Papers - ITOH Hiroshi

腹膜透析単独療法中に神経症状をきたした無尿患者の2症例

丸木 友美, 内山 清貴, 吉田 英莉子, 日鼻 瑛, 中山 尭振, 森本 耕吉, 鷲田 直輝, 伊藤 裕

腎と透析 ((株)東京医学社)  95 ( 別冊 腹膜透析2023 ) 237 - 239 2023.09

ISSN  0385-2156

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症例1は79歳男性で、腎硬化症による末期腎不全に対して5年前に腹膜透析(PD)を開始され、無尿となり体液貯留をきたしたため血液透析(HD)併用療法を導入した。最終HDから5日目より右上肢のミオクローヌスが出現し、その後全身性のミオクローヌス発作が出現したため精査加療目的に入院となった。尿毒症性脳症と診断し、透析効率を上げてHDを施行し、ミオクローヌスは速やかに消失した。症例2は65歳男性で、慢性糸球体腎炎に伴う末期腎不全に対して11年前よりPDを開始された。1ヵ月前より両側下腿脱力と四肢ミオクローヌス、物忘れが出現し、歩行困難となったため当院へ入院した。尿毒症性脳症と診断し、3回のHDでミオクローヌスは消失し歩行可能となった。以降は2症例とも週6回のPDと週1回のHD併用療法にて神経症状の再燃なく経過している。

Characterizing non-Markovian Quantum Process by Fast Bayesian Tomography

R. Y. Su, J. Y. Huang, N. Dumoulin. Stuyck, M. K. Feng, W. Gilbert, T. J. Evans, W. H. Lim, F. E. Hudson, K. W. Chan, W. Huang, Kohei M. Itoh, R. Harper, S. D. Bartlett, C. H. Yang, A. Laucht, A. Saraiva, T. Tanttu, A. S. Dzurak

 2023.07

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To push gate performance to levels beyond the thresholds for quantum error
correction, it is important to characterize the error sources occurring on
quantum gates. However, the characterization of non-Markovian error poses a
challenge to current quantum process tomography techniques. Fast Bayesian
Tomography (FBT) is a self-consistent gate set tomography protocol that can be
bootstrapped from earlier characterization knowledge and be updated in
real-time with arbitrary gate sequences. Here we demonstrate how FBT allows for
the characterization of key non-Markovian error processes. We introduce two
experimental protocols for FBT to diagnose the non-Markovian behavior of
two-qubit systems on silicon quantum dots. To increase the efficiency and
scalability of the experiment-analysis loop, we develop an online FBT software
stack. To reduce experiment cost and analysis time, we also introduce a native
readout method and warm boot strategy. Our results demonstrate that FBT is a
useful tool for probing non-Markovian errors that can be detrimental to the
ultimate realization of fault-tolerant operation on quantum computing.


Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation.

Sho Endo, Asuka Uto, Kazutoshi Miyashita, Masaaki Sato, Hiroyuki Inoue, Kentaro Fujii, Aika Hagiwara, Masaki Ryuzaki, Takuma Oshida, Kenichiro Kinouchi, Hiroshi Itoh

Journal of the Endocrine Society 7 ( 7 ) bvad082 2023.07

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To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This long-term IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 (Ucp3) and carnitine palmitoyl transferase 1b (Cpt1b) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF.

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Impact of Prophylactic Corticosteroid Use on In-hospital Mortality and Respiratory Failure After Esophagectomy for Esophageal Cancer: Nationwide Inpatient Data Study in Japan.

Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y

Annals of surgery 277 ( 6 ) e1247 - e1253 2023.06

ISSN  0003-4932

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Mean annual intradialytic blood pressure decline and cardiovascular events in Japanese patients on maintenance hemodialysis.

Rina Takahashi, Kiyotaka Uchiyama, Naoki Washida, Keigo Shibagaki, Akane Yanai, Takashin Nakayama, Kengo Nagashima, Yasunori Sato, Takeshi Kanda, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 6 ) 1536 - 1546 2023.06

ISSN  09169636

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An intradialytic systolic blood pressure (SBP) decline, which defines intradialytic hypotension, may be associated with higher all-cause mortality. However, in Japanese patients on hemodialysis (HD), the association between intradialytic SBP decline and patient outcomes is unclear. This retrospective cohort study included 307 Japanese patients undergoing HD over 1 year in three dialysis clinics and evaluated the association between the mean annual intradialytic SBP decline (predialysis SBP-nadir intradialytic SBP) and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) by following up for 2 years. The mean annual intradialytic SBP decline was 24.2 (25-75th percentile, 18.3-35.0) mmHg. In the model fully adjusted for intradialytic SBP decline tertile group (T1, <20.4 mmHg; T2, 20.4 to <29.9 mmHg; T3, ≥29.9 mmHg), predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, use of renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, geriatric nutritional risk index, normalized protein catabolism rate, C-reactive protein, hemoglobin, and use of pressor agents, Cox regression analyses showed that the hazard ratio (HR) was significantly higher for T3 than for T1 for MACEs (HR, 2.38; 95% confidence interval 1.12-5.09) and all-cause hospitalization (HR, 1.68; 95% confidence interval 1.03-2.74). Therefore, in Japanese patients on HD, a greater intradialytic SBP decline was associated with worse clinical outcomes. Further studies are warranted to investigate whether interventions to attenuate the intradialytic SBP decline will improve the prognosis of Japanese patients on HD.

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A systematic review and meta-analysis of the clinical impact of stopping renin-angiotensin system inhibitor in patients with chronic kidney disease.

Takashin Nakayama, Ryunosuke Mitsuno, Tatsuhiko Azegami, Yasunori Sato, Kaori Hayashi, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 6 ) 1525 - 1535 2023.06

ISSN  09169636

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Although renin-angiotensin system (RAS) inhibitors reduce the risk of cardiovascular diseases and end-stage kidney disease (ESKD) in chronic kidney disease (CKD) patients, they are often discontinued in clinical practice due to drug-related adverse events. However, limited evidence is available about the clinical impact of RAS inhibitor discontinuation in CKD patients. A comprehensive search of publications investigating the effect of discontinuing RAS inhibitors on clinical outcomes in CKD patients in PubMed, the Cochrane Library, and Web of Science was conducted (inception to November 7, 2022), and potentially relevant studies were searched by hand (through November 30, 2022). Two reviewers independently extracted data according to the PRISMA and MOOSE guidelines and assessed the quality of each study with risk-of-bias tools, RoB2 and ROBINS-I. The pooled hazard ratio (HR) for each outcome was integrated with a random-effect model. A total of 1 randomized clinical trial and 6 observational studies involving 248,963 patients were included in the systematic review. The meta-analysis of observational studies showed that discontinuation of RAS inhibitors was associated with a higher risk of all-cause mortality (HR, 1.41 [95% CI, 1.23-1.62]; I2 = 97%), ESKD (1.32 [95% CI, 1.10-1.57]; I2 = 94%) and MACE (1.20 [95% CI 1.15-1.25]; I2 = 38%), but not with hyperkalemia (0.79 [95% CI 0.55-1.15]; I2 = 90%). Overall risk of bias was moderate-to-serious, and quality of evidence (GRADE system) was low-to-very low. The present study suggests that CKD patients would benefit from continuing RAS inhibitors.

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A higher resting heart rate is associated with cardiovascular event risk in patients with type 2 diabetes mellitus without known cardiovascular disease.

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

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 5 ) 1090 - 1099 2023.05

ISSN  09169636

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A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR ( < 60, 60-69, 70-79, and ≥80 bpm). Patients with a higher RHR were more likely to be younger and had a higher body mass index, blood pressure value, HbA1c value, and estimated glomerular filtration rate and a lower B-type natriuretic peptide value; they also had a higher proportion of current smoking status, neuropathy, and nephropathy. After adjusting for confounders, including the aforementioned risk factors, a RHR of 70-79 bpm and a RHR ≥ 80 bpm were significantly associated with cardiovascular events (hazard ratio 1.50, 95% CI 1.03-2.20; and hazard ratio 1.62, 95% CI 1.11-2.36; respectively) compared to a RHR of 60-69 bpm. The analysis using restricted cubic splines indicated that the cardiovascular risk seemed to be similarly high when the RHR range was ≥70 bpm. In conclusion, in T2DM patients with diabetic retinopathy and without known cardiovascular disease, a high RHR, particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to a RHR of 60-69 bpm. High resting heart rate (RHR), particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to RHR 60-69 bpm in patients with type 2 diabetes mellitus (T2DM), diabetic retinopathy, and hyperlipidemia, but without known cardiovascular disease.

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DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation.

Ran Nakamichi, Akihito Hishikawa, Shunsuke Chikuma, Akihiko Yoshimura, Takashi Sasaki, Akinori Hashiguchi, Takaya Abe, Tomoko Tokuhara, Norifumi Yoshimoto, Erina Sugita Nishimura, Eriko Yoshida Hama, Tatsuhiko Azegami, Takashin Nakayama, Kaori Hayashi, Hiroshi Itoh

Cell reports 42 ( 4 ) 112302 - 112302 2023.04

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Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.

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Impact of Body Mass Index on Major Complications, Multiple Complications, In-hospital Mortality, and Failure to Rescue After Esophagectomy for Esophageal Cancer: A Nationwide Inpatient Database Study in Japan.

Hirano Y, Kaneko H, Konishi T, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Itano O, Yasunaga H, Kitagawa Y

Annals of surgery 277 ( 4 ) e785 - e792 2023.04

ISSN  0003-4932

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Canagliflozin protects the cardiovascular system through effects on the gut environment in non-diabetic nephrectomized rats.

Ayumi Matsui, Ayumi Yoshifuji, Junichiro Irie, Takaya Tajima, Kiyotaka Uchiyama, Tomoaki Itoh, Shu Wakino, Hiroshi Itoh

Clinical and experimental nephrology 27 ( 4 ) 295 - 308 2023.04

ISSN  13421751

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BACKGROUND: The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment. METHODS: Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats. RESULTS: Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin. CONCLUSIONS: The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.

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Significance of podocyte DNA damage and glomerular DNA methylation in CKD patients with proteinuria.

Norifumi Yoshimoto, Kaori Hayashi, Akihito Hishikawa, Akinori Hashiguchi, Ran Nakamichi, Erina Sugita-Nishimura, Eriko Yoshida-Hama, Tatsuhiko Azegami, Takashin Nakayama, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 4 ) 1000 - 1008 2023.04

ISSN  09169636

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The number of chronic kidney disease (CKD) patients is increasing worldwide, and it is necessary to diagnose CKD patients in earlier stages to improve their prognosis. Previously, in a study using human samples, we reported that DNA methylation and DNA damage in podocytes are potential markers for kidney function decline in IgA nephropathy; however, these candidate markers have not been adequately investigated in other glomerular diseases. Here, we report that the association of podocyte DNA damage and DNA methylation with eGFR decline and proteinuria differs depending on the type of glomerular disease. Patients diagnosed with minor glomerular abnormality (MGA, n = 33), membranous nephropathy (MN, n = 9) or diabetic nephropathy (DN, n = 10) following kidney biopsy at Keio University Hospital from 2015 to 2017 were included. In MGA patients, both podocyte DNA damage and glomerular DNA methylation were associated with the severity of proteinuria. In DN patients, podocyte DNA double-strand breaks (DSBs) and glomerular DNA methylation were associated with an eGFR decline. When patients with urinary protein levels of more than 1 g/gCr were examined, fewer podocyte DNA DSBs were detected in MN patients than in MGA patients, and the level of glomerular DNA methylation was lower in MN patients than in MGA or DN patients. These results indicate that investigating podocyte DNA DSBs and DNA methylation changes may be useful for understanding the pathogenesis of CKD with proteinuria in humans. This study suggested the association of podocyte DNA damage and subsequent DNA methylation with proteinuria in minor glomerular abnormalities (MGA) patients and those with eGFR declines in diabetic nephropathy (DN) patients, respectively.

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Diagnosis of monoclonal immunotactoid glomerulopathy with positive λ chain by immunoelectron microscopy.

Erina Sugita, Homare Sonoda, Masaki Ryuzaki, Akinori Hashiguchi, Hirobumi Tokuyama, Shu Wakino, Takeshi Kanda, Hiroshi Itoh

CEN case reports 12 ( 1 ) 7 - 13 2023.02

ISSN  2192-4449

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We report the case of a 73-year-old-man who developed immunotactoid glomerulopathy (ITG). ITG is a rare disease characterized by proliferative glomerulonephritis and capillary wall deposits with a 10-60 nm diameter microtubular substructure. In monoclonal ITG, immunofluorescence analysis typically exhibits IgG with light chain restriction. Recent reviews recommend distinguishing monoclonal ITG from polyclonal ITG because monoclonal ITG is associated with a higher incidence of hematological disorders and better responsiveness to clone-directed therapy and renal prognosis. In our case, IgG, IgA, and IgM were negative by routine immunofluorescence; however, immunoelectron microscopy revealed positive λ chain. At 6 months after renal biopsy, the IgG λ chain was detected in the serum and urine, reflecting possible monoclonality. Therefore, it is useful to perform immunoelectron microscopy and follow-up with serum and urine protein electrophoresis and immunofixation to diagnose monoclonal ITG, even when routine immunofluorescence shows negative or nonspecific findings.

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Early postoperative non-steroidal anti-inflammatory drugs and anastomotic leakage after oesophagectomy

Hirano, Y; Konishi, T; Kaneko, H; Itoh, H; Matsuda, S; Kawakubo, H; Uda, K; Matsui, H; Fushimi, K; Daiko, H; Itano, O; Yasunaga, H; Kitagawa, Y

BJS-BRITISH JOURNAL OF SURGERY 110 ( 2 ) 260 - 266 2023.01

ISSN  0007-1323

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Case report: Importance of early and continuous tocilizumab therapy in nephrotic syndrome associated with idiopathic multicentric Castleman disease: A case series.

Daiki Kojima, Shintaro Yamaguchi, Akinori Hashiguchi, Kaori Hayashi, Kiyotaka Uchiyama, Norifumi Yoshimoto, Keika Adachi, Takashin Nakayama, Ken Nishioka, Takaya Tajima, Kohkichi Morimoto, Jun Yoshino, Tadashi Yoshida, Toshiaki Monkawa, Takeshi Kanda, Hiroshi Itoh

Frontiers in medicine 9   1037032 - 1037032 2023.01

ISSN  2296-858X

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Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

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MEAN ANNUAL INTRADIALYTIC BLOOD PRESSURE DECLINE AND CARDIOVASCULAR EVENTS IN JAPANESE MAINTENANCE HEMODIALYSIS PATIENTS

Takahashi, R; Uchiyama, K; Washida, N; Shibagaki, K; Yanai, A; Nakayama, T; Morimoto, K; Itoh, HI

JOURNAL OF HYPERTENSION 41   E387 - E387 2023.01

ISSN  0263-6352

"MINERALOCORTICOID RECEPTOR (MR)ASSOCIATED HYPERTENSION" IN "GREEDY ORGAN HYPOTHESIS"

Itoh, H

JOURNAL OF HYPERTENSION 41   E143 - E143 2023.01

ISSN  0263-6352

DNA DAMAGE REPAIR AND DNA METHYLATION IN THE KIDNEY AND CKD

Hayashi, K; Itoh, H

JOURNAL OF HYPERTENSION 41   E87 - E87 2023.01

ISSN  0263-6352

DISSOCIATION OF SERUM ALDOSTERONE CONCENTRATIONS BETWEEN THE MEASUREMENT METHODS: A CASE REPORT.

Torimitsu, T; Kinouchi, K; Kato, K; Iwahara, A; Kozuma, T; Nakamura, T; Kobayashi, S; Miyashita, K; Itoh, H

JOURNAL OF HYPERTENSION 41   E345 - E345 2023.01

ISSN  0263-6352

CONTINUOUS NON-MUTAGENIC DNA DAMAGE IN PODOCYTES ACTIVATES PATHOGENIC MEMORY T CELLS THROUGH ALTERED DNA METHYLATION

Nakamichi, R; Hayashi, K; Hishikawa, A; Chikuma, S; Yoshimoto, N; Sugita, E; Yoshida, E; Itoh, H

JOURNAL OF HYPERTENSION 41   E86 - E87 2023.01

ISSN  0263-6352

CLINICAL AND BIOCHEMICAL OUTCOMES OF PATIENTS WITH ALDOSTERONE-PRODUCING ADENOMA AFTER RADIOFREQUENCY ABLATION THERAPY AT KEIO UNIVERSITY HOSPITAL: 2022 REPORT

Kozuma, T; Kobayashi, S; Nakamura, T; Kinouchi, K; Yokota, K; Miyashita, K; Kurihara, I; Takase, K; Nakatsuka, S; Itoh, H

JOURNAL OF HYPERTENSION 41   E314 - E314 2023.01

ISSN  0263-6352