慢性腎臓病を伴う高血圧患者に対するカルシウム拮抗薬ベニジピンの尿蛋白改善作用ならびに抗酸化作用 未治療高血圧患者における層別解析研究
慢性腎臓病 (Chronic Kidney Disease;CKD) が, 世界的に注目されている理由の一つは, CKDが末期腎不全への進展と心血管イベントの危険因子であることが明らかにされたからである. それらを阻止するためには, 厳格な降圧と蛋白尿の改善が重要視されている. 今回, われわれは, 未治療の高血圧CKD患者を対象に, カルシウム拮抗薬ベニジピン投与による降圧効果ならびに蛋白尿減少効果, 抗酸化効果を検討したので報告する. CKD合併未治療高血圧患者34例にカルシウム拮抗薬であるベニジピンを投与し, 1年間追跡した. 血圧, 尿蛋白クレアチニン比 (UP/cre) および過酸化...
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| Published in | 順天堂医学 Vol. 57; no. 6; pp. 610 - 616 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
順天堂医学会
31.12.2011
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0022-6769 2188-2134 |
| DOI | 10.14789/pjmj.57.610 |
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| Abstract | 慢性腎臓病 (Chronic Kidney Disease;CKD) が, 世界的に注目されている理由の一つは, CKDが末期腎不全への進展と心血管イベントの危険因子であることが明らかにされたからである. それらを阻止するためには, 厳格な降圧と蛋白尿の改善が重要視されている. 今回, われわれは, 未治療の高血圧CKD患者を対象に, カルシウム拮抗薬ベニジピン投与による降圧効果ならびに蛋白尿減少効果, 抗酸化効果を検討したので報告する. CKD合併未治療高血圧患者34例にカルシウム拮抗薬であるベニジピンを投与し, 1年間追跡した. 血圧, 尿蛋白クレアチニン比 (UP/cre) および過酸化脂質 (Lipid peroxide;LPO) を投与前後で測定した. 収縮期および拡張期血圧は, 投与前に155.4±17.8/91.5±12.2mmHgであったものが, 投与1年後には133.1±17.6/77.3±10.3mmHgに低下した (それぞれp<0.001). UP/creは, 投与前には1.50±1.50g/g creatinine (g/g cre) であったが, 1年後には0.79±1.06g/g creとなり, 有意に低下した (p=0.012). UP/creの変化率は, 65歳以上のCKD合併高血圧患者では, 65歳未満のその患者に比べ有意に大きかった (83.3%vs. 40.6%, p=0.042). また, LPOは, 投与前に1.39±0.67nmol/mlであったものが, 1年後には0.89±0.23nmol/mlとなり, 有意に低下した (p=0.023). 本研究では, CKD合併高血圧患者のなかで未治療に対象を限定しても, ベニジピンは尿蛋白を高齢者でより強く減少させた. これらの結果から, ベニジピンが尿蛋白改善効果を有することが示唆された. また, ベニジピンの投与によりCKD合併未治療高血圧患者のLPOレベルは低下したため, ベニジピンは抗酸化作用を有することが示唆された. |
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| AbstractList | 慢性腎臓病 (Chronic Kidney Disease;CKD) が, 世界的に注目されている理由の一つは, CKDが末期腎不全への進展と心血管イベントの危険因子であることが明らかにされたからである. それらを阻止するためには, 厳格な降圧と蛋白尿の改善が重要視されている. 今回, われわれは, 未治療の高血圧CKD患者を対象に, カルシウム拮抗薬ベニジピン投与による降圧効果ならびに蛋白尿減少効果, 抗酸化効果を検討したので報告する. CKD合併未治療高血圧患者34例にカルシウム拮抗薬であるベニジピンを投与し, 1年間追跡した. 血圧, 尿蛋白クレアチニン比 (UP/cre) および過酸化脂質 (Lipid peroxide;LPO) を投与前後で測定した. 収縮期および拡張期血圧は, 投与前に155.4±17.8/91.5±12.2mmHgであったものが, 投与1年後には133.1±17.6/77.3±10.3mmHgに低下した (それぞれp<0.001). UP/creは, 投与前には1.50±1.50g/g creatinine (g/g cre) であったが, 1年後には0.79±1.06g/g creとなり, 有意に低下した (p=0.012). UP/creの変化率は, 65歳以上のCKD合併高血圧患者では, 65歳未満のその患者に比べ有意に大きかった (83.3%vs. 40.6%, p=0.042). また, LPOは, 投与前に1.39±0.67nmol/mlであったものが, 1年後には0.89±0.23nmol/mlとなり, 有意に低下した (p=0.023). 本研究では, CKD合併高血圧患者のなかで未治療に対象を限定しても, ベニジピンは尿蛋白を高齢者でより強く減少させた. これらの結果から, ベニジピンが尿蛋白改善効果を有することが示唆された. また, ベニジピンの投与によりCKD合併未治療高血圧患者のLPOレベルは低下したため, ベニジピンは抗酸化作用を有することが示唆された. 慢性腎臓病(Chronic Kidney Disease ; CKD)が, 世界的に注目されている理由の一つは, CKDが末期腎不全への進展と心血管イベントの危険因子であることが明らかにされたからである. それらを阻止するためには, 厳格な降圧と蛋白尿の改善が重要視されている. 今回, われわれは, 未治療の高血圧CKD患者を対象に, カルシウム拮抗薬ベニジピン投与による降圧効果ならびに蛋白尿減少効果, 抗酸化効果を検討したので報告する. CKD合併未治療高血圧患者34例にカルシウム拮抗薬であるベニジピンを投与し, 1年間追跡した. 血圧, 尿蛋白クレアチニン比(UP/cre)および過酸化脂質(Lipid peroxide ; LPO)を投与前後で測定した. 収縮期および拡張期血圧は, 投与前に155.4±17.8/91.5±12.2mmHgであったものが, 投与1年後には133.1±17.6/77.3±10. 3mmHgに低下した(それぞれp<0.001). UP/creは, 投与前には1.50±1.50g/g creatinine(g/g cre)であったが, 1年後には0.79±1.06g/g creとなり, 有意に低下した(p=0.012). UP/creの変化率は, 65歳以上のCKD合併高血圧患者では, 65歳未満のその患者に比べ有意に大きかった(83.3% vs. 40.6%, p=0.042). また, LPOは, 投与前に1.39±0.67nmol/mlであったものが, 1年後には0.89±0.23 nmol/mlとなり, 有意に低下した(p=0.023). 本研究では, CKD合併高血圧患者のなかで未治療に対象を限定しても, ベニジピンは尿蛋白を高齢者でより強く減少させた. これらの結果から, ベニジピンが尿蛋白改善効果を有することが示唆された. また, ベニジピンの投与によりCKD合併未治療高血圧患者のLPOレベルは低下したため, ベニジピンは抗酸化作用を有することが示唆された. |
| Author | 鈴木, 仁 堀越, 哲 高良, 勝彦 富野, 康日己 鈴木, 佑介 |
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| References | 5) Japanese Society of Nephrology: Evidence-based practice guideline for the treatment of CKD. Clin Exp Nephrol, 2009; 13: 537-566. 18) TominoY, HamadaC, KurusuA, et al: One-year results of an open label study in anti-proteinuric effect of benidipine in elderly hypertensive patients with chronic kidney disease, J Nephrol. (in press 26) HayashiK, WakinoS, SuganoN, et al: Ca2+ channel subtypes and pharmacology in the kidney. Circ Res, 2007; 100: 342-353. 16) NakamuraT, SatoE, FujiwaraN, et al: Comparative effects of benidipine and amlodipine on proteinuria, urinary 8-OHdG, urinary L-FABP, and inflammatory and atherosclerosis markers in early-stage chronic kidney disease. Am J Med Sci, 2010; 339: 157-163. 1) IsekiK, IkemiyaY, IsekiC, et al: Proteinuria and the risk of developing end-stage renal disease. Kidney Int, 2003; 63: 1468-1474. 7) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 2002; 288: 2981-2997. 17) OhishiM, TakagiT, ItoN, et al: Renal-Protective Effect of T- and L-type Calcium Channel Blockers in Hypertensive Patients: An Amlodipine-to-Benidipine Changeover (ABC) Study. Hypertens Res, 2007; 30: 797-806. 10) FujitaT, AndoK, NishimuraH, et al: Cilnidipine versus Amlodipine Randomised Trial for Evaluation in Renal Desease (CARTER) Study Investigators. Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease. 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Arch Intern Med, 2007; 167: 2490-2496. 9) SuzukiH, SarutaT: Calcium Antagonist in Progressive Renal Insufficienct Study Group. Effects of calcium antagonist, benidipine, on the progression of chronic renal failure in the elderly: a 1-year follow-up. Clin Exp Hypertens, 2001; 23: 189-201. 11) TakenakaT, TakaneH, OkadaH, et al: Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney diseases. NDT Plus, 2009; 2: 192-193. 24) IinoY, HayashiM, KawamuraT, et al: Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study. Clin Exp Nephrol, 2003; 7: 221-230. 29) FurukawaT, YamakawaT, MideraT, et al: Selectivities of dihydropyridine derivatives in blocking Ca2+channel subtypes expressed in xnopusoocytes. J Pharmacol Exp Ther, 1999; 291: 464-473. 4) Japanese Society of Hypertension Committee, Ogihara T, Kikuchi K, Matsuoka H, et al: The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res, 2009; 32: 3-107. 13) YamadaH, SugaN, MaedaK, et al: Effects of combination therapy with angiotensin II type I receptor blockers and calcium channel blockers on renal function in hypertensive patients/a retrospective, “real-world” comparative study. Arzneimittel-Forschung (Drug Res), 2010; 60: 64-70. 2) IrieF, IsoH, SairenchiT, et al: The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population. Kidney Int, 2006; 69: 1264-1271. 32) YamamotoE, KataokaK, DongYF, et al: Benidipine, a dihydropyridine L-type/T-type calcium channel blocker, affords additive benefits for prevention of cardiorenal injury in hypertensive rats. J Hypertens, 2010; 28: 1321-1329. 15) MiyagawaK, DohiY, NakazawaA, et al: Renoprotective effect of calcium channel blockers in combination with an angiotensin receptor blocker in elderly patients with hypertension. A randomized crossover trial between benidipine and amlodipine. Clin Exp Hypertens, 2010; 32: 1-7. 22) ZhengY, ShiratoI, MaedaA, et al: Temocapril, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. J Nephrol, 2002; 15: 36-41. 31) MorikawaT, OkumuraM, KonishiY, et al: Effects of benidipine on glomerular hemodynamics and proteinuria in patients with nondiabetic nephropathy. Hypertens Res, 2002; 25: 571-576. 6) HemmelgarnBR, MannsBJ, LloydA, et al: Relation between kidney function, proteinuria, and adverse outcomes. JAMA, 2010; 303: 423-429. 8) Shiga Microalbuminuria Reduction Trial (SMART) Group, Uzu T, Sawaguchi M, Maegawa H, et al: Reduction of microalbuminuria in patients with type 2 diabetes: the Shiga Microalbuminuria Reduction Trial (SMART). Diabetes Care, 2007; 30: 1581-1583. 36) ShouI, WangLN, TakahashiY, et al: Effects of benidipine hydrochloride on antioxidant enzyme activity in stroke-prone spontaneous hypertensive rats (SHR-SP). J Clin Lab Anal, 1997; 11: 158-162. 23) TominoY, KawamuraT, KimuraK, et al: Antiproteinuriceffect of olmesartan in patients with IgA nephropathy. J Nephrol, 2009; 22: 224-231. 28) AkizukiO, InayoshiA, KitayamaT, et al: Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295 R. Eur J Pharmacol, 2008; 584: 424-434. 33) StruthersAD, MacDonaldTM: Review of aldosterone-and angiotensin II-induced target organ damage and prevention. Cardiovasc Res, 2004; 61: 663-670. 21) LiaoJ, KobayashiM, KanamaruY, et al: Effects of candesartan, an angiotensin II type 1 receptor blocker, on diabetic nephropathy in KK/Ta mice. J Nephrol, 2003; 16: 841-849. 14) InoueS, TominoY: Effects of calcium antagonists in hypertensive patients with renal dysfunction: a prospective, randomized, parallel trial comparing benidipine and nifedipine. Nephrology, 2004; 9: 265-271. 12) AbeM, OkadaK, MaruyamaT, et al: Comparison of the antiproteinuric effects of the calcium channel blockers benidipine and amlodipine administered in combination with angiotensin receptor blockers to hypertensive patients with stage 3-5 chronic kidney disease. Hypertens Res, 2009; 32: 270-275. 25) AgodoaLY, AppelL, BakrisGL, et al: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA, 2001; 285: 2719-2728. 27) HayashiK, WakinoS, HommaK, et al: Pathophysiological significance of T-type Ca2+ channels: role of T-type Ca2+ channels in renal microcirculation. J Pharmacol Sci, 2005; 99: 221-227. |
| References_xml | – reference: 12) AbeM, OkadaK, MaruyamaT, et al: Comparison of the antiproteinuric effects of the calcium channel blockers benidipine and amlodipine administered in combination with angiotensin receptor blockers to hypertensive patients with stage 3-5 chronic kidney disease. Hypertens Res, 2009; 32: 270-275. – reference: 15) MiyagawaK, DohiY, NakazawaA, et al: Renoprotective effect of calcium channel blockers in combination with an angiotensin receptor blocker in elderly patients with hypertension. A randomized crossover trial between benidipine and amlodipine. Clin Exp Hypertens, 2010; 32: 1-7. – reference: 7) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA, 2002; 288: 2981-2997. – reference: 17) OhishiM, TakagiT, ItoN, et al: Renal-Protective Effect of T- and L-type Calcium Channel Blockers in Hypertensive Patients: An Amlodipine-to-Benidipine Changeover (ABC) Study. Hypertens Res, 2007; 30: 797-806. – reference: 32) YamamotoE, KataokaK, DongYF, et al: Benidipine, a dihydropyridine L-type/T-type calcium channel blocker, affords additive benefits for prevention of cardiorenal injury in hypertensive rats. J Hypertens, 2010; 28: 1321-1329. – reference: 4) Japanese Society of Hypertension Committee, Ogihara T, Kikuchi K, Matsuoka H, et al: The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res, 2009; 32: 3-107. – reference: 28) AkizukiO, InayoshiA, KitayamaT, et al: Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295 R. Eur J Pharmacol, 2008; 584: 424-434. – reference: 6) HemmelgarnBR, MannsBJ, LloydA, et al: Relation between kidney function, proteinuria, and adverse outcomes. JAMA, 2010; 303: 423-429. – reference: 33) StruthersAD, MacDonaldTM: Review of aldosterone-and angiotensin II-induced target organ damage and prevention. Cardiovasc Res, 2004; 61: 663-670. – reference: 8) Shiga Microalbuminuria Reduction Trial (SMART) Group, Uzu T, Sawaguchi M, Maegawa H, et al: Reduction of microalbuminuria in patients with type 2 diabetes: the Shiga Microalbuminuria Reduction Trial (SMART). Diabetes Care, 2007; 30: 1581-1583. – reference: 5) Japanese Society of Nephrology: Evidence-based practice guideline for the treatment of CKD. Clin Exp Nephrol, 2009; 13: 537-566. – reference: 36) ShouI, WangLN, TakahashiY, et al: Effects of benidipine hydrochloride on antioxidant enzyme activity in stroke-prone spontaneous hypertensive rats (SHR-SP). J Clin Lab Anal, 1997; 11: 158-162. – reference: 21) LiaoJ, KobayashiM, KanamaruY, et al: Effects of candesartan, an angiotensin II type 1 receptor blocker, on diabetic nephropathy in KK/Ta mice. J Nephrol, 2003; 16: 841-849. – reference: 34) SunY, ZhangJ, LuL, et al: Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol, 2002; 161: 1773-1781. – reference: 18) TominoY, HamadaC, KurusuA, et al: One-year results of an open label study in anti-proteinuric effect of benidipine in elderly hypertensive patients with chronic kidney disease, J Nephrol. (in press) – reference: 3) AbbateM, ZojaC, RemuzziG: How does proteinuria cause progressive renal damage ? J Am Soc Nephrol, 2006; 17: 2974-2984. – reference: 22) ZhengY, ShiratoI, MaedaA, et al: Temocapril, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. J Nephrol, 2002; 15: 36-41. – reference: 24) IinoY, HayashiM, KawamuraT, et al: Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study. Clin Exp Nephrol, 2003; 7: 221-230. – reference: 19) AnnukM, SoveriI, ZilmerM, et al: Endothelial function, CRP and oxidative stress in chronic kidney disease. J Nephrol, 2005; 18: 721-726. – reference: 26) HayashiK, WakinoS, SuganoN, et al: Ca2+ channel subtypes and pharmacology in the kidney. Circ Res, 2007; 100: 342-353. – reference: 20) HallanS, AstorB, RomundstadS, et al: Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study. Arch Intern Med, 2007; 167: 2490-2496. – reference: 9) SuzukiH, SarutaT: Calcium Antagonist in Progressive Renal Insufficienct Study Group. Effects of calcium antagonist, benidipine, on the progression of chronic renal failure in the elderly: a 1-year follow-up. 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| Snippet | 慢性腎臓病 (Chronic Kidney Disease;CKD) が, 世界的に注目されている理由の一つは, CKDが末期腎不全への進展と心血管イベントの危険因子であることが... 慢性腎臓病(Chronic Kidney Disease ; CKD)が, 世界的に注目されている理由の一つは, CKDが末期腎不全への進展と心血管イベントの危険因子であることが... |
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| StartPage | 610 |
| SubjectTerms | カルシウム拮抗薬 ベニジピン 尿蛋白クレアチニン比 慢性腎臓病 (CKD) 過酸化脂質 |
| Subtitle | 未治療高血圧患者における層別解析研究 |
| Title | 慢性腎臓病を伴う高血圧患者に対するカルシウム拮抗薬ベニジピンの尿蛋白改善作用ならびに抗酸化作用 |
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| ispartofPNX | 順天堂医学, 2011/12/31, Vol.57(6), pp.610-616 |
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