桑原 政成

BACKGROUND: Hyperuricemia is a risk factor for the onset of chronic kidney disease (CKD) and is significantly associated with the progression of CKD. However, there is no sufficient evidence by interventional research supporting a cause-effect relationship. Hyperuricemic patients without gouty arthritis, whose serum urate (SUA) concentration is ≥8.0 mg/dL and who have a complication, are treated by pharmacotherapy in addition to lifestyle guidance. Nevertheless, there is no evidence that rationalizes pharmacotherapy for patients with hyperuricemia who have no complication and whose SUA concentration is below 9.0 mg/dL. METHODS/DESIGN: The FEATHER (FEbuxostat versus placebo rAndomized controlled Trial regarding reduced renal function in patients with Hyperuricemia complicated by chRonic kidney disease stage 3) study is a prospective, multicenter, double-blind, randomized, placebo-controlled trial of febuxostat-a novel, nonpurine, selective, xanthine oxidase inhibitor. The present study will enroll, at 64 medical institutions in Japan, 400 Japanese patients aged 20 years or older who have hyperuricemia without gouty arthritis, who present CKD stage 3, and whose SUA concentration is 7.1-10.0 mg/dL. Patients are randomly assigned to either the febuxostat or the control group, in which febuxostat tablets and placebo are administered orally, respectively. The dosage of the study drugs should be one 10-mg tablet/day at weeks 1 to 4 after study initiation, increased to one 20-mg tablet/day at weeks 5 to 8, and elevated to one 40-mg tablet/day at week 9 and then maintained until week 108. The primary endpoint is estimated glomerular filtration rate (eGFR) slope. The secondary endpoints include the amount and percent rate of change in eGFR from baseline to week 108, the amount and percent rate of change in SUA concentration from baseline to week 108, the proportion of patients who achieved an SUA concentration≤6.0 mg/dL, and the incidence of renal function deterioration. DISCUSSION: The present study aims to examine whether febuxostat prevents a further reduction in renal function as assessed with eGFR in subjects and will (1) provide evidence to indicate the inverse association between a reduction in SUA concentration and an improvement in renal function and (2) rationalize pharmacotherapy for subjects and clarify its clinical relevance. TRIAL REGISTRATION: UMIN Identifier: UMIN000008343.

PURPOSE: Long-term effects of a low-dose hydrochlorothiazide (HCTZ) with losartan (LOS) on uric acid (UA) metabolism as well as glucose metabolism have been studied in hypertensive patients in comparison with those of a low-dose HCTZ with telmisartan (TEL). METHOD: Fifty-nine hypertensive patients were allocated to a combination therapy with either losartan (50 mg/day)/HCTZ (12.5 mg/day) (LOS + HCTZ group: n = 37) or telmisartan (40 mg/day)/HCTZ (12.5 mg/day) (TEL + HCTZ group: n = 22), respectively. Before and 1 year after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. RESULTS: Both systolic and diastolic blood pressures significantly decreased in two groups, without any statistical differences among them. LOS + HCTZ caused no changes in the serum UA level or the ratio of UA clearance to creatinine clearance (CUA/Ccr), whereas TEL + HCTZ significantly increased the serum UA level and reduced CUA/Ccr. LOS + HCTZ did not influence CUA/Ccr in patients with their serum UA below 5.4 mg/dl, while LOS + HCTZ significantly increased CUA/Ccr in patients with their serum UA above 5.5 mg/dl. TEL + HCTZ significantly reduced CUA/Ccr in patients with their serum UA below and above 5.4 mg/dl to increase serum UA level significantly. Neither combination therapies caused any changes in fasting plasma glucose, HbA1c and HOMA-R. In patients with their serum UA level above 5.4 mg/dl, TEL + HCTZ increased HOMA-R, whereas LOS + HCTZ did not. CONCLUSIONS: LOS + HCTZ did not influence UA metabolism as well as glucose metabolism, likely because of inhibitory action of losartan on URAT1, although TEL + HCTZ were accompanied with impairment of the UA metabolism and glucose metabolism.

PURPOSE: To examine effects of a long-acting calcium channel blocker (CCB) azelnidipine on uric acid metabolism in hypertensive patients. METHODS: Azelnidipine was administered to 72 patients at a daily dose of 8 mg or 16 mg. In 22 cases out of the 72 patients, a different CCB was switched to azelnidipine. Blood pressure was measured and biochemical parameters of blood and urine were evaluated before and 2-3 months after the administration. RESULTS: Azelnidipine significantly decreased both systolic and diastolic blood pressure and the heart rate. It decreased both serum urate levels and the urinary uric acid to creatinine ratio (Uur/Ucr), but did not affect the uric acid clearance to creatinine clearance ratio (Cur/Ccr). Azelnidipine decreased both Uur/Ucr and Cur/Ccr in patients with Uur/Ucr ≥ 0.5 or ≥ 0.34, although it did not change these clearance parameters in patients with Uur/Ucr <0.5 or <0.34. Azelnidipine decreased the serum urate levels and Uur/Ucr in hyperuricemic patients with uric acid levels ≥ 7.0 mg/dL in males and ≥ 6.0 mg/dL in females. It did not change these parameters in normouricemic patients with serum urate levels <7.0 mg/dL in males and <6.0 mg/dL in females. Azelnidipine decreased Uur/Ucr and Cur/Ccr in hyperuricemic patients with normal or over excretion of uric acid, although it did not change these clearance parameters in hyperuricemic patients with uric acid hypoexcretion. CONCLUSIONS: Azelnidipine decreased the serum urate acid levels and Uur/Ucr, and this response was most prominent in hyperuricemic patients or patients with normal and over excretion of uric acid.

BACKGROUND: The Kidney Disease: Improving Global Outcomes chronic kidney disease (CKD) guidelines recommend that CKD be classified based on the etiology, glomerular filtration rate (GFR) and degree of albuminuria. The present study aimed to establish a method that predicts the presence of microalbuminuria by measuring the total urine protein-to-creatinine ratio (TPCR) in patients with cardiovascular disease (CVD) risk factors. METHODS AND RESULTS: We obtained urine samples from 1,033 patients who visited the cardiovascular clinic at St. Luke's International Hospital from February 2012 to August 2012. We measured the TPCR and the urine albumin-to-creatinine ratio (ACR) from random spot urine samples. We performed correlation, receiver operating characteristic (ROC) curve, sensitivity, and subgroup analyses. There was a strong positive correlation between the TPCR and ACR (R2 = 0.861, p<0.001). A ROC curve analysis for the TPCR revealed a sensitivity of 94.4%, a specificity of 86.1%, and an area under the curve of 0.903 for detecting microalbuminuria for a TPCR cut-off value of 84 mg/g of creatinine. The subgroup analysis indicated that the cut-off value could be used for patients with CVD risk factors. CONCLUSIONS: These results suggest that the TPCR with an appropriate cut-off value could be used to screen for the presence of microalbuminuria in patients with CVD risk factors. This simple, inexpensive measurement has broader applications, leading to earlier intervention and public benefit.

【目的】急性上腸間膜動脈(Superior Mesenteric Artery:SMA)解離は診断に苦慮する疾患であり、同疾患の特徴について後向き検討を行なった。【方法】2004年4月から2010年8月に、当院の腹部造影CT検査結果よりSMA解離と診断した全症例を抽出。【結果】対象は8症例、2例は症状なく偶発的に発見された。急性SMA解離と診断した6例は全例が男性、年齢53.5±8.2歳。来院時所見は全例で突然発症の腹痛を認めたが、発症から当院受診までの時間、腹痛の部位、既往は多岐にわたっていた。疾患除外に有用と予想された、血圧、D-dimerは有用とはいえなかった。CT検査前に疑われた疾患では、憩室炎4例、大動脈解離1例、虚血性腸炎1例であった。入院後経過は全例良好で退院しており、再発例は認めていない。【結論】SMA解離の特徴として突然発症の腹痛はあげられるが、特異的な所見・検査に乏しく診断は困難といえる。腹痛精査でCT検査を行う際にはSMAの走行に留意し、鑑別にあげる必要があると考える。(著者抄録)

患者は、69歳、男性。高血圧で内服加療中であった。テニスプレー中に意識消失し、心停止のため心肺蘇生開始された。自動体外式除細動器で除細動施行後、呼吸再開し当院搬送となった。来院時、意識はJapan coma scale II-10、心電図で心房細動とV2〜V6でST低下、心エコー図検査で軽度左室肥大、びまん性壁運動低下が認められた。緊急心臓カテーテル検査で左前下行枝に90%狭窄病変が認められ、同部位に経皮的冠動脈形成術を施行された。心電図変化の改善、心エコー図検査で壁運動の改善が認められたが、心筋逸脱酵素の上昇は認められなかった。入院後の心臓MRI検査にて遅延造影陽性となり、心筋生検で心筋の錯綜配列、心筋線維化が認められ肥大型心筋症と診断され、植込み型除細動器の植込み後に退院となった。心臓カテーテル検査で虚血による心停止が疑われた場合でも、他疾患を合併することがあり、十分な鑑別と精査が必要である。(著者抄録)

症例は糖尿病、脂質異常症、統合失調症で近医通院中の77歳、女性。来院3日前に突然の胸部不快感があり、徐々に食思不振が悪化し、当院外来受診。心電図上、II、III、aVFにてST上昇と異常Q波を認め、経胸壁心エコー図で下壁と右室の壁運動の低下があり、亜急性下壁心筋梗塞の診断となった。緊急心臓カテーテル検査施行し、右冠動脈の入口部で完全閉塞、さらに右バルサルバ洞に少量の造影剤の貯留を認めたため、緊急造影CTを施行し、右バルサルバ洞の拡大と偽腔内血栓を伴う限局性解離を認めた。年齢とADLを考慮し、内科的治療を行い、入院第17病日に退院となった。比較的良好な経過が得られ、8ヵ月後に施行したCTでは右バルサルバ洞拡大は残存も偽腔内血栓と解離は消失していた。(著者抄録)

尿酸が心臓や血管に及ぼす影響について、基礎研究で多くのことが示されている。これまで多くの観察研究で、高尿酸血症が心臓疾患の独立した危険因子となるとの報告があるものの、一部の研究では高尿酸血症は心臓疾患の危険因子とはならないとの報告も認められた。数年前までは、前向き介入試験はほとんど認められず、明確なコンセンサスは得られていなかった。しかし、近年になり新しいエビデンスが報告され、高尿酸血症が心臓疾患の独立した危険因子となることが示されてきた。本稿では、尿酸が心臓や血管に及ぼす影響について基礎研究で知られている内容を説明し、最近の臨床試験の結果を含めて紹介する。(著者抄録)

高尿酸血症と高血圧は密接に関係している。本稿では、高血圧に合併する高尿酸血症の発症機序を説明し、高血圧のリスクならびにマーカーとしての高尿酸血症の意義を論じる。また、ガイドラインに則した高血圧管理における尿酸の取り扱いに関して、高尿酸血症の病型分類を考慮した治療法を提示する。降圧薬の選択では、尿酸降下作用をもつと考えられる各薬剤の作用機序を考慮しておこなうのが適切と考えられる。(著者抄録)

It is unknown whether salicylate enhances the action of antiarrhythmic agents on human Na+ channels with state dependency and tissue specificity. We therefore investigated effects of salicylate on quinidine-induced block of human cardiac and skeletal muscle Na+ channels. Human cardiac wild-type (hH1), LQT3-related mutant (ΔKPQ), and skeletal muscle (hSkM1) Na+ channel α subunits were expressed in COS7 cells. Effects of salicylate on quinidine-induced tonic and use-dependent block of Na+ channel currents were examined by the whole-cell patch-clamp technique. Salicylate enhanced the quinidine-induced tonic and use-dependent block of both hH1 and hSkM1 currents at a holding potential (HP) of -100 mV but not at -140 mV. Salicylate decreased the IC50 value for the quinidine-induced tonic block of hH1 at an HP of -100 mV, and produced a negative shift in the steady-state inactivation curve of hH1 in the presence of quinidine. According to the modulated receptor theory, it is probable that salicylate decreases the dissociation constant for quinidine binding to inactivated-state channels. Furthermore, salicylate significantly enhanced the quinidine-induced tonic and use-dependent block of the peak and steady-state ΔKPQ channel currents. The results suggest that salicylate enhances quinidine-induced block of Na+ channels via increasing the affinity of quinidine to inactivated state channels.

63歳男。3日前より胸部違和感を自覚し、就寝中に呼吸苦が出現した。症状が改善しないため、救急搬送となった。急性心筋梗塞を疑い、緊急冠動脈造影を施行した。左前下行枝6番に完全閉塞を認め、経皮的冠動脈インターベンションによるステント留置術を施行した。第4病日に発作性心房細動を認めた。低左心機能で、血圧コントロールが不良であることからアミオダロンを開始した。第5病日に人工呼吸器離脱、リハビリテーション開始となった。第9病日に心室細動(Vf)を発症し、アミオダロンの持続静脈内投与を開始した。その後もVf stormが改善しないため心臓補助装置を導入した。左脚後枝にカテーテルアブレーションを施行し、Vfは認めなくなった。しかし、Vfが再発し、TdPを想起させる多形性VTを認めた。一時的ペースメーカーを挿入し、多形性VTは消失した。第30病日にICD植え込み術を施行し、第77病日に退院した。

【目的】間欠性跛行の症状がある末梢動脈疾患患者への、「週1回、30分のトレッドミルあるいはエルゴメーターを用いた監視下運動リハビリテーション」はQOLの改善に有効か検討した。【方法】3ヵ月間の監視下運動リハビリテーション前後で、WIQ scoreを用いQOLの評価を行った。【結果】トレッドミル群で214±86.9点から290±62.7点と有意な改善(p=0.014)が認められたが、エルゴメーター群では改善傾向は認めるものの有意差は認めなかった。WIQ scoreの各検査項目別の検討では、トレッドミル群において、歩行時の不快感の程度(p=0.0177)、歩行スピード(p=0.0193)、階段を上がる能力(p=0.0293)において有意な改善が認められた。【結論】週1回、30分、3ヵ月間のトレッドミルを用いた監視下運動リハビリテーションはQOLの改善をもたらす可能性が示唆された。(著者抄録)

Both an angiotensin II receptor blocker, losartan (CAS 124750-99-8) and a serum urate lowering agent, benzbromarone (CAS 3562-84-3) exert a uricosuric action by inhibiting urate transporter 1 (URAT1). A recent clinical trial indicated that losartan could reduce the level of serum urate in hypertensive patients treated with urate lowering agents, suggesting the different mode of action of losartan from benzbromarone. In the present study, the effect of losartan and benzbromarone on the level of URAT1 mRNA was determined in transfected HEK293 cells. Losartan caused a significant reduction of its mRNA level, whereas it was not affected by benzbromarone. These results indicate that losartan decreases the level of human URAT1 mRNA, which may underlie the uricosuric action of losartan in hypertensive patients treated with serum urate lowering agents.

68歳男。体力、気力低下を自覚した。不眠、抑うつ気分のために心療内科を紹介受診した。うつ病の診断で、塩酸パロキセチン、塩酸ミアンセリンを処方され、脱力感、歩行困難、筋肉痛が出現した。尿所見で潜血反応強陽性であるにもかかわらず、沈渣RBC陰性であった。血液検査で筋原性酵素の上昇を認めていたことから横紋筋融解症の診断で入院した。各種薬剤の中止と輸液により筋原性酵素は低下を認め、筋痛も改善した。次第に傾眠傾向、発熱を認めた。頭部CT検査を施行し、両側硬膜下血腫を認め、緊急穿頭術を施行した。著明な意識回復を認め、日常会話も可能となった。リハビリテーションを継続し、安静度を徐々に上げていったところ、独歩可能なまでに回復を認めた。リハビリテーションにより歩行が可能になるとともにうつ症状も改善を認めた。