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Papers - ITOH Hiroshi

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Epigenetic Alterations in Podocytes in Diabetic Nephropathy.

Erina Sugita, Kaori Hayashi, Akihito Hishikawa, Hiroshi Itoh

Frontiers in pharmacology 12 759299 - 759299 2021.09

ISSN 1663-9812

Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane-a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.

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特集ヒューマノイドロボットの医療分野での応用生活習慣病治療におけるヒューマノイドロボットの役割

入江潤一郎, 栗原勲, 伊藤裕

医学のあゆみ (医歯薬出版) 278 ( 11 ) 957 - 961 2021.09

ISSN 00392359

Vaccination Against Receptor for Advanced Glycation End Products Attenuates the Progression of Diabetic Kidney Disease.

Tatsuhiko Azegami, Takashin Nakayama, Kaori Hayashi, Akihito Hishikawa, Norifumi Yoshimoto, Ran Nakamichi, Hiroshi Itoh

Diabetes 70 ( 9 ) 2147 - 2158 2021.09

ISSN 00121797

Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease's complicated pathogenic mechanism, activation of the advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor-deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD.

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Statin Exposure and Pancreatic Cancer Incidence: A Japanese Regional Population-Based Cohort Study, the Shizuoka Study.

Kohei Saito, Yoko Sato, Eiji Nakatani, Hideaki Kaneda, Seiichiro Yamamoto, Yoshiki Miyachi, Hiroshi Itoh

Cancer prevention research (Philadelphia, Pa.) 14 ( 9 ) 863 - 872 2021.09

ISSN 19406207

Preclinical studies suggest that statins contribute to the prevention of pancreatic cancer; however, the results of epidemiologic studies are inconsistent. Furthermore, sufficient data are unavailable for the general population of Asia. Here, we conducted an observational study using a comprehensive patient-linked, longitudinal health insurance database comprising the records of 2,230,848 individuals residing in Shizuoka Prefecture, Japan, from April 2012 to September 2018. We included individuals older than 40 years with data for medical examinations and statin exposure (≥365 statin prescription days). To balance baseline characteristics between the statin exposure and statin nonexposure groups, we used inverse probability of treatment propensity score weighting method. We estimated hazard ratios for associations with pancreatic cancer using the Cox proportional hazards regression model. Among 2,230,848 individuals, we included 100,537 in the statin exposure group (24%) and 326,033 in the statin nonexposure group (76%). Among the statin exposure group (352,485 person-years) and the statin nonexposure group (1,098,463 person-years), 394 (1.12 per 1,000 person-years) and 1176 (1.07 per 1,000 person-years) developed pancreatic cancer, respectively (P = 0.464). After adjustments using inverse probability of treatment weighting, the statin exposure group was associated with a decreased incidence of pancreatic cancer (hazard ratio, 0.84; 95% confidence intervals, 0.72-0.99; P = 0.036). In conclusion, the current Japanese regional population-based cohort study shows that statin exposure was associated with a lower incidence of pancreatic cancer. PREVENTION RELEVANCE: This study may support the possible role of statins in preventing pancreatic cancer in the general population in Japan.

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Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression.

Kazuhiro Shiizaki, Asako Tsubouchi, Yutaka Miura, Kinya Seo, Takahiro Kuchimaru, Hirosaka Hayashi, Yoshitaka Iwazu, Marina Miura, Batpurev Battulga, Nobuhiko Ohno, Toru Hara, Rina Kunishige, Mamiko Masutani, Keita Negishi, Kazuomi Kario, Kazuhiko Kotani, Toshiyuki Yamada, Daisuke Nagata, Issei Komuro, Hiroshi Itoh, Hiroshi Kurosu, Masayuki Murata, Makoto Kuro-O

The Journal of clinical investigation 131 ( 16 ) 2021.08

ISSN 00219738

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

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Development of nephropathy in an adult patient after Fontan palliation for cyanotic congenital heart disease.

Kaori Hayashi, Akinori Hashiguchi, Masako Ikemiyagi, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh

CEN case reports 10 ( 3 ) 354 - 358 2021.08

ISSN 2192-4449

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

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Lipid-lowering statin therapy is beneficial in elderly female patients with hypercholesterolaemia and diabetic retinopathy.

Yoshihiro Saito, Atsuko Nakayama, Tatsuyuki Sato, Hiroyuki Morita, Takuya Kawahara, Hiroshi Itoh, Issei Komuro

European journal of preventive cardiology 28 ( 8 ) E7 - E9 2021.08

ISSN 20474873

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Circadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies.

Kenichiro Kinouchi, Yohei Mikami, Takanori Kanai, Hiroshi Itoh

Molecular aspects of medicine 80 100984 - 100984 2021.08

ISSN 00982997

Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

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Intensive treat-to-target statin therapy and severity of diabetic retinopathy complicated by hypercholesterolaemia.

Tomoaki Murakami, Satoshi Kato, Takashi Shigeeda, Hiroshi Itoh, Issei Komuro, Masahiro Takeuchi, Nagahisa Yoshimura

Eye (London, England) 35 ( 8 ) 2221 - 2228 2021.08

ISSN 0950222X

OBJECTIVES: To compare the effects of intensive and standard statin therapy on severity of diabetic retinopathy (DR) complicated by hypercholesterolaemia in a prespecified substudy of the standard vs. intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study. METHODS: Among 5144 patients in the multicentre, prospective, randomized EMPATHY study, this substudy considered 157 patients with seven-field fundus photographs of sufficient quality taken during study enrolment and at the 3-year visit. Eighty-five and seventy-two patients received intensive and standard statin treatments, respectively, in a treat-to-target manner. The primary endpoint was a two-step change in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR severity scale at 36 months. Surrogate markers included changes in hard exudates, changes in visual acuity, and additional ocular treatments during study follow-up. RESULTS: Intensive and standard treatment groups did not differ significantly in terms of changing two or more steps on the DR severity scale (P = 0.4380). In patients with severe DR, defined as ≥47 on the severity scale, exploratory analysis showed more frequent improvement of DR, by at least one step, with intensive vs. standard treatment (83.3% vs. 40.0%; P = 0.0346). The intensive and standard groups did not differ in changes on the hard exudates severity scale (P = 0.3460), logarithm of minimum angle of resolution visual acuity (P = 0.5500), or additional ocular treatment during follow-up. CONCLUSIONS: Intensive and standard statin treatment may have similar effects on DR in the population of all patients with DR and hypercholesterolaemia, but intensive therapy may be more beneficial in patients with severe DR.

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Reduced beta cell number rather than size is a major contributor to beta cell loss in type 2 diabetes.

Hironobu Sasaki, Yoshifumi Saisho, Jun Inaishi, Yuusuke Watanabe, Tami Tsuchiya, Masayoshi Makio, Midori Sato, Masaru Nishikawa, Minoru Kitago, Taketo Yamada, Hiroshi Itoh

Diabetologia 64 ( 8 ) 1816 - 1821 2021.08

ISSN 0012186X

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. METHODS: Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. RESULTS: Both beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 μm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA1c (r = -0.45, p < 0.01). CONCLUSIONS/INTERPRETATION: Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes.

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Fast Bayesian tomography of a two-qubit gate set in silicon

T. J. Evans, W. Huang, J. Yoneda, R. Harper, T. Tanttu, K. W. Chan, F. E. Hudson, K. M. Itoh, A. Saraiva, C. H. Yang, A. S. Dzurak, S. D. Bartlett

Phys. Rev. Applied 17, 024068 (2022) 2021.07

Benchmarking and characterising quantum states and logic gates is essential
in the development of devices for quantum computing. We introduce a Bayesian
approach to self-consistent process tomography, called fast Bayesian tomography
(FBT), and experimentally demonstrate its performance in characterising a
two-qubit gate set on a silicon-based spin qubit device. FBT is built on an
adaptive self-consistent linearisation that is robust to model approximation
errors. Our method offers several advantages over other self-consistent
tomographic methods. Most notably, FBT can leverage prior information from
randomised benchmarking (or other characterisation measurements), and can be
performed in real time, providing continuously updated estimates of full
process matrices while data is acquired.

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Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability.

Shota Ikeda, Keisuke Shinohara, Nobuyuki Enzan, Shouji Matsushima, Takeshi Tohyama, Kouta Funakoshi, Junji Kishimoto, Hiroshi Itoh, Issei Komuro, Hiroyuki Tsutsui

Journal of hypertension 39 ( 7 ) 1435 - 1443 2021.07

ISSN 02636352

BACKGROUND: Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability. METHODS: The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and standard therapy targeting LDL-C ≥100 to <120 mg/dl in T2DM patients with retinopathy without known cardiovascular disease. Using this dataset, we divided the patients into two subpopulations based on standard deviation (SD) and average real variability (ARV) of clinic SBP within the initial 6 months. RESULTS: In a total of 4899 patients, 240 composite cardiovascular events were observed during a median follow-up of 37.3 months. In multivariable-adjusted model comparing intensive versus standard therapy, the hazard ratios for composite cardiovascular events were 0.64 (95% CI 0.45-0.90) and 1.21 (95% CI 0.82-1.80) in patients with high and low SBP variability as defined by SD, respectively. Interaction between SBP variability and statin therapy was significant (P = 0.018). The analysis using ARV of SBP showed similar results. CONCLUSION: Statin intensive therapy targeting LDL-C <70 mg/dl had benefits in primary prevention of cardiovascular events compared with standard therapy among T2DM patients with retinopathy having high, but not low, visit-to-visit SBP variability.

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1-year estimated glomerular filtration rate decline as risk factor of cardiovascular and renal endpoint in high-risk Japanese patients.

Meguro S, Inaishi J, Sato Y, Komuro I, Itoh H

Journal of diabetes investigation 12 ( 7 ) 1212 - 1219 2021.07

ISSN 20401116

Aims/Introduction: As estimated glomerular filtration rate (eGFR) progression might correlate with cardiovascular prognosis, the correlation between 1-year decline in eGFR and cardiovascular incidences and renal outcome was investigated. Materials and Methods: The 1-year percentage decline in eGFR at the first observation year was calculated in a cohort of the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) trial participants. The primary end-point was the composite cardiovascular end-point including the renal end-point. The associations between the incidence of each end-point and clinical markers were analyzed using the Cox proportional hazards regression model. Results: A total of 4,461 patients were analyzed. The mean observation period was 765.3 ± 363.1 days. The best cut-off value of 1-year eGFR decline was 0.099 in the first year for renal end-point prediction by receiver operating characteristic curve analysis. The area under the curve of the model including the 1-year eGFR decline of the first year was significantly larger than the model without it (0.943, 95% confidence interval 0.915–0.971 to 0.967, 95% confidence interval 0.950–0.983, P = 0.019). Primary end-point incidences and the renal end-point were much higher in rapid eGFR decliners compared with non-decliners (P < 0.0001). The cardiovascular end-point incidence, except for the renal end-point, was not different between the groups. According to Cox regression analysis, 1-year eGFR decline during the first year was a significant risk factor for the end-points, including the renal end-point, independent of albuminuria and eGFR at baseline. Conclusions: The 1-year eGFR decline rate provided useful information for cardiovascular end-point predictions, including the renal end-point, in addition to the conventional risk factors.

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BO Ceti: Dwarf Nova Showing Both IW And and SU UMa-Type Features

Taichi Kato, Yusuke Tampo, Naoto Kojiguchi, Masaaki Shibata, Junpei Ito, Keisuke Isogai, Hiroshi Itoh, Franz-Josef Hambsch, Berto Monard, Seiichiro Kiyota, Tonny Vanmunster, Aleksei A. Sosnovskij, Elena P. Pavlenko, Pavol A. Dubovsky, Igor Kudzej, Tomas Medulka

2021.06

IW And stars are a recently recognized subgroup of dwarf novae which are
characterized by (often repetitive) slowly rising standstills terminated by
brightening, but the exact mechanism for this variation is not yet identified.
We have identified BO Cet, which had been considered as a novalike cataclysmic
variable, as a new member of IW And stars based on the behavior in 2019-2020.
In addition to this, the object showed dwarf nova-type outbursts in 2020-2021,
and superhumps having a period 7.8% longer than the orbital one developed at
least during one long outburst. This object has been confirmed as an SU
UMa-type dwarf nova with an exceptionally long orbital period (0.1398 d). BO
Cet is thus the first cataclysmic variable showing both SU UMa-type and IW
And-type features. We obtained a mass ratio (q) of 0.31-0.34 from the
superhumps in the growing phase (stage A superhumps). At this q, the radius of
the 3:1 resonance, responsible for tidal instability and superhumps, and the
tidal truncation radius are very similar. We interpret that in some occasions
this object showed IW And-type variation when the disk size was not large
enough, but that the radius of the 3:1 resonance could be reached as the result
of thermal instability. We also discuss that there are SU UMa-type dwarf novae
above q=0.30, which is above the previously considered limit (q~0.25) derived
from numerical simulations and that this is possible since the radius of the
3:1 resonance is inside the tidal truncation radius. We constrained the mass of
the white dwarf larger than 1.0Msol, which may be responsible for the IW
And-type behavior and the observed strength of the He II emission. The exact
reason, however, why this object is unique in that it shows both SU UMa-type
and IW And-type features is still unsolved.

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Association of childhood anthropometric measurements and laboratory parameters with high blood pressure in young adults.

Tatsuhiko Azegami, Keiko Uchida, Fujiyo Arima, Yasunori Sato, Midori Awazu, Mikako Inokuchi, Ayano Murai-Takeda, Hiroshi Itoh, Mitsuaki Tokumura, Masaaki Mori

Hypertension research : official journal of the Japanese Society of Hypertension 44 ( 6 ) 711 - 719 2021.06

ISSN 09169636

Early intervention to manage high blood pressure (BP) in young adulthood is a promising approach for the prevention of future cardiovascular diseases. We aimed to examine the ability of childhood health information to predict the incidence of young adults with high BP. This cohort study included baseline clinical data of Japanese individuals aged 12-13 years. A total of 1129 participants were followed up for an average of 8.6 years. We examined the association of childhood variables consisting of body weight, body mass index, systolic BP, white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, uric acid, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol with the development of high BP defined as ≥120/80 mmHg at 18-22 years old. At follow-up, the prevalence of high BP was 42.2% in men and 7.7% in women. Young men with high BP had childhood baseline characteristics that included higher body weight, body mass index, systolic BP, red blood cell count, hemoglobin, hematocrit, and uric acid than normotensive men. Young women with high BP had higher body weight, systolic BP, and uric acid at baseline. Multivariable logistic regression analysis revealed that a model including body weight, systolic BP, hematocrit, and uric acid had the highest predictive power (AUC 0.65 [95% CI, 0.62-0.69]) for men, and a model including body weight, systolic BP, and uric acid had the highest predictive power (AUC 0.70 [95% CI, 0.58-0.81]) for women. Comprehensive childhood health information contributes to the prediction of high BP in young adults.

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Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy.

Itaru Yasuda, Kazuhiro Hasegawa, Yusuke Sakamaki, Hirokazu Muraoka, Takahisa Kawaguchi, Ei Kusahana, Takashi Ono, Takeshi Kanda, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh

Journal of the American Society of Nephrology : JASN 32 ( 6 ) 1355 - 1370 2021.06

ISSN 10466673

BACKGROUND: The activation of NAD+-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 NAD+ 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 NAD+ 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 2021.05

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 2021.05

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 2021.05

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 2021.05

ISSN 09169636

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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