Faculty Profiles - TSUJI Kenji

Papers - TSUJI Kenji

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慢性腎臓病におけるSemaphorin3Aを介した腎臓線維化の制御

辻憲二

日本透析医会雑誌 37 ( 3 ) 533 - 536 2022.12

Authorship：Lead author,　Corresponding author Language：Japanese Publisher：(公社)日本透析医会

腎臓線維化は慢性腎臓病進展における共通経路として知られるが,治療法は限られており,新規機序の薬物創出が求められている.Semaphorin3A(SEMA3A)は細胞間の情報伝達物質として機能する分泌型蛋白であり,細胞増殖,血管新生,免疫細胞の制御など多彩な生理活性作用を持つ.SEMA3Aは腎臓では糸球体上皮細胞および尿細管上皮細胞に発現し,腎臓病進展との関連性が報告されるがその機序は不詳である.本研究では一側尿管結紮(unilateral ureteral obstruction;UUO)マウスモデルを用いて,SEMA3Aと腎臓線維化の関連およびSEMA3A阻害剤の効果を検討した.UUOマウスの腎臓にはSEMA3Aおよびその受容体のNeuropilin-1(NRP1)発現が亢進しており,SEMA3A阻害剤によりUUOによる腎臓線維化は有意に軽減した.TGF-β1により誘導される培養ヒト尿細管上皮細胞の上皮間葉転換(epithelial-mesenchymal transition;EMT)はSEMA3A阻害剤により抑制された.JNK:c-Jun N-terminal kinase阻害剤(SP600125)はSEMA3Aにより誘導されるEMTを抑制したことから,JNKシグナルがSEMA3A経路による腎臓線維化に関与すると考えられた.さらに培養線維芽細胞にSEMA3Aを添付すると線維化マーカーの発現亢進が認められた.以上より腎臓線維化に対するSEMA3Aを制御する新たな治療戦略となりうることが示された.(著者抄録)

Co-occurrence of Three Systemic Diseases: ANCA-associated Vasculitis, Sjögren's syndrome and Sarcoidosis. Reviewed

Kenji Tsuji, Yuka Okuyama, Yosuke Asano, Kimitomo Yamaoka, Shinji Kitamura, Jun Wada

Internal medicine (Tokyo, Japan) 2022.11

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Sjögren's syndrome (SjS), and sarcoidosis are systemic diseases targeting multiple organs. While a careful differential diagnosis of these diseases is often required, their co-occurrence in the same patient has been previously reported. We herein report a 58-year-old Japanese man diagnosed with the co-occurrence of three systemic diseases (AAV, SjS, and sarcoidosis) in addition to monoclonal gammopathy of undetermined significance (MGUS), which emphasizes the importance of considering the possible co-occurrence of these diseases as well as their differentiation.

DOI： 10.2169/internalmedicine.0966-22

人工知能を用いたテキストマイニングによる「血液透析」に関する医中誌Web収録原著論文および症例事例論文の考察 Reviewed

喜多村真治, 中納弘幸, 森田峻史, 高橋謙作, 福島和彦, 辻憲二, 和田淳

日本透析医学会雑誌 55 ( 10 ) 563 - 571 2022.10

Language：Japanese Publisher：(一社)日本透析医学会

医学論文数は2000年に入り急増し,増加に伴った情報氾濫が起きており,その適切な情報の取捨選択が重要である.今回われわれは医中誌Webに収蔵されている血液透析の原著論文および症例事例論文の要約をテキストマイニングし解析を行った.医学中央雑誌刊行会にて運営されている医中誌Webにて検索した,1979年以降に収載された「血液透析」の原著論文は26,408報であり,症例事例論文は8,936報であった.それらの原著論文の要旨・抄録を抽出した延べ単語総数は1,637,446語であり,症例事例論文は562,949語であった.原著論文解析では体外循環法や効率,生体適合性などの単語が頻出したのに対し,症例事例論文では実臨床の治療難渋例関連の単語の頻出が多く認められた.以上より医中誌Web収載の血液透析関連の原著論文および症例事例論文に対しテキストマイニングを用いて解析を行い,全論文から血液透析の実臨床の変遷を把握することが可能であった.(著者抄録)

The association between hypothyroidism and proteinuria in patients with chronic kidney disease: a cross-sectional study. Reviewed International journal

Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Yizhen Sang, Kensaku Takahashi, Kazuhiko Fukushima, Hidemi Takeuchi, Kenichi Inagaki, Haruhito A Uchida, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada

Scientific reports 12 ( 1 ) 14999 - 14999 2022.9

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Hypothyroidism is known to be correlated with kidney function and nephrotic range proteinuria. However, it is uncertain whether non-nephrotic proteinuria is associated with hypothyroidism. This study aimed to evaluate the association of proteinuria and hypothyroidism in chronic kidney disease (CKD) patients. We conducted a cross-sectional study composed of 421 CKD patients in a single hospital with measurements of 24-h urine protein excretion (UP) and thyroid function tests. Spearman correlation analysis revealed that 24-h Cr clearance (24hrCcr) was positively (r = 0.273, p < 0.001) and UP was negatively (r = - 0.207, p < 0.001) correlated with free triiodothyronine. Frequency distribution analysis stratified by CKD stage and UP for hypothyroidism revealed that the prevalence of hypothyroidism was higher among participants with higher CKD stage and nephrotic range proteinuria. Multivariate logistic regression analysis revealed that 24hrCcr and UP were significantly correlated with hypothyroidism (24hrCcr/10 mL/min decrease: odds ratio [OR], 1.29; 95% confidence interval [CI], 1.18-1.41; UP/1 g increase: OR, 1.10; 95% CI, 1.03-1.17). In addition, nephrotic range proteinuria, but not moderate UP (UP: 1.5-3.49 g/day), was significantly correlated with hypothyroidism compared to UP < 0.5 g/day. In summary, decreased kidney function and nephrotic range proteinuria, not non-nephrotic proteinuria, are independently associated with the hypothyroidism.

DOI： 10.1038/s41598-022-19226-0

Simulation for ultrasound-guided renal biopsy using boiled egg. Reviewed International journal

Kenji Tsuji, Shinji Kitamura, Haruhito A. Uchida, Jun Wada

Nephrology (Carlton, Vic.) 27 ( 9 ) 753 - 757 2022.6

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Real-time ultrasound-guided renal biopsy is generally applied to diagnose multiple kidney diseases. A practical simulation model is desired since it is an invasive technique with higher risks of complications such as bleeding. We developed a simple simulation tool for ultrasound-guided renal biopsy using boiled eggs. Boiled chicken eggs were embedded in the agar, and a biopsy simulation was performed using a real-time ultrasound-guided technique as the renal biopsy simulator by trainees and biopsy-proficient nephrologists, and the feedback from the participants was obtained. The ultrasonographic evaluation revealed a clear contrast between egg yolk and white, which clearly mimicked the kidney cortex and medulla region. In addition, we observed the needle entering the egg white under needle penetration, and we obtained the biopsy core consisting of egg white. As for the simulations, all the participants succeeded in obtaining the appropriate samples. A total of 92% of the trainees agreed that the simulation could reduce their fears of performing renal biopsies in patients. In addition, all the trainees and biopsy-proficient nephrologists recommend using the simulator for trainees before conducting renal biopsies on patients. The total cost of the simulator was low (<USD 1/simulator). Collectively, our simulation tool using boiled eggs may be a good candidate for practical simulation models of renal biopsy.

DOI： 10.1111/nep.14079

人工知能を用いたテキストマイニングによる「慢性腎臓病」に関する医学中央雑誌収録症例・事例論文の考察 Reviewed

喜多村真治, 辻憲二, 高橋謙作, 福島和彦, 森田峻史, 和田淳

腎と透析 92 ( 4 ) 787 - 793 2022.4

Language：Japanese Publisher：(株)東京医学社

医学中央雑誌に収録された慢性腎臓病に関する症例・事例論文について、人工知能(AI)を用いてテキストマイニングと情報解析を行った。その結果、治療難渋例の報告が多いため透析に関する単語が多く、腎疾患名は糖尿病性腎症、慢性糸球体腎炎、腎硬化症が多かった。

Silica-associated systemic lupus erythematosus with lupus nephritis and lupus pneumonitis: A case report and a systematic review of the literature. Reviewed International journal

Kazuhiko Fukushima, Haruhito A Uchida, Yasuko Fuchimoto, Tomoyo Mifune, Mayu Watanabe, Kenji Tsuji, Katsuyuki Tanabe, Masaru Kinomura, Shinji Kitamura, Yosuke Miyamoto, Sae Wada, Taisaku Koyanagi, Hitoshi Sugiyama, Takumi Kishimoto, Jun Wada

Medicine 101 ( 7 ) e28872 2022.2

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

INTRODUCTION: Several epidemiological studies have shown that silica exposure triggers the onset of systemic lupus erythematosus (SLE); however, the clinical characteristics of silica-associated SLE have not been well studied. PATIENT CONCERNS: A 67-year-old man with silicosis visited a primary hospital because of a fever and cough. His respiratory condition worsened, regardless of antibiotic medication, and he was referred to our hospital. DIAGNOSIS: The patient showed leukopenia, lymphopenia, serum creatinine elevation with proteinuria and hematuria, decreased serum C3 level, and was positive for anti-double stranded DNA antibody, anti-nuclear antibody, and direct Coombs test. He was diagnosed with SLE. Renal biopsy was performed, and the patient was diagnosed with lupus nephritis (class IV-G(A/C) + V defined by the International Society of Nephrology/Renal Pathology Society classification). Computed tomography revealed acute interstitial pneumonitis, bronchoalveolar lavage fluid showed elevation of the lymphocyte fraction, and he was diagnosed with lupus pneumonitis. INTERVENTIONS: Prednisolone (50 mg/day) with intravenous cyclophosphamide (500 mg/body) were initiated. OUTCOMES: The patient showed a favorable response to these therapies. He was discharged from our hospital and received outpatient care with prednisolone slowly tapered off. He had cytomegalovirus and herpes zoster virus infections during treatment, which healed with antiviral therapy. REVIEW: We searched for the literature on sSLE, and selected 11 case reports and 2 population-based studies. The prevalence of SLE manifestations in sSLE patients were comparative to that of general SLE, particularly that of elderly-onset SLE. Our renal biopsy report and previous reports indicate that lupus nephritis of sSLE patients show as various histological patterns as those of general SLE patients. Among the twenty sSLE patients reported in the case articles, three patients developed lupus pneumonitis and two of them died of it. Moreover, two patients died of bacterial pneumonia, one developed aspergillus abscesses, one got pulmonary tuberculosis, and one developed lung cancer. CONCLUSION: Close attention is needed, particularly for respiratory system events and infectious diseases, when treating patients with silica-associated SLE using immunosuppressive therapies.

DOI： 10.1097/MD.0000000000028872

The Association of Postprandial Triglyceride Variability with Renal Dysfunction and Microalbuminuria in Patients with Type 2 Diabetic Mellitus: A Retrospective and Observational Study. Reviewed International journal

Natsumi Matsuoka-Uchiyama, Haruhito A Uchida, Shugo Okamoto, Yasuhiro Onishi, Katsuyoshi Katayama, Mariko Tsuchida-Nishiwaki, Hidemi Takeuchi, Rika Takemoto, Yoshiko Hada, Ryoko Umebayashi, Naoko Kurooka, Kenji Tsuji, Jun Eguchi, Hirofumi Nakajima, Kenichi Shikata, Jun Wada

Journal of diabetes research 2022 3157841 - 3157841 2022

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

OBJECTIVE: We examined whether or not day-to-day variations in lipid profiles, especially triglyceride (TG) variability, were associated with the exacerbation of diabetic kidney disease. METHODS: We conducted a retrospective and observational study. First, 527 patients with type 2 diabetes mellitus (DM) who had had their estimated glomerular filtration rate (eGFR) checked every 6 months since 2012 for over 5 years were registered. Variability in postprandial TG was determined using the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) during the first three years of follow-up. The endpoint was a ≥40% decline from baseline in the eGFR, initiation of dialysis or death. Next, 181 patients who had no micro- or macroalbuminuria in February 2013 were selected from among the 527 patients for an analysis. The endpoint was the incidence of microalbuminuria, initiation of dialysis, or death. RESULTS: Among the 527 participants, 110 reached a ≥40% decline from baseline in the eGFR or death. The renal survival was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0073, 0.0059, and 0.0195, respectively). A lower SD, lower Adj-SD, and lower MMD were significantly associated with the renal survival in the adjusted model (hazard ratio, 1.62, 1.66, 1.59; 95% confidence intervals, 1.05-2.53, 1.08-2.58, 1.04-2.47, respectively). Next, among 181 participants, 108 developed microalbuminuria or death. The nonincidence of microalbuminuria was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0241, 0.0352, and 0.0474, respectively). CONCLUSIONS: Postprandial TG variability is a novel risk factor for eGFR decline and the incidence of microalbuminuria in patients with type 2 DM.

DOI： 10.1155/2022/3157841

Mesenchymal stem cells-derived extracellular vesicles as 'natural' drug delivery system for tissue regeneration Reviewed

Kenji Tsuji, Shinji Kitamura, Jun Wada

BIOCELL 46 ( 4 ) 899 - 902 2022

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：TECH SCIENCE PRESS

Mesenchymal stem cells (MSCs) have abilities to mediate tissue protection through mechanisms of antiapoptosis, anti-oxidative stress and anti-fibrosis as well as tissue regeneration through mechanisms of cell proliferation, differentiation and angiogenesis. These effects by MSCs are mediated by a variety of factors, including growth factors, cytokines and extracellular vesicles (EVs). Among these factors, EVs, containing proteins, mRNA and microRNAs (miRNA), may carry their contents into distant tissues with high stability. Therefore, the treatment with MSC-derived EVs may be promising as 'natural' drug delivery systems (DDS). Especially, the treatment of MSCderived EVs with the manipulation of specific miRNAs expression has been reported to be beneficial under a variety of diseases and tissue injuries. The overexpression of specific miRNAs in the EVs might be through pre-loading method using the gene editing system by plasmid vector or post-loading method to load miRNA mimics into EVs by electroporation or calcium chloride-mediated transfection. Despite current several challenges for clinical use, it should open the next era of regenerative medicine for a variety of diseases. In this article, we highlight the therapeutic potential of MSC-derived EVs as 'natural' DDS and current challenges.

DOI： 10.32604/biocell.2022.018594

Masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism. Reviewed International journal

Natsumi Uchiyama-Matsuoka, Kenji Tsuji, Haruhito A Uchida, Shinji Kitamura, Yoshihiko Itoh, Yuki Nishiyama, Eisaku Morimoto, Satoshi Fujisawa, Tomohiro Terasaka, Takayuki Hara, Kanako Ogura-Ochi, Kenichi Inagaki, Jun Wada

Frontiers in endocrinology 13 1048863 - 1048863 2022

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: While it is well known that thyroid function may affect kidney function, the transition of the chronic kidney disease (CKD) status before and after treatment for thyroid disorders, as well as the factors affecting this change, remains to be explored. In the present study, we focused on the change in kidney function and their affecting factors during the treatment for both hyperthyroidism and hypothyroidism. METHODS: Eighty-eight patients with hyperthyroidism and fifty-two patients with hypothyroidism were enrolled in a retrospective and longitudinal case series to analyze the changes in kidney function and their affecting factors after treatment for thyroid disorders. RESULTS: Along with the improvement of thyroid function after treatment, there was a significant decrease in estimated glomerular filtration rate (eGFR) in hyperthyroidism (an average ΔeGFR of -41.1 mL/min/1.73 m2) and an increase in eGFR in hypothyroidism (an average ΔeGFR of 7.1 mL/min/1.73 m2). The multiple linear regression analysis revealed that sex, eGFR, free thyroxine (FT4) and free triiodothyronine (FT3) could be considered independent explanatory variables for ΔeGFR in hyperthyroidism, while age, eGFR, and FT3 were detected as independent explanatory variables in hypothyroidism. In addition, the stratification by kidney function at two points, pre- and post-treatment for thyroid disorders, revealed that 4.5% of the participants with hyperthyroidism were pre-defined as non-CKD and post-defined as CKD, indicating the presence of "masked" CKD in hyperthyroidism. On the other hand, 13.5% of the participants with hypothyroidism presented pre-defined CKD and post-defined non-CKD, indicating the presence of "reversible" CKD status in hypothyroidism. CONCLUSIONS: We uncovered the population of masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism, thereby re-emphasizing the importance of a follow-up to examine kidney function after treatment for hyperthyroidism and the routine evaluation of thyroid function in CKD patients as well as the appropriate hormone therapy if the patient has hypothyroidism.

DOI： 10.3389/fendo.2022.1048863

Potential Strategies for Kidney Regeneration With Stem Cells: An Overview. Reviewed International journal

Kenji Tsuji, Shinji Kitamura, Jun Wada

Frontiers in cell and developmental biology 10 892356 - 892356 2022

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Kidney diseases are a major health problem worldwide. Despite advances in drug therapies, they are only capable of slowing the progression of kidney diseases. Accordingly, potential kidney regeneration strategies with stem cells have begun to be explored. There are two different directions for regenerative strategies, de novo whole kidney fabrication with stem cells, and stem cell therapy. De novo whole kidney strategies include: 1) decellularized scaffold technology, 2) 3D bioprinting based on engineering technology, 3) kidney organoid fabrication, 4) blastocyst complementation with chimeric technology, and 5) the organogenic niche method. Meanwhile, stem cell therapy strategies include 1) injection of stem cells, including mesenchymal stem cells, nephron progenitor cells, adult kidney stem cells and multi-lineage differentiating stress enduring cells, and 2) injection of protective factors secreted from these stem cells, including growth factors, chemokines, and extracellular vesicles containing microRNAs, mRNAs and proteins. Over the past few decades, there have been remarkable step-by-step developments in these strategies. Here, we review the current advances in the potential strategies for kidney regeneration using stem cells, along with their challenges for possible clinical use in the future.

DOI： 10.3389/fcell.2022.892356

Semaporin3A-inhibitor ameliorates renal fibrosis through the regulation of JNK signaling. Reviewed International journal

Yizhen Sang, Kenji Tsuji, Kazuhiko Fukushima, Kensaku Takahashi, Shinji Kitamura, Jun Wada

American journal of physiology. Renal physiology 321 ( 6 ) F740-F756 2021.11

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Renal fibrosis is the common pathological pathway in progressive renal diseases. In the study, we analyzed the roles of Semaphorin 3A (SEMA3A) on renal fibrosis and the effect of SEMA3A-inhibitor (SEMA3A-I) using unilateral ureteral obstruction (UUO) mouse model. The expression of SEMA3A in the proximal tubulus and neuropilin-1 (NRP1), a recepor of SEMA3A, in fibloblast and tubular cells were increased in the UUO kidneys. The increased expression of myofibroblast marker tenascin-C and fibronection as well as renal fibrosis were increased in UUO kidneys, all of which were ameliorated by SEMA3A-I. In addition, c-Jun N-terminal kinase (JNK) signaling pathway known as the target of SEMA3A signaling, was activated in proximal tubular cells and fibroblast cells after UUO surgery while SEMA3A-I significantly attenuated the activation. In vitro, treatments with SEMA3A as well as transforming growth factor-β1 (TGF-β1) in human proximal tubular cells lost epithelial cell characters while SEMA3A-I significantly ameliorated this transformation. JNK inhibitor, SP600125, partially reversed SEMA3A and TGF-β1-induced cell transformation, indicating that JNK signaling is involved in SEMA3A-induced renal fibrosis. In addition, the treatment with SEMA3A in fibroblast cells activated the expression of tenascin-C, collagen type I and fibronection, indicating that SEMA3A may accelerate renal fibrosis through the activation of fibroblast cells. The analysis of human data revealed the positive correlation between urinary SEMA3A and urinary N-acetyl-β-D-glucosaminidase, indicating the association between SEMA3A and tubular injury. In conclusion, SEMA3A signaling is involved in renal fibrosis through JNK signaling pathway and SEMA3A-I might be the therapeutic option for protecting from renal fibrosis.

DOI： 10.1152/ajprenal.00234.2021

人工知能を用いたテキストマイニングによる「慢性腎臓病」に関する医学中央雑誌収録原著論文の考察 Reviewed

喜多村真治, 高橋謙作, 福島和彦, 辻憲二, 森田峻史, 和田淳

日本腎臓学会誌 63 ( 8 ) 995 - 1006 2021.11

Language：Japanese Publisher：(一社)日本腎臓学会

医学の進歩は著しく,腎臓疾患の概念や診断・治療も大きく変化している。医学論文数は2000年に入り急増し,増加に伴った情報氾濫が起きており,その適切な情報の取捨選択は限られた時間の中では困難である。今回われわれは医学中央雑誌に収蔵されている腎臓領域の原著論文の要約を全てテキストマイニングし解析を行った。医学中央雑誌にて検索した1982年以降に収載された「慢性腎臓病」関連の論文数(症例報告・事例を除く)は12,801報であった。それらの原著論文の要約・アブストラクトから抽出した述べ単語総数は8,556,712語であった。「慢性腎臓病」で医学中央雑誌から論文を抽出しているにも関わらず,上位に挙がった単語には「透析」,「血液透析」などが「慢性腎臓病」,「慢性腎不全」よりも出現頻度は高かった。単語のネットワーク構造解析では,「透析」,「血圧」,「慢性腎臓病」,「透析条件」などのグループが認められ,トピックとして多くの論文があることが示唆された。単語頻度推移解析では年代ごとの出現単語頻度を解析したところ,「慢性腎臓病」や慢性腎臓病の機能を評価する「eGFR」は2005年以降に多く記載されており,「慢性腎不全」は1982年以降認められていたが,2002年以降には徐々にその割合は減少しており,慢性腎不全といった腎機能低下を示す包括的な単語使用から,慢性腎臓病の提唱により単語出現頻度が移行していることが示唆された。以上より「慢性腎臓病」関連論文では透析に関係する単語が多く抽出された。一方,各糸球体性疾患の病名は多岐にわたり,反対に末期腎不全の腎代替療法は血液透析や腹膜透析に集約されている可能性も示唆された。医学中央雑誌に収載されている慢性腎臓病関連の原著論文をテキストマイニングの手法を用いて解析を行い,慢性腎臓病関連の変動を把握することが可能であった。(著者抄録)

Kidney cyst infection through a fistula between bladder and retroperitoneal abscess in a polycystic kidney disease patient. Reviewed International journal

Takato Nakadoi, Kenji Tsuji, Takehiro Iwata, Eriko Eto, Hisashi Masuyama, Koji Tomita, Takao Hiraki, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada

Nephrology (Carlton, Vic.) 27 ( 4 ) 383 - 384 2021.8

The resolution of immunofluorescent pathological images affects diagnosis for not only artificial intelligence but also human Reviewed

Kensaku Takahashi, Shinji Kitamura, Kazuhiko Fukushima, Yizhen Sang, Kenji Tsuji, Jun Wada

Journal of Nephropathology 10 ( 3 ) 2021

Publishing type：Research paper (scientific journal)

Introduction: For human, the resolution of images is important for diagnosis. Many clinical applications of artificial intelligence have been studied, however there are few reports on the difference in diagnosis between humans and artificial intelligence on the point of the renal pathological image resolution. Objectives: We examined whether the resolution of renal pathological images affects diagnosis of artificial intelligence and human. Patients and Methods: From 885 renal biopsy patients, we collected renal IgA immunofluorescent pathological images that resolution is 4, 16, 32, 64, 128, 256 and 512 pixels for each patient, and divided into training data set and validation data set, and created optimum deep learning models for each resolution. To compare with artificial intelligence nephrologist also tried to diagnose by using the same validation data set images. Results: We inputted IgA immunofluorescent pathological images into each optimum model. Human could not identify specific staining site with four pixels images, however, each resolution optimum model showed high accuracy, average over 80%. The each accuarcy was observed higher depending on the resolution. The area under the curve (AUC) showed higher diagnosis ratio depending on the resolution, too. Nephrologist performed high diagnosis sensitivity depending on resolution images as same as artificial intelligence. However, nephrologists’ diagnosis observed large variations in specificity depending on resolution. These results suggested that the resolution might affect specificity for human not artificial intelligence Conclusion: The resolution of images might be important for not AI but human on the point of specificity.

DOI： 10.34172/jnp.2021.26

Sodium-Glucose Cotransporter 2 Inhibitors Work as a "Regulator" of Autophagic Activity in Overnutrition Diseases. Reviewed International journal

Kazuhiko Fukushima, Shinji Kitamura, Kenji Tsuji, Jun Wada

Frontiers in pharmacology 12 761842 - 761842 2021

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

Several large clinical trials have shown renal and cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetes patients, and the protective mechanisms need to be elucidated. There have been accumulating studies which report that SGLT2 inhibitors ameliorate autophagy deficiency of multiple organs. In overnutrition diseases, SGLT2 inhibitors affect the autophagy via various signaling pathways, including mammalian target of rapamycin (mTOR), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) pathways. Recently, it turned out that not only stagnation but also overactivation of autophagy causes cellular damages, indicating that therapeutic interventions which simply enhance or stagnate autophagy activity might be a "double-edged sword" in some situations. A small number of studies suggest that SGLT2 inhibitors not only activate but also suppress the autophagy flux depending on the situation, indicating that SGLT2 inhibitors can "regulate" autophagic activity and help achieve the appropriate autophagy flux in each organ. Considering the complicated control and bilateral characteristics of autophagy, the potential of SGLT2 inhibitors as the regulator of autophagic activity would be beneficial in the treatment of autophagy deficiency.

DOI： 10.3389/fphar.2021.761842

MicroRNAs as Biomarkers for Nephrotic Syndrome. Reviewed International journal

Kenji Tsuji, Shinji Kitamura, Jun Wada

International journal of molecular sciences 22 ( 1 ) 2020.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.

DOI： 10.3390/ijms22010088

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