative. The SPIREN trial failed to show improvements in kidney function, proteinuria, and histological parameters among 90 KTR randomized to spironolactone therapy, compared to those on placebo [72]. A recent meta-analysis of five RCTs assessing MRA therapy in KTR highlighted a fourfold increased risk of hyperkalemia without any evidence of kidney protection [73]. Further, there are currently no published studies of non-steroidal MRA agents in KTR (although there are ongoing studies as discussed in later sections). Thus, the absence of evidence for cardioprotection, negative results for renal protection, and notable risk of hyperkalemia likely all serve as barriers for initiating MRA in KTR.

Sodium–Glucose Cotransporter 2 Inhibitors

SGLT2i have become first-line agents for treating both HF and CKD [21, 74]. In a recent-meta analysis of 10 studies involving 70,361 participants, SGLT2i were found to reduce the risk of CKD progression and kidney failure across all categories of eGFR and proteinuria levels [75]. The limitation of this analysis is the absence of studies that include patients with advanced CKD or KTR. The landmark studies that have evaluated kidney and HF outcomes have excluded participants with eGFR < 20 mL/min/1.73 m² [56, 57, 59, 76]. A recent observational study reported a lower risk of major adverse cardiovascular events among KTR being treated with SGLT2i; however, no difference was found for the outcome of HF hospitalization. Of note, this study included all KTR with diabetes (rather than restricting to only those with HF) [77].

In addition to this lack of evidence, there are also heightened fears about SGLT2i-induced glucosuria leading to increased genitourinary infections [78]. KTR are already at increased risk for infections due to their immunosuppressive state. They are especially susceptible to urinary tract infections (UTIs) due to the high prevalence of vesicourethral reflux in the transplanted kidney (related to short transplant ureters and absence of a sphincter between the bladder and ureter) [79]. Studies have shown that there is an increased risk of genital mycotic infections in the setting of SGLT2i use. A meta-analysis of 86 RCTs involving 50,880 patients found that the relative risk of genital mycotic infections in patients receiving versus not receiving SGLT2i was 3.37 (95% CI 2.89–3.93) [80]. Although this risk was largely attributed to female patients being treated with SGLT2i, a recent observational study of 239,757 participants found that male patients with diabetes being treated with SGLT2i were also at increased risk (i.e., more likely to develop genital mycotic infections compared to male patients with diabetes being treated with glucagon-like peptide 1 receptor agonists (hazard ratio [HR], 1.65; 95% CI 1.59–1.71) [81].

However, the signal for an association between SGLT2i use and UTIs has been inconsistent [78, 80, 82–85]. In a large population-based cohort analysis of adult patients with type 2 diabetes, SGLT2i use did not increase the risk of severe UTI (hospitalization for primary UTI, sepsis with UTI, or pyelonephritis) or outpatient UTI treated with antibiotics, compared to those being treated with glucagon-like peptide 1 receptor agonists (GLP1RA) or dipeptidyl peptidase 4 inhibitors [84]. A prospective cohort analysis reported that the incidence of UTI (6.6%) and genital mycotic infections (0.6%) was low among KTR treated with SGLT2i in the first year post transplant [86]. Further, a recent RCT studying the physiological effects of SGLT2i in KTR reported no genitourinary infections over 12 weeks of follow-up [85]. Thus, there is no definitive link between SGLT2i and UTIs. Further, while there is an increased risk of genital mycotic infections, it is not clear if this risk disproportionally impacts KTR (compared to the general population). Overall, SGLT2i should be considered safe to use in KTR from an infection perspective.

An additional consideration for using SGLT2i in KTR is the risk of secondary erythrocytosis. Previous reports in non-transplant cohorts have shown that SGLT2i therapy can raise hemoglobin to abnormal levels and manifest as polycythemia [87, 88]. While certain causes of polycythemia are associated with increased risk of thromboembolism and CV events including HF [89, 90], this association has not been well studied in the cases of SGLT2i-induced erythrocytosis. Further, in reported cases, the erythrocytosis resolved after discontinuation of SGLT2i [87, 88]. Independent of SGLT2i use, KTR may be at an increased risk of post-transplant erythrocytosis due to increased total erythropoietin release from both the native kidneys and new allograft, amongst other mechanisms [91]. This condition is often managed by utilizing ACEi or ARB therapy (which inhibit renin–angiotensin mediated erythropoiesis) and phlebotomy if needed. Thus, extra vigilance is needed to monitor for the development of erythrocytosis in KTR when using SGLT2i.

Beta-Blockers

Retrospective data suggest improved survival of KTR taking both beta-blockers and ACEi/ARB therapy, compared to those not taking either or only taking one [92]. Despite the lack of interventional studies supporting the use of beta-blockers to treat HF in KTRs, they are the most utilized GDMT among KTR with HF [41, 55]. The reasons for this are likely multifactorial. First, beta-blockers are usually generally well tolerated from an allograft perspective as they tend to have less impact on kidney perfusion/function (compared to RASi) and do not pose hypothetical infection risks (such as SGLT2i). Second, among patients undergoing dialysis, beta-blockers have been shown to reduce CV risk and all-cause mortality for patients with HF [93, 94] and have been shown to be superior to ACEi in preventing CV morbidity and all-cause hospitalizations [95], supporting their use among patients undergoing dialysis in the pre-transplant phase. Third, unlike other GDMT agents, beta-blockers do not need to be interrupted perioperatively (and indeed cardiovascular risk is increased with perioperative cessation) [96, 97], and so are less prone to permanent, unintentional discontinuation during the post-transplant phase. Fourth, given the significant interaction between CNI and non-dihydropyridine calcium channel blockers [98], patients being treated with diltiazem and verapamil for arrhythmias may need to be switched to a beta-blocker preoperatively. Thus, beta-blockers have fewer barriers for utilization (compared to other GDMT agents) and are seemingly well tolerated in the KTR population. It is worth noting, however, that there is limited data characterizing which specific beta-blockers are being utilized in KTR. Further work is needed to characterize the uptake of cardioselective beta-blockers recommended for HF management (i.e., bisoprolol, sustained-release metoprolol, and carvedilol) and associated outcomes among KTR.

Potential Solutions and Future Directions

There is a need to develop strategies to enhance the uptake of GDMT for HF in KTR. Previous analyses of GDMT agents in KTR have assessed kidney-specific outcomes, and there is a lack of interventional studies looking at treating HF in KTR. However, given the (1) substantial burden of HF among KTR [6, 9, 10, 13, 15, 16], (2) poor prognosis associated with advanced HF [21], and (3) potential impact of LV dysfunction on being re-listed for repeat kidney transplantation, until which time more definitive studies are available, it has been recommended to treat HF in this population as would be treated in the general population (even in the absence of high-quality evidence) [18, 99]. Further, while evidence generation (via RCTs) will be critical to understanding the role of these agents in KTR, adequately powered studies in transplant populations will likely be insufficient to increase the uptake of these medications alone. Instead, a multifaceted approach is needed that also involves (1) strategies to address adverse effects of GDMT such as hyperkalemia, (2) implementation-based techniques to address the various barriers and facilitators of medication utilization among KTR, and (3) multispecialty collaboration between cardiology and transplant nephrology.

Managing Hyperkalemia

A recent analysis of a heart function clinic registry found that among patients with eGFR < 30 ml/min/1.73 m² who developed hyperkalemia, 45% had their HF medications reduced or discontinued and only 23% were prescribed potassium binders [100]. The utilization of oral potassium binders can minimize the additional risk of hyperkalemia from using RASi and MRA and facilitate more permanent use of GDMT. Patiromer is a non-absorbed calcium ion-based potassium exchanger that has been shown to reduce hyperkalemia among patients with CKD being treated with RASi [101]. Sodium zirconium cyclosilicate is another potassium binder that utilizes hydrogen and sodium ions for potassium binding and is more effective with typically fewer side effects compared to sodium polystyrene sulfonate [102, 103]. The REALIZE-K trial randomized patients with heart failure and reduced ejection fraction (HFrEF) on GDMT at baseline but without MRA (due to hyperkalemia) and found those receiving sodium zirconium cyclosilicate were more likely to remain on optimal dose spironolactone and less likely to have it downtitrated/discontinued [104]. Thus, both patiromer and sodium zirconium cyclosilicate should be considered when utilizing and uptitrating RASi and MRA in KTR [105].

Another strategy to minimize hyperkalemia risk is to utilize non-steroidal MRA. Phase II data of participants with mild to moderate CKD showed that finerenone had lower incidences of hyperkalemia and worsening renal function compared to spironolactone (5.3% vs. 12.7%, respectively, P = 0.048) and was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04–0.30 vs. 0.45 mmol/L, respectively, p < 0.0001–0.0107) [106]. Since this study, emerging data has shown the benefits for renal protection [107] and cardiovascular protection among diabetic patients with CKD—notably driven by HF-related events [108]. The recent FINEARTS trail showed that finerenone was associated with a reduction in recurrent unplanned hospitalization or urgent visits for HF (rate ratio, 0.82; 95% CI 0.71–0.94; P = 0.006) among participants with LVEF > 40% [109]. Thus, use of finerenone (as opposed to steroidal MRA) may facilitate greater utilization of optimal GDMT while reducing the risk of hyperkalemia in this population.

Finally, in addition to oral potassium binders and utilization of non-steroidal MRAs, SGLT2i therapies can be used to increase distal sodium excretion and facilitate renal potassium excretion [110]. A meta-analysis of six trials by Neuen et al. showed a 16% lower risk of developing serum potassium ≥ 6.0 mmol/ L (HR 0.84; 95% CI 0.76–0.93) with SGLT2i among people with type 2 diabetes and elevated cardiovascular risk or with CKD [111]. Similarly, a joint analysis of two RCTs showed that the risk of discontinuing RASi was 15% lower among patients receiving concurrent SGLT2i [112]. Thus, the use of SGLT2i may help facilitate the utilization of other GDMT (notably RASi and MRA) by reducing the risk of developing hyperkalemia. Overall, the risk of hyperkalemia from GDMT in KTR can be mitigated via the strategic use of oral potassium binders, non-steroidal MRAs, and SGLT2i.

Evidence Generation

Although managing hyperkalemia may help facilitate uptake of RASi and MRA, it does not address the issue of missing evidence in this population. Patients with advanced CKD and KTR have historically been excluded from the large RCTs of GDMT and there is a need for both (1) inclusion of KTR in CV-based trials and (2) dedicated trials for assessment of these agents in the KTR population. Currently, there are two notable trials underway to assess the use of these agents in transplant populations. The EFFEKTOR Study is an ongoing phase 2, multicenter study assessing finerenone in KTR targeting recruitment of 150 participants who will undergo 2:1 randomization to finerenone versus placebo [113]. In addition to highlighting safety, tolerability, and feasibility of finereone in KTR, this study will also assess relative changes in albuminuria, eGFR slope, and the relative difference in the need for acute care for congestive HF as exploratory endpoints. Conversely, RENAL-LIFECYCLE is a multicenter, pragmatic placebo-controlled trial assessing the effects of SGLT2i therapy on incidence of kidney failure, HF, and mortality among patients with advanced CKD and kidney failure (including KTR). The study aims to randomize 1500 participants to placebo or dapagliflozin 10 mg to assess the composite of HF hospitalization and all-cause mortality for patients with being treated with hemodialysis or peritoneal dialysis, KTR with eGFR ≤ 45 ml/min/1.73 m², and those with eGFR ≤ 25 ml/min/1.73 m². The composite outcome will also include kidney failure for patients not being treated with dialysis [114].

Clinical trails in the KTR population, however, have additional challenges that require consideration. For example, there is a relatively high rate of surgical complications and death in the first year of transplant [3, 115], and so implementation of GDMT in this period may be limited by high rates of discontinuation and death. Instead, it would be more feasible to implement GDMT only among those who survive beyond the first year (despite the selection bias introduced by this design). Additionally, trialists will need to consider that despite the absence of high-quality evidence, an increasing number of patients may be prescribed these therapies for HF and other indications (e.g., RASi for hypertension, SGLT2i for diabetes). This increased uptake of GDMT, although positive in many ways, may interfere with recruitment into large clinical trails. For example, the increasing use of RASi among KTR was cited as a major limitation in recruiting patients into a large RCT of ramipril versus placebo in KTR [61]. If KTR are already increasingly being prescribed GDMT, clinicians may question the utility of conducting such trials; this highlights the time-sensitive requirement to conduct and complete clinical trials in this space. Thus, there remain many challenges for successful implementation of clinical trials to study GDMT in KTR.

In addition to clinical trials, utilization of registry data and observational studies also has the potential to close gaps in knowledge regarding the management of HF among KTR. For example, retrospective analyses of data from RCTs and administrative databases have identified a subgroup of patients who recover LVEF when treated with appropriate GDMT, also known as HFrecoveryEF [116]. Although these patients have improved prognosis compared to patients with HFpEF and persistent HFrEF [116], discontinuation of GDMT is associated with a significantly higher risk of relapse characterized by a decline in LVEF [117]. Given the numerous potential reasons for discontinuation of GDMT in KTR (hyperkalemia, renal dysfunction, infections, pill burden, etc.), and the challenges of conducting adequately powered trials in this population, leveraging the use of administrative registry data to characterize predictors and prognosis of HFrecoveryEF and assess long-term consequences from discontinuation of GDMT becomes increasingly important, acknowledging the inherent limitations of observational studies.

Implementation

Generating evidence and publishing guidelines does not necessarily translate into increased uptake of guideline-based therapy. As an example, a recent analysis of statin utilization among patients with CKD found that statin use for primary prevention of CVD was not increased after publication of the 2013 KDIGO Guidelines on Lipid Management [118]. Further, a previous study showed less than 75% of KTR with established CVD were prescribed a statin or ASA [119]. Similarly, despite the well-established role of GDMT for HFrEF, less than 20% of eligible patients with HFrEF receive treatment with quadruple GDMT [120]. In other words, publishing guidelines does not always lead to meaningful change. Instead, enhancing uptake of GDMT use in KTR will require implementation-based approaches to understand the barriers and facilitators for medication uptake across the level of the individual, organization, and health system [121, 122].

Among KTR with HF, barriers at the individual level may involve understanding reasons for clinicians not prescribing GDMT. This may be due to concerns about hyperkalemia and graft function with RASi and MRA, genitourinary infections with SGLT2i, general discomfort due to inexperience prescribing these medications, or lack of familiarity with HF guidelines. One method to identify these barriers is the use of focus groups, which can be used to explore both provider perspectives of GDMT [123], and target specific barriers using educational interventions (e.g., highlighting the strategies mentioned above to manage hyperkalemia, or shedding light on data suggesting there is no increased risk of severe UTIs from SGLT2i). In addition to identifying barriers, understanding facilitators of positive behavior change will be important. For example, if KTR who are being managed by cardiologists at a heart function clinic are more often being prescribed GDMT agents than patients followed through their transplant clinic in isolation, then management at a dedicated heart function clinic may be seen as a facilitator.

At the organizational level, it is worth understanding (1) who is managing HF for KTR locally (cardiologist vs. transplant nephrologist), (2) who is authorizing prescriptions for cardiorenal medications, and (3) what is the standard procedure to acquire these medications. For example, in a KTR with type 2 diabetes, HF, and proteinuria, SGLT2i may be prescribed by their nephrologist, cardiologist, endocrinologist, or family physician. However, without clarity regarding which provider will be taking charge of prescribing this medication (and for which indication), it may be deferred among providers and default to the family physician (who may have the least experience and comfort with prescribing SGLT2i in this specialized population). Increasing prescriptions from primary care providers may limit the positive impact from transplant pharmacists in counselling, promoting adherence, and reducing medication errors [124]. In this setting, disorganization of responsibilities in prescribing GDMT may be seen as a barrier, and utilization of specialist pharmacists may be viewed as a facilitator. Incorporating computerized clinical decision support tools into electronic medical records may help provide direction to relevant prescribers and can be used to address these barriers at the organization level [125–127].

At the health system level, medication costs and disparities in access may serve as barriers to utilization of GDMT. In the USA, patients with no insurance or Medicare are less likely to be on quadruple GDMT for HFrEF [120]. A separate study found that target achievement rates of GDMT was lower among patients from the most disadvantaged neighborhoods compared to the least disadvantaged [128]. Thus, disparities in medication coverage are a major barrier to optimal medical usage across different health systems and warrants further policy change to promote equal access.

Multispecialty Clinics

There is emerging interest in the utilization of multispecialty clinics that combine expertise from different specialists in one setting [129]. This approach underscores the importance of appreciating the various comorbidities, risk factors, and role of disease-modifying medications shared between different specialities, and reduces the burden on patients to coordinate care [130]. One such example is having a cardio-renal-endocrine clinic that involves decision-making and expertise from cardiologists, nephrologists, endocrinologists, specialized pharmacists, and also provides a unique learning opportunity for trainees [129]. In the renal setting, having a combined multispecialty clinic has been shown to both reduce healthcare costs [131] and improve uptake of statins, SGLT2i, and GLP1RA [129].

The expertise and structure of these clinics may also target the multiple barriers that exist in utilizing GDMT. For example, these clinics may have a more organized structure regarding which physician/speciality is responsible for prescribing certain agents, and who has the most comfort and experience managing potential adverse effects (e.g., hyperkalemia). Interaction between specialists may also lead to increased knowledge transfer and promote the development of cardiorenal curriculums and cross-disciplinarity training [132]. Further, specialized expertise from pharmacists, pharmacy technicians, and social workers in these clinics who may also have more refined knowledge on how to access non-generic medications (e.g., finerenone) can reduce socioeconomic barriers to accessing GDMT. Although there are limited data on the role of multispecialty clinics for KTR, there are likely substantial benefits that can be derived.

Conclusion

With an increasing need for kidney replacement therapy globally, the number of KTR will continue to grow. This will lead to increasing demands on cardiologists and nephrologists to manage CVD in KTR, which remains the leading cause of mortality in this population. HF is especially common in this population, and there are various nontraditional risk factors for developing HF among KTR. Potential barriers to utilization of GDMT in KTR include lack of high-quality evidence, concerns related to hyperkalemia, and fears about UTIs from using SGLT2i. While there are ongoing trials looking at utilization of certain GDMT agents in this population [113, 114], generating evidence will likely not be enough to increase medication uptake. Further work is needed to target the various barriers and facilitators for optimal behavior change using implementation-based techniques. Further, the role of multispecialty clinics to manage KTR with HF warrants further investigation.

Funding

No funding or sponsorship was received for publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Karthik Tennankore has conducted advisory board work with Otsuka Canada, and received grant support for an investigator-initiated project. Karthik Tennankore has also conducted advisory board work for Virtual Hallway. S. Joseph Kim is a member of the Data Monitoring Committee of a clinical trial sponsored by Eledon Pharmaceuticals to test a novel kidney transplant therapeutic. Sunita K. Singh has received dapagliflozin and matching placebo from AstraZeneca for an investigator-initiated study. Anukul Ghimire, Gaeth Al-Zaneen, Jacob B. Michaud, George Worthen, Christie Rampersad, Ngan N. Lam, and Amanda Vinson have no conflicts of interest to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.