Breaking barriers: Neprilysin inhibition in chronic cardiorenal syndrome

Abstract

Over the last decade, neprilysin inhibition has been established as the cornerstone of therapy in heart failure (HF). Patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) have a high prevalence of HF; the concomitant presence of HF and CKD or ESKD, conventionally termed chronic cardiorenal syndrome, is associated with a higher rate of adverse outcomes, including increased hospitalizations and mortality. The use of this novel class of medications in patients with advanced CKD or ESKD has been limited due to uncertainty about their efficacy and safety. Herein, we provide an overview of the available evidence on the use of neprilysin inhibition in HF and discuss how those concepts would apply to patients with concomitant CKD or ESKD.

Key Words: Neprilysin inhibitor; Sacubitril/valsartan; Heart failure; Chronic kidney disease; End-stage kidney disease

Core Tip: Patients with advanced chronic kidney disease and end-stage kidney disease face disproportionally high rates of heart failure and mortality. Currently, there is an unmet need for medical therapies for heart failure in these populations. This review summarizes information regarding the safety and efficacy of the use of angiotensin receptor/neprilysin inhibition in patients with heart failure with reduced ejection fraction and advanced chronic kidney disease or end-stage kidney disease to help guide safe clinical management.

INTRODUCTION

Every seventh adult in the United States has chronic kidney disease (CKD), and its prevalence approaches 34% for those over the age of 65[1]. Advanced CKD is defined as an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m². CKD is rarely an isolated diagnosis and is often caused by or accompanied by other systemic diseases, including heart failure (HF). It is well known that nearly half of all HF patients have CKD[2]. The pathophysiological relationship between CKD and HF, termed chronic cardiorenal syndrome, leads to increased morbidity and mortality in these patients. Both CKD and HF share top causative factors, such as diabetes, hypertension, smoking, and older age, as well as pathophysiological pathways, including the pathological activation of the neurohormonal system and renin-angiotensin-aldosterone system (RAAS). HF contributes to the development and progression of CKD by decreasing renal plasma flow through a reduction of renal perfusion and increased central venous pressure due to venous congestion (i.e. low forward flow and high backward pressure). Advanced CKD contributes to HF due to inadequate fluid excretion, worsening hypertension, accelerating arterial calcification, and chronic inflammation that may accelerate pathological cardiac remodeling[3,4]. When CKD progresses to end-stage kidney disease (ESKD), the pathophysiology of HF is also modulated by non-traditional factors that include uremic toxins, anemia, and bone mineral disease, as well as lack of natriuresis in patients with anuria.

Despite recent developments in medical management of CKD, the incidence of ESKD remains high and is thought to be due to limited access to healthcare and the overall aging of the population. Approximately 130000 people in the United States reach ESKD every year for a total of 550000 currently living with ESKD requiring maintenance dialysis[5]. In 2021, the United States Renal Data System reported that approximately 44% of all patients with ESKD had HF; 45.3% of all patients were receiving hemodialysis, and 33% of all patients were receiving peritoneal dialysis[6,7]. In these people, one-year mortality was shown to be as high as 50%[8,9]. Despite this, very few therapies have unfortunately been approved to treat HF in patients with advanced CKD and ESKD.

NEPRILYSIN INHIBITION: VASODILATION, NATRIURESIS, AND BEYOND

The last decade brought neprilysin inhibition to the forefront of therapy for HF with reduced ejection fraction (HFrEF).

Neprilysin is an endopeptidase found in several tissues, including the heart and kidneys[10,11]. It is embedded in the cellular plasma membrane with its active site facing the extracellular space[12-14]. This allows neprilysin to cleave more than 50 targets, including natriuretic peptides, adrenomedullin, angiotensin I and II, endothelin, substance P, and bradykinin[11,15]. Thus, the inhibition of neprilysin can increase the levels of natriuretic peptides to help manage ventricular preload and afterload through both their vasodilatory and natriuretic effects.

In its wide range of targets also lies its weakness. Neprilysin increases concentrations of vasoconstrictive peptides angiotensin I and II, endothelin, and neurotensin, generating unwanted responses. This problem has been addressed in part through the addition of the angiotensin receptor blocker valsartan and in part through the ability of natriuretic peptides to antagonize RAAS[16]. In fact, the first in-class angiotensin receptor-neprilysin inhibitor (ARNI) is sacubitril/valsartan, which has been used in all landmark clinical trials. Decreased degradation of bradykinin can increase the risk of dry cough and angioedema, which is why neprilysin was not studied in combination with angiotensin-converting enzyme inhibitors that can produce the same side effect. Ongoing studies are investigating mutations that can increase the specificity of neprilysin and lower the spectrum of its targets[17,18].

From the standpoint of pharmacokinetics, sacubitril is primarily excreted in urine (52%-68%) while valsartan’s excretion in urine is only 13%[19]. Thus, concern was raised about the accumulation of sacubitril/valsartan in patients with advanced CKD and even more so in people with ESKD. However, a study by Feng et al[20] in 11 patients with ESKD receiving hemodialysis showed that the concentration of sacubitril/valsartan remains in the safe range in this patient population. Another significant concern is regarding the efficacy of sacubitril/valsartan in patients who are oliguric or anuric since it will not be able to produce a sufficient natriuretic effect. The ability of natriuretic peptides to modulate not only fluid homeostasis but also systemic vascular resistance by reducing vascular tone can have a favorable effect, counteracting the pathological cardiac remodeling[21].

THE UNIQUE CHALLENGES OF HF MANAGEMENT IN ADVANCED CKD

The patients with advanced CKD and ESKD have been historically excluded from clinical trials that investigated fundamental therapies for HF, including sacubitril/valsartan, sodium-glucose cotransporter-2 inhibitors, spironolactone, and finerenone. A more precise estimate of representation of patients with advanced CKD in cardiorenal trials comes from a systematic review of 1194 recent randomized controlled trials (RCTs) involving over 2.2 million participants[22]. It showed that only 23 RCTs (2%) had reported results for patients with an eGFR below 30 mL/minute/1.73 m² and only 15 RCTs (1%) for patients receiving dialysis[22]. All included trials were published between 2000 and 2021, and evaluated the effectiveness of essential cardiovascular medications designed to lower blood pressure, glucose, or cholesterol, as well as anticoagulants and antiplatelet medications. Many of these medications have altered the landscape of cardiovascular disease management for patients with mild or moderate kidney disease. However, it remains unclear if their beneficial effects and safety profile will extend to patients with advanced CKD and ESKD.

LANDMARK TRIALS OF SACUBITRIL/VALSARTAN IN PATIENTS WITH HF

According to current guidelines, the use of sacubitril/valsartan is limited to patients with eGFR above 30 mL/minute/1.73 m²[23]. The landmark Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF (PARADIGM-HF) trial demonstrated that compared to angiotensin converting enzyme inhibitor enalapril, a combination tablet of sacubitril and valsartan reduced cardiovascular and all-cause mortality as well as hospitalizations for HF by 20%, 16% and 21%, respectively. This study included 8442 patients with a mean age of 64 years and an ejection fraction of 40% or lower[24]. A post-hoc analysis of this trial revealed that 26% of its participants had CKD classified as Kidney Disease Improving Global Outcomes high or very high risk category based on eGFR and proteinuria, but only 0.5% with eGFR < 30 mL/minute/1.73 m²[25]. Several studies have looked at the possibility of expanding the use of ARNI in patients with advanced CKD and ESKD. In persons with eGFR 20-45 (mean eGFR of 34), the United Kingdom Heart and Renal Protection-III trial showed that sacubitril/valsartan has no additional effects on kidney function and albuminuria compared with irbesartan[26].

The Prospective Comparison of ARNI with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial investigated ARNI in HF patients with preserved ejection fraction who had a left ventricular ejection fraction of 45% or higher[27]. There was no impact on hospitalizations for HF or death from cardiovascular causes. A total of 1304 participants of PARADIGM-HF and PARAGON-HF had eGFR below 30 mL/minute/1.73 m² at least once during the study. Interestingly, a post-hoc parallel trial analysis of their data could reveal that continuation of ARNI in patients with eGFR less than 30 mL/minute/1.73 m² was indeed associated with persistent clinical benefit[28]. It is important to note that although the number of adverse events increased with declining kidney function, the rate of adverse events was not different between the groups[28].

EMERGING DATA ON THE BENEFITS OF SACUBITRIL/VALSARTAN IN ESKD

While no large-scale RCTs have been carried out to date to examine the safety and efficacy of sacubitril/valsartan in patients with advanced CKD or ESKD and concomitant HFrEF, there have been several observational studies (Table 1).

Table 1 Studies exploring the impact of sacubitril/valsartan in concomitant heart failure with reduced ejection fraction and chronic kidney disease or end-stage kidney disease treated with hemodialysis.

Year	Ref.	Study design	eGFR	Total number of participants	Duration of follow-up	Main findings for ARNI vs RAASi	Comments
2018	Haynes et al[26]	HARP-III trial	20-60 (mean eGFR 34)	414 (207 in ARNI, 207 in control group)	12 months	No significant difference in eGFR at 3, 6, 9, or 12 months or proteinuria	No difference in incidence of serios adverse effects or nonserious adverse reactions
2024	Chatur et al[28]	Post-hoc parallel trial analysis of PARADIGM-HF and PARAGON-HF	eGFR < 30	691 in PARADIGM-HF and 613 in PARAGON-HF		A trend towards decreased HF hospitalizations and CV death (RR = 0.81; 95%CI: 0.58-1.15)	No incremental increase in adverse events
2022	Hsiao et al[29]	Retrospective multi-institutional cohort	eGFR < 30	1105 (206 in ARNI, 833 in RAASi) group	7.3 months	Similar risk of composite of mortality, HF hospitalizations and progression to ESKD	Subgroup analysis of 14% of patients who progressed to ESKD had a trend towards increased HF hospitalizations in ARNI group
2024	Le et al[8]	Retrospective, 1:1 propensity score-matched comparative effectiveness study	ESKD	2868 (1434 in ARNI and 1434 in RAASi group)	10.8 months	ARNI was associated with 18% lower all-cause mortality and 14% lower all-cause hospitalizations, but no difference in CV mortality or HF hospitalizations	No increase in hyperkalemia or hypotension
2024	Lin et al[9]	Retrospective cohort	ESKD	178 (61 in ARNI and 117 in RAASi group)	9 months	ARNI was associated with 54% lower mortality but had a non-significant trend for increased all-cause hospitalizations	High variability in reported LVEF
2021	Feng et al[20]	Prospective cohort	ESKD	11 (before and after ARNI)	18 months	ARNI concentrations remained in safe range
2021	Lihua et al[30]	Prospective single center cohort	ESKD	110 (before and after ARNI)	12 months	LVEF increase from 35.1% to 49.8%, P < 0.001	Improvement in NYHA symptom severity
2022	Niu et al[31]	Case-control study	ESKD	49 (26 in ARNI, 23 in RAASi group)	12 months	LVEF increase from 31.3% to 45.1%, P < 0.0001	No increase in hyperkalemia or hypotension

eGFR: Estimated glomerular filtration rate; ARNI: Angiotensin receptor-neprilysin inhibitor; RAASi: Renin-angiotensin-aldosterone system inhibitor; HARP-III: Heart and Renal Protection-III; PARADIGM-HF: Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; PARAGON-HF: Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in Heart Failure with Preserved Ejection Fraction; CV: Cardiovascular; RR: Relative risk; CI: Confidence interval; ESKD: End-stage-kidney disease; HF: Heart failure; NYHA: New York Heart Association; LVEF: Left ventricular ejection fraction.

Le et al[8] have recently published a large retrospective comparative effectiveness cohort study of 2686 patients within the United States Renal Data System and receiving hemodialysis between 2015 and 2020. They found that the administration of sacubitril/valsartan as compared to RAAS inhibitor therapy was associated with an 18% decrease in all-cause mortality and a 14% decrease in all-cause hospitalizations, with no difference in cardiovascular mortality or HF hospitalizations. These data need to be interpreted with caution given the retrospective nature of the study and its reliance on the International Classification of Diseases codes for the diagnosis of HFrEF. The investigators observed no difference in the risk of hypotension and no increase in hyperkalemia.

A retrospective cohort study of sacubitril/valsartan as compared to valsartan or candesartan in 178 participants, showed that the administration of ARNI for at least 9 months was associated with a reduction in the 5-year all-cause mortality and a non-significant trend towards increased hospitalizations in ARNI group[9]. It is also important to note that the reported left ventricular ejection fraction was very low and variable in both groups at the end of this study (14.5% and 6.9% for those on ARNI and control groups, respectively). A retrospective study by Hsiao in 206 patients with HFrEF receiving ARNI and 833 taking RAAS inhibitors and an eGFR below 30 showed no difference in risk of composite of mortality, HF hospitalizations and progression to ESKD[29]. Subgroup analysis of 14% of patients who progressed to ESKD showed a trend towards increased HF hospitalizations in ARNI. Finally, in a study of 110 hemodialysis patients, Lihua et al[30] showed that ARNI administration for one year was associated with a significant improvement in ejection fraction from 35.1% to 49.8%, and similar results were demonstrated by Niu et al[31].

CONCLUSION

In patients with advanced CKD or ESKD, chronic cardiorenal syndrome is prevalent and associated with high morbidity and mortality. HF is present in nearly half of all patients with ESKD and further worsens the already grave prognosis. Exclusion of patients with eGFR below 30 mL/minute/1.73 m² from nearly all RCTs that have assessed the efficacy and safety of cardiorenal medications, has created a barrier to evidence-based management strategies for patients with advanced CKD or ESKD. There is an unmet need for high-quality data for management of these serious conditions and an opportunity to expand RCTs to this large patient population.