View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector http://www.kidney-international.org original article & 2007 International Society of Nephrology Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease T Fujita1, K Ando1, H Nishimura2, T Ideura3, G Yasuda4, M Isshiki1 and K Takahashi1 on behalf of the Cilnidipine versus Amlodipine Randomized Trial for Evaluation in Renal Disease (CARTER) Study Investigators 1Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Division of Internal Medicine, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; 3Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan and 4Division of Nephrology, Yokohama City University Medical Center, Yokohama, Japan Cilnidipine, a dual L-/N-type calcium channel blocker, dilates Based on the accumulating data from a large number of both efferent and afferent arterioles and is renoprotective. clinical mega-trials,1–5 it has been established that an Our multi-center, open-labeled, and randomized trial inhibitor of the renin–angiotensin system (RAS), such as an compared the antiproteinuric effect of cilnidipine with that angiotensin-converting enzyme (ACE) inhibitor and an of amlodipine in hypertensive patients with kidney disease. angiotensin II type 1 receptor blocker (ARB), has an apparent A group of 339 patients, already receiving renin–angiotensin renoprotective effect. Although the guidelines for the system inhibitor treatment, were randomly assigned to management of hypertension6–8 recommend that blood cilnidipine or amlodipine. The primary endpoint was a pressure (BP) should be strictly controlled in hypertensive decrease in the urinary protein to creatinine ratio. After patients with kidney disease, adequate BP levels are seldom 1-year of treatment, systolic and diastolic blood pressures achieved with only one RAS inhibitor. Actually, combination of were significantly reduced in both groups which did not two to three antihypertensive drugs is required to decrease BP differ between them. The urinary protein to creatinine ratio to target levels, especially in patients with kidney disease.9 One significantly decreased in the cilnidipine compared to the of the main candidates for a combination with an RAS inhibitor amlodipine group. Cilnidipine exerted a greater is a dihydropyridine-type calcium channel blocker (CCB), antiproteinuric effect than amlodipine even in the subgroup because it reduces BP even in patients who are sometimes whose blood pressure fell below the target level. This study considered relatively resistant to antihypertensive drugs.10 suggests that cilnidipine is superior to amlodipine in However, evidence for the renoprotective effect of preventing the progression of proteinuria in hypertensive dihydropyridine CCBs is inconsistent. For example, ramipril patients when coupled with a renin–angiotensin system had a greater renoprotective effect compared with amlodi- inhibitor. pine in the African American Study of Kidney Disease and 4 Kidney International (2007) 72, 1543–1549; doi:10.1038/sj.ki.5002623; Hypertension (AASK) study. Moreover, the risk of a published online 17 October 2007 doubling of the serum creatinine (Cr) was similar between KEYWORDS: L-/N-type calcium channel blocker; L-type calcium channel amlodipine and placebo groups in the Irbesartan Diabetic blocker; proteinuria; kidney disease; hypertension Nephropathy Trial (IDNT).11 In a recent meta-analysis, the mean change in urinary protein was approximately þ 2% for dihydropyridine CCBs.12 On the other hand, the antiprotei- nuric effect of cilnidipine has been shown in several types of hypertensive animal models13,14 and hypertensive patients with kidney disease.15,16 The addition of a dihydropyridine CCB to treatment with an RAS inhibitor is also associated with inconsistent renal effects. The Blood-pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease Trial (REIN-2) group showed that the addition Correspondence: T Fujita, Department of Nephrology and Endocrinology, of felodipine was not of further renal benefit in patients with University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, non-diabetic proteinuric nephropathies and background of 17 Tokyo 113-8655, Japan. E-mail: [email protected] ramipril therapy. On the other hand, cilnidipine further Received 28 May 2007; revised 3 August 2007; accepted 14 August reduced urinary albumin in patients with type II diabetic 18 2007; published online 17 October 2007 nephropathy under treatment with valsartan. Kidney International (2007) 72, 1543–1549 1543 original article T Fujita et al.: Antiproteinuric effect of cilnidipine This inconsistency may be due to the different specificity group: diuretic n ¼ 14, a-blocker n ¼ 4, b-blocker n ¼ 1). for calcium channels of each dihydropyridine CCB;19 there During treatment, 32 subjects from the cilnidipine group are several variants of calcium channels, such as L, N, T, P/Q, (adverse reaction: n ¼ 9, cardiovascular event: n ¼ 1, death: and R.20,21 Actually, cilnidipine, an L-/N-type dihydro- n ¼ 2, lost to follow-up: n ¼ 20 (discontinuation: n ¼ 13, pyridine CCB, was shown to suppress renal injury in moving away: n ¼ 4, protocol violation: n ¼ 3)) and 30 hypertensive animals and humans13–16 but amlodipine4,11 subjects from the amlodipine group (adverse reaction: and felodipine,17 an L-type CCBs, were not. Cilnidipine had a n ¼ 13, cardiovascular event: n ¼ 4, death: n ¼ 3, lost to greater renoprotective effect than amlodipine in rat14 and follow-up: n ¼ 10 (discontinuation: n ¼ 8, moving away: small-size clinical studies.16 The blockade of N-type calcium n ¼ 2)) withdrew from the study. channels is able to inhibit renal sympathetic nerve activity14 and the resulting efferent arteriolar vasodilation protected the Changes in BP and heart rate glomeruli through the attenuation of glomerular hyperten- Systolic BP was slightly but significantly (Po0.05) greater at sion.13 However, because L-type calcium channels do not 2 months of treatment in the amlodipine group than in the express in glomerular efferent arterioles,22 the renoprotective cilnidipine group but did not differ at the other time points effects of an L-type CCB are expected to be lower than those of an L-/N-type CCB. There is still a lack of clinical trials comparing the renoprotective effects of an L-/N-type and L- Table 1 | Baseline characteristics type CCBs added to treatment with an RAS inhibitor, which Variable Cilnidipine Amlodipine P-value is frequently prescribed for hypertensive disease in clinical n 179 160 practice. Thus, we compared the antiproteinuric effects of Age (years) 59.9713.3 59.3712.9 NS cilnidipine with those of amlodipine in hypertensive patients Sex (male/female) 121/58 93/67 NS with kidney disease who were already under treatment with an RAS inhibitor. Causative disease Diabetic nephropathy 70 59 Primary renal disease 57 61 RESULTS Hypertensive 34 26 NS Study population nephrosclerosis g Three hundred and fifty subjects were enrolled for this study Others 18 14 and of them 11 were excluded based on the selection criteria BP (Figure 1). Thus, 339 subjects (these were 90.2% of required Systolic BP (mm Hg) 152.4714.8 152.4714.8 NS sample size with our estimation) were randomly allocated to Diastolic BP (mm Hg) 86.979.6 88.079.4 NS the cilnidipine group (n ¼ 179) or amlodipine group Heart rates (beats per min) 76712 74710 NS (n ¼ 160). The baseline characteristics of the subjects in the Body mass index (kg mÀ2) 24.673.7 24.874.1 NS two groups are shown in Table 1 and baseline medication is Urinary protein/Cr ratio 192172126 171271572 NS shown in Table 2. There were no significant differences (mg gÀ1) Serum Cr (mg dlÀ1) 1.2770.58 1.2970.60 NS between the two groups. The final dose was 7 7 7 À1 Serum total cholesterol 210 44 218 43 NS 11.5 5.6 mg day in the cilnidipine group and (mg dlÀ1) À1 5.372.4 mg day in the amlodipine group. Twenty subjects Serum HDL cholesterol 56720 55716 NS from the cilnidipine group and 17 from the amlodipine (mg dlÀ1) 7 7 group were added antihypertensive drugs other than a CCB Serum triglycerides 169 183 182 112 NS (mg dlÀ1) or an RAS inhibitor during the treatment (cilnidipine group: Diabetes mellitus 81 (45%) 67 (42%) NS diuretic n ¼ 12, a-blocker n ¼ 5, b-blocker n ¼ 5; amlodipine Cerebrovascular disease 11 (6%) 7 (4%) NS Ischemic heart disease 9 (5%) 9 (6%) NS BP, blood pressure, Cr, creatinine, HDL, high-density lipoprotein; NS, not significant. 350 assessed for eligibility 11 excluded as ineligible Table 2 | Baseline medication 339 randomized Medication Cilnidipine Amlodipine P-value 179 cilnidipine 160 amlodipine RAS inhibitor ARB 114 98 32 discontinued study drug 30 discontinued study drug ACE inhibitor 41 45 NS 9 adverse reaction g 13 adverse reaction ARB+ACE inhibitor 24 17 1 cardiovascular events 4 cardiovascular events Diuretics 45 45 NS 2 died 3 died 20 lost to follow-up 10 lost to follow-up b-Blocker 16 17 NS a-Blocker 17 16 NS Central sympatholytic agent 1 1 NS 147 completed study 130 completed study ACE, angiotensin-converting enzyme; ARB, angiotensin II type 1 blocker; NS, not Figure 1 | Flow of participants throughout the study. significant; RAS, renin-angiotensin system. 1544 Kidney International (2007) 72, 1543–1549 T Fujita et al.: Antiproteinuric effect of cilnidipine original article (Figure 2). Diastolic BP did not differ between the two but not in the amlodipine group ( þ 13.977.7%: s.e.m.), groups during the treatment. In the last month of treatment, showing a significant (Po0.01) difference between the two systolic (cilnidipine; 133.1715.6 mm Hg, amlodipine; groups. Even in subgroups with different baseline, urinary 134.5716.6 mm Hg, NS) and diastolic (75.678.7 vs protein/Cr ratio, age, sex, or BP after the 12 months of 77.979.4 mm Hg, NS) BP did not differ either.