What are the considerations for using Angiotensin Receptor-Neprilysin Inhibitors (ARNI) in patients with Chronic Kidney Disease (CKD)?

ARNI Use in Chronic Kidney Disease

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) are recommended for patients with CKD who have heart failure with reduced or mildly reduced ejection fraction, but should be used with careful monitoring of renal function and potassium levels, especially in advanced CKD. 1

Indications for ARNI in CKD

• ARNIs (specifically sacubitril/valsartan) are strongly recommended for patients with CKD who have heart failure with reduced ejection fraction (HFrEF) or heart failure with mildly reduced ejection fraction (HFmrEF, EF 41-49%) 1
• ARNIs are preferred over ACE inhibitors or ARBs in patients with CKD who have heart failure with ejection fraction up to 55-60% 1
• For patients with CKD and heart failure with preserved ejection fraction (HFpEF, EF ≥50%), ARNIs may be considered as part of the treatment regimen 1

Dosing Considerations in CKD

• For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), start sacubitril/valsartan at half the usually recommended starting dose 2
• After initiation with the reduced dose, increase according to the recommended dose escalation schedule as tolerated 2
• The standard adult heart failure starting dose is 49/51 mg orally twice daily, with titration to 97/103 mg twice daily as the target maintenance dose 2

Monitoring Requirements

• Check serum creatinine, potassium, and blood pressure within 2-4 weeks of initiation or dose increase of ARNI 1
• Tolerate acute eGFR decreases of ≤30% after initiation of therapy—do not discontinue therapy prematurely 1
• If >30% decline in eGFR occurs, ensure euvolemia (adjust diuretic dosage), discontinue nonessential nephrotoxic agents, and evaluate alternative etiologies 1
• Monitor for hyperkalemia, especially in advanced CKD 1, 3

Benefits of ARNI in CKD Patients

• ARNIs have shown substantial benefits in reducing cardiovascular events in heart failure patients with CKD 4
• In patients with HFrEF and moderate-to-severe CKD, ARNI therapy has demonstrated:
  • Lower rates of death due to cardiovascular disease compared to ACEi/ARB therapy 4
  • Lower incidence of rehospitalization for heart failure 4
  • Improvements in NYHA class, ejection fraction, and NT-proBNP levels 3, 4

Potential Mechanisms of Benefit

• NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin-angiotensin system 5
• These effects could act as a potentially beneficial counter-regulatory system in states of RAS activation such as CKD 6

Cautions and Contraindications

• In a study of patients with advanced CKD (eGFR <30 mL/min/1.73 m²), approximately 15% of patients had to discontinue ARNI due to hyperkalemia or significant decrease in eGFR within 1 month 3
• ARNI may increase albuminuria compared to RAS inhibitors alone, raising questions about long-term renoprotective effects 7
• Avoid combination of ARNI with ACEi due to increased risk of angioedema 6
• Wait 36 hours after discontinuing ACEi before initiating ARNI to reduce angioedema risk 2

Special Considerations for Different CKD Populations

• For patients with CKD and diabetes, an SGLT2 inhibitor should be considered as first-line therapy, with ARNI as part of the comprehensive treatment approach for those with heart failure 1
• In patients with advanced CKD (stages 4-5), ARNI can be used with careful monitoring of potassium and renal function 3
• For patients on dialysis with heart failure, limited data exists but suggests potential benefit with careful monitoring 3

Management of Adverse Effects

• For hyperkalemia associated with ARNI use:
  • Consider potassium binders to facilitate ongoing use of evidence-based therapies 1
  • Implement low potassium diet 1
  • Consider diuretic initiation or sodium bicarbonate in those with metabolic acidosis 1
• For significant decline in renal function:
  • Continue ARNI unless serum creatinine rises by more than 30% within 4 weeks following initiation or dose increase 1
  • Consider reducing the dose or discontinuing ARNI in cases of symptomatic hypotension or uncontrolled hyperkalemia despite medical treatment 1

ARNIs represent an important therapeutic option for patients with CKD, particularly those with concomitant heart failure, but require careful patient selection and monitoring to maximize benefits while minimizing risks.