Does Entresto (sacubitril/valsartan) affect kidney function?

Effect of Entresto (Sacubitril/Valsartan) on Kidney Function

Entresto (sacubitril/valsartan) can both protect kidney function and cause renal impairment in susceptible individuals, with the overall effect being generally favorable for most patients with heart failure, particularly those with reduced ejection fraction. 1

Mechanism of Action on Kidneys

Entresto affects kidney function through two primary mechanisms:

1. Valsartan component: Acts as an angiotensin receptor blocker (ARB), inhibiting the renin-angiotensin-aldosterone system (RAAS)
2. Sacubitril component: Inhibits neprilysin, preventing the breakdown of natriuretic peptides

Beneficial Effects on Kidney Function

• Slows decline in kidney function: ARBs like valsartan have been shown to slow the decrease in kidney function in patients with kidney disorders, particularly diabetic kidney disease and glomerulonephritis 2
• Protects filtration barrier: Recent research demonstrates Entresto can protect the glomerular filtration barrier and reduce albuminuria 3, 4
• Improves GFR in uninjured kidneys: Studies show Entresto can increase GFR in uninjured kidneys by approximately 23 mL/min 3
• Reduces renal decline: Meta-analysis data indicates sacubitril/valsartan decreases the number of patients with >50% reduction in eGFR compared to ACE inhibitors/ARBs alone 4

Potential Adverse Effects on Kidneys

• Acute kidney injury risk: As with all RAAS inhibitors, Entresto can cause decreases in renal function in susceptible individuals 1
• Hyperkalemia: Through its actions on RAAS, Entresto may cause elevated potassium levels, requiring monitoring 1
• Hypotension: Can lead to reduced kidney perfusion, especially in volume-depleted patients 1

High-Risk Populations

Entresto requires special consideration in:

1. Bilateral renal artery stenosis: Patients with this condition are at particularly high risk for worsening renal function 5
2. Severe renal impairment: Safety not established in patients with CrCl ≤30 mL/min 5
3. Volume-depleted patients: Greater risk of symptomatic hypotension affecting kidney perfusion 1
4. Patients on multiple RAAS inhibitors: Combining an ARB with both an ACE inhibitor and aldosterone antagonist increases risk of renal dysfunction 5

Monitoring Recommendations

• Baseline assessment: Check renal function parameters (serum creatinine, eGFR) before starting therapy 5
• Follow-up monitoring: Monitor serum creatinine within 1-2 weeks after initiation or dose increase 2
• Electrolyte monitoring: Check potassium levels periodically, especially in patients with risk factors for hyperkalemia 1
• Dose adjustment: In severe renal impairment (eGFR <30 mL/min/1.73 m²), reduce starting dose to 24/26 mg twice daily 2

Management of Renal Impairment

If renal function worsens:

• Hold medication: If serum creatinine rises significantly or signs of acute kidney injury develop 5
• Reassess: Monitor blood chemistry closely and reassess renal function within 3-7 days 5
• Consider restart: If renal function improves and stabilizes, consider restarting at a lower dose with careful monitoring 5

Clinical Evidence Summary

The most recent evidence from a 2024 meta-analysis of six trials with 6,217 CKD patients showed that sacubitril/valsartan:

• Reduced risk of cardiovascular death or heart failure hospitalization by 32% (OR: 0.68) 4
• Prevented serum creatinine elevation (OR: 0.79) 4
• Decreased the number of patients with >50% reduction in eGFR (OR: 0.52) 4
• Showed a trend toward reduced end-stage renal disease (ESRD) incidence (OR: 0.59) 4
• Increased risk of hypotension (OR: 1.71) but did not significantly increase hyperkalemia risk 4

Conclusion

While Entresto can cause renal impairment in susceptible individuals, the overall evidence suggests it generally has a protective effect on kidney function, particularly in patients with heart failure. Careful monitoring of renal function and appropriate patient selection are essential to maximize benefits while minimizing risks.