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Papers - Ito, Hiroshi

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Home-based Aerobic Exercise and Resistance Training in Peritoneal Dialysis Patients: A Randomized Controlled Trial

Uchiyama K., Washida N., Morimoto K., Muraoka K., Kasai T., Yamaki K., Miyashita K., Wakino S., Itoh H.

Scientific Reports (Scientific Reports) 9 ( 1 ) 2019.12

© 2019, The Author(s). Potential effects of aerobic and resistance training in peritoneal dialysis (PD) patients have been partially elucidated. We investigated effects of a home-based exercise program on physical functioning and health-related quality of life (HRQOL) in PD patients. Patients were randomly assigned to exercise (n = 24) and usual care (n = 23) groups. The exercise patients performed aerobic exercise thrice weekly and resistance training twice weekly at home for 12 weeks. The usual care patients received no specific intervention. The distance in incremental shuttle walking test significantly improved in the exercise group compared with the usual care group (P = 0.02). Among the HRQOL subscales assessed using the Kidney Disease Quality of Life-Short Form questionnaire, kidney disease component summary (P = 0.03), physical role functioning (P = 0.01), emotional role functioning (P < 0.01), and role/social component summary (P < 0.01) significantly improved in the exercise group. Moreover, serum albumin was significantly maintained in the exercise group (P = 0.03). There were no reported adverse events associated with the intervention. To our knowledge, this is the first randomized controlled trial to indicate the beneficial effects of a 12-week home-based exercise program exclusively in PD patients.

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Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Hiratsuka K., Monkawa T., Akiyama T., Nakatake Y., Oda M., Goparaju S., Kimura H., Chikazawa-Nohtomi N., Sato S., Ishiguro K., Yamaguchi S., Suzuki S., Morizane R., Ko S., Itoh H., Ko M.

Scientific Reports (Scientific Reports) 9 ( 1 ) 2019.12

© 2019, The Author(s). The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2 + SALL1 + nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8 + LHX1 + pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.

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Hypertension as a Metabolic Disorder and the Novel Role of the Gut

Tanaka M., Itoh H.

Current Hypertension Reports (Current Hypertension Reports) 21 ( 8 ) 2019.08

ISSN 15226417

© 2019, The Author(s). Purpose of Review: Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. Recent Findings: Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of “salt-induced obesity”; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. Summary: SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.

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Influence of antihypertensive drugs in the subtype diagnosis of primary aldosteronism by adrenal venous sampling

Nagasawa M., Yamamoto K., Rakugi H., Takeda M., Akasaka H., Umakoshi H., Tsuiki M., Takeda Y., Kurihara I., Itoh H., Ichijo T., Katabami T., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Ogo A., Okamura S., Miyauchi S., Yanase T., Suzuki T., Kawamura T., Naruse M.

Journal of Hypertension (Journal of Hypertension) 37 ( 7 ) 1493 - 1499 2019.07

ISSN 02636352

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives:Because of the influence on the renin-angiotensin-aldosterone system, it is recommended to avoid, if possible, the use of angiotensin-converting-enzyme inhibitors, angiotensin II type 1 receptor blockers, diuretics, β-blockers, and mineralocorticoid receptor antagonists during the diagnostic period of primary aldosteronism. A laterality index more than 4 in adrenocorticotropic hormone (ACTH)-stimulated adrenal venous sampling (ACTH-AVS) is a widely used classification of the unilateral subtype that can benefit from adrenalectomy. Here, we revealed clinical features of patients taking drugs that could affect the primary aldosteronism diagnosis (DAPD) and investigated whether the classification with laterality index more than 4 in ACTH-AVS is applicable to these patients.Patients and methods:Using a large database of primary aldosteronism patients in Japan, we analyzed 2122 patients with successful ACTH-AVS.Results:Patients who received any DAPD (n = 209) showed higher prevalence of comorbidity burdens and took more antihypertensive drugs compared with patients without DAPD. In patients taking DAPD, those with laterality index more than 4 had a higher prevalence of hypokalemia, a higher aldosterone-to-renin ratio and a higher prevalence of adrenal mass than those with laterality index of 4 or less. Adrenalectomy was performed in 76% patients with laterality index more than 4 and 20% with laterality index of 4 or less. Patients who underwent adrenalectomy showed biochemical cure in 89% with laterality index more than 4 and 50% with laterality index of 4 or less (P = 0.001). Multivariate regression analysis showed that laterality index more than 4 was an independent predictor of a biochemical cure. Biochemical cure rate in patients with laterality index more than 4 was consistently high, irrespective of the potential effect of individual DAPD on laterality index.Conclusion:Our findings suggest that in primary aldosteronism patients to whom DAPD were administrated due to severe clinical features, laterality index more than 4 in ACTH-AVS could accurately predict a biochemical cure after adrenalectomy.

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Efficacy and safety of esaxerenone (CS-3150) for the treatment of essential hypertension: a phase 2 randomized, placebo-controlled, double-blind study

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

Journal of Human Hypertension (Journal of Human Hypertension) 33 ( 7 ) 542 - 551 2019.07

ISSN 09509240

© 2019, Springer Nature Limited. This was a phase 2, multicenter, randomized, double-blind, placebo-controlled, open-label comparator study to investigate the efficacy and safety of esaxerenone (CS-3150), a novel non-steroidal mineralocorticoid receptor blocker, in Japanese patients with essential hypertension. Eligible patients (n = 426) received esaxerenone (1.25, 2.5, or 5 mg/day), placebo, or eplerenone (50–100 mg/day) for 12 weeks. The primary efficacy endpoint was the change from baseline in sitting systolic and diastolic blood pressure (BP). Safety endpoints included adverse events and serum K+ elevation. There were significant dose–response reductions in the 2.5 and 5 mg/day esaxerenone groups for sitting BP (both p < 0.001) and 24-h BP (both p < 0.0001) compared with placebo, with a mean (95% confidence interval) change in sitting BP of −7.0 (−9.5 to −4.6)/−3.8 (−5.2 to −2.4) mmHg in the placebo group, and −10.7 (−13.2 to −8.2)/−5.0 (−6.4 to −3.6) mmHg, −14.3 (−16.8 to −11.9)/−7.6 (−9.1 to −6.2) mmHg, and −20.6 (−23.0 to −18.2)/ −10.4 (−11.8 to −9.0) mmHg for the 1.25, 2.5, and 5 mg/day esaxerenone groups, respectively, while the change was −17.4 (−19.9 to −15.0)/−8.5 (−9.9 to −7.1) mmHg for eplerenone. The incidence of adverse events was similar in all treatment groups. Serum K+ levels initially increased in proportion with esaxerenone dose but were stable from week 2 until week 12. Plasma esaxerenone concentration increased in proportion with the dose. In conclusion, esaxerenone is an effective and tolerable treatment option for patients with essential hypertension.

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DNA Damage Repair and DNA Methylation in the Kidney

Hayashi K., Hishikawa A., Itoh H.

American Journal of Nephrology (American Journal of Nephrology) 50 ( 2 ) 81 - 91 2019.07

ISSN 02508095

© 2019 © 2019 S. Karger AG, Basel. Copyright: All rights reserved. The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

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Acute Interstitial Nephritis With Karyomegalic Epithelial Cells After Nivolumab Treatment—Two Case Reports

Ryuzaki M., Tokuyama H., Uchiyama K., Nakaya H., Hasegawa K., Miyashita K., Konishi K., Hashiguchi A., Wakino S., Itoh H.

Clinical Medicine Insights: Case Reports (Clinical Medicine Insights: Case Reports) 12 2019.06

© The Author(s) 2019. Clinical application of immune checkpoint inhibitors (CPIs) including nivolumab is expanding in the field of oncology treatment. Nivolumab is an anti-programmed death 1 protein (PD-1) antibody designed to augment an immunologic reaction against cancer cells. On the contrary, CPIs are known to cause a unique variety of side effects termed as immune-related adverse events, which can affect any organ including kidney. However, the characteristics of renal disorders by nivolumab treatment are poorly described. We describe two cases of acute kidney injury that were treated with nivolumab. Two patients, one with renal-cell carcinoma and the other with lung cancer, exhibited progressive renal dysfunction after the initiation of nivolumab treatment. By kidney biopsy, each case was diagnosed as acute interstitial nephritis (AIN). Of note, tubular epithelial cells enlarged with hyperchromatic nuclei were focally observed, and this finding was consistent with karyomegalic tubular epithelial cells. In immunostaining, most of the enlarged tubular epithelial cells were positive for Ki-67, which suggested regeneration of tubular epithelial cells. Clinically, in one case, renal function was partially recovered with the discontinuation of nivolumab, while in another case renal function was fully recovered with additional corticosteroid treatment. We presented nivolumab-induced AIN with karyomegalic changes of tubular epithelia. We propose that immunosuppressive therapy may be necessary for the full recovery from renal impairment.

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High prevalence of diabetes in patients with primary aldosteronism (PA) associated with subclinical hypercortisolism and prediabetes more prevalent in bilateral than unilateral PA: A large, multicenter cohort study in Japan

Akehi Y., Yanase T., Motonaga R., Umakoshi H., Tsuiki M., Takeda Y., Yoneda T., Kurihara I., Itoh H., Katabami T., Ichijo T., Wada N., Shibayama Y., Yoshimoto T., Ashida K., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Yamamoto K., Ogo A., Okamura S., Miyauchi S., Fukuoka T., Izawa S., Hashimoto S., Yamada M., Yoshikawa Y., Kai T., Suzuki T., Kawamura T., Naruse M.

Diabetes Care (Diabetes Care) 42 ( 5 ) 938 - 945 2019.05

ISSN 01495992

© 2019 by the American Diabetes Association. OBJECTIVE To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan. RESEARCH DESIGN AND METHODS The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA1c] ‡6.5% [‡48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected subclinical hypercortisolism (SH; serum cortisol ‡1.8 mg/dL after 1-mg dexamethasone suppression test), and PA laterality on the prevalence of diabetes or prediabetes (5.7% £ HbA1c <6.5% [39 mmol/mol £ HbA1c <48 mmol/mol]) were examined. RESULTS Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30–69 years. Logistic regression or x2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA. CONCLUSIONS Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA.

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β-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects

Tajima T., Yoshifuji A., Matsui A., Itoh T., Uchiyama K., Kanda T., Tokuyama H., Wakino S., Itoh H.

Kidney International (Kidney International) 95 ( 5 ) 1120 - 1137 2019.05

ISSN 00852538

© 2019 International Society of Nephrology Ketone bodies including β-hydroxybutyrate (β-OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of β-OHB on renal ischemia/reperfusion injury (IRI). Mice were treated with a continuous infusion of β-OHB using an osmotic mini-pump before and after IRI. We also tested the effects of increasing endogenous serum β-OHB levels by fasting. Renal IRI was attenuated by β-OHB treatment compared to saline control, with similar results in the fasting condition. β-OHB treatment reduced the number of terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL)-positive cells and increased expression of forkhead transcription factor O3 (FOXO3), an upstream regulator of pyroptosis. Although β-OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase-1 and proinflammatory cytokines, indicating that β-OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, β-OHB reduced cell death in a FOXO3-dependent fashion. Histone acetylation was decreased in kidneys exposed to IRI and in proximal tubular cells exposed to hypoxia and reoxygenation, and this effect was ameliorated by β-OHB through the inactivation of histone deacetylases. In vitro, β-OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of β-OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, β-OHB attenuates renal IRI through anti-pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.

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Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy

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

Cell Reports (Cell Reports) 27 ( 1 ) 199 - 212.e5 2019.04

© 2019 The Author(s) Nicotinamide adenine dinucleotide (NAD + ) metabolism plays a critical role in kidneys. We previously reported that decreased secretion of a NAD + precursor, nicotinamide mononucleotide (NMN), from proximal tubules (PTs) can trigger diabetic albuminuria. In the present study, we investigated the role of NMN-producing enzyme nicotinamide phosphoribosyltransferase (Nampt) in diabetic nephropathy. The expression of Nampt in PTs was downregulated in streptozotocin (STZ)-treated diabetic mice when they exhibited albuminuria. This albuminuria was ameliorated in PT-specific Nampt-overexpressing transgenic (TG) mice. PT-specific Nampt-conditional knockout (Nampt CKO) mice exhibited TBM thickening and collagen deposition, which were associated with the upregulation of the profibrogenic gene TIMP-1. Nampt CKO mice also exhibited the downregulation of sirtuins, particularly in Sirt6. PT-specific Sirt6-knockout mice exhibited enhanced fibrotic phenotype resembling that of Nampt CKO mice with increased Timp1 expression. In conclusion, the Nampt-Sirt6 axis in PTs serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy. Muraoka et al. reveal that the Nampt-Sirt6 axis in proximal tubules serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.

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A Case Report of Autosomal Dominant Polycystic Kidney Disease Under Peritoneal Dialysis With Cyst Infection and Culture-Positive Peritoneal Fluid

Yasuda I., Hasegawa K., Tokuyama H., Washida N., Shinozuka K., Yasuda M., Ryuzaki M., Urai H., Wakino S., Itoh H.

Clinical Medicine Insights: Case Reports (Clinical Medicine Insights: Case Reports) 12 2019.04

© The Author(s) 2019. Background: Cyst infection is a complication sometimes seen in patients with autosomal dominant polycystic kidney disease (ADPKD) and often shows through a positive blood culture. However, there have been no reports of ADPKD patients whose cyst infection propagate to peritoneal fluid leading to positive peritoneal fluid culture. Case presentation: A 74-year-old Japanese man with ADPKD under peritoneal dialysis (PD) was presented with left flank pain, fever, and chills at our hospital. He did not show any symptoms or signs suggestive of peritonitis. There were no elevated cell counts or polymorphonuclear leucocytes in his PD fluid. There were some complicated cysts found in computed tomography and magnetic resonance imaging examinations. We clinically diagnosed him as having a renal cyst infection rather than PD-related peritonitis. We initiated treatment by administering ceftriaxone with an immediate favorable response. As the possibility of accompanying prostatitis still remained, we switched to intravenous levofloxacin on the second day. On the 10th day, Helicobacter cinaedi was detected in 2 sets of blood culture as well as in PD fluid. We switched back to ceftriaxone and this treatment was entirely successful. Conclusions: This is the first report of H cinaedi cyst infection which propagates to peritoneal fluid in a patient with ADPKD.

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Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study

Itoh H., Komuro I., Takeuchi M., Akasaka T., Daida H., Egashira Y., Fujita H., Higaki J., Hirata K., Ishibashi S., Isshiki T., Ito S., Kashiwagi A., Kato S., Kitagawa K., Kitakaze M., Kitazono T., Kurabayashi M., Miyauchi K., Murakami T., Murohara T., Node K., Ogawa S., Saito Y., Seino Y., Shigeeda T., Shindo S., Sugawara M., Sugiyama S., Terauchi Y., Tsutsui H., Ueshima K., Utsunomiya K., Yamagishi M., Yamazaki T., Yo S., Yokote K., Yoshida K., Yoshimura M., Yoshimura N., Nakao K., Nagai R.

Diabetes, Obesity and Metabolism (Diabetes, Obesity and Metabolism) 21 ( 4 ) 791 - 800 2019.04

ISSN 14628902

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Aims: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. Materials and Methods: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. Results: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). Conclusions: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

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Pre-emptive medicine for hypertension and its prospects

Itoh H., Hayashi K., Miyashita K.

Hypertension Research (Hypertension Research) 42 ( 3 ) 301 - 305 2019.03

ISSN 09169636

© 2018, The Japanese Society of Hypertension. Pre-emptive medicine is a novel medical concept proposed in Japan that aims to precisely predict the onset and progression of diseases and to provide therapeutic interventions during early stages, before symptoms appear. The concept of pre-emptive medicine considers the time-course of a disease in each individual and seeks medical interventions to prevent disease progression. Suitable and promising targets for pre-emptive medicine are non-communicable diseases, including hypertension. Recent advances in genomic analysis, information technology, and artificial intelligence should make this medical concept feasible in the near future. In this review, we focused on pre-emptive medicine for hypertension, referring to concrete plans for the future direction of this research. The ultimate goal of pre-emptive medicine is to completely prevent the onset and progression of hypertension by precisely predicting the elevation of blood pressure and performing interventions to avoid it. The diagnostic processes of hypertension, from the standpoint of pre-emptive medicine, should include the detection of abnormal blood pressure regulation as the earliest manifestation of the disease, the depiction of the present status of hypertension in an individual (“nowcasting”), and a prediction of the future trajectory of the disease (“forecasting”). Novel therapeutic strategies for hypertension, from the standpoint of pre-emptive medicine, should aim for the regression of hypertension through early treatments and the remission of hypertension through intermittent intensive therapies. An efficient modification of lifestyle and therapies, according to the progression of hypertension, should be required. If pre-emptive medicine for hypertension becomes established, it would greatly contribute to the extension of a healthy lifespan, which cannot yet be satisfactorily achieved.

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Usefulness of hemoglobin a1c and glycated albumin measurements for insulinoma screening: An observational case-control study

Torimoto K., Okada Y., Tanaka Y., Matsuoka A., Hirota Y., Ogawa W., Saisho Y., Kurihara I., Itoh H., Inada S., Koga M.

BMC Cancer (BMC Cancer) 19 ( 1 ) 2019.02

© 2019 The Author(s). Background: Insulinoma represents hypoglycemia as a predominant symptom; the autonomic symptoms may be resolved by chronically recurrent hypoglycemia resulting in the persistence of non-specific symptoms alone. Therefore, it has been estimated that there are many patients in whom the disease takes longer to diagnose and has remained undiagnosed. Although some parameters exist for the definitive diagnosis of the disease, there are currently no indices for early screening. Indices of glycemic control, hemoglobin A1c (HbA1c), and glycated albumin (GA) may be useful for the screening of patients with insulinoma having chronic hypoglycemia because the values become low in such a condition. Because there are no articles that have reported the point, we examine the effective cutoff values of HbA1c and GA for the diagnosis of insulinoma in the present study. Methods: In a multicenter cross-sectional study, 31 patients with insulinoma were included for comparison with 120 control subjects with normal glucose tolerance based on 75 g oral glucose tolerance tests whose characteristics were matched to the patients. The primary outcomes were optimal cutoff values of HbA1c and GA for the screening of insulinoma. Results: HbA1c was significantly lower in the insulinoma group at 4.7 ± 0.4% compared to the healthy control group at 5.7 ± 0.3% (p < 0.001), and GA was significantly lower in the insulinoma group at 11.6 ± 1.8% compared to the healthy control group at 14.5 ± 1.0% (p < 0.001). According to a receiver operating characteristic (ROC) analysis, optimal cutoff values of HbA1c and GA for the diagnosis of insulinoma were 5.0 and 12.4%, respectively. Area under the curve values of HbA1c and GA were 0.970 and 0.929, respectively, showing no significant difference (p = 0.399). Conclusions: In the present study, HbA1c and GA values in patients with insulinoma were significantly lower compared to the healthy controls, and effective cutoff values for screening were shown in the diagnosis of insulinoma for the first time. HbA1c and GA can be useful indices for insulinoma screening. Because malignant insulinoma have a similar diagnostic process to that of benign insulinoma, these could be useful for malignant insulinoma.

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Zfp238 Regulates the Thermogenic Program in Cooperation with Foxo1

Kita M., Nakae J., Kawano Y., Asahara H., Takemori H., Okado H., Itoh H.

iScience (iScience) 12 87 - 101 2019.02

© 2019 The Author(s) Obesity has become an explicit public health concern because of its relevance to metabolic syndrome. Evidence points to the significance of beige adipocytes in regulating energy expenditure. Here, using yeast two-hybrid screening, we show that Zfp238 is a Foxo1 co-repressor and that adipose-tissue-specific ablation of Zfp238 (Adipo-Zfp238KO)in mice leads to obesity, decreased energy expenditure, and insulin resistance under normal chow diet. Adipo-Zfp238KO inhibits induction of Ucp1 expression in subcutaneous adipose tissue upon cold exposure or CL316243, but not in brown adipose tissue. Furthermore, knockdown of Zfp238 in 3T3-L1 cells decreases Ucp1 expression in response to cool incubation or forskolin significantly compared with control cells. In contrast, overexpression of Zfp238 in 3T3-L1 cells significantly increases Ucp1 expression in response to forskolin. Finally, double knockdown of both Zfp238 and Foxo1 normalizes Ucp1 induction. These data suggest that Zfp238 in adipose tissue regulates the thermogenic program in cooperation with Foxo1.

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Efficacy and safety of switching to insulin glargine 300 U/mL from 100 U/mL in Japanese patients with type 2 diabetes: A 12-month retrospective analysis

Sugiyama K., Meguro S., Saisho Y., Irie J., Tanaka M., Itoh H.

Heliyon (Heliyon) 5 ( 2 ) 2019.02

ISSN 24058440

© 2019 The Authors Aims: To evaluate the efficacy and safety of switching to insulin glargine 300 U/mL (Gla-300) from insulin glargine 100 U/mL (Gla-100) in Japanese patients with type 2 diabetes (T2DM). Methods: This was a 12-month retrospective study comprising 109 patients. Primary endpoint was glycated hemoglobin (HbA1c) level at month 12. Secondary endpoints were hypoglycemia for the overall study period as well as body weight and insulin dose at month 12. Results: Similar glycemic control was achieved with mean (standard deviation) HbA1c level of 7.7 (1.1)% (61 [12] mmol/mol) at baseline and 7.7 (1.3)% (61 [14] mmol/mol) at month 12. Fewer confirmed (<3.0 mmol/L [< 54 mg/dL]) or severe hypoglycemic events were observed (0.52 vs. 0.85 events per patient-year; rate ratio 0.61; 95% confidence interval 0.38–0.97; p = 0.037), but the percent of patients experiencing ≥1 hypoglycemic event did not differ. There was no difference in confirmed (≤3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycemia and nocturnal hypoglycemia. Conclusions: In Japanese patients with T2DM who switched to Gla-300 from Gla-100, similar glycemic control was achieved with fewer confirmed (<3.0 mmol/L [< 54 mg/dL]) or severe hypoglycemic events over a 12-month period, although the absolute benefit was marginal.

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Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes

Hishikawa A., Hayashi K., Abe T., Kaneko M., Yokoi H., Azegami T., Nakamura M., Yoshimoto N., Kanda T., Sakamaki Y., Itoh H.

Cell Reports (Cell Reports) 26 ( 5 ) 1318 - 1332.e4 2019.01

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Exercise capacity and association with quality of life in peritoneal dialysis patients

Uchiyama K., Washida N., Muraoka K., Morimoto K., Kasai T., Yamaki K., Miyashita K., Wakino S., Itoh H.

Peritoneal Dialysis International (Peritoneal Dialysis International) 39 ( 1 ) 66 - 73 2019.01

ISSN 08968608

© 2019 International Society for Peritoneal Dialysis. Background: Muscle wasting, common and progressive in uremic patients, is associated with a high probability for morbidity, lower health-related quality of life (HRQOL), and mortality. However, exercise tolerance in peritoneal dialysis (PD) patients has not been fully elucidated. The aim of this study was to evaluate exercise capacity, its determinants, and its association with HRQOL in PD patients. ♦♦ Methods: Outpatients treated with PD at Keio University Hospital from December 2016 to March 2018 were included in this single-center cross-sectional observational study. Exercise capacity was assessed by incremental shuttle walking test (ISWT) and handgrip and quadriceps strength. In addition to evaluation of PD-related parameters, HRQOL was assessed by the Kidney Disease Quality of Life-Short Form questionnaire. ♦♦ Results: Among the 50 recruited PD outpatients, age and PD vintage were 63.8 ± 9.6 and 3.8 ± 2.8 years, respectively. Physical examination revealed ISWT of 312.0 ± 138.2 m, handgrip strength of 27.5 ± 6.9 kg, and quadriceps strength of 23.3 ± 10.0 kg. Multivariate analysis showed that younger age and male sex were significantly associated with higher ISWT and handgrip and quadriceps strength. Skeletal mass index (SMI) remained a significant predictor of handgrip and quadriceps strength. Moreover, only ISWT was strongly correlated with higher HRQOL scores, including physical, mental, and kidney-specific domains, even after adjustment for age and sex. ♦♦ Conclusions: Exercise tolerance in PD patients was partially determined by age, sex, and SMI. Moreover, this is the first study to demonstrate the strong relationship between aerobic capacity and HRQOL in PD patients.

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Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Meguro S., Matsui S., Itoh H.

Current Medical Research and Opinion (Current Medical Research and Opinion) 2019

ISSN 03007995

© 2019, © 2019 Takeda Pharmaceutical Company Limited. Published by Informa UK Limited, trading as Taylor & Francis Group. Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8 weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i. Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8 weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8 weeks of treatment with each agent, and safety. Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n = 30); baseline characteristics were similar between groups. After 16 weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p =.014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8 weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles. Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.

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Satisfaction level of glycemic control in patients with diabetes and its related factors

Saisho Y., Itoh H.

Journal of the Japan Diabetes Society (Journal of the Japan Diabetes Society) 62 ( 1 ) 1 - 8 2019

ISSN 0021437X

© 2019 Japan Diabetes Society. All rights reserved. Although the current guidelines recommend the use of "individualized" HbA1c goals for patient-centered diabetes care, information regarding the satisfaction of patients with their glycemic control is insufficient. In this study, we aimed to clarify the satisfaction of patients with their glycemic control and to determine the related factors. Outpatients with diabetes were asked to answer questionnaires that included a question about their satisfaction with their glycemic control, and responses were obtained from 254 patients with type 2 diabetes and 22 patients with type 1 diabetes. Twenty-eight percent of the patients answered "satisfied", while 18 % answered "not satisfied". The satisfaction with glycemic control was significantly correlated with HbA1c, adherence to dietary therapy, satisfaction with doctor and clinic, satisfaction with medical cost, intention to drop out and satisfaction with diabetes treatment. Thus, patient satisfaction with glycemic control should be recognized as an important patient-reported outcome, and may be affected by the self-efficacy of dietary therapy and the patient's relationship with medical staff.

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