Amlodipine Renal Protection or Renal Risk: What the Evidence Actually Shows

Does amlodipine protect the kidneys?

Amlodipine is a dihydropyridine calcium channel blocker. The label describes it as a peripheral arterial vasodilator that lowers peripheral vascular resistance and blood pressure, with a greater effect on vascular smooth muscle than on cardiac muscle [1]. Its labeled uses are hypertension, chronic stable angina, vasospastic angina, and reducing the risk of angina hospitalization and of coronary revascularization in patients with documented coronary artery disease who do not have heart failure or an ejection fraction below 40% [1]. For hypertension, the label frames the benefit in cardiovascular terms: lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions [1].

A 2013 review that compared amlodipine with lercanidipine went further on the kidney question. It concluded that amlodipine is overall less effective for renal protection than the other antihypertensives tested, and that its benefit in retarding progression of renal disease is achievable only when it is combined with a blocker of the renin-angiotensin system [3].

Calcium-channel blockers can dilate the blood vessel entering the kidney (the afferent arteriole), as described in a review of their use against cyclosporine nephrotoxicity [6]. That effect does not establish why ramipril performed better than amlodipine in AASK [2].

What AASK showed about amlodipine and kidney outcomes

AASK randomized 1,094 Black adults aged 18 to 70 with hypertensive renal disease and a GFR of 20 to 65 mL/min/1.73 m² to amlodipine 5 to 10 mg (n=217), ramipril 2.5 to 10 mg (n=436), or metoprolol 50 to 200 mg (n=441), with other agents added to reach one of two blood pressure goals [2]. The ramipril-versus-amlodipine comparison was made after the amlodipine arm was discontinued in September 2000 [2].

Among participants with a urinary protein-to-creatinine ratio above 0.22 (roughly more than 300 mg of protein a day), ramipril produced a 36% slower mean decline in GFR over three years (P=0.006) and a 48% lower risk of the combined outcome of substantial GFR loss, end-stage renal disease, or death (95% CI 20%-66%) than amlodipine [2]. Across the whole cohort, mean GFR decline from baseline to three years did not differ significantly between groups (P=0.38). After adjustment for baseline covariates, however, ramipril was associated with a 38% lower risk of the combined outcome (95% CI 13%-56%), a 36% slower mean GFR decline after three months (P=0.002), and less proteinuria (P<0.001) [2].

ACCOMPLISH: a combination trial, not a kidney-protection trial

ACCOMPLISH randomized 11,506 high-risk hypertensive patients to benazepril plus amlodipine or benazepril plus hydrochlorothiazide [5]. It was stopped early after a mean follow-up of 36 months [5]. After dose adjustment, mean blood pressure was 131.6/73.3 mm Hg with benazepril-amlodipine and 132.5/74.4 mm Hg with benazepril-hydrochlorothiazide [5]. The primary cardiovascular composite occurred in 552 patients (9.6%) on benazepril-amlodipine and 679 (11.8%) on benazepril-hydrochlorothiazide, a relative risk reduction of 19.6% (HR 0.80, 95% CI 0.72-0.90, P<0.001) [5].

Both ACCOMPLISH arms included benazepril, and its primary endpoint was cardiovascular events. It does not establish amlodipine's kidney benefit on its own [5].

Creatinine, potassium and the edema question

The label reports that amlodipine has not been associated with clinically significant changes in routine laboratory tests, and that no clinically relevant changes were noted in serum potassium, glucose, triglycerides, cholesterol, uric acid, blood urea nitrogen, or creatinine [1].

Edema is the most common adverse reaction and it is dose related: 1.8% at 2.5 mg (N=275), 3.0% at 5 mg (N=296), 10.8% at 10 mg (N=268), versus 0.6% on placebo (N=520). It was more frequent in women, 14.6% versus 5.1% on placebo [1].

Documented renal risks: drug interactions

Amlodipine is a weak CYP3A inhibitor and is itself affected by CYP3A inhibitors, which raise its exposure and may require dose reduction; the label says to monitor for hypotension and edema. Diltiazem 180 mg daily with amlodipine 5 mg raised amlodipine exposure by 60% in elderly hypertensive patients [1].

A population-based Ontario cohort studied older adults, mean age 76, who were already taking a calcium-channel blocker and were newly prescribed clarithromycin (n=96,226) or azithromycin (n=94,083). Within 30 days, hospitalization with acute kidney injury occurred in 0.44% after clarithromycin versus 0.22% after azithromycin (OR 1.98, 95% CI 1.68-2.34) [4]. Amlodipine was the most commonly prescribed calcium-channel blocker in the cohort, at more than half of patients, but the findings covered the class as a whole and were not specific to amlodipine [4].

Amlodipine also may raise exposure to the transplant drugs. Cyclosporine trough levels rose by an average of 40% in renal transplant patients (N=11). Tacrolimus exposure rose 2.5- to 4-fold in healthy Chinese volunteers who express CYP3A5 (N=9) but not in non-expressers (N=6); a 3-fold rise was reported in one non-expresser transplant patient. The label recommends monitoring trough levels of both drugs and adjusting their dose [1].

Dosing when kidney function is low

The label says renal impairment does not significantly change amlodipine's pharmacokinetics, so patients with renal failure may take the usual starting dose [1]. The usual adult starting dose is 5 mg once daily, maximum 10 mg; small, fragile or elderly patients, patients with hepatic insufficiency, and patients adding amlodipine to other antihypertensives may be started on 2.5 mg once daily [1].

Putting it together

In AASK, ramipril had better kidney outcomes than amlodipine, especially in participants with more protein in their urine [2]. A review found that amlodipine's benefit in slowing kidney disease was seen when it was combined with a renin-angiotensin system blocker [3]. The label reports no clinically relevant change in creatinine or potassium [1]. In older adults taking calcium-channel blockers, clarithromycin was associated with more hospitalizations for acute kidney injury than azithromycin [4]. Amlodipine can also raise cyclosporine and tacrolimus levels; the label recommends monitoring their trough levels [1].