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Lisinopril Dosing in Renal Impairment: Evidence-Based Adjustments by GFR Stage

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At a glance

  • CrCl above 30 mL/min / Label: no dose adjustment [1]
  • CrCl 10 to 30 mL/min / Label recommends halving the usual initial dose: hypertension 5 mg, heart failure 2.5 mg, acute MI 2.5 mg [1]
  • CrCl below 10 mL/min or hemodialysis / Label: initial dose 2.5 mg once daily [1]
  • Usual adult hypertension start / Label: 10 mg once daily [1]
  • Heart failure start / Label: 5 mg once daily; 2.5 mg if serum sodium below 130 mEq/L [1]
  • Renal-impairment maximum / Label maximum after titration: 40 mg daily [1]
  • Elimination / Excreted unchanged in urine; removed by hemodialysis [1]
  • Monitoring / Label directs periodic renal function and serum potassium checks [1]

What are the label's creatinine clearance cutoffs?

For adults, the FDA label for lisinopril tablets gives renal dosing in creatinine clearance rather than CKD stage [1]. There are three categories.

  • Above 30 mL/min: no adjustment [1].
  • 10 to 30 mL/min: halve the usual initial dose. For hypertension, 5 mg once daily; for heart failure, 2.5 mg once daily; for acute MI, 2.5 mg [1]. The label says to titrate to a maximum of 40 mg daily [1].
  • Below 10 mL/min or on hemodialysis: initial dose 2.5 mg once daily [1].

Why does kidney function change the dose?

Lisinopril is an ACE inhibitor: it blocks the enzyme that converts angiotensin I to the vasoconstrictor angiotensin II, and lower angiotensin II also means less aldosterone [1]. The drug is not metabolized and is not bound to serum proteins; it is excreted unchanged in the urine [1]. Clinically important accumulation occurs only when GFR is below 30 mL/min, and the drug is removed by hemodialysis [1]. The label ties its renal adjustment to creatinine clearance [1].

CrCl above 30 mL/min: no adjustment

For adults with hypertension, the label's initial dose is 10 mg once daily; the usual range is 20 to 40 mg once daily, and doses up to 80 mg have been used but do not appear to give greater effect [1]. If the patient is already on a diuretic, the label's starting dose is 5 mg once daily [1].

The label's heart failure starting dose is 5 mg once daily, or 2.5 mg when serum sodium is below 130 mEq/L, with titration to a maximum of 40 mg once daily [1].

After acute MI, the label's sequence is 5 mg, then 5 mg after 24 hours, 10 mg after 48 hours, then 10 mg once daily for at least six weeks. The label starts at 2.5 mg when systolic BP is above 100 and up to 120 mmHg during the first three days [1].

For children 6 years and older with GFR above 30, the label's starting dose is 0.07 mg/kg once daily, up to 5 mg; the maximum is 0.61 mg/kg once daily, up to 40 mg [1]. The label does not recommend lisinopril for children under 6 or with GFR below 30 [1].

CrCl 10 to 30 mL/min: halve the initial dose

At CrCl 10 to 30 mL/min, the label says to give half the usual initial dose: 5 mg for hypertension, 2.5 mg for heart failure, and 2.5 mg for acute MI [1]. The dose can then be titrated to a maximum of 40 mg daily [1].

The label warns that starting lisinopril in a patient who is on a diuretic can cause an excessive blood pressure drop. It lists decreasing or stopping the diuretic, increasing salt intake, or using a lower starting dose as options [1].

The label names renal insufficiency, diabetes, potassium-sparing diuretics, potassium supplements, and potassium-containing salt substitutes as hyperkalemia risk factors [1]. In trials, serum potassium above 5.7 mEq/L occurred in 2.2% of hypertensive patients and 4.8% of heart failure patients [1].

CrCl below 10 mL/min and hemodialysis

For CrCl below 10 mL/min or hemodialysis, the label recommends an initial dose of 2.5 mg once daily [1]. Lisinopril is removed by hemodialysis [1].

Sudden, potentially life-threatening anaphylactoid reactions have occurred in patients dialyzed with high-flux membranes who were taking an ACE inhibitor. The label says to stop dialysis immediately and give aggressive therapy, and to consider a different membrane or antihypertensive class [1].

What should be monitored?

The label directs periodic monitoring of renal function and serum potassium in patients taking lisinopril [1]. It also says to consider withholding or discontinuing lisinopril in patients who develop a clinically significant decrease in renal function [1].

NSAIDs, including COX-2 inhibitors, can worsen kidney function in elderly, volume-depleted, or renally impaired patients taking an ACE inhibitor, with possible acute renal failure that is usually reversible. The label says to monitor renal function periodically during combined use [1].

Dual blockade of the renin-angiotensin system raises the risk of hypotension, hyperkalemia, and renal changes including acute renal failure [1]. In VA NEPHRON-D, 1448 patients with type 2 diabetes and GFR 30 to 89.9 mL/min received losartan plus lisinopril 10 to 40 mg or placebo. The combination gave no added benefit and more hyperkalemia (6.3 vs 2.6 events per 100 person-years) and acute kidney injury (12.2 vs 6.7) [2]. The label says in general to avoid combined RAS inhibitors [1].

What evidence exists in people with renal impairment?

One 12-week open study enrolled 26 adults with hypertension and GFR 60 mL/min or less. Lisinopril started at 2.5 mg when GFR was below 30 mL/min and 5 mg otherwise, and was titrated to a maximum of 40 mg daily; the median dose was 10 mg daily. Mean GFR was 36 mL/min at baseline and 39 mL/min after 12 weeks [3].

A randomized open-label trial in 411 patients with advanced, progressive CKD (eGFR below 30 mL/min/1.73 m2) compared discontinuing with continuing RAS inhibitors (ACE inhibitors or ARBs, not lisinopril alone). At 3 years, mean eGFR was 12.6 in the discontinuation group and 13.3 in the continuation group, a difference of -0.7 (95% CI -2.5 to 1.0; P=0.42) [5]. ESKD or renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and 115 (56%) in the continuation group (HR 1.28, 95% CI 0.99 to 1.65) [5].

What did ATLAS show about high-dose lisinopril in heart failure?

ATLAS randomized 3164 patients with NYHA class II to IV heart failure and ejection fraction 30% or less to low-dose lisinopril (2.5 to 5 mg daily) or high-dose lisinopril (32.5 to 35 mg daily) for 39 to 58 months. High-dose lisinopril had a nonsignificant 8% lower risk of death (P=0.128), a 12% lower risk of death or hospitalization for any reason (P=0.002), and 24% fewer heart failure hospitalizations [6]. Dizziness and renal insufficiency were more frequent in the high-dose group [6].

Label data from ATLAS: creatinine increased in 10% of the high-dose group and 7% of the low-dose group; hyperkalemia occurred in 6% and 4%; dizziness in 19% and 12%; hypotension in 11% and 7%; syncope in 7% and 5% [1].

Frequently asked questions

Does lisinopril need a lower dose at CrCl 30 or below?
Yes. At CrCl 10 to 30 mL/min, the label says to halve the usual initial dose: 5 mg for hypertension, 2.5 mg for heart failure, and 2.5 mg for acute MI [1]. At CrCl below 10 mL/min or on hemodialysis, the label recommends an initial dose of 2.5 mg [1].
Is the adjustment based on eGFR or CKD stage?
For adults, the label writes the renal cutoffs in creatinine clearance rather than CKD stage [1]. Only the pediatric dosing is written in GFR, with lisinopril not recommended below 30 mL/min/1.73 m2 [1].
Is lisinopril removed by dialysis?
Yes. The label says lisinopril is removed by hemodialysis, and for patients on hemodialysis it recommends an initial dose of 2.5 mg once daily [1].
What is the maximum dose in renal impairment?
The label says to titrate to a maximum of 40 mg daily after the reduced starting dose [1]. For hypertension, the usual range is 20 to 40 mg daily, and doses up to 80 mg have been used but do not appear to give greater effect [1].
What potassium and kidney changes does the label warn about?
The label says to monitor serum potassium and renal function periodically [1]. In trials, potassium above 5.7 mEq/L occurred in 2.2% of hypertensive patients and 4.8% of heart failure patients, and minor BUN or creatinine rises occurred in about 2% of hypertensive patients and 11.6% of heart failure patients on diuretics [1].
Can lisinopril be combined with an ARB in CKD?
The label says in general to avoid combined RAS inhibitors [1]. In VA NEPHRON-D, adding lisinopril 10 to 40 mg to losartan in 1448 patients with type 2 diabetes and GFR 30 to 89.9 mL/min gave no added benefit and more hyperkalemia and acute kidney injury [2].

References

  1. U.S. National Library of Medicine, DailyMed. LISINOPRIL prescribing information. LISINOPRIL label
  2. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-903. Combined angiotensin inhibition for the treatment of diabetic nephropathy
  3. Donohoe JF, Kelly J, Laher MS, Doyle GD. Lisinopril in the treatment of hypertensive patients with renal impairment. Am J Med. 1988;85(3B):31-4. Lisinopril in the treatment of hypertensive patients with renal impairment
  4. . Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet. 1997;349(9068):1787-92. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group
  5. Bhandari S, Mehta S, Khwaja A, Cleland JGF, Ives N, Brettell E, et al. Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease. N Engl J Med. 2022;387(22):2021-2032. Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease
  6. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100(23):2312-8. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group
Evidence overview for Lisinopril Dosing in Renal Impairment: Evidence-Based Adjustments by GFR Stage