How to Enhance Cardiorenal Benefits in Patients With Chronic Heart Failure?

Abstract

Chronic heart failure (CHF) is frequently complicated by chronic kidney disease (CKD), a comorbidity that profoundly influences disease progression, therapeutic decision-making, and clinical outcomes. The management of CHF in patients with advanced CKD presents substantial challenges, often requiring dose adjustments or even discontinuation of standard therapies. Effective therapeutic strategies must prioritize cardiorenal protection during the early stages of disease progression. Recent advancements in pharmacotherapy, including angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have demonstrated remarkable dual cardiorenal protective effects. These therapies not only reduce the risk of de novo heart failure in high-risk populations and improve clinical outcomes in CHF patients, but also slow the progression of renal dysfunction by targeting critical pathophysiological processes, such as glomerular hyperfiltration, inflammation, ischemia, and endothelial dysfunction. Although transient declines in estimated glomerular filtration rate may occur upon initiating these agents, renal function typically stabilizes over time, facilitating sustained clinical benefits, particularly in patients with diabetes mellitus, albuminuric CKD, and CHF. This review focuses on the latest advancements in heart failure pharmacotherapy, emphasizing the cardiorenal protective mechanisms and clinical efficacy of novel therapeutic agents. It underscores the importance of bridging knowledge gaps and personalizing therapy to enhance cardiorenal benefits avoiding adverse effects.

Keywords: Cardio-renal syndrome; Cardiology; Cardiovascular diseases; Heart failure; Randomized controlled trial.

Figure 1. Structure and function of the nephron. (A) The nephron consists of the glomerulus and renal tubule, serving as the kidney’s primary filtration unit. The glomerulus filters primary urine, while the renal tubules reabsorb essential substances to maintain homeostasis. Blood enters through afferent arterioles, with filtered plasma forming primary urine, and exits via efferent arterioles, which also supply oxygen and nutrients to the tubules. (B) The nephron regulates filtration through autoregulation of the afferent and efferent arterioles via TGF mechanism, adapting to hemodynamic changes and compensating for nephron loss. Dysregulated filtration leads to glomerular hypertension, albuminuria, tubular overload, and ultimately end-stage renal disease.

TGF = tubule-glomerular feedback; NO = nitric oxide; Ang II = angiotensin II; eGFR = estimated glomerular filtration rate; UACR = urinary albumin to creatinine ratio.

Figure 2. Included randomized controlled trials for evaluating cardiorenal protection evidence on the Kidney Disease: Improving Global Outcomes heat map.

eGFR = estimated glomerular filtration rate; UACR = urinary albumin to creatinine ratio; GLP-1-RA = glucagon-like peptide-1 receptor agonist; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; DM = diabetes mellitus; CKD = chronic kidney disease; SGLT2i = sodium-glucose cotransporter 2 inhibitor; ARNI = angiotensin receptor-neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist; CHF = chronic heart failure.

Figure 3. Renal surrogate markers. (A) The eGFR slope in type 2 diabetes mellitus, chronic kidney disease, and chronic heart failure; (B) the eGFR slope, UACR, and novel heart failure therapies. (A) The eGFR slope, indicating the rate of eGFR decline, serves as a reliable surrogate endpoint for kidney disease progression and an efficacy indicator of heart failure therapies. In healthy aging, eGFR declines by ~1 mL/min/1.73 m² annually, while steeper declines of 3–4 mL/min/1.73 m² occur in T2DM and CKD due to glomerular hyperfiltration. CHF patients exhibit an intermediate decline of 2–3 mL/min/1.73 m² annually. (B) Trials of SGLT2i, non-steroidal MRAs, and GLP-1-RAs have shown a less pronounced eGFR decline and significant reductions in UACR, with a transient eGFR decline ("initial dip"). In contrast, ARNI preserves eGFR without inducing UACR reduction or an initial dip.

eGFR = estimated glomerular filtration rate; CHF = chronic heart failure; T2DM = type 2 diabetes mellitus; CKD = chronic kidney disease; UACR = urinary albumin to creatinine ratio; ARNI = angiotensin receptor-neprilysin inhibitor; SGLT2i = sodium-glucose cotransporter 2 inhibitor; MRA = mineralocorticoid receptor antagonist; GLP-1-RA = glucagon-like peptide-1 receptor agonist. ^*The between-group difference in eGFR slope was evaluated from baseline in the PARADIGM-HF trial, from week 2 in the DAPA-CKD trial, and from week 12 in the FIDELIO-DKD and FLOW trials, accounting for the exclusion of the initial dip effect.

Figure 4. Outcomes of randomized controlled trials with angiotensin receptor-neprilysin inhibitor on the KDIGO heat map. The KDIGO heat map highlights the PARADIGM-HF trial (orange star: mean eGFR: 68 mL/min/1.73 m², median UACR: 9 mg/g) and PARAGON-HF trial (blue star: mean eGFR: 63 mL/min/1.73 m²), with dotted boxes indicating inclusion criteria. Primary outcomes were CV death or first HHF in the PARADIGM-HF trial, and CV death and total HHF in the PARAGON-HF trial. Renal outcomes included a sustained ≥50% eGFR reduction, end-stage renal disease, and death from renal causes in both trials. Treatment effects are presented as HRs (95% confidence interval).

eGFR = estimated glomerular filtration rate; UACR = urinary albumin to creatinine ratio; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; NA = not available; HHF = hospitalization for heart failure; CV death = cardiovascular death; HR = hazard ratio; KDIGO = The Kidney Disease: Improving Global Outcomes. ^*This represents the modified renal outcome in the integrated analysis of the PARAGON-HF trial.

Figure 5. Outcomes of RCTs with SGLT2 inhibitors on the KDIGO heat map: (A) RCTs with SGLT2 inhibitors targeting type 2 diabetes mellitus at high risk of cardiovascular disease; (B) RCTs with SGLT2 inhibitors targeting CKD. (A) The KDIGO heat map highlights the EMPA-REG trial (yellow star: mean eGFR: 74 mL/min/1.73 m², median UACR: 18 mg/g), CANVAS program trial (blue star: mean eGFR: 77 mL/min/1.73 m², median UACR: 12 mg/g), and DECLEARE-TIMI58 trial (green star: mean eGFR: 86 mL/min/1.73 m², median UACR: 13 mg/g), with dotted boxes indicating inclusion criteria. Primary outcomes across all trials included a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Renal outcomes included a doubling of serum creatinine, the need for renal replacement therapy, or death from renal causes in the EMPA-REG trial, and a sustained ≥40% reduction in the eGFR, the need for renal replacement therapy, or death from renal causes in the CANVAS program and DECLEARE-TIMI58 trial. Treatment effects are presented as HRs (95% confidence interval). (B) The KDIGO heat map highlights the DAPA-CKD trial (yellow star: mean eGFR: 43 mL/min/1.73 m², median UACR: 949 mg/g), and EMPA-KIDNEY trial (purple star: mean eGFR: 38 mL/min/1.73 m², median UACR: 412 mg/g), with dotted boxes indicating inclusion criteria. Primary outcomes were a sustained ≥50% reduction in the eGFR, progression to end-stage renal disease or renal or CV death in the DAPA-CKD trial, and a sustained ≥40% reduction in the eGFR, eGFR <10 mL/min/1.73 m², end-stage renal disease or death from CV causes in the EMPA-KIDNEY trial. Renal outcomes included a sustained ≥50% reduction in the eGFR, progression to end-stage renal disease or death from renal causes in the DAPA-CKD trial. and a sustained ≥40% reduction in the eGFR, eGFR <10 mL/min/1.73 m², or end-stage renal disease in the EMPA-KIDNEY. Treatment effects are presented as HRs (95% confidence interval).

eGFR = estimated glomerular filtration rate; UACR = urinary albumin to creatinine ratio; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; HHF = hospitalization for heart failure; MACE = major adverse cardiovascular event; GFR = glomerular filtration rate; CV death = cardiovascular death; HR = hazard ratio; CKD = chronic kidney disease; RCT = randomized controlled trial; SGLT2 = sodium-glucose cotransporter 2; KDIGO = The Kidney Disease: Improving Global Outcomes.

Figure 6. Outcome of randomized controlled trials with non-steroidal mineralocorticoid receptor antagonist on the KDIGO heat map. The KDIGO heat map highlights the FIDELIO-DKD trial (blue star: mean eGFR: 44 mL/min/1.73 m², median UACR: 851 mg/g), FIGARO-DKD trial (green star: mean eGFR: 68 mL/min/1.73 m², median UACR: 312 mg/g), and FINEARTS-HF trial (yellow star: mean eGFR: 62 mL/min/1.73 m², median UACR: 18 mg/g), with dotted boxes indicating inclusion criteria. Primary outcomes included a sustained ≥40% eGFR reduction or renal death in the FIDELIO-DKD trial, CV death, nonfatal myocardial infarction/stroke, or HHF in the FIGARO-DKD trial, and WHF events (either a hospitalization or an urgent visit for HF) or CV death in the FINEARTS-HF trial. Renal outcomes included a sustained ≥57% eGFR reduction (equivalent to a doubling of the serum creatinine level), or renal death in the FIGARO-DKDtrial, a sustained ≥40% eGFR reduction or renal death in the FIDELIO-DKD trial, and a sustained ≥50% eGFR reduction, eGFR <15 mL/min/1.73 m², or the need for dialysis or transplantation in the FINEARTS-HF trial. Treatment effects are presented as HRs (95% confidence interval).

GFR = glomerular filtration rate; UACR = urinary albumin to creatinine ratio; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; eGFR = estimated glomerular filtration rate; CKD = chronic kidney disease; T2DM = type 2 diabetes mellitus; HHF = hospitalization for heart failure; WHF = worsening heart failure; HR = hazard ratio; MACE = major adverse cardiovascular event; CV death = cardiovascular death; KDIGO = The Kidney Disease: Improving Global Outcomes; HF = heart failure.

Figure 7. Outcomes of randomized controlled trials with glucagon-like peptide-1 receptor agonists on the KDIGO heat map. The KDIGO heat map highlights the SELECT trial (yellow star: mean eGFR: 83 mL/min/1.73 m², median UACR: 7 mg/g), FLOW trial (gray star: mean eGFR: 47 mL/min/1.73 m², median UACR: 568 mg/g), and SUMMIT trial (blue star: mean eGFR: 64 mL/min/1.73 m²), with dotted boxes indicating inclusion criteria. Primary outcomes were a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke in the SELECT trial, a sustained ≥50% eGFR reduction, eGFR <15 mL/min/1.73 m², or the need for dialysis/transplantation, or renal or CV death in the FLOW trial, and a composite of death from any cause or WHF event combined with changes at 52 weeks in the the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score and in the 6-minute walk distance in the SUMMIT trial. Renal outcomes included a five-component composite of death from renal causes, the need for dialysis, eGFR <15 mL/min/1.73 m², a sustained ≥50% eGFR, or persistent macroalbuminuria in the SELECT trial, a sustained ≥50% eGFR reduction, the need for dialysis/transplantation, eGFR <15 mL/min/1.73 m², or death from renal causes in the FLOW trial. Treatment effects are presented as HRs (95% confidence interval).

GFR = glomerular filtration rate; UACR = urinary albumin to creatinine ratio; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; HFpEF = heart failure with preserved ejection fraction; CKD = chronic kidney disease; T2DM = type 2 diabetes mellitus; HHF = hospitalization for heart failure; WHF = worsening heart failure; MACE = major adverse cardiovascular event; HR = hazard ratio; CV death = cardiovascular death; QOL = quality of life; KDIGO = The Kidney Disease: Improving Global Outcomes.

Figure 8. Overview of novel heart failure therapies and renoprotective mechanism.

GLP-1-RA = glucagon-like peptide-1 receptor agonist; ARNI = angiotensin receptor-neprilysin inhibitor; SGLT2i = sodium-glucose cotransporter 2 inhibitor; MRA = mineralocorticoid receptor antagonists; ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; TLV = tolvaptan; GDMT = guideline-directed medical therapy.