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Papers - ITOH Hiroshi

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DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages

Nishimura E.S., Hishikawa A., Nakamichi R., Akashio R., Chikuma S., Hashiguchi A., Yoshimoto N., Hama E.Y., Maruki T., Itoh W., Yamaguchi S., Yoshino J., Itoh H., Hayashi K.

Nature Communications 16 ( 1 ) 3958 2025.12

DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6Chi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.

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Patient education status regarding peritoneal dialysis: a questionnaire-based survey study

Ryuzaki M., Inoue S., Morimoto K., Wakabayashi K., Yoshifuji A., Komatsu M., Fujii K., Kato A., Honjoh H., Wakino S., Uchiyama K., Itoh H.

Renal Replacement Therapy 11 ( 1 ) 2025.12

Background: The number of patients undergoing peritoneal dialysis (PD) in Japan has recently increased. However, Japanese guidelines for such patients’ education are not yet available. Therefore, we aimed to investigate the present status of patient education regarding PD in Japan. Methods: We used one questionnaire to perform two rounds of surveys (2019 and 2021) at institutes that managed ten patients or more on PD at the end of each year. We evaluated the facilities’ characteristics, catheter placement, PD guidance, educational content, education management, home-care environment, care of exit site, and bathing and retraining. Results: A total of 76 facilities (response rate: 26.8%) responded to the first survey, and 86 (response rate: 28.3%) to the second. The incidence of peritonitis in the valid responding institutes was 0.21 per patient-year in 2019 and 0.19 per patient-year in 2021, similar to the incidence of 0.20 per patient-year in 2022 reported by the Japanese Society for Dialysis Therapy Renal Data Registry. This indicates that the valid responding institutes may have been representative of the typical Japanese clinical level in terms of PD. In terms of catheter placement, exit-site positions were preoperatively marked by nurse in 41% of facilities in 2019 and in 37% in 2021. In terms of PD guidance, regarding the timing of the education’s initiation, the periods before PD catheter placement or during catheter embedding were more common than 1–6 days after placement in both years. In terms of the duration, 30-min to 1-h education sessions were most common, and the majority of facilities provided guidance for more than 7 days in both years. These results were different from the schedules recommended by the International Society for Peritoneal Dialysis (3 h per session for more than 5 days, initiated 10 days after the operation). Regarding educational content, most facilities provided education on PD procedures and bathing; however, in some facilities, the content did not include dietary guidance, the importance of residual kidney function, medications, laboratory data, troubleshooting, medical security, or social resources. In both years, approximately 70% of the instructional items comprised the PD procedure, exit-site care, bathing, and infection prevention. Regarding education management, the patients’ levels of understanding were evaluated via manual or oral tests in most of the facilities. Regarding the method of demonstration, the entire procedure was explained during the demonstration in almost all institutes. Nurses in > 50% of facilities visited the patients’ homes either when PD was introduced or as needed. The majority of facilities did not use cognitive-function tests when PD was introduced to older adults. Regarding exit-site care and bathing, no consensus existed. Almost half of facilities performed regular, scheduled retraining. Conclusions: In this study, patients’ PD-related educational situations differed from those recommended by the International Society for Peritoneal Dialysis, and no consensus for exit-site care or bathing existed. To improve the clinical level of PD practice in Japan, original Japanese guidelines for patients’ PD education are required, for which our results may serve as the foundation.

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Effect of administration and withdrawal of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, on renal protection in individuals with type 2 diabetes mellitus and diabetic nephropathy: A multicenter, single-arm study (RESTORE-nephropathy study)

Shigeta A., Tanaka M., Meguro S., Morimoto J., Imai T., Yamauchi A., Kanazawa Y., Kawai T., Azuma K., Yamada S., Endo S., Itoh H., Hayashi K.

Journal of Diabetes Investigation 16 ( 5 ) 817 - 826 2025.05

ISSN 20401116

Aims/Introduction: The mechanisms of the renoprotective effects of sodium-glucose cotransporter 2 inhibitors are unknown. This study aimed to explore the effect and mechanism of tofogliflozin on urinary albumin by administration, withdrawal, and re-administration. Materials and Methods: Individuals with type 2 diabetes mellitus and stage 2 or 3 diabetic nephropathy were enrolled. Tofogliflozin was administered for 24 weeks, withdrawn for 12 weeks (withdrawal period), and re-administered for 24 weeks. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR). The secondary endpoints included hemoglobin A1c (HbA1c), hepatic biomarkers, lipid profiles, physical examinations, and blood counts. Results: A total of 47 individuals were enrolled. UACR significantly decreased throughout the observation period. It also significantly decreased, increased, and again decreased during the period of the 1st administration, withdrawal, and re-administration, respectively. HbA1c, body weight, waist circumference, and systolic blood pressure also showed the same tendency. Aspartate aminotransferase and alanine aminotransferase significantly decreased throughout the observation period, but did not increase during the withdrawal period. Conclusions: Urinary albumin improved during the administration of tofogliflozin and worsened during its withdrawal, suggesting the reversibility of its renoprotective effect. The administration of tofogliflozin should be continued to avoid the reversal of glycemic control, renoprotective effects, and other beneficial effects.

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A Randomized Clinical Trial of ICT-based Interventions for Sodium and Potassium Regulation in Healthy Adults.

Yuichiro Yano, Kaori Kitaoka, Takayoshi Ohkubo, Tomonori Okamura, Hiroshi Kanegae, Katsushi Yoshita, Rumi Tsukinoki, Yukiko Okami, Koichi Node, Hiromi Rakugi, Hiroshi Itoh, Katsuyuki Miura

American journal of hypertension 2025.04

ISSN 0895-7061

BACKGROUND: There is limited knowledge regarding effective strategies, including information and communication technology (ICT)-based interventions, to reduce sodium intake and increase potassium intake in healthy individuals. METHODS: We conducted a three-month randomized controlled trial involving healthy adult employees with spot urine sodium-to-potassium ratios (spot UNa/UK) ≥4.0 or estimated 24-hour salt intake ≥10g. Estimated 24-hour UNa and UK were calculated using the Tanaka formula. Participants were assigned to one of four groups: (1) online education, where participants monitored their spot UNa/UK and received feedback from dieticians (n=84); (2) messaging, with similar self-monitoring and dietician messages (n=84); (3) self-learning, provided with an educational leaflet (n=87); and (4) a control group (n=87). The primary outcome was the change in spot UNa/UK ratios, and secondary outcomes included changes in estimated 24-hour UNa and UK. The trial protocol specified a hierarchical order for testing the interventions, anticipating the highest efficacy in the online education group. RESULTS: After the intervention, the online education group showed a decrease in spot UNa/UK ratios (mean -0.9 [95% CI -1.8 to 0.0], p=0.052) compared to the control group. The increase in estimated 24-hour UK excretion was larger in the online education compared to control group (mean +2.5 mmol/day [95% CI -0.3 to 5.3], p=0.085). The difference in estimated 24-hour UNa excretion between the online education and control groups was -4.3 mmol/day (95% CI -15.5 to 6.9, p=0.45). CONCLUSIONS: Combining self-monitoring of sodium and potassium intake with ICT-based interventions, including online nutritional education, was associated with a modest reduction in the estimated ratios of sodium and potassium intake in healthy individuals.

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Efficacy of Esaxerenone Plus a Renin-Angiotensin System Inhibitor or Calcium Channel Blocker for Nocturnal Hypertension: A Post Hoc Analysis.

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

American journal of hypertension 2025.04

ISSN 0895-7061

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Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report

Nagasaka T., Uchiyama K., Hama E.Y., Kojima D., Kaneko K., Yoshimoto N., Yasuda I., Yamada M., Miya F., Suzuki H., Tajima T., Yamaguchi S., Hayashi K., Kanda T., Hashiguchi A., Kosaki K., Itoh H.

CEN Case Reports 14 ( 2 ) 208 - 216 2025.04

Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1–2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1–2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

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Open-Label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients With ADPKD Receiving Tolvaptan

Uchiyama K., Kamano D., Nagasaka T., Hama E.Y., Shirai R., Sumura R., Kusahana E., Yanai A., Nakayama T., Kimura T., Takahashi R., Kasai T., Tajima T., Hosoya K., Azegami T., Yamaguchi S., Yoshino J., Ito J., Hayashi M., Kanda T., Ishibashi Y., Washida N., Itoh H., Hayashi K.

Kidney International Reports 10 ( 4 ) 1063 - 1075 2025.04

ISSN 24680249

Introduction: Although dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, delays the progression of chronic kidney disease (CKD), its effect on patients with autosomal dominant polycystic kidney disease (ADPKD) has not been established. We conducted an open-label, randomized controlled crossover trial to evaluate the additive effects of dapagliflozin in patients with ADPKD receiving tolvaptan. Methods: A total of 27 patients were randomly counterbalanced to receive dapagliflozin 10 mg or usual care without dapagliflozin for 6 months. The primary endpoint was the slope of the estimated glomerular filtration rate (eGFR) determined by linear regression from 1 to 6 months, and the secondary endpoints included changes in total kidney volume (TKV). eGFR was calculated based on creatinine levels (eGFR<inf>cr</inf>), cystatin C levels (eGFR<inf>cys</inf>), and the mean of eGFR<inf>cr</inf> and eGFR<inf>cys</inf> (eGFR<inf>cr-cys</inf>). Results: There were significant attenuations in the eGFR<inf>cr-cys</inf> and eGFR<inf>cys</inf> slopes during the dapagliflozin trial compared with the one without dapagliflozin (2.57 ± 7.88 vs. −5.65 ± 9.57 ml/min per 1.73 m2 per year, P = 0.002; 3.91 ± 11.40 vs. −8.43 ± 13.44 ml/min per 1.73 m2 per year, P = 0.003, respectively). Meanwhile, the eGFR<inf>cr</inf> slope was potentially moderate during the trial with dapagliflozin (1.03 ± 10.78 vs. −3.66 ± 8.88 ml/min per 1.73 m2 per year, P = 0.06). The 6-month change in TKV was significantly attenuated during the trial with dapagliflozin compared with the one without dapagliflozin (−0.44 ± 4.91% vs. 5.04 ± 8.09%, P = 0.01). Conclusion: In patients with ADPKD treated with tolvaptan, dapagliflozin may have an additive effect in slowing ADPKD progression.

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Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring

Yao N., Kinouchi K., Katoh M., Ashtiani K.C., Abdelkarim S., Morimoto H., Torimitsu T., Kozuma T., Iwahara A., Kosugi S., Komuro J., Kato K., Tonomura S., Nakamura T., Itoh A., Yamaguchi S., Yoshino J., Irie J., Hashimoto H., Yuasa S., Satoh A., Mikami Y., Uchida S., Ueki T., Nomura S., Baldi P., Hayashi K., Itoh H.

Cell Metabolism 37 ( 2 ) 395 - 412.e6 2025.02

ISSN 15504131

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

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A machine learning model for predicting worsening renal function using one-year time series data in patients with type 2 diabetes

Watanabe M., Meguro S., Kimura K., Furukoshi M., Masuda T., Enomoto M., Itoh H.

Journal of Diabetes Investigation 16 ( 1 ) 93 - 99 2025.01

ISSN 20401116

Background and Aims: To prevent end-stage renal disease caused by diabetic kidney disease, we created a predictive model for high-risk patients using machine learning. Methods and Results: The reference point was the time at which each patient's estimated glomerular filtration rate (eGFR) first fell below 60 mL/min/1.73 m2. The input period spanned the reference point to 1 year prior. The primary endpoint was a 50% decrease in eGFR from the mean of the input period over the 3 year evaluation period. We created predictive models for patients’ primary endpoints using time series data of various variables over the input period. Among 2,533 total patients, 1,409 had reference points, 31 had records for their input and evaluation periods and had reached their primary endpoints, and 317 patients had not. The area under the curve (AUC) of the predictive model peaked (0.81) when the minimum eGFR, the difference between maximum and minimum eGFR, and both maximum and minimum urinary protein values were included in the features. Conclusion: The accuracy of prognosis prediction can be improved by considering the variable components of urinary protein and eGFR levels. This model will allow us to identify patients whose renal functions are relatively preserved with eGFR of more than 60 mL/min/1.73 m2 and are likely to benefit clinically from immediate treatment intensification.

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Ghrelin Promotes Lipid Uptake into White Adipose Tissue via Endothelial Growth Hormone Secretagogue-Receptor in Mice

Urai H., Azegami T., Komatsu M., Takahashi R., Kubota Y., Hasegawa K., Tokuyama H., Wakino S., Hayashi K., Kanda T., Itoh H.

Nutrients 17 ( 1 ) 2025.01

Background/Objectives: Endothelial peroxisome proliferator-activated receptor gamma (PPARγ) regulates adipose tissue by facilitating lipid uptake into white adipocytes, but the role of endothelial lipid transport in systemic energy balance remains unclear. Ghrelin conveys nutritional information through the central nervous system and increases adiposity, while deficiency in its receptor, growth hormone secretagogue-receptor (GHSR), suppresses adiposity on a high-fat diet. This study aims to examine the effect of ghrelin/GHSR signaling in the endothelium on lipid metabolism. Methods: We compared the effects of ghrelin on adiposity and lipid uptake into adipocytes in wild-type and GHSR-null mice. Transgenic mice expressing GHSR selectively in endothelial cells were also generated and compared with global GHSR-null and wild-type mice. The impact of ghrelin on lipid uptake-related genes was assessed in cultured endothelial cells. Results: Ghrelin increased adiposity and triglyceride clearance in wild-type but not in GHSR-null mice. GHSR-null mice showed higher serum triglyceride after olive oil gavage and lower white adipose tissue (WAT) weight on a high-fat diet, suggesting impaired lipid uptake. Restoring GHSR expression in endothelial cells increased lipoprotein lipase activity, lipid uptake into WAT, and WAT weight. Ghrelin enhanced free fatty acid uptake and the expression of lipid uptake genes in cultured endothelial cells, whereas these effects were absent in GHSR-null mice-derived endothelial cells. Knockdown of PPARγ revealed that ghrelin/GHSR signaling in endothelial cells promoted lipid uptake via endothelial PPARγ. Conclusions: Endothelial GHSR is key for regulating lipid metabolism via PPARγ in response to ghrelin and for the role of endothelium in regulating white adipocyte metabolism. Targeting endothelial ghrelin signaling may be a promising therapeutic approach for managing excessive adiposity and associated metabolic disorders.

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Pancreatic cancer risk in diabetic patients using the Japanese Regional Insurance Claims

Satoh T., Nakatani E., Ariyasu H., Kawaguchi S., Ohno K., Itoh H., Hayashi K., Usui T.

Scientific Reports 14 ( 1 ) 16958 2024.12

Pancreatic cancer presents a critical health issue characterized by low survival rates. Identifying risk factors in specific populations, such as those with diabetes, is crucial for early detection and improved outcomes. This study aimed to identify risk factors for pancreatic cancer in diabetic patients using a longitudinal cohort from the Shizuoka Kokuho database, spanning April 2012 to September 2021. Diabetic patients were identified and monitored for the onset of pancreatic cancer. Factors analyzed included age, sex, the Elixhauser comorbidity index, and specific comorbidities. Statistical analyses involved univariate and multivariate Cox proportional hazards regression. The study identified 212,775 as diabetic patients and 1755 developed pancreatic cancer during the period. The annual incidence rate of pancreatic cancer in this group was 166.7 cases per 100,000 person-years. The study identified older age, male sex, a history of liver disease, chronic pancreatitis, and pancreatic cystic lesions as significant risk factors for pancreatic cancer in diabetic patients. The study also highlighted the absence of a significant association between diabetes type or diabetic complications and the onset of pancreatic cancer. These findings may aid in the early diagnosis of pancreatic cancer in diabetic patients and may inform revisions in screening practices in diabetic patients.

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Predicting exacerbation of renal function by DNA methylation clock and DNA damage of urinary shedding cells: a pilot study.

Akihito Hishikawa, Erina Sugita Nishimura, Norifumi Yoshimoto, Ran Nakamichi, Eriko Yoshida Hama, Wataru Ito, Tomomi Maruki, Kengo Nagashima, Ryoko Shimizu-Hirota, Hiromasa Takaishi, Hiroshi Itoh, Kaori Hayashi

Scientific reports 14 ( 1 ) 11530 - 11530 2024.12

Recent reports have shown the feasibility of measuring biological age from DNA methylation levels in blood cells from specific regions identified by machine learning, collectively known as the epigenetic clock or DNA methylation clock. While extensive research has explored the association of the DNA methylation clock with cardiovascular diseases, cancer, and Alzheimer's disease, its relationship with kidney diseases remains largely unexplored. In particular, it is unclear whether the DNA methylation clock could serve as a predictor of worsening kidney function. In this pilot study involving 20 subjects, we investigated the association between the DNA methylation clock and subsequent deterioration of renal function. Additionally, we noninvasively evaluated DNA damage in urinary shedding cells using a previously reported method to examine the correlation with the DNA methylation clock and worsening kidney function. Our findings revealed that patients with an accelerated DNA methylation clock exhibited increased DNA damage in urinary shedding cells, along with a higher rate of eGFR decline. Moreover, in cases of advanced CKD (G4-5), the DNA damage in urinary shedding cells was significantly increased, highlighting the interplay between elevated DNA damage and eGFR decline. This study suggests the potential role of the DNA methylation clock and urinary DNA damage as predictive markers for the progression of chronic kidney disease.

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Diurnal variation in the association between the scan frequency of isCGM and CGM metrics: post hoc analysis of the ISCHIA study

Meguro S., Sakane N., Hosoda K., Hirota Y., Itoh A., Kato K., Kodani N., Kuroda A., Matsuhisa M., Miura J., Shimada A., Tone A., Toyoda M., Murata T., Fukunaga M., Kouyama K., Tanaka T., Tenta M., Matsushita Y., Takeda M., Iseda I., Hida K., Nagao T., Taniguchi R., Tanaka N., Abe K., Hitaka Y., Matoba Y., Katsuno T., Kusunoki Y., Fukuda T., Shimizu I., Tsuchiya T., Yagi K., Sugiyama K., Yamaguchi S., Kinouchi K., Inaishi J., Nakajima Y., Mitsuishi M., Tanaka M., Irie J., Saisho Y., Itoh H., Kawashima S., Haisa A., Satomura A., Oikawa Y., Saito N., Kimura M., Tsuchida Y., Shimura K., Hoshina S., Takagi S., Kobayashi H., Shen Z., Suganuma A., Watanabe T., Ito Y., Suzuki S., Kasama S., Kasahara M., Kouyama R., Satoh-Asahara N., Miyamoto Y., Nishimura K.

Diabetology International 15 ( 4 ) 828 - 836 2024.10

ISSN 21901678

Background and aims: To investigate the association between the frequency of intermittent-scanning continuous glucose monitoring (isCGM) and diurnal variation of time in range (TIR), time above range (TAR), and time below range (TBR), we performed a post hoc analysis of the ISCHIA study, a multicenter, prospective, open-label, randomized crossover study of patients with type 1 diabetes mellitus. Method: Data of 93 people who completed the ISCHIA study were used. We calculated scan frequency, TAR, TIR, and TBR of four approximately 6-h intervals: 6:00–11:59 (morning), 12:00–17:59 (afternoon), 18:00–23:59 (evening), and 0:00–5:59 (night). The correlation between scan frequency and diurnal variation of CGM metrics was analyzed using nonparametric Spearman correlation analysis. Results: More frequent scanning was associated with higher TIR in the afternoon (rho = 0.343, P < 0.001), evening (rho = 0.243, P = 0.019), and night (rho = 0.218, P = 0.036); furthermore, it was associated with lower TAR in the afternoon (rho = -0.275, P = 0.008) and TBR in the evening (rho = -0.235, P = 0.024). Concern about the effect of blood glucose fluctuation on social communication affected the number of scans during the day. Concerns about loneliness and hypoglycemia when alone also influenced the number of nighttime scans. Conclusion: Scan frequency is influenced by psychological factors. Afternoon scans were associated with the highest increase in TIR and decrease in TAR. Evening scans were linked to a reduction in TBR.

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Impact of dietary habits on renal function in Saku, a rural Japanese town: a cohort study.

Keika Adachi, Marie Yasuda, Makiko Ida, Takeshi Kanda, Akemi Morita, Shu Wakino, Shaw Watanabe, Hiroshi Itoh

Clinical and experimental nephrology 28 ( 8 ) 751 - 763 2024.08

ISSN 13421751

BACKGROUND: High protein intake leads to a decline in renal function in the advanced stages of chronic kidney disease (CKD). An effective diet for maintaining renal function in healthy individuals or patients in the early stages of CKD has not been established. This cohort study was conducted in Saku, Nagano Prefecture, Japan, to investigate the impact of dietary habits on renal function. METHODS: In this cross-sectional cohort study, we used the Saku Control Obesity Program (UMIN000016892), including 4,446 participants who submitted a brief-type self-administered diet history questionnaire and underwent routine physical examination. The amount of food intake was divided into quartiles. After adjusting for age and sex, multivariate logistic regression analysis was used to calculate the odds ratio (OR) for the risk of developing CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2). RESULTS: In total, 3,899 participants were analyzed. The overall prevalence of patients with eGFR < 60 mL/min/1.73 m2 was 11% (n = 434, male; 7.1%, female; 4.1%). The groups with a high intake of chicken (approximately 63.4 g/day, adjusted OR: 0.632, P = 0.003), natto (fermented bean; approximately 21.7 g/day, adjusted OR: 0.679, P = 0.01), and plant protein (approximately 0.8 g/ideal body weight/day, adjusted OR: 0.695, P = 0.042) showed a low risk of developing CKD compared to the group with the lowest intake. CONCLUSIONS: Our cross-sectional study showed that the intake of chicken meat, natto, and plant protein was associated with high eGFR levels. This information can be of value for preventing CKD incidence in healthy Japanese individuals.

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A sensor-augmented pump with a predictive low-glucose suspend system could lead to an optimal time in target range during pregnancy in Japanese women with type 1 diabetes

Tamura R.K., Kodani N., Itoh A., Meguro S., Kajio H., Itoh H.

Diabetology International 15 ( 3 ) 447 - 455 2024.07

ISSN 21901678

Introduction: It is challenging for pregnant women with type 1 diabetes to maintain optimum glucose level to attain good neonatal outcomes. This study evaluated the efficacy of sensor-augmented insulin pump (SAP) with a predictive low-glucose suspend (PLGS) system in pregnant Japanese women with type 1 diabetes. Materials and methods: SAP with PLGS was used in 11 of the 22 women with type 1 diabetes who delivered between 2011 and 2021 at the two medical institutions in Japan. Glucose management, insulin delivery suspension time (IST) and neonatal outcomes were retrospectively studied. Results: In SAP with PLGS cases (n = 11), average glycated hemoglobin levels were < 6.5% throughout the pregnancy, and the time in range (TIR, 63–140 mg/dl) was > 70% in the second and third trimesters. PLGS was safely used without inducing ketoacidosis. Positive correlation was observed between IST and TIR (r = 0.62, p < 0.01). Negative correlation was observed between IST and time below range (TBR) (r = − 0.40, p = 0.02), and IST and time above range (TAR) (r = − 0.45, p = 0.01). Total daily insulin dose was adequately increased without increasing hypoglycemia. There was only one heavy-for-date HFD) infant among the 11 newborns in SAP with PLGS cases. In cases without SAP (n = 11), target glycemic levels were difficult to achieve and there were 5 HFD infants among the 11 newborns. Conclusion: SAP with PLGS was safely and effectively used in pregnant women with type 1 diabetes to achieve target glucose levels without increasing the risk of hypoglycemia, which may have led to good neonatal outcomes.

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Predictors of the effectiveness of isCGM usage in adults with type 1 diabetes mellitus: post-hoc analysis of the ISCHIA study

Fukunaga M., Kouyama K., Tanaka T., Tenta M., Matsushita Y., Takeda M., Iseda I., Hida K., Nagao T., Taniguchi R., Tanaka N., Abe K., Hitaka Y., Matoba Y., Katsuno T., Kusunoki Y., Fukuda T., Shimizu I., Kodani N., Tsuchiya T., Yagi K., Sugiyama K., Itoh A., Yamaguchi S., Kinouchi K., Inaishi J., Nakajima Y., Mitsuishi M., Tanaka M., Irie J., Saisho Y., Itoh H., Meguro S., Kawashima S., Haisa A., Satomura A., Oikawa Y., Shimada A., Saito N., Kimura M., Tsuchida Y., Shimura K., Hoshina S., Takagi S., Kobayashi H., Shen Z., Suganuma A., Watanabe T., Ito Y., Suzuki S., Kasama S., Kasahara M., Tone A., Miura J., Kouyama R., Kato K., Kuroda A., Matsuhisa M., Hirota Y., Toyoda M., Satoh-Asahara N., Sakane N., Miyamoto Y., Nishimura K., Hosoda K., Murata T.

Diabetology International 15 ( 3 ) 400 - 405 2024.07

ISSN 21901678

Aim: The Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus (ISCHIA) study was a randomized, crossover trial that reported the decrease in time below range (TBR) by the use of intermittent-scanning continuous glucose monitoring (isCGM) combined with structured education in adults with type 1 diabetes (T1D) treated by multiple daily injections. The participants were instructed to perform frequent scanning of the isCGM sensor (10 times a day or more) and ingest sugar when impending hypoglycemia is suspected by tracking the sensor glucose levels and the trend arrow. We conducted post-hoc analysis to identify factors affecting difference in TBR (∆TBR), in time in range (∆TIR), and in time above range (∆TAR). Participants and methods: Data from 93 participants who completed the ISCHIA study were used. Multiple regression analyses were performed to identify factors affecting CGM metrics. Results: Pearson’s correlation analysis showed the negative association between log-transformed scan frequency and with ∆TBR (r = − 0.255, P = 0.015), while there was no significant association of log-transformed scan frequency with ∆TIR (r = 0.172, P = 0.102) and ∆TAR (r = 0.032, P = 0.761), respectively. The log-transformed scan frequency was an independent predictor of ∆TBR (Beta = − 7.712, P = 0.022), but not of ∆TIR(Beta = 7.203, P = 0.091) and of ∆TAR (Beta = 0.514, P = 0.925). Conclusions: Our findings suggest that more frequent scanning of isCGM may be beneficial to reduce TBR in T1D adults.

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Podocyte Ercc1 is indispensable for glomerular integrity.

Eriko Yoshida Hama, Ran Nakamichi, Akihito Hishikawa, Miho Kihara, Takaya Abe, Norifumi Yoshimoto, Erina Sugita Nishimura, Hiroshi Itoh, Kaori Hayashi

Biochemical and biophysical research communications 704 149713 - 149713 2024.04

ISSN 0006291X

As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44+CD8+ memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs.

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Antimicrobial Prophylaxis With Ampicillin-sulbactam Compared With Cefazolin for Esophagectomy: Nationwide Inpatient Database 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 279 ( 4 ) 640 - 647 2024.04

ISSN 0003-4932

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3) Deep Medicine: SDGs (Sustainable Development Goals) for the Conquest of NCDs (Non-communicable Diseases)

Itoh Hiroshi

Nihon Naika Gakkai Zasshi (The Japanese Society of Internal Medicine) 113 ( 3 ) 391 - 395 2024.03

ISSN 00215384

Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease.

Kenji Kaneko, Ryunosuke Mitsuno, Daiki Kojima, Tatsuhiko Azegami, Shotaro Kosugi, Toshifumi Nakamura, Akinori Hashiguchi, Yoshitake Yamada, Masahiro Jinzaki, Shintaro Yamaguchi, Hiroshi Itoh, Jun Yoshino, Kaori Hayashi

Obesity research & clinical practice 18 ( 2 ) 118 - 123 2024.03

ISSN 1871403X

OBJECTIVE: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. METHODS: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). RESULTS: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = -0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = -0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = -0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). CONCLUSION: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

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