ORIGINAL ARTICLEComparison of the antiproteinuric effects of thecalcium channel blockers benidipine and amlodipineadministered in combination with angiotensin receptorblockers to hypertensive patients with stage 3–5chronic kidney diseaseMasanori Abe, Kazuyoshi Okada, Takashi Maruyama, Noriaki Maruyama and Koichi MatsumotoBenidipine, an L- and T-type calcium channel blocker, dilates both efferent and afferent arterioles and reduces glomerularpressure. Thus, it may exert renoprotective effects. We conducted an open-labeled, randomized trial to compare the bloodpressure (BP)-lowering effect and antiproteinuric effect of benidipine with those of amlodipine in hypertensive patients withmoderate-to-advanced-stage chronic kidney disease (CKD) (stages 3–5). These patients were already being administered thecurrent maximum recommended doses of angiotensin receptor blockers (ARBs). Patients with BP X140/90 mm Hg, despitetreatment with the maximum recommended dose of ARBs, were randomly assigned to two groups. The patients received eitherof the following treatment regimens: 4 mgdayÀ1of benidipine, which was increased up to a dose of 16 mgdayÀ1(B group;n¼24), and 2.5 mgdayÀ1of amlodipine, which was increased up to a dose of 10 mgdayÀ1amlodipine (A group; n¼23).After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was seen in both groups.The decrease in the urinary protein to creatinine ratio in the B group was significantly lower than that in the A group. Benidipineexerted antiproteinuric effect to a greater extent than did amlodipine, even in patients with diabetic nephropathy. We concludethat the addition of benidipine, rather than amlodipine, ameliorates urinary protein excretion in hypertensive patients with CKDwho are already being administered ARBs. Therefore, we propose a combination therapy with benidipine and ARBs, even forpatients with moderate-to-advanced-stage CKD.Hypertension Research advance online publication, 27 February 2009;doi:10.1038/hr.2009.11Keywords: angiotensin receptor blocker; benidipine; chronic kidney disease; proteinuriaINTRODUCTIONOn the basis ofthe results ofseveral mega trials, including the MDRD(Modification ofDiet in Renal Disease) study, a strict control ofbloodpressure (BP) is recommended in hypertensive patients with chronickidney disease (CKD).1Proteinuria is one of the clinical parametersfor diagnosing renal damage, particularly in glomerular hypertension,and it has been reported to be a risk factor and predictor ofcardiovascular events.2,3Therefore, suppression of proteinuria is amajor goal in the treatment of hypertensive patients with CKD. Therenoprotective effects of angiotensin receptor blockers (ARBs) andangiotensin-converting enzyme inhibitors (ACEIs) have been shownearlier.4–6Blockade ofthe renin–angiotensin system (RAS) with ARBsor ACEIs is currently the most effective pharmacological tool forrenoprotection. These agents reduce proteinuria more effectively thanother antihypertensive agents.7,8On the basis of these results, ARBsand ACEIs are recommended as first-choice drugs for the treatment ofhypertensive patients with CKD, according to the Japanese Society ofHypertension Guidelines for the Management of Hypertension(JSH 2004).9However, it is difficult-to-control BP with monotherapy,particularly in patients with CKD; this highlights the need for acombination drug therapy.10,11Calcium channel blockers (CCBs) reduce BP and are useful anti-hypertensive drugs. There are three types ofcalcium channels: L-typecalcium channels, which are distributed widely in smooth muscle cellsofperipheral resistance arteries; N-type channels, which are located inthe cells ofthe brain; and T-type channels, which are localized to thesinus node and the brain. In renal tissues, the L-type calcium channelsare present only in the afferent arterioles, whereas the N-type andT-type calcium channels are localized in both efferent and afferentarterioles.12,13Amlodipine is a representative CCB that is used widelyReceived 24 October 2008; revised 25 December 2008; accepted 12 January 2009Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, JapanCorrespondence: Dr M Abe, Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-kamimachi,Itabashi-ku, Tokyo 173-8610, Japan.E-mail: mabe@med.nihon-u.ac.jpHypertension Research (2009), 1–6& 2009 The Japanese Society of Hypertension All rights reserved 0916-9636/09 $32.00www.nature.com/hr
