How to use Angiotensin Receptor Neprilysin Inhibitor (ARNI) in patients with Chronic Kidney Disease (CKD)?

ARNI Use in CKD Patients

Direct Recommendation

ARNI (sacubitril/valsartan) should be initiated in CKD patients with heart failure (HFrEF, HFmrEF, or HFpEF) at eGFR ≥20 mL/min/1.73 m², starting at reduced doses for severe renal impairment (eGFR <30), with careful monitoring of potassium and renal function. 1

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Indications for ARNI in CKD

Heart Failure with Reduced Ejection Fraction (HFrEF, EF ≤40%)

• ARNI is the preferred RAAS inhibitor over ACE inhibitors or ARBs in CKD patients with HFrEF 1
• Use as part of quadruple therapy: ARNI + β-blocker + SGLT2 inhibitor + mineralocorticoid receptor antagonist (MRA) 1
• Provides superior cardiovascular outcomes compared to enalapril, with potentially lower hyperkalemia rates when combined with MRA 1

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, EF 41-49%)

• ARNI is recommended as first-line RAAS inhibitor (preferred over ACE inhibitor or ARB) 1
• Combine with β-blocker, SGLT2 inhibitor, and MRA 1

Heart Failure with Preserved Ejection Fraction (HFpEF, EF ≥50%)

• ARNI or ARB should be considered, with ARNI preferred for EF up to 55-60% 1
• Particularly beneficial when combined with SGLT2 inhibitor 1

Hypertension in CKD

• ARNI provides superior blood pressure reduction compared to standard RAAS inhibitors in CKD patients 2, 3
• Consider when blood pressure remains uncontrolled on conventional therapy 1

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Dosing Algorithm by Renal Function

eGFR ≥30 mL/min/1.73 m²

• Start at standard dose: 49/51 mg twice daily 4
• Titrate to target dose of 97/103 mg twice daily after 2-4 weeks as tolerated 4
• No dose adjustment needed for mild-to-moderate renal impairment 1

eGFR <30 mL/min/1.73 m² (Severe Renal Impairment)

• Start at half the usual dose: 24/26 mg twice daily 1, 4
• After initiation, increase dose following standard escalation schedule 1, 4
• Can be used even in CKD stage 5, including dialysis patients, with careful monitoring 5

eGFR <20 mL/min/1.73 m²

• Limited clinical trial data below eGFR 20, but can be initiated with extreme caution 1
• Real-world evidence supports use in advanced CKD (stages 4-5) with appropriate monitoring 5
• Once initiated at higher eGFR, continue even if eGFR falls below 20 unless not tolerated 1

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Monitoring Protocol

Initial Monitoring (First 1-4 Weeks)

• Check potassium and creatinine within 1-2 weeks after initiation or dose increase 1
• Assess blood pressure for symptomatic hypotension 1
• Monitor for signs of angioedema (rare but serious) 4

Acceptable Changes After Initiation

• Tolerate eGFR decreases ≤30% without discontinuing therapy 1
• If eGFR decline >30%: ensure euvolemia, adjust diuretics, discontinue nephrotoxic agents, evaluate alternative causes 1
• Initial mild worsening of renal function is expected and does not predict adverse long-term outcomes 1

Ongoing Monitoring

• Potassium and renal function monthly for first 3 months, then every 3 months 1
• Monitor natriuretic peptides (NT-proBNP or BNP) to assess disease progression 1
• Check urine albumin-creatinine ratio (UACR) at least annually 1

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Managing Hyperkalemia (K+ >5.0 mEq/L)

Step-by-Step Approach

1. Recheck elevated potassium before making therapeutic changes 1
2. Do not discontinue ARNI prematurely - hyperkalemia can often be managed without stopping therapy 1
3. Implement dietary potassium restriction: educate patients to avoid potassium supplements, salt substitutes, and high-potassium foods 1
4. Consider potassium binders (patiromer or sodium zirconium cyclosilicate) to facilitate continued use of ARNI 1
5. Discontinue or reduce potassium supplements if previously prescribed 1
6. Avoid NSAIDs and other medications that increase hyperkalemia risk 1

When to Reduce or Stop ARNI

• Uncontrolled hyperkalemia despite medical management 1
• Severe hyperkalemia (K+ >6.0 mEq/L) with ECG changes 1
• Only after exhausting other management strategies 1

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Critical Contraindications and Precautions

Absolute Contraindications

• Do not use within 36 hours of ACE inhibitor due to angioedema risk 4
• History of angioedema with previous ACE inhibitor or ARB therapy 4
• Concomitant use with aliskiren in diabetic patients 4
• Pregnancy (causes fetal harm) 4

Avoid Triple RAAS Blockade

• Never combine ACE inhibitor + ARB + MRA - associated with excessive hyperkalemia 1
• ARNI can be combined with MRA, but not with ACE inhibitor or ARB simultaneously 1

Special Populations

• Diabetes + CKD: Higher hyperkalemia risk (11.8% in trials), but ARNI may have lower rates than enalapril 1
• Moderate hepatic impairment (Child-Pugh B): Start at half the usual dose 4
• Severe hepatic impairment: Not recommended 4

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Practical Implementation Strategy

Switching from ACE Inhibitor or ARB

1. Discontinue ACE inhibitor 36 hours before starting ARNI 4
2. ARB can be stopped immediately when switching to ARNI 1
3. Start ARNI at appropriate dose based on renal function 1, 4

Combination with Other CKD Therapies

• Continue SGLT2 inhibitor - synergistic benefits for cardiovascular and renal outcomes 1
• Add MRA after optimizing ARNI and β-blocker in patients with eGFR >30 1
• Optimize diuretics for volume management without compromising renal function 1

When to Refer to Cardiology

• All CKD patients with heart failure should have cardiology involvement 1
• Natriuretic peptide screening can guide timing of referral 1
• Complex cases with severe CKD (eGFR <20) and heart failure benefit from multidisciplinary management 5

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Evidence Quality Considerations

The strongest evidence comes from the 2024 DCRM guidelines 1 and 2021 ACC Expert Consensus 1, which provide the most recent and comprehensive recommendations. The PARADIGM-HF trial demonstrated 20% reduction in cardiovascular death or heart failure hospitalization with ARNI versus enalapril 6. Real-world evidence from advanced CKD populations (eGFR <30) shows safety and efficacy with appropriate monitoring 5, though this represents lower-quality evidence than guideline recommendations for less severe CKD.