What are the considerations for using Angiotensin Receptor Neprilysin Inhibitor (ARNI) (e.g. sacubitril/valsartan) in a patient with Chronic Kidney Disease (CKD) grade 5 and potential comorbidities such as hypertension and diabetes?

ARNI Use in CKD Grade 5

ARNI (sacubitril/valsartan) can be used in CKD stage 5 patients with heart failure, but requires careful patient selection, dose reduction, and intensive monitoring for hyperkalemia and renal function. 1, 2, 3

Eligibility and Contraindications

ARNI is recommended for CKD stage 5 patients with heart failure (HFrEF, HFmrEF, or HFpEF) at eGFR ≥20 mL/min/1.73 m², including those on hemodialysis. 1, 2 The American College of Cardiology guidelines explicitly support use down to eGFR 20, and emerging evidence demonstrates safety even in dialysis-dependent patients. 1, 2, 4

• Absolute contraindications include pregnancy, history of angioedema, and concurrent ACE inhibitor use (requires 36-hour washout). 2, 3
• Volume depletion must be corrected before initiation to minimize hypotension risk. 3
• Black patients have higher angioedema risk (2.4% vs 0.5% with enalapril), requiring heightened vigilance. 3

Dosing Strategy for CKD Stage 5

Start at 24/26 mg twice daily (half the usual starting dose) in patients with eGFR <30 mL/min/1.73 m². 1, 2, 3

• Titrate every 2-4 weeks based on tolerance, targeting 97/103 mg twice daily, though submaximal doses provide significant clinical benefit. 1, 2
• For hemodialysis patients specifically, the same reduced starting dose applies, with careful titration based on blood pressure and potassium levels. 2, 4
• The FDA label confirms no dose adjustment needed for eGFR ≥30, but recommends starting at reduced doses for severe renal impairment. 3

Monitoring Requirements

Monitor potassium and renal function monthly for the first 3 months, then every 3 months thereafter. 1

• Check serum creatinine at each visit; down-titrate or interrupt if clinically significant decline occurs. 3
• Monitor for symptomatic hypotension, but do not discontinue for asymptomatic hypotension as mortality benefits persist. 2
• Measure NT-proBNP or BNP to assess disease progression. 1
• Check urine albumin-creatinine ratio (UACR) at least annually. 1
• Watch for angioedema symptoms and discontinue immediately if it occurs. 2, 3

Managing Hyperkalemia

Hyperkalemia is the most common reason for discontinuation in advanced CKD (occurred in 5 of 34 patients with eGFR <30 in one study). 4

• Implement dietary potassium restriction (<2.3 g/day sodium also recommended). 5, 1
• Discontinue potassium supplements and avoid NSAIDs. 1
• Consider potassium binders (e.g., patiromer, sodium zirconium cyclosilicate) to facilitate continued ARNI use. 1
• Reduce or stop ARNI if potassium >5.5 mEq/L despite interventions, or if severe hyperkalemia with ECG changes occurs. 1, 3
• During the PARADIGM-HF trial, approximately 16% of patients had potassium >5.5 mEq/L, but this was similar to enalapril. 3

Combination Therapy in CKD Stage 5

ARNI should be part of quadruple therapy: ARNI + β-blocker + SGLT2 inhibitor + mineralocorticoid receptor antagonist (MRA). 1

• Continue SGLT2 inhibitors for synergistic cardiovascular and renal benefits. 1
• Add MRA after optimizing ARNI and β-blocker, but only if eGFR >30 mL/min/1.73 m² per most guidelines. 1
• For CKD stage 5, MRA use requires extreme caution due to hyperkalemia risk; potassium binders may be necessary. 1
• Optimize loop diuretics (required when eGFR <30) for volume management without compromising renal function. 5, 1
• Never combine ARNI with ACE inhibitors or ARBs—this increases adverse events without benefit. 5

Expected Outcomes in Advanced CKD

Real-world evidence demonstrates ARNI stabilizes or improves renal function in CKD stage 4-5 patients with heart failure. 4, 6

• In a study of 26 patients with eGFR <30 (including 8 on hemodialysis), ARNI significantly reduced hospitalizations (2.04±1.03 to 0.23±0.51), improved NYHA class (3.77±0.43 to 2.19±0.56), and decreased NT-proBNP without significant eGFR decline over 6 months. 4
• Another study of CKD stages 1-4 showed LVEF improved from 31±9% to 39±15% (p<0.001) with stable GFR after initial improvement at 1 month. 6
• Only 10.6% withdrew from treatment in the latter study, demonstrating good tolerability. 6

Critical Warnings

Three patients (9%) in one study required ARNI discontinuation due to eGFR decrease >30% within 1 month. 4 This emphasizes the need for:

• Close monitoring during the first month of therapy
• Reassessment of volume status if creatinine rises (may indicate prerenal azotemia from overdiuresis)
• Distinguishing hemodynamic changes from true nephrotoxicity
• Not automatically discontinuing for modest creatinine increases if patient is clinically improving

Hypotension occurs in 18% of ARNI-treated patients (vs 12% with enalapril), with orthostasis in 2.1% and falls in 1.9%. 3 In CKD stage 5, especially dialysis patients, this risk is amplified by:

• Interdialytic fluid shifts
• Autonomic dysfunction
• Concurrent antihypertensive medications requiring adjustment

Practical Algorithm for Initiation

1. Confirm heart failure diagnosis (HFrEF, HFmrEF, or HFpEF) with appropriate natriuretic peptide elevation 1
2. Assess volume status and correct depletion before starting 3
3. Check baseline potassium (must be ≤5.4 mEq/L), creatinine, and blood pressure 1, 3
4. Ensure 36-hour washout from ACE inhibitors if switching 2
5. Start 24/26 mg twice daily for eGFR <30 1, 2, 3
6. Recheck labs at 1-2 weeks: if potassium ≤4.8 mEq/L and eGFR stable, increase to 49/51 mg twice daily 1
7. Recheck labs at 4-6 weeks: if tolerated, increase to 97/103 mg twice daily 1
8. Continue monthly monitoring for 3 months, then every 3 months 1

Cardiology Referral

All CKD patients with heart failure should have cardiology involvement, with natriuretic peptide screening guiding referral timing. 1 For CKD stage 5 specifically, co-management between nephrology and cardiology is essential given the complexity of medication management, dialysis considerations, and cardiovascular risk stratification. 5, 1