Role of Angiotensin Receptor-Neprilysin Inhibitors (ARNi) in Chronic Kidney Disease (CKD)
ARNi therapy, specifically sacubitril/valsartan, is beneficial for CKD patients, particularly those with comorbid heart failure with reduced ejection fraction (HFrEF), as it provides both cardiovascular and renal protection beyond standard RAS inhibition alone.
Mechanism and Benefits of ARNi in CKD
ARNi combines an angiotensin receptor blocker (valsartan) with a neprilysin inhibitor (sacubitril) that prevents the breakdown of natriuretic peptides. This dual mechanism:
- Blocks the harmful effects of the renin-angiotensin-aldosterone system (RAAS)
- Enhances the beneficial effects of natriuretic peptides
- Provides complementary cardio-renal protection 1
Evidence for ARNi Use in CKD Patients
CKD with Heart Failure
- ARNi significantly reduces the risk of cardiovascular death and heart failure hospitalizations in CKD patients with HFrEF compared to ACE inhibitors/ARBs (OR: 0.68,95% CI 0.61-0.76) 2
- Sacubitril/valsartan improves left ventricular ejection fraction (LVEF) in CKD patients with HFrEF 3
- Recent evidence shows ARNi can be safely used even in advanced CKD (stages 4-5) with appropriate monitoring 4
Renal Protection
- ARNi prevents serum creatinine elevation in CKD patients (OR: 0.79,95% CI 0.67-0.95) 2
- With long-term follow-up, ARNi significantly decreases the number of patients with >50% reduction in eGFR compared to ACE inhibitors/ARBs 2
- Some studies show improvement or stabilization of GFR after initiating sacubitril/valsartan in advanced CKD patients 5
Guideline Recommendations
According to the 2024 DCRM guidelines, sacubitril/valsartan:
- Reduces blood pressure and the risk of death and heart failure hospitalizations
- May help preserve kidney function
- Should not be used with other RAS inhibitors (including ARBs, ACE inhibitors, or aliskiren) 6
The American Heart Association and Heart Failure Society of America note that:
- ARNi use in CKD patients with HFrEF may be beneficial
- Rates of hyperkalemia might be slightly lower with sacubitril/valsartan than with enalapril, particularly during concomitant treatment with an MRA 6
Practical Approach to ARNi Use in CKD
Patient Selection
Consider ARNi for CKD patients with:
- Comorbid HFrEF
- Persistent proteinuria despite maximal RAS blockade
- eGFR >15 mL/min/1.73m²
Start with low doses in advanced CKD (eGFR <30 mL/min/1.73m²) and titrate cautiously
Monitoring
- Monitor serum potassium and creatinine within 2-4 weeks of initiation or dose change
- Watch for hypotension (most common side effect with ARNi in CKD patients) 2
- Continue monitoring renal function throughout treatment
Safety Considerations
- Hypotension is more common with ARNi than with ACEi/ARBs (OR: 1.71,95% CI 1.15-2.56) 2
- Hyperkalemia risk appears similar to ACEi/ARBs 2
- ARNi should not be combined with other RAS inhibitors 6
- Contraindicated in pregnancy due to fetal toxicity 7
- Angioedema risk is higher in Black patients 7
Common Pitfalls to Avoid
- Combining with other RAS inhibitors: Never combine ARNi with ACEi, ARB, or aliskiren 6
- Inadequate monitoring: Always check potassium and renal function after initiation
- Starting at full dose: Begin with lower doses in advanced CKD and titrate gradually
- Overlooking volume status: Correct volume depletion before starting ARNi to reduce hypotension risk 7
- Ignoring drug washout period: Ensure a 36-hour washout period when switching from ACEi to ARNi to prevent angioedema
ARNi represents an important therapeutic option for CKD patients, especially those with heart failure, offering benefits beyond traditional RAS blockade while maintaining a reasonable safety profile even in advanced kidney disease when used appropriately.