研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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Development of Alveolar Hemorrhage After Pfizer-BioNTech COVID-19 mRNA Vaccination in a Patient With Renal-Limited Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report

Nishioka K., Yamaguchi S., Yasuda I., Yoshimoto N., Kojima D., Kaneko K., Aso M., Nagasaka T., Yoshida E., Uchiyama K., Tajima T., Yoshino J., Yoshida T., Kanda T., Itoh H.

Frontiers in Medicine 9 874831 - 874831 2022年04月

ISSN 2296-858X

Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19+ B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

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Eosinophilic Reaction at the Time of Catheter Insertion Predicts Survival in Patients Initiating Peritoneal Dialysis

Uchiyama K., Washida N., Kusahana E., Nakayama T., Morimoto K., Itoh H.

Blood Purification 51 （ 4 ） 355 - 364 2022年04月

ISSN 02535068

Introduction: Despite excellent biocompatibility, insertion of silicone peritoneal dialysis (PD) catheters can induce minor foreign body reaction, affecting long-term patient outcomes. We evaluated the effect of eosinophilic reaction associated with PD catheter insertion on outcomes of patients initiating PD. Methods: Eosinophilic reaction to PD catheter insertion was defined as the ratio of peripheral blood eosinophil count at 1 week after insertion (E1W) to pre-insertion eosinophil count (E0), and the association of E1W/E0 with technique survival, peritonitis-free survival, and heart failure (HF)-related hospitalization-free survival was analyzed. Results: This retrospective cohort study included 116 patients (89 male patients) who underwent PD catheter insertion between January 2008 and June 2018 (61.3 ± 12.9 years). The follow-up duration was 46.2 (23.8-75.3) months. E1W was significantly higher than E0 (median, 333 vs. 234/μL, p < 0.001), with a median E1W/E0 of 1.54. The log-rank test showed that technique survival, peritonitis-free survival, and HF-related hospitalization-free survival were significantly better in patients with E1W/E0 < 1.54 than in those with E1W/E0 ≥ 1.54 (p = 0.002, <0.001, and <0.001, respectively). By the Cox regression analysis adjusted for age, sex, the Charlson comorbidity index, the estimated glomerular filtration rate, and the geriatric nutritional risk index, E1W/E0 remained a significant risk factor for technique failure, peritonitis, and hospitalization for HF (hazard ratio (HR) 1.68, p = 0.01; HR 2.19, p < 0.001; HR 2.15, p < 0.001, respectively). Conclusion: Eosinophilic reaction at the time of PD catheter insertion is a novel marker that may predict outcomes in patients initiating PD.

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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., Itoh H.

Endocrinology (United States) （Endocrinology (United States)） 163 （ 4 ） 2022年04月

ISSN 00137227

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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Home-Based Exercise Program Ameliorates Renal Function Decline in Patients With CKD Stage 4

Adachi K., Uchiyama K., Muraoka K., Nakayama T., Yasuda M., Miyashita K., Tokuyama H., Wakino S., Itoh H.

Kidney International Reports 7 （ 4 ） 899 - 903 2022年04月

ISSN 24680249

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Lysine-specific demethylase 1 as a corepressor of mineralocorticoid receptor

Kohata N., Kurihara I., Yokota K., Kobayashi S., Murai-Takeda A., Mitsuishi Y., Nakamura T., Morisaki M., Kozuma T., Torimitsu T., Kawai M., Itoh H.

Hypertension Research 45 （ 4 ） 641 - 649 2022年04月

ISSN 09169636

Mineralocorticoid receptor (MR) and its ligand aldosterone play a central role in controlling blood pressure by promoting sodium reabsorption in the kidney. Coregulators are recruited to regulate the activation of steroid hormone receptors. In our previous study, we identified several new candidates for MR coregulators through liquid chromatography-tandem mass spectrometry analysis using a biochemical approach. Lysine-specific demethylase 1 (LSD1) was identified as a candidate. The relationship between LSD1 and salt-sensitive hypertension has been reported; however, the role of MR in this condition is largely unknown. Here, we investigated the functions of LSD1 as a coregulator of MR. First, a coimmunoprecipitation assay using HEK293F cells showed specific interactions between MR and LSD1. A chromatin immunoprecipitation study demonstrated LSD1 recruitment to the gene promoter of epithelial Na+ channel (ENaC), a target gene of MR. Reduced LSD1 expression by treatment with shRNA potentiated the hormonal activation of ENaC and serum/glucocorticoid-regulated kinase 1, another target gene of MR, indicating that LSD1 is a corepressor of MR. In an animal study, mice with kidney-specific LSD1 knockout (LSD1flox/floxKSP-Cre mice) developed hypertension after a high-salt diet without elevation of aldosterone levels, which was counteracted by cotreatment with spironolactone, an MR antagonist. In conclusion, our in vitro and in vivo studies demonstrated that LSD1 is a newly identified corepressor of MR.

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"Greedy Organs Hypothesis" for sugar and salt in the pathophysiology of non-communicable diseases in relation to sodium-glucose co-transporters in the intestines and the kidney

Itoh, H; Tanaka, M

METABOLISM OPEN 13 100169 - 100169 2022年03月

Deposition of visceral fat and insulin resistance play central role in the development of non-communicable diseases (NCDs) including obesity, hypertension and type 2 diabetes. However, we shed more light upon the intestines and the kidney as a strong driver of NCDs. Based upon unexpected outcomes of clinical trials using sodium-glucose cotransporter (SGLT) 2 inhibitors to demonstrate their actions for not only body weight reduction and blood glucose fall but also remarkable cardiorenal protection, we speculate that hyperfunction of the intestines and the kidney is one of critical contributing factors for initiation of NCDs. By detecting high amount of glucose and sodium chloride around them by sweet/salt taste sensors, the intestines and the kidney are designed to (re)absorb these nutrients by up-regulating SGLT1 or SGLT2. We designate these hyperfunctioning organs for nutrient uptake as "greedy organs". The greedy organs can induce NCDs ("greedy organ hypothesis"). SGLTs are regulated by glucose and sodium chloride, and SGLTs or other genes can be "greedy genes." Regulating factors for greedy organs are renin-angiotensin system, renal sympathetic nervous activity, gut inflammation/microbiota or oxidative stress. Mitigation of organ greediness by SGLT2 inhibitors, ketone bodies, bariatric surgery, and regular lifestyle to keep rhythmicity of biological clock are promising.

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Analysis of the IW And star ASAS J071404+7004.3

Taichi Kato, Kiyoshi Kasai, Elena P. Pavlenko, Nikolaj V. Pit, Aleksei A. Sosnovskij, Hiroshi Itoh, Hidehiko Akazawa, Stephen M. Brincat, Leonid E. Keir, Sergei N. Udovichenko, Yusuke Tampo, Naoto Kojiguchi, Masaaki Shibata, Yasuyuki Wakamatsu, Tamas Tordai, Tonny Vanmunster, Charles Galdies

2022年02月

We made a time-resolved photometric campaign of the bright cataclysmic
variable ASAS J071404+7004.3 in 2020. Inight et al. (2022, arXiv/2109.14514)
recently published time-resolved optical spectroscopy, X-ray observations and
long- and short-term optical variations. Although their results were correct in
many parts, they classified ASAS J071404+7004.3 as a VY Scl-type novalike
object. By comparing the ASAS-SN data of this object and the IW And-type object
HO Pup, we showed that their type classification was incorrect. ASAS
J071404+7004.3 showed outbursts from a standstill followed by shallow dips,
which is the defining characteristic of an IW And star. This object
predominantly showed states with low-amplitude dwarf nova-type oscillations,
some of which could be identified as the "heartbeat"-type state as a variety of
the IW And-type phenomenon. The low state described by Inight et al. (2022) was
not a true low state of a VY Scl star, but a dwarf nova-type state with
increased outburst amplitudes. Both ground-based (our campaign) and TESS
observations detected orbital variations whose periods [0.136589(5) d by the
ground-based campaign and 0.1366476(3) d by the TESS data] are in very good
agreement with the one obtained by radial-velocity studies by Inight et al.
(2022). The standstill in 2019-2020 in ASAS J071404+7004.3 was not brighter
than its dwarf nova-type states. The brightest moment of this object occurred
when the amplitudes of dwarf nova-type variations were large, which challenges
the widely accepted interpretation that standstills in Z Cam stars occur when
the mass-transfer rates are high.

Amiodarone-induced multiple organ damage in an Alström syndrome patient with end-stage renal disease and hepatic cirrhosis

Torimitsu T., Yoshida T., Makiuchi S., Itoh H., Oya M.

CEN case reports 11 （ 1 ） 11 - 16 2022年02月

ISSN 2192-4449

Alström syndrome (AS) is an extremely rare disease accompanied by blindness, hearing loss, obesity, type 2 diabetes, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. The life span of AS patients rarely exceeds 50 years, and thus there are very few reports describing the implementation of renal replacement therapy for these patients. We here report a case of AS patient who exhibited dilated cardiomyopathy, end-stage renal disease, and hepatic cirrhosis. He underwent hemodialysis therapy more than 3 years. Although he eventually died of amiodarone-induced multiple organ damage in the lungs and liver, the present case suggests that hemodialysis therapy can be a choice of renal replacement therapy for AS patients with end-stage renal disease.

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Fabry disease associated with multiple myeloma: a case report

Adachi K., Tokuyama H., Oshima Y., Itoh T., Hashiguchi A., Yamakawa H., Togawa T., Sakuraba H., Wakino S., Itoh H.

CEN case reports 11 （ 1 ） 146 - 153 2022年02月

ISSN 2192-4449

Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.

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Activation of the intestinal tissue renin-angiotensin systemby transient sodium loading in saltsensitive rats

Ryuzaki M., Miyashita K., Sato M., Inoue H., Fujii K., Hagiwara A., Uto A., Endo S., Oshida T., Kinouchi K., Itoh H.

Journal of Hypertension 40 （ 1 ） 33 - 45 2022年01月

ISSN 02636352

Background: The renal tissue renin-angiotensin system is known to be activated by salt loading in salt-sensitive rats; however, the response in other organs remains unclear. Method: Spontaneously hypertensive rats were subjected to normal tap water or transient high-salt-concentration water from 6 to 14 weeks of age and were thereafter given normal tap water. From 18 to 20 weeks of age, rats given water with a high salt concentration were treated with an angiotensin II type 1 receptor blocker, valsartan. Results: Sustained blood pressure elevation by transient salt loading coincided with a persistent decrease in the fecal sodium content and sustained excess of the circulating volume in spontaneously hypertensive rats. Administration of valsartan sustainably reduced the blood pressure and normalized the fecal sodium levels. Notably, transient salt loading persistently induced the intestinal tissue renin-angiotensin system and enhanced sodium transporter expression exclusively in the small intestine of salt-sensitive rats, suggesting the potential connection of intestinal sodium absorption to salt sensitivity. Conclusion: These results reveal the previously unappreciated contribution of the intestinal tissue reninangiotensin system to sodium homeostasis and blood pressure regulation in the pathophysiology of salt-sensitive hypertension.

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Effect of esaxerenone on nocturnal blood pressure and natriuretic peptide in different dipping phenotypes

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

Hypertension Research 45 （ 1 ） 97 - 105 2022年01月

ISSN 09169636

There are limited data on the nighttime blood pressure (BP)-lowering effect of esaxerenone and its effect on N-terminal pro b-type natriuretic peptide (NT-proBNP), a predictor of cardiovascular risk, according to different dipping patterns of nocturnal BP. This was a post hoc analysis of a multicenter, open-label, long-term phase 3 study of esaxerenone, a new highly selective mineralocorticoid receptor blocker, in patients with essential hypertension. Patients were classified by dipping pattern (extreme dippers, dippers, non-dippers, risers). Mean changes in BP, changes in dipping pattern, mean NT-proBNP levels, and percentage of patients with normal NT-proBNP levels (<55 pg/mL) at baseline and Weeks 12 and 28 were evaluated. Nighttime systolic BP decreased in all dipping pattern groups at Week 28, with the riser group showing the greatest change (−25.5 mmHg). A significant shift in dipping pattern and riser/non-dipper pattern changes to dipper/extreme dipper pattern were found from baseline to Week 28 (p < 0.0001). The prevalence of the riser pattern decreased from 14.4% to 9.8%, and that of the non-dipper pattern from 44.7% to 39.2%. The decrease in NT-proBNP from baseline to Week 28 was statistically significant in risers, non-dippers, dippers, and extreme dippers (p < 0.001, respectively). At baseline, the proportion of patients with NT-proBNP <55 pg/mL was lowest in risers versus the other dipping pattern types, but after reductions in NT-proBNP in all groups to Week 28, these differences disappeared. Long-term administration of esaxerenone may be a useful treatment option for nocturnal hypertension, especially in patients with a riser pattern.

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Efficacy of dexmedetomidine on peritoneal dialysis catheter insertion

Nakayama T., Uchiyama K., Morimoto K., Washida N., Kasai T., Nakamichi R., Kusahana E., Wakino S., Itoh H.

International Urology and Nephrology 54 （ 1 ） 209 - 215 2022年01月

ISSN 03011623

Purpose: Dexmedetomidine (DEX) is a sedative agent with minimal respiratory and hemodynamic effects. The present study aimed to evaluate its effectiveness in peritoneal dialysis (PD) catheter insertion. Methods: This single-center retrospective study included patients who underwent PD catheter insertion under spinal anesthesia in our hospital between January 2016 and December 2020. Patients were divided into the DEX and non-DEX groups according the use of DEX. After 1:1 propensity score matching to adjust for age, sex, body mass index, mean blood pressure (BP), and Charlson comorbidity index, we compared operation-related outcomes, including peak numerical rating scale (NRS), occurrence of nausea, vital signs, or operative time between the two groups. Results: Of a total of 44 patients, 9 patients received DEX, and 35 did not. After propensity score matching, each group consisted of 8 patients. Peak NRS was significantly lower (P = 0.003) in the DEX group compared with the non-DEX group. Maximum mean BP during the operation was also significantly lower in the DEX group compared with the non-DEX group (P = 0.020), with no significant differences in minimum mean BP between the two groups (P = 0.831). The DEX group showed a trend of shortened operative time (P = 0.068). There were no significant differences in the occurrence of nausea (P = 1.000). Moreover, there was no clinically important adverse event associated with use of DEX. Conclusion: The use of DEX in PD catheter insertion under spinal anesthesia could safely improve operative analgesia.

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Comparison and commutability study between standardized liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent enzyme immunoassay for aldosterone measurement in blood

Nishikawa T., Satoh F., Takashi Y., Yanase T., Itoh H., Kurihara I., Shibata H., Oki Y., Naruse M., Sasamoto H., Kuwa K.

Endocrine Journal （一般社団法人日本内分泌学会） 69 （ 1 ） 45 - 54 2022年

ISSN 09188959

A commutability confirmation test for the blood aldosterone measurement was performed on liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) as a designated comparison method (DCM) and four chemiluminescent enzyme immunoassay (CLEIA) measurement procedures based on metrological traceability. A conventional radioimmunoassay (RIA) and two measurement procedures of CLEIA which obtains RIA equivalent values were also compared. The relationship between the DCM value and the CLEIA value with respect to 120 pg/mL of the RIA value, which is the screening criterion of primary aldosteronism (PA) was clarified. For the correlation test, 75 samples of patient serum and plasma were used. Regression analysis revealed that the standardized LC-MS/MS and four CLEIA measurement procedures were in good agreement. This is the effect of measurement specificity and calibration using by certified reference material (CRM). The median of the LC-MS/MS corresponding to 120 pg/mL of RIA was 48.5 pg/mL. In the mean of standardized four CLEIA values corresponding to the 48.5 pg/mL of LC-MS/MS value was 47.51 pg/mL and the standard deviation (SD) was 2.93 pg/mL. However, the correlation between the RIA value and the RIA equivalent of the two measurement procedures by CLEIA differed depending on the measurement procedure. This is due to the influence of RIA measurement performance. Standardized CLEIA measurements are suitable for routine measurement procedure. When converting the LC-MS/MS equivalent value by the standardized CLEIA to the conventional RIA value, it is necessary to use the conversion formula.

Fibronectin Glomerulopathy Confused with Glomerular Endothelial Injury in a Patient with Takotsubo Cardiomyopathy

Azegami T., Hashiguchi A., Nakayama T., Hayashi K., Kanda T., Itoh H.

Internal Medicine （一般社団法人日本内科学会） 61 （ 13 ） 2027 - 2032 2022年

ISSN 09182918

A 46-year-old woman developed takotsubo cardiomyopathy and nephrotic syndrome. The first kidney biopsy suggested non-immune-complex-mediated membranoproliferative glomerulonephritis (MPGN), and she was diagnosed with glomerular endothelial injury associated with takotsubo cardiomyopathy. A second biopsy was performed two years later because of persistent proteinuria despite renin-angiotensin system inhibition. This biopsy indicated non-immune-complex-mediated MPGN, but a mesangial and subendothelial substance of a higher electron density than that in the first biopsy was detected, suggesting the possibility of glomerular disease with non-immune deposits rather than endothelial injury. Finally, she was diagnosed with fibronectin nephropathy. Although rare, fibronectin glomerulopathy should be considered in non-immune-complex-mediated MPGN.

Increased alpha cell to beta cell ratio in patients with pancreatic cancer

Tsuchiya T., Saisho Y., Inaishi J., Sasaki H., Sato M., Nishikawa M., Masugi Y., Yamada T., Itoh H.

Endocrine Journal （一般社団法人日本内分泌学会） 69 （ 12 ） 1407 - 1414 2022年

ISSN 09188959

The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age-and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.

Remission of Angiographically Confirmed Minocycline-induced Renal Polyarteritis Nodosa: A Case Report and Literature Review

Yokota K., Kurihara I., Nakamura T., Nakatsuka S., Miyashita K., Kobayashi S., Murai-Takeda A., Sone M., Itoh H.

Internal Medicine （一般社団法人日本内科学会） 61 （ 1 ） 103 - 110 2022年

ISSN 09182918

A 23-year-old man presented with severe hypertension. Based on his history of minocycline treatment for over three years and clinical symptoms, such as myalgias and renovascular hypertension with multiple intrarenal aneurysms, he was diagnosed with minocycline-induced renal polyarteritis nodosa (PAN). After minocycline treatment cessation and management of the hypertension, his blood pressure, renin-aldosterone levels, and urinary protein levels gradually improved. Seven and a half years later, repeated angiography found that the aneurysms had resolved. This is the first report in English describing a case of minocycline-induced renal PAN that was reversed functionally and morphologically without steroids or immunosuppressive drugs.

DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation

Hishikawa A., Hayashi K., Kubo A., Miyashita K., Hashiguchi A., Kinouchi K., Yoshimoto N., Nakamichi R., Akashio R., Sugita E., Azegami T., Monkawa T., Suematsu M., Itoh H.

iScience 24 （ 12 ） 103436 - 103436 2021年12月

The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

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Age-stratified comparison of clinical outcomes between medical and surgical treatments in patients with unilateral primary aldosteronism

Nakamaru R., Yamamoto K., Akasaka H., Rakugi H., Kurihara I., Yoneda T., Ichijo T., Katabami T., Tsuiki M., Wada N., Yamada T., Kobayashi H., Tamura K., Ogawa Y., Kawashima J., Inagaki N., Fujita M., Watanabe M., Kamemura K., Okamura S., Tanabe A., Naruse M., Itoh H., Fukuda H., Umakoshi H., Shibayama Y., Murakami M., Yoshimoto T., Haze T., Sone M., Takahashi K., Matsuda Y., Shibata H., Otsuki M., Fujii Y., Ogo A., Miyauchi S., Yanase T., Suzuki T., Kawamura T., Asano M., Fukuoka T., Kai T., Izawa S., Yoshikawa Y., Hashimoto S., Yamada M., Sakamoto R., Chiba Y., Okamoto R., Oki K., Yabe D.

Scientific Reports 11 （ 1 ） 2021年12月

Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥ 65 years) and 702 younger patients (< 65 years) with uPA, treated either with ADX or mineralocorticoid receptor antagonist (MRA) in the Japan PA Study, and compared the estimated glomerular filtration rate (eGFR) or blood pressure over a 36-month period after treatments. ADX-treated patients showed severer biochemical indicators than MRA-treated patients. During 6 and 36 months, the eGFR decreased more prominently in older but not in younger patients with ADX than in those with MRA, which remained significant after adjustment with the inverse probability of treatment weighting (IPTW). There was a significant interaction between the age-groups and the treatment choices in the change of the eGFR with IPTW-adjusted analysis. The post-treatment dose of antihypertensive medication was lower in younger and higher in older patients with ADX than those with MRA. The clinical benefit of ADX differed between younger and older patients with uPA. These findings indicate the need for further validation on whether ADX can benefit older patients with uPA.

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Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells

Kawaguchi T., Hasegawa K., Yasuda I., Muraoka H., Umino H., Tokuyama H., Hashiguchi A., Wakino S., Itoh H.

Scientific Reports 11 （ 1 ） 1515 - 1515 2021年12月

ISSN 2045-2322

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

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Clinical utility of 1-month postpartum random plasma glucose and glycated hemoglobin combined with pre-pregnancy body mass index for detecting postpartum glucose intolerance in Japanese women with gestational diabetes

Sugiyama K., Saisho Y., Kasuga Y., Ochiai D., Itoh H.

Journal of Diabetes Investigation 12 （ 12 ） 2242 - 2246 2021年12月

ISSN 20401116

During the coronavirus disease 2019 pandemic, the Japanese Society of Diabetes and Pregnancy proposed the use of random plasma glucose and glycated hemoglobin measured 1 month after delivery combined with pre-pregnancy body mass index to detect postpartum glucose intolerance instead of carrying out the oral glucose tolerance test in women with gestational diabetes. We retrospectively evaluated the clinical utility of this strategy to detect postpartum glucose intolerance evaluated by the oral glucose tolerance test after delivery. A total of 275 Japanese women with gestational diabetes were included in the present study. The specificity of 1-month postpartum random plasma glucose and glycated hemoglobin combined with pre-pregnancy body mass index to predict postpartum glucose intolerance was 98.0%, with a negative predictive value of 72.6%. However, sensitivity was 6.4%, with a positive predictive value of 55.6%. In conclusion, this Japanese Society of Diabetes and Pregnancy strategy showed high specificity, but low sensitivity, for detecting glucose intolerance postpartum.

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