Faculty Profiles - SAITO Akihiko

Papers - SAITO Akihiko

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Urinary A- and C-megalin predict progression of diabetic kidney disease: an exploratory retrospective cohort study. International journal

Tomomichi Iida, Michihiro Hosojima, Hideyuki Kabasawa, Keiko Yamamoto-Kabasawa, Sawako Goto, Takahiro Tanaka, Nobutaka Kitamura, Mitsutaka Nakada, Shino Itoh, Shinya Ogasawara, Ryohei Kaseda, Yoshiki Suzuki, Ichiei Narita, Akihiko Saito

Journal of diabetes and its complications 36 ( 11 ) 108312 - 108312 2022.9

Language：English Publishing type：Research paper (scientific journal)

AIMS: Megalin, a proximal tubular endocytosis receptor, is excreted in urine in two forms: ectodomain (A-megalin) and full-length (C-megalin). We explored whether urinary megalin levels can be used as independent prognostic biomarkers in the progression of diabetic kidney disease (DKD). METHODS: The associations between baseline urinary A-megalin/creatinine (Cr) and/or C-megalin/Cr levels and the subsequent estimated glomerular filtration rate (eGFR) slope were analyzed using a generalized estimating equation. Patients were categorized into higher or lower groups based on the optimal cutoff values, obtained from a receiver operating characteristic curve, of the two forms of urinary megalin. RESULTS: We retrospectively analyzed 188 patients with type 2 diabetes. The eGFR slopes of the higher A-megalin/Cr and higher C-megalin/Cr groups were - 0.904 and -0.749 ml/min/1.73 m2/year steeper than those of the lower groups, respectively. Moreover, the eGFR slope was -1.888 ml/min/1.73 m2/year steeper in the group with both higher A- and higher C-megalin/Cr than in the other group. These results remained significant when adjusted for known urinary biomarkers (albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-d-glucosaminidase). CONCLUSIONS: Urinary A- and C-megalin/Cr levels are likely to be prognostic biomarkers in the progression of DKD independent of other urinary biomarkers.

DOI： 10.1016/j.jdiacomp.2022.108312

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Intradialytic parenteral nutrition using a standard amino acid solution not for renal failure in maintenance hemodialysis patients with malnutrition: a multicenter pilot study

Ryota Yasukawa, Michihiro Hosojima, Hideyuki Kabasawa, Aya Takeyama, Daisuke Ugamura, Yoshiki Suzuki, Akihiko Saito, Ichiei Narita

RENAL REPLACEMENT THERAPY 8 ( 1 ) 2022.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BMC

Background Standard amino acid solutions have recently been removed from the contraindications for use in dialysis patients in Japan. However, the details of their safety and efficacy in these patients are still not known. In this study, we investigated the safety and efficacy of intradialytic parenteral nutrition (IDPN) using ENEFLUID (R) injection containing standard amino acids, glucose, electrolytes, fats, and water-soluble vitamins in maintenance hemodialysis patients with malnutrition. Methods This clinical trial was designed as a multicenter, prospective, non-randomized, open-label, single-arm, observational pilot study. The participants were patients on maintenance hemodialysis who were in the nutritional high-risk group according to the Nutritional Risk Index for Japanese Hemodialysis Patients. One bag of ENEFLUID (R) injection was administered during every hemodialysis session for 12 weeks. The primary endpoint was change in serum transthyretin levels between before and after the 12-week period. As safety endpoints, we evaluated changes in body fluid volume and blood biochemical tests, including blood urea nitrogen and electrolytes, as well as blood glucose variability using flash glucose monitoring (FGM). Results The mean age and body mass index of the 13 participants were 79.0 +/- 10.7 years and 18.0 +/- 1.7 kg/m(2), respectively. No significant changes were observed in nutritional parameters, including serum transthyretin, between before and after the start of the study. After IDPN initiation, there was no obvious fluid overload or significant changes in blood biochemical tests, including electrolytes, and the treatment could be safely continued for 12 weeks. In the FGM analysis, asymptomatic hypoglycemia during hemodialysis was observed at the beginning of the study, but there was a trend toward improvement after 12 weeks (area over the curve < 70 mg/dl per dialysis session: 747.5 +/- 1333.9 to 21.6 +/- 54.3, P = 0.09). Conclusions IDPN using ENEFLUID (R) injection can be safely continued, although it does not significantly improve markers of nutritional status. It also showed the potential to ameliorate asymptomatic hypoglycemia during hemodialysis sessions. More detailed studies of the improvement in nutritional indicators are needed. Trial registration: This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on May 9, 2021 (registration ID, UMIN000044051).

DOI： 10.1186/s41100-022-00432-5

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An exploratory clinical trial on the efficacy and safety of glucagon-like peptide-1 receptor agonist dulaglutide in patients with type 2 diabetes on maintenance hemodialysis

Daisuke Ugamura, Michihiro Hosojima, Hideyuki Kabasawa, Naohito Tanabe, Yuta Yoshizawa, Yoshiki Suzuki, Akihiko Saito, Ichiei Narita

RENAL REPLACEMENT THERAPY 8 ( 1 ) 2022.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BMC

Background Dulaglutide is a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). However, the efficacy and safety of dulaglutide remain unclear in insulin-treated patients with T2DM on maintenance hemodialysis (HD). Methods Dulaglutide treatment was initiated, and the insulin dose was adjusted according to the needs of individual participants. Primary outcomes were changes in the mean and standard deviation (SD) of blood glucose (BG) levels and mean amplitude of glycemic excursions (MAGE) evaluated by continuous glucose monitoring (CGM) for six days, glycated albumin (GA), glycated hemoglobin (HbA1c), pre-dialysis blood glucose levels, and daily total insulin dose from the baseline over 24 weeks. Secondary outcomes were changes in treatment satisfaction and QOL levels from the baseline, measured by using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Diabetes Therapy-Related Quality of Life questionnaire (DTR-QOL) scores. Results The analysis was performed on the 12 participants who completed the study. The GA level (median - 1.8 [interquartile range - 6.6, - 0.3] %; p = 0.026) and daily total insulin dose (- 15.0 [- 24.5, - 9.4] U/day; p = 0.002) significantly decreased without increasing hypoglycemia (area over the glucose curve < 70 mg/dL: 0.0 [- 0.2, 0.0] mg center dot 24 h/dl; p = 0.917). Four patients successfully withdrew from insulin therapy. The levels of HbA1c, SD of BG, and MAGE showed a decreasing tendency, but no significant improvement. Regarding treatment satisfaction and QOL, the total scores of DTSQ (8.0 [0.3, 12.5]; p = 0.041) and DTR-QOL (15.5 [- 1.8, 42.0]; p = 0.023) significantly improved. Conclusion Dulaglutide may help improve glycemic control, treatment satisfaction, and QOL without increasing hypoglycemia in insulin-treated patients with T2DM on maintenance HD. Trial registration This study was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on October 11, 2016 (registration ID, UMIN000024283).

DOI： 10.1186/s41100-022-00409-4

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2型糖尿病患者における尿中メガリン測定による腎予後予測

飯田倫理, 細島康宏, 蒲澤秀門, 蒲澤佳子, 後藤佐和子, 田中崇裕, 北村信隆, 忰田亮平, 鈴木芳樹, 成田一衛, 斎藤亮彦

日本腎臓学会誌 64 ( 3 ) 240 - 240 2022.5

2型糖尿病患者における尿中メガリンの腎予後予測能の検討

飯田倫理, 細島康宏, 蒲澤秀門, 蒲澤佳子, 後藤佐和子, 田中崇裕, 北村信隆, 忰田亮平, 鈴木芳樹, 成田一衛, 斎藤亮彦

糖尿病 65 ( Suppl.1 ) S - 150 2022.4

Association of metabolic syndrome traits with urinary biomarkers in Japanese adults. International journal

Keiko Kabasawa, Michihiro Hosojima, Yumi Ito, Kazuo Matsushima, Junta Tanaka, Masanori Hara, Kazutoshi Nakamura, Ichiei Narita, Akihiko Saito

Diabetology & metabolic syndrome 14 ( 1 ) 9 - 9 2022.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although metabolic syndrome traits are risk factors for chronic kidney disease, few studies have examined their association with urinary biomarkers. METHODS: Urinary biomarkers, including A-megalin, C-megalin, podocalyxin, albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-D-glucosaminidase, were cross-sectionally assessed in 347 individuals (52.7% men) with a urine albumin-to-creatinine ratio (ACR) < 300 mg/g in a health checkup. Metabolic syndrome traits were adopted from the National Cholesterol Education Program (third revision) of the Adult Treatment Panel criteria modified for Asians. RESULTS: Participants had a mean body mass index, estimated glomerular filtration rate (eGFR), and median ACR of 23.0 kg/m2, 74.8 mL/min/1.73 m2, and 7.5 mg/g, respectively. In age- and sex-adjusted logistic regression analysis, A-megalin and albumin were significantly associated with the clustering number of metabolic syndrome traits (3 or more). After further adjustment with eGFR, higher quartiles of A-megalin and albumin were each independently associated with the clustering number of metabolic syndrome traits (adjusted odds ratio for A-megalin: 1.30 per quartile, 95% CI 1.03-1.64; albumin: 1.42 per quartile, 95% CI 1.12-1.79). CONCLUSIONS: Both urinary A-megalin and albumin are associated with the clustering number of metabolic syndrome traits. Further research on urinary A-megalin is warranted to examine its role as a potential marker of kidney damage from metabolic risk factors.

DOI： 10.1186/s13098-021-00779-5

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Urinary FABP1 is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury. International journal

Ryo Kawakami, Miki Matsui, Ayumu Konno, Ryosuke Kaneko, Shreya Shrestha, Suman Shrestha, Hiroaki Sunaga, Hirofumi Hanaoka, Sawako Goto, Michihiro Hosojima, Hideyuki Kabasawa, Masaru Obokata, Norimichi Koitabashi, Hiroki Matsui, Tsutomu Sasaki, Akihiko Saito, Motoko Yanagita, Hirokazu Hirai, Masahiko Kurabayashi, Tatsuya Iso

The Journal of pathology 255 ( 4 ) 362 - 373 2021.12

Language：English Publishing type：Research paper (scientific journal)

Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte- or in a PTEC-specific manner, or both. Upon administration of diphtheria toxin (DT), massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

DOI： 10.1002/path.5775

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CKD・DKD診療の新展開高齢CKD・DKD診療の現状

細島康宏, 蒲澤秀門, 鈴木芳樹, 斎藤亮彦, 成田一衛

日本腎臓学会誌 63 ( 6-E ) 665 - 665 2021.9

Rice Endosperm Protein Improves the Anti-Inflammatory Effects of High-Density Lipoprotein and Produces Lower Atherosclerotic Lesion Accelerated by the Renal Mass Reduction than Casein in a Mouse Model. International journal

Ryohei Kaseda, Michihiro Hosojima, Shoji Kuwahara, Hideyuki Kabasawa, Hiroyuki Aoki, Yuki Higuchi, Valentina Kon, Ichiei Narita, Akihiko Saito

Journal of the American College of Nutrition 41 ( 7 ) 1 - 11 2021.8

Language：English Publishing type：Research paper (scientific journal)

Chronic kidney disease (CKD) impairs the anti-inflammatory effects of high-density lipoprotein (HDL) and increases cardiovascular mortality. Though the potential role of dietary interventions to manage HDL is well studied, the clinical trials aimed to increase HDL levels have failed to reduce cardiovascular risk, rendering HDL function to be explored as a more relevant clinical parameter. This study investigates the effects of rice endosperm protein (REP), a plant-based protein, on the anti-inflammatory properties of HDL and renal injury-driven atherosclerosis in comparison with casein, an animal protein. Ten-week-old apolipoprotein E-deficient hyperlipidemic mice underwent uninephrectomy. The mice (n = 6 each) were pair-fed a normal casein-based diet or a REP-based diet (both with 20.0% protein content) for seven weeks. Atherosclerotic lesions were detected by en face Sudan IV staining of the aorta. The number and sizes of the atherosclerotic lesions were significantly lower in the REP-based diet-fed group than the casein-based diet-fed group (p = 0.038). However, the REP-based diet neither elicited an ameliorative effect on kidney function or histology nor impacted the cholesterol profiles. Furthermore, HDL from the REP-based diet-fed mice significantly suppressed the inflammatory cytokine response of human umbilical vein endothelial cells than that from the casein-based diet-fed mice (MCP-1, p = 0.010; IL-6, p = 0.011; IL-1β, p = 0.028). The REP-based diet has a higher potential to lessen the atherosclerotic lesions accelerated by renal mass reduction than a casein-based diet, which could be associated with the anti-inflammatory effects of HDL.

DOI： 10.1080/07315724.2021.1950584

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Measurement of Plasma Glucagon Levels Using Mass Spectrometry in Patients with Type 2 Diabetes on Maintenance Hemodialysis. International journal

Yuta Yoshizawa, Michihiro Hosojima, Hideyuki Kabasawa, Naohito Tanabe, Atsushi Miyachi, Hitoshi Hamajima, Eri Mieno, Masaki Kobayashi, Tadahiro Kitamura, Ichiei Narita, Akihiko Saito

Kidney & blood pressure research 46 ( 5 ) 1 - 5 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Recently, attention has been focused on the effect of glucagon on blood glucose variability. The dynamics of glucagon have attracted attention as a new target in the treatment of diabetes patients. However, the dynamics of glucagon in hemodialysis (HD) patients with type 2 diabetes mellitus (T2DM) remain unclear. OBJECTIVES: The aim of this study was to assess the dynamics of glucagon in HD patients with T2DM. MATERIALS AND METHODS: We measured plasma glucagon in HD patients with T2DM by liquid chromatography-high-resolution mass spectrometry (LC-HRMS), sandwich enzyme-linked immunosorbent assay (ELISA), and radioimmunoassay (RIA). The glucagon levels measured by each method were compared. We used the glucagon levels determined by our developed LC-HRMS method as the standard in this study. RESULTS: Plasma glucagon levels measured by LC-HRMS before HD were significantly higher than those measured after HD. Plasma glucagon levels measured using sandwich ELISA had a significantly higher correlation with those measured using LC-HRMS compared with RIA. CONCLUSIONS: This was the first study to assess glucagon levels in HD patients with T2DM using LC-HRMS, which is considered a highly accurate method. Sandwich ELISA was shown to measure glucagon levels accurately as well.

DOI： 10.1159/000518027

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糸球体結節性病変と係蹄壁へのIgG線状沈着を呈した境界型糖尿病の1例

山口浩毅, 細島康宏, 蒲澤秀門, 後藤佐和子, 後藤慧, 伊藤由美, 今井直史, 金子佳賢, 鈴木芳樹, 齋藤亮彦, 成田一衛

糖尿病 64 ( 7 ) 411 - 411 2021.7

糸球体結節性病変と係蹄壁へのIgG線状沈着を呈した境界型糖尿病の1例

山口浩毅, 細島康宏, 蒲澤秀門, 後藤佐和子, 後藤慧, 伊藤由美, 今井直史, 金子佳賢, 鈴木芳樹, 齋藤亮彦, 成田一衛

糖尿病 64 ( 7 ) 411 - 411 2021.7

進行期CKD患者における栄養指導の実際(横断研究) REACH-J-CKDコホート研究より

細島康宏, 蒲澤秀門, 村山稔子, 若杉三奈子, 鈴木芳樹, 斎藤亮彦, 岡田浩一, 和田隆志, 山縣邦弘, 柏原直樹, 成田一衛

日本腎臓学会誌 63 ( 4 ) 461 - 461 2021.6

進行期CKD患者における栄養指導の実際(横断研究) REACH-J-CKDコホート研究より

細島康宏, 蒲澤秀門, 村山稔子, 若杉三奈子, 鈴木芳樹, 斎藤亮彦, 岡田浩一, 和田隆志, 山縣邦弘, 柏原直樹, 成田一衛

日本腎臓学会誌 63 ( 4 ) 461 - 461 2021.6

透析患者における経腸栄養と静脈栄養 up to date 維持血液透析患者における透析時静脈栄養(IDPN)の実際

細島康宏, 蒲澤秀門, 鈴木芳樹, 斎藤亮彦, 成田一衛

日本透析医学会雑誌 54 ( Suppl.1 ) 217 - 217 2021.5

小児尿中メガリン基準値の設定

金子昌弘, 山田剛史, 後藤佐和子, 蒲澤秀門, 細島康宏, 斎藤亮彦

日本小児腎臓病学会雑誌 34 ( 1Suppl. ) 136 - 136 2021.5

2型糖尿病患者におけるCOVID-19の流行が食事習慣に及ぼす影響に関する自記式食事歴法質問票(DHQ)を用いた検討

蒲澤秀門, 細島康宏, 村山稔子, 桑原頌治, 鈴木芳樹, 成田一衛, 斎藤亮彦

糖尿病 64 ( Suppl.1 ) I - 5 2021.5

小児尿中メガリン基準値の設定

金子昌弘, 山田剛史, 後藤佐和子, 蒲澤秀門, 細島康宏, 斎藤亮彦

日本小児腎臓病学会雑誌 34 ( 1Suppl. ) 136 - 136 2021.5

腎臓における脂肪酸処理の正しく評価されていないメカニズム脂肪酸再吸収のための優れた機能(Unappreciated mechanisms of fatty acids handling in the kidney: Remarkable capability for fatty acid reabsorption)

川上亮, 大日方英, 花岡宏史, 金井彩香, 中野大介, 齋藤亮彦, 西山成, 柳田素子, 倉林正彦, 磯達也

日本内分泌学会雑誌 96 ( 4 ) 1116 - 1116 2021.4

Effects of the Once-Weekly DPP4 Inhibitor Omarigliptin on Glycemic Control in Patients with Type 2 Diabetes Mellitus on Maintenance Hemodialysis: A 24-Week Open-Label, Multicenter Randomized Controlled Study

Yuta Yoshizawa, Michihiro Hosojima, Hideyuki Kabasawa, Naohito Tanabe, Daisuke Ugamura, Yutaka Koda, Hisaki Shimada, Tetsuya Takasawa, Takahito Ito, Tadahiro Kitamura, Masaki Kobayashi, Yoshiki Suzuki, Ichiei Narita, Akihiko Saito

DIABETES THERAPY 12 ( 3 ) 655 - 667 2021.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER HEIDELBERG

Introduction: Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used in patients with type 2 diabetes mellitus (T2DM) on maintenance hemodialysis (HD), but the efficacy of the once-weekly DPP4 inhibitor omarigliptin is not known.Methods: This prospective, randomized, open-label, parallel-group, non-inferiority/superiority, once-daily DPP4 inhibitor linagliptin-controlled, multicenter study examined glycemic control and safety of omarigliptin (UMIN000024284). Sample size was calculated to confirm non-inferiority in terms of changes in glycated hemoglobin (HbA1c). We enrolled 33 patients with T2DM on maintenance HD who had been treated with linagliptin for at least 3 months. The patients were randomized to receive omarigliptin (12.5 mg/week; n = 16) or linagliptin (5 mg/day; n = 17). Primary endpoints were changes in HbA1c and glycoalbumin (GA) over 24 weeks.Results: Differences in the mean change in primary endpoint values between the omarigliptin and linagliptin groups were - 0.61% [- 1.14, - 0.09] for HbA1c, with a two-tailed upper 95% limit (i.e., one-tailed 97.5% upper limit) of 0.25%, below the non-inferiority limit, and - 1.67% [- 4.23, + 0.88] for GA, with a two-tailed upper 95% limit of 0.75%, above the non-inferiority limit. At 24 weeks, the omarigliptin group showed significantly greater reduction in HbA1c than the linagliptin group (- 0.2% +/- 0.6% vs. 0.4% +/- 0.8%, two-tailed p = 0.024) and significantly greater reduction in blood glucose after a single HD session (- 18.4 +/- 31.4 mg/dL vs. 25.2 +/- 59.5 mg/dL, respectively, two-tailed p = 0.019). No subjects in the omarigliptin group developed hypoglycemia.Conclusions: Our data showed that omarigliptin was non-inferior to linagliptin in glycemic control. Omarigliptin is feasible for glycemic control in patients with T2DM on maintenance HD.

DOI： 10.1007/s13300-020-00991-y

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