論文 - 伊藤　裕

Pre-emptive short-term nicotinamide mononucleotide treatment in a mouse model of diabetic nephropathy

Yasuda I., Hasegawa K., Sakamaki Y., Muraoka H., Kawaguchi T., Kusahana E., Ono T., Kanda T., Tokuyama H., Wakino S., Itoh H.

Journal of the American Society of Nephrology 32 （ 6 ） 1355 - 1370 2021年06月

ISSN  10466673

　概要を見る

Background The activation of NAD¹-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. Methods Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). Results At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of db/db mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD¹ and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. Conclusions: Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD¹ salvage pathway, both of which indicate NMN legacy effects on DN.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yoshimura, M; Yamakawa, S

AMERICAN JOURNAL OF HYPERTENSION 34 （ 5 ） 540 - 551 2021年05月

ISSN  0895-7061

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study.

Kazuomi Kario, Sadayoshi Ito, Hiroshi Itoh, Hiromi Rakugi, Yasuyuki Okuda, Motonobu Yoshimura, Satoru Yamakawa

American journal of hypertension 34 （ 5 ） 540 - 551 2021年05月

　概要を見る

BACKGROUND: Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS: This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS: Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS: Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study.

Kario K, Ito S, Itoh H, Rakugi H, Okuda Y, Yoshimura M, Yamakawa S

American journal of hypertension 34 （ 5 ） 540 - 551 2021年05月

ISSN  0895-7061

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Diverse pathological lesions of primary aldosteronism and their clinical significance

Nishimoto K., Umakoshi H., Seki T., Yasuda M., Araki R., Otsuki M., Katabami T., Shibata H., Ogawa Y., Wada N., Sone M., Okamura S., Izawa S., Miyauchi S., Yoshimoto T., Tsuiki M., Naruse M., Fukuda H., Tanaka Y., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Ichijo T., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Kamemura K., Otsuki M., Fujii Y., Rakugi H., Yamamoto K., Ogo A., Yanase T., Suzuki T., Kawamura T., Fukuoka T., Kai T., Yoshikawa Y., Hashimoto S., Yamada M., Sakamoto R., Yoshiro C.

Hypertension Research 44 （ 5 ） 498 - 507 2021年05月

ISSN  09169636

　概要を見る

Primary aldosteronism (PA) is mainly clinically classified as unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism. Immunohistochemistry for aldosterone synthase reveals a diverse PA pathology, including pathological APA and aldosterone-producing cell clusters. The relationship between PA pathology and adrenalectomy outcomes was examined herein. Data from 219 unilaterally adrenalectomized PA cases were analyzed. Pathological analyses revealed diverse putative aldosterone-producing lesions. Postoperative biochemical outcomes in 114 cases (test cohort) were classified as complete success (n = 85), partial success (n = 19), and absent success (n = 10). Outcomes in the large and small PA lesion groups, rather than between PA lesion types, were compared at five threshold values for PA lesion sizes (2–6 mm with 1-mm increments) to streamline the results. The proportion of complete success was significantly higher in the large PA lesion group than in the small PA lesion group at the 5-mm threshold only. The proportion of absent success was significantly higher in the small PA lesion group than in the large PA lesion group at all thresholds. Univariate and multivariate analyses of the test cohort identified serum K as an independent predictive factor for the small PA lesion group, which was confirmed in the 105-case validation cohort. Chi-squared automatic interaction detector analysis revealed that the best threshold of serum K for predicting large PA lesions was 2.82 mEq/L. These results will be beneficial for treating PA in clinical settings because patients with low serum K levels and apparent adrenal masses on CT may be subjected to adrenalectomy even if the adrenal venous sampling test is unavailable.

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Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma

Yasuda I., Tokuyama H., Hashiguchi A., Hasegawa K., Uchiyama K., Ryuzaki M., Yasuda M., Mizuno R., Ishidoya S., Wakino S., Itoh H.

Cen Case Reports 10 （ 2 ） 281 - 286 2021年05月

ISSN  2192-4449

　概要を見る

Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.

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Effect of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, on nocturnal hypertension: A post hoc analysis of the esax-htn study

Kario K., Ito S., Itoh H., Rakugi H., Okuda Y., Yoshimura M., Yamakawa S.

American Journal of Hypertension 34 （ 5 ） 540 - 551 2021年05月

ISSN  08957061

　概要を見る

BACKGROUND Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns. METHODS This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected. RESULTS Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients. CONCLUSIONS Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.

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Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Ito S., Itoh H., Rakugi H., Okuda Y., Iijima S.

Hypertension Research 44 （ 5 ） 489 - 497 2021年05月

ISSN  09169636

　概要を見る

Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

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Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A <i>Post Hoc</i> Analysis of the ESAX-HTN Study

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yoshimura, M; Yamakawa, S

AMERICAN JOURNAL OF HYPERTENSION 34 （ 5 ） 540 - 551 2021年05月

ISSN  0895-7061

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A CASE OF ACUTE KIDNEY INJURY CAUSED BY INTERSTITIAL NEPHRITIS COMPLICATED WITH DRESS SYNDROME

Oshima, Y; Tokuyama, H; Minakuchi, H; Wakino, S; Itoh, H

JOURNAL OF HYPERTENSION 39   E297 - E298 2021年04月

ISSN  0263-6352

CLINICAL AND BIOCHEMICAL OUTCOMES AFTER RADIOFREQUENCY ABLATION FOR ALDOSTERONE-PRODUCING ADENOMA AT KEIO UNIVERSITY HOSPITAL-2020 ANNUAL REPORT

Kozuma, T; Kurihara, I; Kobayashi, S; Yokota, K; Miyashita, K; Kohata, N; Takase, K; Nakatsuka, S; Itoh, H

JOURNAL OF HYPERTENSION 39   E221 - E221 2021年04月

ISSN  0263-6352

CASZ1b is a novel transcriptional corepressor of mineralocorticoid receptor

Yokota K., Shibata H., Kurihara I., Kobayashi S., Murai-Takeda A., Itoh H.

Hypertension Research 44 （ 4 ） 407 - 416 2021年04月

ISSN  09169636

　概要を見る

Aldosterone is a biological ligand for mineralocorticoid receptor (MR) that elevates blood pressure by promoting sodium reabsorption in the kidneys. However, the molecular mechanisms of aldosterone-MR-mediated transcription and the role of this transcription in hypertension remain largely unknown. In this study, we aimed to identify novel MR coregulators and elucidate one of the molecular mechanisms of hypertension. We purified MR-interacting factors from HEK293F cells stably expressing FLAG-MR through a biochemical approach and identified the zinc finger protein castor homolog 1 isoform b (CASZ1b) as a candidate novel MR coregulator via liquid chromatography—tandem mass spectrometry analysis. The CASZ1 gene has been implicated in hypertension in genome-wide single-nucleotide polymorphism studies, but its role in the development of hypertension remains unclear. We found that CASZ1b colocalized with MR in the kidneys and interacted with MR in an aldosterone-dependent manner. In luciferase assays using HEK293F cells, overexpression of CASZ1b reduced aldosterone-dependent MR transcriptional activity by ~50%. In contrast, knockdown of CASZ1b via RNA interference increased the expression levels of the aldosterone-induced MR target genes epithelial Na+ channel-α (ENaCα) and serum/glucocorticoid regulated kinase 1 (SGK1) by approximately twofold and 2.3-fold, respectively. Upon aldosterone-MR binding, CASZ1b interacted with MR and formed a protein complex with nucleosome remodeling deacetylase (Mi-2/NuRD), a corepressor complex with chromatin remodeling and histone deacetylation activity, which suppressed ENaCα and SGK1. These findings reveal a critical role of CASZ1b in regulating MR-mediated transcriptional activity and provide new insights into the pathophysiology of hypertension.

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BIRTH WEIGHT AND RISK FACTORS FOR ATHEROSCLEROSIS -RETROSPECTIVE COHORT STUDY IN JAPANESE WORKERS

Azegami, T; Takeda, A; Yokoyama, H; Wainai, Y; Hirose, H; Makino, S; Nishimura, T; Goto, N; Itoh, H; Mori, M

JOURNAL OF HYPERTENSION 39   E170 - E171 2021年04月

ISSN  0263-6352

ASSOCIATION OF CHILDHOOD PHYSICAL EXAMINATION AND LABORATORY PARAMETERS WITH HIGH BLOOD PRESSURE IN JAPANESE YOUNG ADULTS

Azegami, T; Uchida, K; Arima, F; Sato, Y; Awazu, M; Inokuchi, M; Takeda, A; Itoh, H; Tokumura, M; Mori, M

JOURNAL OF HYPERTENSION 39   E41 - E41 2021年04月

ISSN  0263-6352

ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION

Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Iijima, S

JOURNAL OF HYPERTENSION 39   E53 - E53 2021年04月

ISSN  0263-6352

ACUTE MYOCARDIAL INFARCTION AND STROKE PREVENTION WITH AMLODIPINE/ ATORVASTATIN SINGLE-PILL THERAPY FOR PATIENTS WITH HYPERTENSION AND DYSLIPIDEMIA

Nakaya, H; Sasamura, H; Saito, I; Inoue, Y; Kobayashi, M; Itoh, H

JOURNAL OF HYPERTENSION 39   E377 - E377 2021年04月

ISSN  0263-6352

ACTIVE IMMUNOTHERAPY AGAINST RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS ATTENUATES THE PROGRESSION OF DIABETIC KIDNEY DISEASE

Azegami, T; Hayashi, K; Hishikawa, A; Yoshimoto, N; Nakayama, T; Itoh, H

JOURNAL OF HYPERTENSION 39   E303 - E303 2021年04月

ISSN  0263-6352

EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON NOCTURNAL HYPERTENSION: A POST HOC ANALYSIS OF ESAX-HTN STUDY

Kario, K; Ito, S; Itoh, H; Rakugi, H; Okuda, Y; Yamakawa, S

JOURNAL OF HYPERTENSION 39   E374 - E374 2021年04月

ISSN  0263-6352

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

Satoh F., Ito S., Itoh H., Rakugi H., Shibata H., Ichihara A., Omura M., Takahashi K., Okuda Y., Iijima S.

Hypertension Research 44 （ 4 ） 464 - 472 2021年04月

ISSN  09169636

　概要を見る

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] −17.7 [−20.6, −14.7] and −9.5 [−11.7, −7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

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RELATIONSHIP BETWEEN SERUM TOTAL BILIRUBIN CONCENTRATION AND MACROVASCULAR COMPLICATIONS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Tanaka, M; Nishimura, T; Meguro, S; Irie, J; Saisho, Y; Mitsuishi, M; Itoh, A; Inaishi, J; Nakajima, Y; Itoh, H

JOURNAL OF HYPERTENSION 39   E208 - E208 2021年04月

ISSN  0263-6352