Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria

ABSTRACT Benidipine inhibits both L- and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an

open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with

mild-to-moderate stage chronic kidney disease (CKD). Patients with BP⩾130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30–90 ml min−1 per 1.73 m2, and with albuminuria>30

 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of

the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (_n_=52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10

 mg per day (_n_=52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to

Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels

were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be

concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction. SIMILAR CONTENT BEING

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CHANNEL BLOCKER VERSUS ANGIOTENSIN RECEPTOR BLOCKER Article Open access 12 October 2024 INTRODUCTION According to the hyperfiltration theory, an increase in glomerular capillary pressure

(that is, glomerular hypertension) has an important role in the progression of diabetic and non-diabetic kidney disease.1, 2 Intraglomerular capillary pressure is dependent on the tone of

the glomerular arterioles as well as the level of systemic arterial pressure. Because angiotensin II is a potent constrictor of the efferent arterioles, angiotensin-converting enzyme (ACE)

inhibitors and angiotensin II receptor blockers (ARBs), which inhibit the generation or functions of angiotensin II, are effective in alleviating glomerular hypertension.3 Therefore, ACE

inhibitors or ARBs are the first-line treatment options for patients with chronic kidney disease (CKD). Following recent molecular biological studies, Ca channels have been classified into

five subtypes, namely, L, T, N, P/Q and R, according to their location and function.4, 5 Three types of Ca channel blockers (CCBs), the L-, T-, and N-type CCBs, are in clinical use. Both

L-type and T-type Ca channels are present in the afferent arterioles, whereas only T-type Ca channels are present in the efferent arterioles. Benidipine has been shown to block both L-type

and T-type Ca channels and causes dilatation of both efferent and afferent arterioles.6 Aldosterone has an important role in the pathophysiology of hypertension, cardiac hypertrophy and

heart failure. Targeting aldosterone synthesis and/or secretion represents a potentially useful approach for the prevention of cardiovascular disease.7 Aldosterone is synthesized in the zona

glomerulosa of the adrenal glands, in which it is secreted in a Ca2+-dependent manner in response to stimuli such as angiotensin II, adrenocorticotropic hormone and increased extracellular

K+.8 Furthermore, T-type Ca channels are present in the adrenal glands and the results of a recent _in vivo_ study have demonstrated that T-type CCBs inhibit aldosterone production in

cultured adrenal cells.9 However, there have been few clinical studies indicating the role of CCBs in reducing plasma aldosterone concentration in patients with CKD. Therefore, we considered

that it would be intriguing to compare the effects of a T-type CCB and an L-type CCB on albuminuria and on the renin–angiotensin–aldosterone system in patients with CKD. In the present

randomized study, we compared the clinical effects of benidipine (an L- and T-type CCB) with amlodipine (an L-type CCB) in albuminuric patients with mild-to-moderate stage CKD. METHODS We

conducted a 6-month, single-center, prospective, randomized and open-label clinical trial. This study was designed to compare the effects of benidipine and amlodipine on blood pressure (BP),

plasma aldosterone levels and urinary albumin excretion ratio in hypertensive and albuminuric patients with CKD. Participants were already receiving the maximum recommended dose of ARBs.

All study participants provided written informed consent, and the trial protocol was approved by the ethics committee of our institution. This study was conducted in accordance with the

Declaration of Helsinki. This prospective study was conducted between June 2009 and May 2010 and the subjects were followed up for 6 months. The enrollment criteria included (1) hypertension

(that is, systolic/diastolic BP⩾130/80 mm Hg, measured in the sitting position on at least two separate clinic visits); (2) stage 2–3 CKD (that is, an estimated glomerular filtration rate

(eGFR) of 30–90 ml min−1 per 1.73 m2) with albuminuria (that is, urinary albumin/creatinine (Cr) ratio⩾30 mg g−1; average of two consecutive measurements taken during a 4-week period before

treatment); and (3) treatment with the maximum recommended dose of an ARB (80 mg per day telmisartan or 40 mg per day olmesartan) for at least 8 weeks before the study. The exclusion

criteria were (1) age <20 years or >80 years; (2) hypertensive emergency; (3) history of severe heart failure, angina, myocardial infarction or stroke within 6 months before the start

of the trial; (4) previous treatment with steroids or immunosuppressants; (5) renovascular hypertension, as determined by renal Doppler ultrasonography before enrollment in the study, or

endocrine hypertension; and (6) severe diabetes mellitus, resulting in hospitalization because of extremely high plasma glucose, or with complications such as diabetic ketoacidosis. Subjects

were randomly assigned to two groups before the start of the study. An independent investigator, who had no previous knowledge of the subjects before the commencement of the trial,

monitored randomization in the order of entry of the subjects; then, the details of assignment were immediately given to the individual investigators. Dynamic balancing randomization was

carried out on the basis of the levels of serum Cr (sCr), urinary albumin/Cr ratio measured at the time of registration, and the presence or absence of diabetic nephropathy. Thus, we ensured

that there were no significant differences between the baseline characteristics of the two groups. Patients received either of the following two treatment regimens: benidipine, 2 mg per

day, which was increased to daily doses of 8 mg (benidipine group), and amlodipine, 2.5 mg per day, which was increased to daily doses of 10 mg (amlodipine group). In addition, none of the

subjects from our previous study10 was included in either group in this study. BP was measured at the outpatient clinic at fixed times after the medications were administered. BP measurement

was carried out according to the Japanese Society of Hypertension 2009 guidelines.11 BP was measured monthly using a sphygmomanometer (Nippon Colin, Tokyo, Japan) in duplicate with the

patient in the sitting position after a 5-min rest. Patients, particularly those with dietary restrictions, were given guidance on how to maintain their diet. Doses of ARBs and ACE

inhibitors were not altered during the study period. The target BP level was <130/80 mm Hg. During the study period, patients were administered combination drug therapy together with

other conventional antihypertensive agents at baseline. Withdrawal of treatment was considered for patients who developed an allergy/intolerance to benidipine or amlodipine during the study

period, developed a hypertensive emergency, or developed any other condition or received another therapy that, in the opinion of the investigators, might pose a risk for the patient or

confound the results of the study. Furthermore, patients who were administered additional antihypertensive medications (other than ARBs or CCBs) to achieve the target BP, because benidipine

or amlodipine failed to reduce the BP to the target level, were not included in the analysis. The primary end point was change in urinary albumin/Cr ratio measured from baseline to 1, 3 and

6 months after the start of treatment. All parameters for monitoring the effects of the drugs were evaluated once a month during the 6-month period of treatment. Laboratory values of, for

example, sCr and electrolytes were measured using commercial kits employing routinely used clinical chemistry procedures. To assess urinary albumin excretion, we measured the urinary

concentrations of albumin and Cr (albumin/Cr ratio) in an early-morning spot urine sample. Urinary albumin was measured by the pyrogallol red method. Treatment compliance and safety

variables were monitored at each visit to our hospital. Plasma renin activity and aldosterone concentrations were measured by radioimmunoassay at a contact laboratory (SRL, Tokyo, Japan) at

baseline and at the end of the study in the supine position after a 20-min rest. To assess urinary Na and K excretion, we measured the urinary concentrations of Na and K (urinary Na/K ratio)

at baseline and at the end of the study by using early-morning spot urine sample. Glomerular filtration rate was estimated using the final recommended modified equation for Japanese

patients by the Japanese Society of Nephrology-CKD Initiatives (JSN-CKDI), because eGFR obtained by this method is more accurate for Japanese patients with CKD.12 The following formula was

used: eGFR (ml min−1 per 1.73 m2)=194 × sCr–1.094 × age–0.287 ( × 0.739 for women). STATISTICAL ANALYSIS Data were analyzed according to the randomly assigned groups, regardless of

participants' subsequent medication (intention-to-treat analysis) and expressed as mean±s.e.m. Baseline characteristics of the enrolled patients were compared between treatment groups

using the unpaired _t_-test. The mean values of the two groups were compared by the unpaired _t_-test. Analysis of variance with repeated measurements and subsequent multiple comparison

tests were applied to determine the effect of treatment on BP, heart rate and urinary albumin/Cr ratio. Statistical significance was set at _P_<0.05. RESULTS STUDY POPULATION AND BASELINE

CHARACTERISTICS A total of 104 subjects were enrolled in this study and randomly allocated to the benidipine group (_n_=52) or amlodipine group (_n_=52). Baseline characteristics and

medications at baseline in the two groups are shown in Table 1. No significant differences were observed between the two groups with regard to baseline characteristics or the number of

patients with diabetic nephropathy. Adequate BP control had not been achieved at baseline in any of the enrolled patients. During treatment, two subjects from each group withdrew from the

study because additional antihypertensive medications (benidipine group: furosemide, _n_=1; thiazide diuretics, _n_=1; amlodipine group: furosemide, _n_=2) were required to achieve the

target BP or improve the edema. Therefore, 100 subjects completed the trial. BP-LOWERING EFFECT The final doses of benidipine and amlodipine were 6.3±0.3 and 5.4±0.4 mg per day,

respectively, in the two groups. Figure 1 shows that systolic and diastolic BPs were significantly lower in both groups at 1 month after the initiation of CCB therapy compared with baseline

values. Systolic and diastolic BP did not differ between the two groups during the course of treatment. In the last month of treatment, no differences were observed between systolic BP

(benidipine group: 128.3±1.0 mm Hg; amlodipine group: 127.7±1.0 mm Hg, not significant (NS)) and diastolic BP (benidipine group: 73.3±1.4 mm Hg; amlodipine group: 73.3±1.5 mm Hg, NS) in the

two groups. The target BP value (130/80 mm Hg) was achieved in 56.0 and 60.0% of all subjects in the benidipine and amlodipine groups (NS), respectively. As shown in Figure 1, heart rate at

the end of the study was significantly reduced in the benidipine group compared with baseline (benidipine group: from 75.1±1.4 to 73.7±1.3 beats per min, _P_<0.001; amlodipine group: from

74.5±1.7 to 74.8±1.6 beats per min, NS), but this difference was not observed between the two groups at the end of the trial (benidipine group: 73.7±1.3 beats per min; amlodipine group:

74.8±1.6 beats per min, NS). RENOPROTECTIVE EFFECTS sCr levels were not significantly changed in either group after 6 months of treatment, and the difference observed at the end of the study

between the two groups was not significant (benidipine group: 1.30±0.07 mg per 100 ml; amlodipine group: 1.30±0.06 mg per 100 ml, NS). Furthermore, eGFR was not significantly changed in

either group at the end of the study period; the difference between the groups was also not significant (benidipine group: 44.3±2.1 ml min−1 per 1.73 m2; amlodipine group: 42.7±1.9 ml min−1

per 1.73 m2, NS). Although the urinary albumin/Cr ratio did not change significantly in the amlodipine group throughout the study period, it did decrease significantly in the benidipine

group from 3 months of treatment compared with the baseline value. Furthermore, the urinary albumin/Cr ratio in the last month was significantly lower in the benidipine group than in the

amlodipine group (benidipine group: 120±14 mg per g Cr; amlodipine group: 163±34 mg per g Cr, _P_<0.01). When the percent change from baseline was calculated, there was a significant

difference between the two groups from 3 months of treatment (−24.8±4.6 % _vs_. −0.5±0.1%, _P_<0.0001) (Figure 2). PLASMA RENIN ACTIVITY AND ALDOSTERONE LEVELS As shown in Figure 3,

plasma renin activity was not significantly changed in either group after 6 months of treatment, and the difference at the end of the study between the two groups was not significant

(benidipine group: from 1.75±0.18 to 1.98±0.18 ng ml−1 per hour; amlodipine group: from 1.75±0.25 to 1.97±0.33 ng ml−1 per hour, NS). Plasma aldosterone levels were not significantly changed

in the amlodipine group. However, plasma aldosterone levels were decreased in the benidipine group, and there was a significant difference between the two groups at the end of study

(71.9±5.0 _vs_. 90.4±5.0 pg ml−1, _P_<0.05). SERUM AND URINARY NA+ AND K+ LEVELS Although the urinary Na/Cr ratio tended to increase in both groups, this was not statistically

significant. However, the urinary K/Cr ratio was significantly decreased and the Na/K ratio was significantly increased in the benidipine group compared with the baseline value. In contrast,

there were no significant changes in serum Na or K level in either group (Table 2). ADVERSE EVENTS Adverse reactions were not observed in the benidipine group or the amlodipine group.

However, during treatment, two subjects from each group withdrew from the study because additional antihypertensive medications (furosemide, _n_=3; thiazide diuretics, _n_=1) were required

to achieve the target BP (_n_=1), and edema developed in the lower limbs (_n_=3). Edema resolved with diuretic therapy without discontinuation of CCBs. There were no severe adverse reactions

in any of the subjects in either group. DISCUSSION Proteinuria is detrimental to the kidney because ultrafiltration of proteins across the glomerular basement membrane brings about

mesangial and tubular protein overload, which provokes inflammation and ultimately results in glomerulosclerosis and tubulo-interstitial fibrosis.13, 14 It is known that proteinuria is

associated with the risk of cardiovascular disease.15, 16, 17 Therefore, because of the antiproteinuric effect, benidipine would seem to be more advantageous than an L-type CCB, not only by

slowing the progression of renal tissue injuries but also by reducing the incidence of cardiovascular events in patients with CKD. In terms of reducing proteinuria in diabetic and

non-diabetic renal disease, ACE inhibitors and ARBs have been shown to be more effective than other classes of antihypertensive agents.18, 19 However, it has been reported that the

antiproteinuric effects of T-type CCBs are not mediated by angiotensin II inhibition but by blockade of T-type Ca channels in the glomerular arterioles.6 Furukawa _et al._20 surveyed the

blocking activity of various CCBs on L-/T-/N-type Ca current in Xenopus oocytes. Although both benidipine and amlodipine exhibited blocking function on both L- and T-type Ca channels,

benidipine predominantly blocked the T-type Ca channel, whereas amlodipine predominantly blocked the L-type Ca channel. Furthermore, the concentration required for benidipine to exert the

inhibitory effect on T-type Ca channels can be achieved at clinically relevant doses of benidipine used for the treatment of hypertension.20, 21 Therefore, benidipine, an L-/T-type CCB,

should offer additive benefits over CCB-inhibiting L-type Ca channels, but not T-type Ca channels. Furthermore, T-type Ca channels are distributed in the cardiac sinus node and are closely

associated with pacemaking potentials.4, 22, 23 Therefore, in this study, it was suggested that the significant decrease in heart rate was induced by the benidipine treatment. However,

further studies are needed to clarify the effect of benidipine in this regard because little data exist for this finding. Recently, it has been demonstrated that aldosterone can directly

damage various organs, including the heart and blood vessels, via mineralocorticoid receptors, independent of changes in BP.24, 25, 26 It has been suggested that hypertensive incidents and

organ damage in humans may occur even at plasma aldosterone levels within the normal physiological range.24, 27, 28, 29 Therefore, targeting aldosterone synthesis and release may be

clinically important in preventing cardiovascular disease. Ca2+ ions are conveyed through the T-type Ca channel to the mitochondria, where they activate aldosterone synthesis, which in turn

stimulates T-type Ca channel expression,30, 31 creating a positive feedback loop of aldosterone biosynthesis in adrenal cells. Efonidipine, another T-type CCB, has been shown to inhibit

aldosterone synthesis and secretion _in vitro_,9 as well as in both healthy subjects and patients with essential hypertension.32, 33 In this study, benidipine and amlodipine had no

significant effect on clinic blood pressure, but both heart rate and plasma aldosterone level were significantly decreased in the benidipine treatment group. T-type CCBs inhibit renin

secretion and renin gene expression _in vivo_, whereas L-type CCBs function as stimulators of the renin system.34, 35 T-type CCBs have a dual effect on plasma renin activity and renin

messenger RNA expression _in vivo_, with low concentrations stimulating and high concentrations inhibiting the renin system.36 However, in this study, plasma renin activity did not change

significantly; therefore, the change in aldosterone may not have been due to the effect of renin but rather to a direct inhibition of aldosterone secretion. Furthermore, although serum Na

and K levels were not changed after treatment with either CCB, urinary K/Cr and Na/K ratios were decreased in the benidipine group without any decrease in eGFR. Therefore, these findings

suggest that benidipine decreased plasma aldosterone levels without any effect on serum Na and K levels when administered to patients with mild-to-moderate stage CKD. Thus, in addition to

lowering blood pressure, benidipine would be expected to provide renoprotection by inhibiting aldosterone production. Long-term treatment with ACE inhibitors or ARBs can cause escape or

rebound of plasma aldosterone levels. In such a situation, addition of a mineralocorticoid receptor blocker has been shown to reduce proteinuria in patients taking inhibitors of the

renin–angiotensin–aldosterone system for the treatment of hypertension and kidney disease; a T-type CCB might be a suitable addition for the purpose of inhibiting aldosterone production and

managing aldosterone escape. Our study is limited by the relatively small sample size and short period of treatment. Moreover, although a prospective, randomized, open-label and

parallel-group comparison design was used in this study, more longitudinal, double-blind, comparative and multicenter clinical trials should be conducted in a larger number of patients in

order to further clarify the comparative usefulness of these two agents. To examine the effects of aldosterone reduction, we measured the urinary Na/K ratio using early-morning spot urine.

However, because this method might not accurately reflect the plasma aldosterone reduction, measuring the urinary Na/K ratio of a 24-h urine collection is needed. In addition to BP profile,

the requirement for renal replacement therapy and other renal or cardiovascular events should also be considered as end points. In conclusion, the present study showed that benidipine, an L-

and T-type CCB, results in a greater reduction of albuminuria and plasma aldosterone than amlodipine, an L-type CCB, in patients with CKD. These effects of benidipine would seem to make the

drug more advantageous in terms of the progression of renal dysfunction and preventing cardiovascular tissue and organ injuries in patients with hypertension and CKD. However, further

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AND AFFILIATIONS * Division of Nephrology, Department of Internal Medicine, Hypertension and Endocrinology, Nihon University School of Medicine, Tokyo, Japan Masanori Abe, Kazuyoshi Okada, 

Noriaki Maruyama, Shiro Matsumoto, Takashi Maruyama, Takayuki Fujita, Koichi Matsumoto & Masayoshi Soma * Division of General Medicine, Department of Internal Medicine, Nihon University

School of Medicine, Tokyo, Japan Masayoshi Soma Authors * Masanori Abe View author publications You can also search for this author inPubMed Google Scholar * Kazuyoshi Okada View author

publications You can also search for this author inPubMed Google Scholar * Noriaki Maruyama View author publications You can also search for this author inPubMed Google Scholar * Shiro

Matsumoto View author publications You can also search for this author inPubMed Google Scholar * Takashi Maruyama View author publications You can also search for this author inPubMed Google

Scholar * Takayuki Fujita View author publications You can also search for this author inPubMed Google Scholar * Koichi Matsumoto View author publications You can also search for this

author inPubMed Google Scholar * Masayoshi Soma View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Masanori Abe.

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Abe, M., Okada, K., Maruyama, N. _et al._ Benidipine reduces albuminuria and plasma aldosterone in

mild-to-moderate stage chronic kidney disease with albuminuria. _Hypertens Res_ 34, 268–273 (2011). https://doi.org/10.1038/hr.2010.221 Download citation * Received: 09 July 2010 * Revised:

12 August 2010 * Accepted: 24 August 2010 * Published: 02 December 2010 * Issue Date: February 2011 * DOI: https://doi.org/10.1038/hr.2010.221 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * albuminuria * aldosterone * amlodipine * benidipine * chronic kidney disease