Details of a Researcher - Yamaguchi, Shintaro

Papers - Yamaguchi, Shintaro

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Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Yamaguchi S, Franczyk MP, Chondronikola M, Qi N, Gunawardana SC, Stromsdorfer KL, Porter LC, Wozniak DF, Sasaki Y, Rensing N, Wong M, Piston DW, Klein S, Yoshino J.

Proc Natl Acad Sci U S A. (Proceedings of the National Academy of Sciences of the United States of America) 116 ( 47 ) 23822 - 23828 2019.11

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 00278424

Nicotinamide adenine dinucleotide (NAD(+)) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD(+) metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD(+) biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD(+)-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD(+) synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD(+) biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

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Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice

Nagahisa, T., Yamaguchi, S., Kosugi, S., Homma, K., Miyashita, K., Irie, J., Yoshino, J. and Itoh, H.

Endocrinology 163 ( 4 ) 2022.02

Corresponding author, Accepted, ISSN 0013-7227

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

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Diurnal variation in PDK4 expression is associated with plasma free fatty acid availability in people.

Shintaro Yamaguchi, Anna C Moseley, Paloma Almeda-Valdes Kelly L Stromsdorfer, Michael P Franczyk, Adewole L Okunade,Bruce W Patterson, Samuel Klein, Jun Yoshino

J Clin Endocrinol Metab. (Journal of Clinical Endocrinology and Metabolism) 103 ( 3 ) 1068 - 1076 2018.03

Research paper (scientific journal), Joint Work, Lead author, Accepted, ISSN 0021972X

CONTEXT: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the interrelationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people. OBJECTIVE: We tested the hypothesis that the diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFAs), is associated with plasma FFA concentration and clock genes. DESIGN AND METHODS: We analyzed peripheral blood mononuclear cells (PBMCs), subcutaneous adipose tissue, and plasma samples obtained serially during 24 hours from metabolically healthy women (n = 10) and evaluated the interrelationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMCs and adipocytes. RESULTS: We found that PDK4 diurnal expression patterns were similar in PBMCs and adipose tissue (ρ = 0.84, P < 0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA and insulin (ρ = 0.86 and 0.63, respectively, both P < 0.001) concentrations than clock genes. Data obtained from primary culture experiments demonstrated that FFAs directly induced PDK4 gene expression, at least in part through activation of peroxisome proliferator-activated receptor α. CONCLUSIONS: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and we identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.

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Adipose tissue NAD(+) biology in obesity and insulin resistance: From mechanism to therapy

Shintaro Yamaguchi, Jun Yoshino

BIOESSAYS 39 ( 5 ) 2017.05

Research paper (scientific journal), Joint Work, Lead author, ISSN 0265-9247

Nicotinamide adenine dinucleotide (NAD(+) ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD(+) biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD(+) biosynthesis, together with its key downstream mediator, namely the NAD(+) -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD(+) biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD(+) biology.

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NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

Stromsdorfer, Kelly L., Yamaguchi, Shintaro*(*Co-first author), Yoon, Myeong Jin, Moseley, Anna C., Franczyk, Michael P., Kelly, Shannon C., Qi, Nathan, Imai, Shin-ichiro, Yoshino, Jun

CELL REPORTS 16 ( 7 ) 1851 - 1860 2016.08

Research paper (scientific journal), Joint Work, Lead author, ISSN 2211-1247

Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.

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NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Logan RW1, Parekh PK, Kaplan GN, Becker-Krail DD, Williams WP 3rd, Yamaguchi S, Yoshino J, Shelton MA, Zhu X, Zhang H, Waplinger S, Fitzgerald E, Oliver-Smith J, Sundarvelu P, Enwright JF 3rd, Huang YH, McClung CA.

Mol Psychiatry. (Molecular Psychiatry) 24 ( 11 ) 1668 - 1684 2018.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13594184

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.

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Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Junichiro Irie, Emi Inagaki, Masataka Fujita, Hideaki Nakaya, Masanori Mitsuishi, Shintaro Yamaguchi, Kazuya Yamashita, Shuhei Shigaki, Takashi Ono, Hideo Yukioka, Hideyuki Okano, Yo-ichi Nabeshima, Shin-ichiro Imai, Masato Yasui, Kazuo Tsubota, Hiroshi Itoh

Endocr J (Endocrine Journal) 67 ( 2 ) 153 - 160 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 09188959

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD(+)) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD(+) prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

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NAD+-dependent deacetylase SIRT3 in adipocytes is dispensable for maintaining normal adipose tissue mitochondrial function and whole-body metabolism.

Porter LC, Franczyk MP, Pietka T, Yamaguchi S, Lin JB, Sasaki Y, Verdin E, Apte RS, Yoshino J.

Am J Physiol Endocrinol Metab. (American Journal of Physiology - Endocrinology and Metabolism) 315 ( 4 ) E520 - E530 2018.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 01931849

Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.

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Generation of kidney tubular organoids from human pluripotent stem cells

Yamaguchi, Shintaro, Morizane, Ryuji, Homma, Koichiro, Monkawa, Toshiaki, Suzuki, Sayuri, Fujii, Shizuka, Koda, Muneaki, Hiratsuka, Ken, Yamashita, Maho, Yoshida, Tadashi, Wakino, Shu, Hayashi, Koichi, Sasaki, Junichi, Hori, Shingo, Itoh, Hiroshi

SCIENTIFIC REPORTS 6 38353 2016.12

Research paper (scientific journal), Joint Work, Lead author, ISSN 2045-2322

Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3β inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells.

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The role of microRNA-145 in human embryonic stem cell differentiation into vascular cells

Yamaguchi, Shintaro, Yamahara, Kenichi, Homma, Koichiro, Suzuki, Sayuri, Fujii, Shizuka, Morizane, Ryuji, Monkawa, Toshiaki, Matsuzaki, Yumi, Kangawa, Kenji, Itoh, Hiroshi

ATHEROSCLEROSIS 219 ( 2 ) 468 - 474 2011.12

Research paper (scientific journal), Joint Work, Lead author, ISSN 0021-9150

BACKGROUND: Recent studies have reported that microRNA-145 (miR-145) is a critical mediator in the regulation of proliferation, differentiation, and phenotype expression of smooth muscle cells (SMCs). Previously, we established a system for differentiating human ESCs into vascular cells including endothelial cells (ECs) and vascular smooth muscle cells (SMCs). In the present study, we investigated the role of miR-145 in the differentiation process from human ESCs into ECs and SMCs. METHODS AND RESULTS: Undifferentiated human ESCs were induced to differentiate into vascular lineage according to our established method. Quantitative RT-PCR analysis revealed that human ESC-derived precursor of SMCs (ES-pre-SMCs), similar to human aortic SMCs, expressed a significant amount of miR-145 as well as smooth muscle-specific proteins, compared to undifferentiated human ESCs, adult ECs, or ESC-derived ECs (ES-ECs). However, morphological analysis revealed that human ES-pre-SMCs appeared round and flattened in shape, though human aortic SMCs exhibited the typical spindle-like morphology of SMCs. In addition, Krüppel-like factor 4 and 5 (KLF4 and 5), direct targets of miR-145 and suppressors of smooth muscle differentiation, were upregulated in ES-pre-SMCs compared to aortic SMCs, indicating ES-pre-SMCs were not fully differentiated SMCs. Overexpression of miR-145 in ES-pre-SMCs upregulated the expression of smooth muscle markers, repressed KLF4 and 5 expressions, and changed their morphology into a differentiated spindle-like shape. Furthermore, by introduction of miR-145, ES-pre-SMC proliferation was significantly inhibited and carbachol-stimulated contraction of ES-pre-SMCs was significantly increased. In contrast, downregulation of miR-145 in ES-pre-SMCs upregulated KLF4 and 5 expressions, suppressed the expression of smooth muscle markers, and left unchanged their proliferation and contractility. In ES-ECs, miR-145 overexpression did not induce the synthesis of smooth muscle-related proteins nor suppress the expression of endothelial nitric oxide synthase. CONCLUSION: We showed that miR-145 can regulate the fate and phenotype of human ES-pre-SMCs as they become fully differentiated SMCs. Overexpression of miR-145 on human ES-pre-SMCs is a promising method to obtain functional mature SMCs from human ESCs, which are required for reliable experimental research in the fields of atherosclerosis, hypertension and other vascular diseases.

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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. and Itoh, H.

Cell Metab 2025.01

ISSN 1550-4131

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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Open-label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients with Autosomal Dominant Polycystic Kidney Disease Receiving Tolvaptan

Uchiyama, Kiyotaka, Kamano, Daisuke, Nagasaka, Tomoki, Hama, Eriko Yoshida, Shirai, Ryoichi, Sumura, Rena, Kusahana, Ei, Yanai, Akane, Nakayama, Takashin and Kimura, Takahide

Kidney International Reports 2025

ISSN 2468-0249

Early Initiation of Icodextrin Reduces Peritoneal Dialysis-Associated Peritonitis Risk: A Retrospective Cohort Study

Mitsuno, R., Nakayama, T., Morimoto, K., Uchiyama, K., Washida, N., Kusahana, E., Yoshida Hama, E., Tonomura, S., Yoshimoto, N., Hishikawa, A., Hagiwara, A., Azegami, T., Yoshino, J., Monkawa, T., Yoshida, T., Yamaguchi, S. and Hayashi, K.

Blood Purif 1 - 10 2024.12

ISSN 0253-5068

INTRODUCTION: Peritonitis is a common and serious complication of peritoneal dialysis (PD) that leads to its discontinuation and death. Icodextrin (ICO) improves peritoneal ultrafiltration and its early use reduces mortality. However, its effectiveness in reducing PD-associated infections remains to be elucidated. METHODS: This retrospective observational study enrolled patients who underwent PD between September 2011 and March 2020. The patients were classified into two groups: those who received ICO at the initiation of PD therapy (early ICO) and those who received ICO later or not at all (late/no ICO) and were followed up from PD induction until PD cessation, death, or 3 years had passed. RESULTS: Of the 82 patients (age, 61 [53-72] years), 21 received early ICO. During follow-up (36 [14-36] months), the incidence of PD-associated peritonitis was 0.17 episodes per patient-year. Log-rank tests indicated that PD-associated peritonitis and tunnel infection (TI)-free survival rates were significantly better with the early use of ICO than with late/no ICO (p = 0.02 and p = 0.01, respectively). The early use of ICO remained significantly associated with decreased incidence of both peritonitis and TI (hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.69 and HR, 0.10; 95% CI, 0.01-0.78, respectively) using Cox regression analysis adjusted for potential confounders. CONCLUSION: Beginning ICO administration at the initiation of PD shows promise for mitigating the risks of PD-associated peritonitis and TI.

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Efficacy of sucrose and povidone-iodine mixtures in peritoneal dialysis catheter exit-site care

Nakayama, T., Morimoto, K., Uchiyama, K., Washida, N., Kusahana, E., Hama, E. Y., Mitsuno, R., Tonomura, S., Yoshimoto, N., Hishikawa, A., Hagiwara, A., Azegami, T., Yoshino, J., Monkawa, T., Yoshida, T., Yamaguchi, S. and Hayashi, K.

BMC Nephrol (BMC Nephrology) 25 ( 1 ) 151 2024.12

ISSN 1471-2369

BACKGROUND: Exit-site infection (ESI) is a common recurring complication in patients undergoing peritoneal dialysis (PD). Sucrose and povidone-iodine (SPI) mixtures, antimicrobial ointments that promote wound healing, have been used for the treatment of ulcers and burns, but their efficacy in exit-site care is still unclear. METHODS: This single-center retrospective observational study included patients who underwent PD between May 2010 and June 2022 and presented with episodes of ESI. Patients were divided into SPI and non-SPI groups and followed up from initial ESI onset until PD cessation, death, transfer to another facility, or June 2023. RESULTS: Among the 82 patients (mean age 62, [54-72] years), 23 were treated with SPI. The median follow-up duration was 39 months (range, 14-64), with an overall ESI incidence of 0.70 episodes per patient-year. Additionally, 43.1% of second and 25.6% of third ESI were caused by the same pathogen as the first. The log-rank test demonstrated significantly better second and third ESI-free survival in the SPI group than that in the non-SPI group (p < 0.01 and p < 0.01, respectively). In a Cox regression analysis, adjusting for potential confounders, SPI use was a significant predictor of decreased second and third ESI episodes (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.10-0.52 and HR, 0.22; 95%CI, 0.07-0.73, respectively). CONCLUSIONS: Our results showed that the use of SPI may be a promising option for preventing the incidence of ESI in patients with PD. TRIAL REGISTRATION: This study was approved by the Keio University School of Medicine Ethics Committee (approval number 20231078) on August 28, 2023. Retrospectively registered.

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Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome

Nakayama, T., Azegami, T., Yamaguchi, S., Hirano, K., Komatsu, M., Fujii, K., Futatsugi, K., Urai, H., Kawaguchi, T., Itoh, T., Yoshimoto, N., Hagiwara, A., Hishikawa, A., Matsuda, H., Ando, T., Yamaji, Y., Murakami, M., Hashiguchi, A., Kaneko, Y., Yokoo, T. and Hayashi, K.

Sci Rep 14 ( 1 ) 23755 2024.12

ISSN 2045-2322

Proteinuria selectivity index (PSI) is a potential tool for histological classification and prediction of treatment response in nephrotic syndrome, but evidence is insufficient. Clinical relevance of fractional excretion of sodium (FENa) in nephrotic syndrome remains largely unexplored. This multicenter retrospective study included patients with nephrotic syndrome who underwent kidney biopsy between January 2012 and June 2022. Optimal cutoffs for predicting complete remission based on PSI and FENa were determined using receiver operating characteristic curves. Patients were divided into two groups using these cutoffs and followed until complete remission. Of the 611 patients included, 177 had minimal change disease (MCD), 52 had focal segmental glomerulosclerosis (FSGS), and 149 had membranous nephropathy (MN). Median (interquartile range) PSI were 0.14 (0.09-0.19) for MCD, 0.33 (0.23-0.40) for FSGS, and 0.20 (0.14-0.30) for MN. FENa were 0.24 (0.09-0.68), 1.03 (0.50-2.14), and 0.78 (0.41-1.28). Patients with low PSI and FENa had a higher incidence of complete remission. Cox regression analyses demonstrated that both parameters were associated with achieving complete remission (HR 2.73 [95% CI 1.97-3.81] and HR 1.93 [95% CI 1.46-2.55], respectively). PSI and FENa may be useful for histological classification and predicting remission in nephrotic syndrome.

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False-positive Serum Antiglomerular Basement Membrane Antibody due to Bovine Serum Albumin-containing Surgical Adhesive: A Case Report

Yoshida, R., Azegami, T., Yamaguchi, S., Hagiwara, A., Hishikawa, A., Yoshimoto, N., Hashiguchi, A. and Hayashi, K.

Kidney Med 6 ( 10 ) 100880 2024.10

ISSN 2590-0595

Antiglomerular basement membrane (GBM) disease has a poor prognosis. The rapid detection of serum anti-GBM antibody using an enzyme immunoassay, which has a high sensitivity and specificity, leads to an early diagnosis and improved prognosis. We report a case of acute kidney injury with false-positive anti-GBM antibody. A man in his early fifties underwent aortic arch replacement using bovine serum albumin (BSA)-containing surgical adhesion. After intravenous administration of vancomycin for a fever, he developed acute kidney injury without an abnormal urinalysis, and his anti-GBM antibody titer (fluorescence enzyme immunoassay [FEIA]) was 70.4 IU/mL. A kidney biopsy showed acute tubular injury and minor glomerular abnormalities without immunoglobulin G deposits, suggesting no evidence of anti-GBM glomerulonephritis. Consistent with the false-positive anti-GBM antibody test results, anti-GBM antibody determined using a chemiluminescent enzyme immunoassay was negative. A serum sample showed crossbinding to the FEIA plate from which the GBM antigen was removed. This finding indicated a nonspecific reaction to BSA, which contains a coating solution for the FEIA plate. This reaction was likely caused by anti-BSA antibody produced using BSA-containing surgical adhesion. Our findings suggest emerging challenges in diagnosing anti-GBM disease. Nephrologists must remain vigilant regarding false-positive anti-GBM antibody test results, particularly in cases evaluated with immunoassays that contain BSA.

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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. and Murata, T.

Diabetol Int 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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Adipocyte-specific inactivation of NAMPT, a key NAD(+) biosynthetic enzyme, causes a metabolically unhealthy lean phenotype in female mice during aging

Qi, N., Franczyk, M. P., Yamaguchi, S., Kojima, D., Hayashi, K., Satoh, A., Ogiso, N., Kanda, T., Sasaki, Y., Finck, B. N., DeBosch, B. J. and Yoshino, J.

Am J Physiol Endocrinol Metab (American Journal of Physiology - Endocrinology and Metabolism) 327 ( 1 ) E81 - E88 2024.07

ISSN 01931849

Nicotinamide adenine dinucleotide (NAD(+)) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD(+) metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD(+) biosynthesis, mediated by a rate-limiting NAD(+) biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤4-mo-old), middle aged (10-14-mo-old), and old (≥18-mo-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic-euglycemic clamp procedure (HECP) demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPAR-γ) in an age-dependent manner. In addition, administration of a PPAR-γ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD(+)-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue, and whole body metabolic function in female mice during aging.NEW & NOTEWORTHY Defective NAD(+) metabolism is associated with aging and age-associated metabolic diseases. In the present study, we provided in-depth metabolic assessments in female mice with adipocyte-specific inactivation of a key NAD(+) biosynthetic enzyme NAMPT and revealed an unexpected role of adipose tissue NAMPT-NAD(+)-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue and whole body metabolic health during the aging process.

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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

Murata, T., Hirota, Y., Hosoda, K., Kato, K., Kouyama, K., Kouyama, R., Kuroda, A., Matoba, Y., Matsuhisa, M., Meguro, S., Miura, J., Nishimura, K., Sakane, N., Shimada, A., Suzuki, S., Tone, A. and Toyoda, M.

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

Kaneko, K., Mitsuno, R., Kojima, D., Azegami, T., Kosugi, S., Nakamura, T., Hashiguchi, A., Yamada, Y., Jinzaki, M., Yamaguchi, S., Itoh, H., Yoshino, J. and Hayashi, K.

Obes Res Clin Pract 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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