In a patient with acute kidney injury and a serum creatinine of 2.5 mg/dL (eGFR <30 mL/min), should sacubitril/valsartan (Entresto) be discontinued?

Management of Sacubitril/Valsartan in Acute Kidney Injury with Creatinine 2.5 mg/dL

In a patient with acute kidney injury and serum creatinine of 2.5 mg/dL (eGFR <30 mL/min/1.73 m²), you should temporarily hold sacubitril/valsartan until volume status is optimized and renal function stabilizes, then restart at a reduced dose once creatinine trends downward. 1, 2

Immediate Management During Acute Phase

Hold Sacubitril/Valsartan Temporarily

• ACE inhibitors, ARBs, and ARNI (sacubitril/valsartan) must be held during the acute phase when GFR is unstable or volume status is not optimized. 1, 2
• The FDA label explicitly warns that sacubitril/valsartan can cause decreases in renal function in susceptible individuals, and clinicians should "closely monitor serum creatinine, and down-titrate or interrupt sacubitril/valsartan in patients who develop a clinically significant decrease in renal function." 3
• This temporary discontinuation differs from permanent cessation—the goal is stabilization, not abandonment of therapy. 1

Optimize Volume Status First

• Assess for volume depletion or overload immediately, as patients with activated renin-angiotensin systems (volume/salt-depleted, high-dose diuretics) are at greatest risk for worsening renal function with RAAS inhibition. 3
• Correct volume depletion with cautious fluid administration (50 mL/hour in heart failure patients, not boluses) or treat fluid overload with diuretics before considering medication restart. 4

Monitor Renal Function Intensively

• Check serum creatinine and eGFR daily during the acute phase. 1
• Monitor serum potassium daily to twice daily, as hyperkalemia risk increases with declining renal function. 1
• Establish a clear trajectory of renal function—is creatinine rising, stable, or declining? 1

Criteria for Restarting Sacubitril/Valsartan

When to Restart

• Restart sacubitril/valsartan only after GFR stabilizes and volume status is optimized. 1, 2
• Stabilization means creatinine is no longer rising and preferably trending downward, even if not back to baseline. 1
• Volume status must be euvolemic—neither depleted nor overloaded. 2

How to Restart

• Resume at a reduced dose (typically 24/26 mg twice daily if previously on higher doses). 3
• The FDA label recommends starting at lower doses in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). 3
• Uptitrate gradually only after demonstrating tolerance at the lower dose for 2-4 weeks. 5

Evidence Supporting Continuation in Chronic eGFR <30

Distinction Between AKI and Chronic Low eGFR

• Critical distinction: The recommendation to hold applies to acute kidney injury with unstable renal function, not chronic stable eGFR <30. 1, 6
• In the PARADIGM-HF and PARAGON-HF post-hoc analysis, patients who experienced deterioration of eGFR to <30 mL/min/1.73 m² but remained on sacubitril/valsartan had persistent clinical benefit with no incremental safety risk compared to those on RAS inhibitors. 6
• Among 691 PARADIGM-HF patients and 613 PARAGON-HF patients with eGFR <30 during follow-up, continuation of sacubitril/valsartan was associated with lower rates of the primary outcome (cardiovascular death or heart failure hospitalization) with similar safety profiles between treatment groups. 6

Renal Outcomes with Sacubitril/Valsartan

• Meta-analysis of 10 randomized trials (18,362 patients) demonstrated sacubitril/valsartan reduced composite renal impairment by 16% (RR 0.84,95% CI 0.72-0.96), reduced ESRD development by 47% (RR 0.53,95% CI 0.30-0.96), and slowed eGFR decline (mean difference 0.56 mL/min/1.73 m²) compared to RAS inhibitors. 7
• Drug discontinuation due to renal events was 42% lower with sacubitril/valsartan (RR 0.58,95% CI 0.40-0.83). 7

Common Pitfalls to Avoid

Do Not Permanently Discontinue Prematurely

• Permanent discontinuation is rarely required—most patients can be restarted once the acute insult resolves. 3
• The FDA label states "permanent discontinuation of therapy is usually not required" for hypotension, and the same principle applies to transient renal dysfunction. 3

Do Not Confuse AKI with Expected Creatinine Rise

• Small creatinine elevations up to 30% from baseline with RAS blockade are expected and do not represent true AKI. 5
• In the ACCORD-BP trial, patients with up to 30% creatinine increase on intensive blood pressure lowering had no increase in mortality or progressive kidney disease. 5
• However, a rise from baseline to 2.5 mg/dL likely exceeds 30% in most patients and represents true AKI requiring temporary drug hold. 1

Monitor for Hyperkalemia

• Sacubitril/valsartan increases hyperkalemia risk, especially with eGFR <30. 3
• If potassium rises above 5.5 mmol/L, halve the dose; if above 6.0 mmol/L, stop immediately. 5
• Severe hyperkalemia occurred less frequently with sacubitril/valsartan than RAS inhibitors in meta-analysis (RR 0.80,95% CI 0.68-0.93). 7

Assess for Alternative Causes of AKI

• Systematically evaluate for prerenal (volume depletion, hypotension), intrarenal (acute tubular necrosis, interstitial nephritis), and postrenal (obstruction) causes. 1
• One case report documented valsartan-induced acute interstitial nephritis requiring glucocorticoid therapy, though this is rare. 8
• Discontinue all other nephrotoxins (NSAIDs, aminoglycosides, contrast) immediately. 1

Practical Algorithm

1. Day 1 of AKI recognition: Hold sacubitril/valsartan immediately. 1, 2
2. Days 1-3: Optimize volume status, check daily creatinine/potassium, eliminate other nephrotoxins. 1
3. Days 3-7: If creatinine stabilizes or trends downward and volume is euvolemic, restart at reduced dose (24/26 mg BID). 1, 3
4. Weeks 2-4: Monitor creatinine twice weekly; if stable, continue current dose. 5
5. After 4 weeks: Consider gradual uptitration if creatinine remains stable and patient tolerates therapy. 5
6. If creatinine continues rising: Keep drug held, consider nephrology consultation, evaluate for dialysis if indicated. 1