Faculty Profiles - TSUJI Kenji

Papers - TSUJI Kenji

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A Case of IgA Nephropathy With Membranoproliferative Glomerulonephritis-Like Features. Reviewed International journal

Miyu Kanazawa, Kenji Tsuji, Ryoya Aoki, Mihiro Sue, Hiromasa Miyake, Naruhiko Uchida, Hiroyuki Nakanoh, Kazuhiko Fukushima, Haruhito A Uchida, Jun Wada

Nephrology (Carlton, Vic.) 30 ( 5 ) e70057 2025.5

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

A 73-year-old man was referred due to the onset of nephrotic-range proteinuria. He had been diagnosed with rheumatoid arthritis 18 years prior and had achieved remission with treatment, including methotrexate and janus kinase (JAK) inhibitor. Although routine follow-ups had not revealed any urinary abnormalities, subsequent tests detected proteinuria and hematuria in the absence of infection or other symptoms. As the urinary abnormalities persisted, with a serum albumin decrease and proteinuria measuring 5.7 g/day, indicating nephrotic syndrome, the patient was referred to our hospital for further evaluation, and a renal biopsy was performed. Light microscopy revealed mesangial cell proliferation, endocapillary proliferation and double-contoured basement membranes. Immunofluorescence microscopy showed IgA-dominant deposits in both mesangial areas and glomerular capillary walls. Transmission electron microscopy demonstrated electron-dense deposits in the mesangium and subendothelial regions, leading to the diagnosis of membranoproliferative glomerulonephritis (MPGN)-type IgA nephropathy. Immunostaining with the Gd-IgA1 (galactose-deficient IgA1)-specific antibody (KM55) was positive, consistent with the diagnosis. Following the initiation of steroid therapy, proteinuria rapidly decreased, achieving complete remission within 5 months. IgA nephropathy with MPGN-like features often presents as nephrotic syndrome, differing from the typical pathological and clinical presentation of IgA nephropathy, making differentiation from secondary MPGN and other diseases sometimes challenging. This case suggests that KM55 staining may offer additional information in differentiating atypical IgA nephropathy with non-classical pathological features.

DOI： 10.1111/nep.70057

Text mining for case report articles on "peritoneal dialysis" from PubMed database. Reviewed International journal

Kazuhiko Fukushima, Kenji Tsuji, Hiroyuki Nakanoh, Naruhiko Uchida, Soichiro Haraguchi, Shinji Kitamura, Jun Wada

Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2025.3

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

INTRODUCTION: The number of published medical articles on peritoneal dialysis (PD) has been increasing, and efficiently selecting information from numerous articles can be difficult. In this study, we examined whether artificial intelligence (AI) text mining can be a good support for efficiently collecting PD information. METHODS: We performed text mining and analyzed all the abstracts of case reports on PD in the PubMed database. In total, 3137 case reports with abstracts related to "peritoneal dialysis" published from 1970 to 2021 were identified. RESULTS: A total of 280 347 relevant words were extracted from all the abstracts. Word frequency analysis, word dependency analysis, and word frequency transition analysis showed that peritonitis, encapsulating peritoneal sclerosis, and child have been important keywords. Theseanalyses not only reflected historical background but also anticipated future trends of PD study. CONCLUSION: These suggest that text mining can be a good support for efficiently collecting PD information.

DOI： 10.1111/1744-9987.70013

Supplement-induced acute kidney injury reproduced in kidney organoids. Reviewed International journal

Hiroyuki Nakanoh, Kenji Tsuji, Kazuhiko Fukushima, Soichiro Haraguchi, Shinji Kitamura, Jun Wada

American journal of nephrology 1 - 15 2025.2

Authorship：Corresponding author Language：English

INTRODUCTION: Acute kidney injury (AKI) associated with the consumption of Beni-koji CholesteHelp supplements, which contain red yeast rice (Beni-Koji), has become a significant public health concern in Japan. While renal biopsy findings from several case reports have suggested tubular damage, no definitive causal relationship has been established, and the underlying mechanisms of kidney injury remain poorly understood. The complexity of identifying toxic substances in supplements containing various bioactive compounds makes conventional investigative approaches both time-consuming and challenging. This highlights an urgent need to establish a reliable platform for assessing organ-specific toxicity in such supplements. In this study, we utilized a kidney organoid model derived from adult rat kidney stem cells (KS cells) to assess the potential tubular toxicity of these supplements. METHODS: KS cell clusters were cultured in three-dimensional system supplemented with growth factors to promote kidney organoids. The organoids were subsequently exposed to Beni-koji CholesteHelp supplements or cisplatin, followed by histological and molecular analyses to evaluate structural and molecular impacts. RESULTS: Established organoids had the kidney-like structures including tubular-like structures and glomerulus-like structures at the tips of multiple tubules. Treatment with Beni-koji CholesteHelp supplements induced significant tubular damage in the organoids, characterized by epithelial cell thinning, structural disruption, and increase in cleaved caspase-3-positive apoptotic tubular cells, similar to the organoids treated with cisplatin. CONCLUSIONS: These findings provide the first evidence suggesting that certain toxicants in specific batches of Beni-koji CholesteHelp supplements cause direct renal tubular injury. This KS cell-based organoid system represents a cost-effective, reproducible, and technically simple platform for nephrotoxicity screening.

DOI： 10.1159/000544795

The Gut-Kidney Axis in Chronic Kidney Diseases. Reviewed International journal

Kenji Tsuji, Naruhiko Uchida, Hiroyuki Nakanoh, Kazuhiko Fukushima, Soichiro Haraguchi, Shinji Kitamura, Jun Wada

Diagnostics (Basel, Switzerland) 15 ( 1 ) 2024.12

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

The gut-kidney axis represents the complex interactions between the gut microbiota and kidney, which significantly impact the progression of chronic kidney disease (CKD) and overall patient health. In CKD patients, imbalances in the gut microbiota promote the production of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which impair renal function and contribute to systemic inflammation. Mechanisms like endotoxemia, immune activation and oxidative stress worsen renal damage by activating pro-inflammatory and oxidative pathways. Insights into these mechanisms highlight the impact of gut-derived metabolites, bacterial translocation, and immune response changes on kidney health, suggesting new potential approaches for CKD treatment. Clinical applications, such as dietary interventions, prebiotics, probiotics and fecal microbiota transplantation, are promising in adjusting the gut microbiota to alleviate CKD symptoms and slow disease progression. Current research highlights the clinical relevance of the gut-kidney axis, but further study is essential to clarify these mechanisms' diagnostic biomarkers and optimize therapeutic interventions. This review emphasizes the importance of an integrated approach to CKD management, focusing on the gut microbiota as a therapeutic target to limit kidney injury.

DOI： 10.3390/diagnostics15010021

Presumed Choroidopathy of IgG4-Related Disease Discovered During 16-Year Follow-Up of a Patient With Polycystic Kidney Disease. Reviewed International journal

Toshihiko Matsuo, Takehiro Tanaka, Kenji Tsuji

Cureus 16 ( 10 ) e70865 2024.10

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

Immunoglobulin G4 (IgG4)-related disease is characterized by infiltration with IgG4-producing plasma cells in different organs and the elevation of serum IgG4. We present a patient with polycystic kidney disease in long-term follow-up who developed bilateral lacrimal gland enlargement and presumed IgG4-related choroidopathy at different time points. A 45-year-old woman developed bilateral upper eyelid swelling. Head MRI showed bilateral lacrimal gland enlargement, and the resection on both sides revealed foci of infiltration with lymphocytes and plasma cells in bilateral lacrimal glands. The IgG4-immunostaining did not satisfy the diagnostic criteria. She had been taking oral valsartan 40 mg daily for hypertension with polycystic kidney disease. The patient was well until the age of 49 years, when she noticed yellowish vision in the right eye compared to the left eye. The right eye showed multiple yellowish spotty lesions in the deep retina to choroid with a mildly hyperemic optic disc, while the left eye showed the normal fundus. No inflammation was noted in the anterior segments of both eyes. Fundus angiography demonstrated early-phase no-filling with late-phase leakage by fluorescein dye and both early-phase and late-phase no-filling by indocyanine green dye, leading to the diagnosis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). She began to have oral prednisolone tapered from 30 mg daily and discontinued in a year. At the age of 52 years, she switched to candesartan 8 mg daily and began to have tolvaptan (a selective competitive vasopressin receptor 2 (V2) antagonist) 90 mg daily for polycystic kidney disease with liver cysts. At that time, the lesions in the right eye had mild degeneration. The patient was followed once a year ophthalmologically to maintain good vision. At 57 years, serum IgG4, which was measured for the first time on suspicion of IgG4-related disease, was elevated to 269.6 mg/dL. In the following four years to the latest visit at 61 years, she kept stable but high levels of serum IgG4 around 300 mg/dL. Serum IgG4 measurement is helpful to make a clinical diagnosis and, hence, a clinical decision since the spectrum of IgG4-related disease remains obscure.

DOI： 10.7759/cureus.70865

A case of renal hypouricemia due to T217M mutation in SLC22A12 incidentally associated with IgA nephropathy. Reviewed International journal

Yoshimasa Sakurabu, Haruhito A Uchida, Toshihisa Tahara, Tomohiko Asakawa, Haruka Yamasaki, Katsuyoshi Katayama, Shugo Okamoto, Yasuhiro Onishi, Natsumi Matsuoka-Uchiyama, Keiko Tanaka, Hidemi Takeuchi, Kenji Tsuji, Ryoko Umebayashi, Yuki Ohashi, Kimiyoshi Ichida, Jun Wada

Clinical case reports 12 ( 9 ) e9368 2024.9

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

A T217M heterozygous mutation in the SLC22A12 gene caused renal hypouricemia; this patient with IgA nephropathy had no findings other than IgA nephropathy on renal biopsy. Hypouricemia was susceptible to oxidative stress, but IgA nephropathy in the patient with hypouricemia could be treated with steroid pulse therapy without adverse events.

DOI： 10.1002/ccr3.9368

A case of membranous nephropathy complicated by Cronkhite-Canada syndrome successfully treated with mizoribine. Reviewed

Hiroyuki Nakanoh, Kenji Tsuji, Shiho Morimoto, Kazuhiko Fukushima, Masaya Iwamuro, Haruhito A Uchida, Jun Wada

CEN case reports 2024.7

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

Cronkhite-Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic hamartomatous gastrointestinal polyposis, hair loss, nail atrophy, hyperpigmentation, and diarrhea. While the relationship between CCS and nephritis remains unclear, seven cases of nephritis complicated by CCS have been reported to date, all of which were membranous nephropathy (MN). A 57-year-old man presented with taste disturbance, hair loss, nail plate atrophy, skin pigmentation, and frequent diarrhea. Endoscopic findings showed multiple polyposis of the stomach and large intestine. Given the above, he was diagnosed with CCS. The symptoms gradually improved with prednisolone treatment, although urinary protein and hypoproteinemia appeared during the tapering of prednisolone. He was diagnosed with MN using a renal biopsy, and immunofluorescence microscopy with IgG subclass staining showed predominantly diffuse granular capillary wall staining of IgG4. The cause of secondary MN was not found, including malignant tumors. Nephrotic-range proteinuria persisted despite treatment with prednisolone and cyclosporine. Additional treatment with mizoribine resulted in incomplete remission type 1 of nephrotic syndrome, suggesting that mizoribine may be a treatment option for patients with CCS with steroid-resistant MN. Considering a high prevalence of hypoproteinemia due to chronic diarrhea and protein-losing enteropathy in patients with CCS, proteinuria might be overlooked; thus, follow-up urinalysis would be recommended in patients with CCS.

DOI： 10.1007/s13730-024-00908-9

Successful treatment for life threatening recurrent non-traumatic rectus sheath hematoma in a case with microscopic polyangiitis with rapidly progressive glomerulonephritis. Reviewed

Hiroyuki Nakanoh, Hidemi Takeuchi, Morimoto Shiho, Yuya Terajima, Shugo Okamoto, Yasuhiro Onishi, Keiko Tanaka, Takayuki Katsuyama, Kenji Tsuji, Yoshinori Matsumoto, Katsuyuki Tanabe, Hiroshi Morinaga, Mayu Uka, Koji Tomita, Haruhito A Uchida, Takao Hiraki, Jun Wada

Internal medicine (Tokyo, Japan) 2024.4

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

A 68-year-old woman was admitted to our hospital because of a rapid progression of renal dysfunction with positive myeloperoxidase antineutrophil cytoplasmic antibody and was diagnosed with rapidly progressive glomerulonephritis associated with microscopic polyangiitis (MPA). Severe right rectus sheath hematoma (RSH) bleeding from the inferior epigastric artery developed after starting hemodialysis, which required 4 transarterial embolizations due to recurrent bleeding. After additional treatment with methylprednisolone pulse therapy and rituximab, no rebleeding occurred. Although the giant hematoma reached the pelvis, it shrank spontaneously without any intervention. Nontraumatic RSH should therefore be considered when treating patients with multiple risk factors.

DOI： 10.2169/internalmedicine.3239-23

Effects of HIF-PHD inhibitors in kidney development. Reviewed International journal

Soichiro Haraguchi, Kenji Tsuji, Hiroyuki Nakanoh, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2024.3

平滑筋肉腫の両側腎臓への転移に対して両腎摘出術を契機に血液透析導入とした一例 Reviewed

浅川知彦, 竹内英実, 岡本修吾, 大西康博, 田中景子, 辻憲二, 田邊克幸, 森永裕士, 内田治仁, 和田淳

中国腎不全研究会誌 32 2024

SLE透析例のESA低反応性貧血に対しベリムマブにて改善2症例と急性ループス肺炎の剖検例の考察 Reviewed

原口総一郎, 成清武文, 蒲生直幸, 喜多村真治, 辻憲二, 佐田憲映

中国腎不全研究会誌 32 2024

当院における非外傷性腹直筋血腫5症例の報告 Reviewed

中納弘幸, 竹内英実, 森本志帆, 寺嶋悠也, 岡本修吾, 大西康博, 田中景子, 勝山隆行, 辻憲二, 田邊克幸, 森永裕士, 宇賀麻由, 冨田晃司, 平木隆夫, 内田治仁, 和田淳

中国腎不全研究会誌 32 2024

Kidney Veno-Muscular Characteristics and Kidney Disease Progression: A Native Kidney-Biopsy Study. Reviewed International journal

Kenji Tsuji, Hiroyuki Nakanoh, Kensaku Takahashi, Takafumi Morita, Yizhen Sang, Kazuhiko Fukushima, Natsumi Matsuoka-Uchiyama, Yasuhiro Onishi, Haruhito A Uchida, Shinji Kitamura, Jun Wada

Kidney medicine 5 ( 12 ) 100733 - 100733 2023.12

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

RATIONALE & OBJECTIVE: Assessment of kidney biopsies provides crucial information for diagnosis and disease activity, as well as prognostic value. Kidney-biopsy specimens occasionally contain veno-muscular complex (VMC), which consists of muscle tissues around the kidney venous system in the corticomedullary region. However, the role of VMC and the clinical significance of VMC variants are poorly understood. In the present study, we investigated kidney prognostic values of VMC variants. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Among 808 patients who underwent a kidney biopsy from 2011 to 2019, 246 patients whose kidney biopsy specimens contained VMC were enrolled. PREDICTORS: VMC variants; inflammatory-VMC (an infiltration of ≥80 inflammatory cells/mm2-VMC area) and VMC hypertrophy (hyper-VMC, a VMC average width ≥850 μm), and the interstitial fibrosis/tubular atrophy (IFTA) score. OUTCOMES: A decline in estimated glomerular filtration rate (eGFR) ≥40% from the baseline or commencement of kidney replacement therapy. ANALYTICAL APPROACH: Cox proportional hazards model. RESULTS: Among 246 patients with data on VMC, mean baseline eGFR was 56.0±25.6 ml/min per 1.73 m2; 80 had high inflammatory-VMC, and 62 had VMC hypertrophy. There were 51 kidney events over median follow-up of 2.5 years. We analyzed 2 VMC variants. Multivariable logistic regression analysis revealed that eGFR negatively correlated with the presence of both inflammatory-VMC and hyper-VMC. A Cox proportional hazards analysis revealed that inflammatory-VMC (but not hyper-VMC) was independently associated with the primary outcome after adjustments for known risk factors of progression, including proteinuria, eGFR, and the interstitial fibrosis/tubular atrophy (IFTA) score (hazard ratio, 1.97; 95% confidence interval, 1.00-3.91). LIMITATIONS: Single-center study and small sample size. CONCLUSIONS: Assessment of inflammatory-VMC provides additional kidney prognostic information to known indicators of kidney disease progression in patients who undergo kidney biopsy. PLAIN-LANGUAGE SUMMARY: Assessment of kidney biopsies provides crucial information for diagnosis, disease activity, and prognostic value. Kidney-biopsy specimens occasionally contain veno-muscular complex (VMC), which consists of muscle tissues around the kidney venous system. Currently, the role of VMC in kidney health and diseases and the clinical significance of VMC variants are poorly understood. In the present study, we have shown that an infiltration of ≥80 inflammatory cells/mm2-VMC area (inflammatory-VMC) is independently associated with kidney disease progression after adjustments for known risk factors of progression. Therefore, assessment of inflammatory-VMC provides additional kidney prognostic information to known indicators of kidney disease progression in patients who undergo kidney biopsy.

DOI： 10.1016/j.xkme.2023.100733

Preventive effect of culture supernatant of epithelial-like peritoneal mesothelial cells on peritoneal fibrosis. Reviewed International journal

Kensaku Takahashi, Kenji Tsuji, Hiroyuki Nakanoh, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada

Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis 8968608231213577 - 8968608231213577 2023.11

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

Peritoneal fibrosis (PF) is a primary reason for discontinuing peritoneal dialysis, which involves characteristic changes of peritoneal mesothelial cells (PMCs). We previously reported preventive effects of implanting human epithelial-like PMCs (P-Epi) for mouse PF caused by mechanical peritoneum scrapings. In the present study, we analysed the preventive effects of culture supernatant of P-Epi in PF. Concentrated culture supernatant of P-Epi or human fibroblast-like PMCs (P-Fibro) or vehicles was injected into nude mice that had undergone mechanical scraping of the parietal and visceral peritoneum, and thickness and amount of adhesions were analysed. Although increased peritoneal adhesions and peritoneum thickening were observed in the vehicle-injected positive control group compared to the sham operation group, fewer number of adhesions and less thickness were observed in the mice treated with culture supernatant of P-Epi, but not P-Fibro, compared to the vehicle-injected positive controls. Immunofluorescent analysis revealed that the expression of extracellular matrix, type I collagen and fibronectin, was lower in the mice treated with culture supernatant of P-Epi than in the vehicle-injected positive controls. In addition, exosomes from P-Epi significantly reduced transforming growth factor-β (TGF-β)-induced expressions of type I collagen and fibronectin in 3T3 fibroblast cells. Collectively, culture supernatant of P-Epi has preventive effects on PF, thus cell therapy is not necessarily required. Further exploration of substances secreted by P-Epi and their protective mechanisms could lead to the development of therapeutic strategies to limit PF.

DOI： 10.1177/08968608231213577

Role of Semaphorin 3A in Kidney Development and Diseases. Reviewed International coauthorship International journal

Yizhen Sang, Kenji Tsuji, Hiroyuki Nakanoh, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada

Diagnostics (Basel, Switzerland) 13 ( 19 ) 2023.9

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

Kidney diseases are worldwide public health problems affecting millions of people. However, there are still limited therapeutic options against kidney diseases. Semaphorin 3A (SEMA3A) is a secreted and membrane-associated protein, which regulates diverse functions, including immune regulation, cell survival, migration and angiogenesis, thus involving in the several pathogeneses of diseases, including eyes and neurons, as well as kidneys. SEMA3A is expressed in podocytes and tubular cells in the normal adult kidney, and recent evidence has revealed that excess SEMA3A expression and the subsequent signaling pathway aggravate kidney injury in a variety of kidney diseases, including nephrotic syndrome, diabetic nephropathy, acute kidney injury, and chronic kidney disease. In addition, several reports have demonstrated that the inhibition of SEMA3A ameliorated kidney injury via a reduction in cell apoptosis, fibrosis and inflammation; thus, SEMA3A may be a potential therapeutic target for kidney diseases. In this review article, we summarized the current knowledge regarding the role of SEMA3A in kidney pathophysiology and their potential use in kidney diseases.

DOI： 10.3390/diagnostics13193038

MicroRNAs as Biomarkers and Therapeutic Targets for Acute Kidney Injury. Reviewed International journal

Kenji Tsuji, Hiroyuki Nakanoh, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada

Diagnostics (Basel, Switzerland) 13 ( 18 ) 2023.9

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

Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolytes and acid base. It is associated with poor prognosis and prolonged hospitalization. Therefore, an early diagnosis and treatment to avoid the severe AKI stage are important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for the early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

DOI： 10.3390/diagnostics13182893

Elderly Brothers With Fabry Disease Exhibiting Cardiac and Renal Manifestations Reviewed

Keiko Tanaka, Hitoshi Sugiyama, Hiroshi Morinaga, Akifumi Onishi, Yuzuki Kano, Hidemi Takeuchi, Kenji Tsuji, Motoki Kubo, Katsuyuki Tanabe, Haruhito A. Uchida, Kazufumi Nakamura, Jun Wada

Annals of Internal Medicine: Clinical Cases 2 ( 5 ) 2023.5

The Effect of Medical Cooperation in the CKD Patients: 10-Year Multicenter Cohort Study. Reviewed International journal

Yasuhiro Onishi, Haruhito A Uchida, Yohei Maeshima, Yuka Okuyama, Nozomu Otaka, Haruyo Ujike, Keiko Tanaka, Hidemi Takeuchi, Kenji Tsuji, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Morinaga, Masaru Kinomura, Shinji Kitamura, Hitoshi Sugiyama, Kosuke Ota, Keisuke Maruyama, Makoto Hiramatsu, Yoshiyuki Oshiro, Shigeru Morioka, Keiichi Takiue, Kazuyoshi Omori, Masaki Fukushima, Naoyuki Gamou, Hiroshi Hirata, Ryosuke Sato, Hirofumi Makino, Jun Wada

Journal of personalized medicine 13 ( 4 ) 2023.3

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

INTRODUCTION: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. METHODS: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. RESULTS: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 ± 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). CONCLUSION: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.

DOI： 10.3390/jpm13040582

スチレン系軟質樹脂を用いた腎生検シミュレーターの開発と有用性の検討 Reviewed

辻憲二, 喜多村真治, 和田淳

日本腎臓学会誌 65 ( 2 ) 105 - 111 2023.3

Authorship：Lead author,　Corresponding author Language：Japanese Publisher：(一社)日本腎臓学会

超音波ガイド経皮的針腎生検は,種々の腎臓病の診断および活動性の評価のために必要な検査であるが,出血などの合併症のリスクが高い侵襲的な技術であり,実用的なシミュレーションモデルが望まれる。われわれは鶏卵を用いた簡易的腎生検シミュレーターを開発したが,耐久性が低く長期保存が困難であった。今回われわれは幅広く適用されるモデルを目指して,スチレン系軟質樹脂を用いた新たな腎生検シミュレーターを開発した。作製したモデルは,超音波下で腎臓の皮質・髄質に該当する部分のコントラストは実際の腎臓のものに類似しており,針穿刺の際にモデル内に針が侵入する様子が超音波下で観察可能であった。本モデルの検証のため,岡山大学病院の腎生検経験20例未満の研修生10名に腎生検模擬を実施し,腎生検経験20例以上の腎生検に熟達した腎臓内科医20名がその様子を観察あるいは模擬を実施した。また,腎生検模擬後に全参加者にアンケート調査を実施した。90%の研修生が,今回の腎生検模擬によって患者への腎生検に対する不安が軽減されると回答した。また,すべての参加者が,研修生が本腎生検模擬を行うことを推奨すると回答した。耐久性の評価では,約100回穿刺後の形態および超音波下の画像ともに継続使用可能と考えられた。以上から,開発したシミュレーターは腎生検の実用的なシミュレーションモデルの良い候補になり得る。(著者抄録)

Association between Urinary Creatinine Excretion and Hypothyroidism in Patients with Chronic Kidney Disease. Reviewed International journal

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

Diagnostics (Basel, Switzerland) 13 ( 4 ) 2023.2

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

While hypothyroidism increases serum creatinine (Cr) levels, it is uncertain whether the elevation is mediated via a decline in the glomerular filtration rate (GFR) or the reflection of enhanced Cr production from the muscles or both. In the present study, we explored an association between urinary Cr excretion rate (CER) and hypothyroidism. A total of 553 patients with chronic kidney disease were enrolled in a cross-sectional study. Multiple linear regression analysis was performed to explore the association between hypothyroidism and urinary CER. The mean urinary CER was 1.01 ± 0.38 g/day and 121 patients (22%) had hypothyroidism. The multiple linear regression analysis revealed explanatory variables with urinary CER, including age, sex, body mass index, 24 h Cr clearance (24hrCcr), and albumin while hypothyroidism was not considered an independent explanatory variable. In addition, scatter plot analysis with regression fit line representing the association between estimated GFR calculated using s-Cr (eGFRcre) and 24hrCcr revealed that eGFRcre and 24hrCcr had strong correlations with each other in hypothyroid patients as well as euthyroid patients. Collectively, hypothyroidism was not considered an independent explanatory variable for urinary CER in the present study and eGFRcre is a useful marker to evaluate kidney function regardless of the presence of hypothyroidism.

DOI： 10.3390/diagnostics13040669

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

Tubulointerstitial Nephritis Cases With IgM-Positive Plasma Cells. Reviewed International journal

Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Kazuhiko Fukushima, Shinji Kitamura, Haruhito A Uchida, Hitoshi Sugiyama, Naoki Takahashi, Masayuki Iwano, Jun Wada

Kidney international reports 5 ( 9 ) 1576 - 1580 2020.9

Podocytopathy as 'stand-alone' involvement in systemic lupus erythematosus: a case report. Reviewed International journal

Kenji Tsuji, Yoko Takatsu, Yu Katayama, Kazuhiko Fukushima, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada

Lupus 29 ( 9 ) 1148 - 1150 2020.8

Tubulointerstitial Nephritis and Uveitis Caused by Sjögren Syndrome Without Dryness. Reviewed International journal

Soichiro Sugitani, Kenji Tsuji, Toshio Yamanari, Yoichi Hasegawa, Kentaro Inoue, Yuka Sogabe, Yukari Nakano, Shinji Kitamura, Tsutomu Ishizu, Jun Wada

Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 2020.7

Deep Learning Could Diagnose Diabetic Nephropathy with Renal Pathological Immunofluorescent Images. Reviewed International journal

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

Diagnostics (Basel, Switzerland) 10 ( 7 ) 2020.7

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

Artificial Intelligence (AI) imaging diagnosis is developing, making enormous steps forward in medical fields. Regarding diabetic nephropathy (DN), medical doctors diagnose them with clinical course, clinical laboratory data and renal pathology, mainly evaluate with light microscopy images rather than immunofluorescent images because there are no characteristic findings in immunofluorescent images for DN diagnosis. Here, we examined the possibility of whether AI could diagnose DN from immunofluorescent images. We collected renal immunofluorescent images from 885 renal biopsy patients in our hospital, and we created a dataset that contains six types of immunofluorescent images of IgG, IgA, IgM, C3, C1q and Fibrinogen for each patient. Using the dataset, 39 programs worked without errors (Area under the curve (AUC): 0.93). Five programs diagnosed DN completely with immunofluorescent images (AUC: 1.00). By analyzing with Local interpretable model-agnostic explanations (Lime), the AI focused on the peripheral lesion of DN glomeruli. On the other hand, the nephrologist diagnostic ratio (AUC: 0.75833) was slightly inferior to AI diagnosis. These findings suggest that DN could be diagnosed only by immunofluorescent images by deep learning. AI could diagnose DN and identify classified unknown parts with the immunofluorescent images that nephrologists usually do not use for DN diagnosis.

DOI： 10.3390/diagnostics10070466

Adult kidney stem/progenitor cells contribute to regeneration through the secretion of trophic factors. Reviewed International journal

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

Stem cell research 46 101865 - 101865 2020.7

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

Adult kidney stem cells are known to have important roles in renal regeneration after acute kidney injury. Although trophic factors from tissue stem cells have been reported to promote the regeneration of other organs, there is limited number of evidence of this phenomenon in the kidneys. Here, we explored the effects of secreted factors from kidney stem cells. We intraperitoneally administered culture supernatant obtained from adult rat kidney stem/progenitor cells into rat kidney ischemia/reperfusion injury models, and the treatment significantly ameliorated renal tubulointerstitial injury, suppressed tubular cell apoptosis, diminished inflammation and promoted the proliferation of both residual renal cells and immature cells. In vitro, treatment with culture supernatant from kidney stem cells significantly promoted cell proliferation and suppressed cisplatin-induced cell apoptosis in both normal rat kidney cells and kidney stem cells. In addition, treatment with culture supernatant increased the expression of nestin in normal rat kidney cells, suggesting the dedifferentiation of tubular cells into stem-like cells. Analysis of the culture supernatant revealed that it contained a variety of growth factors. Taken together, the results suggest that these factors together lead to renal regeneration. In conclusion, adult kidney stem cells contribute to renal regeneration indirectly through the secretion of regenerative factors.

DOI： 10.1016/j.scr.2020.101865

Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury. Reviewed International journal

Yizhen Sang, Kenji Tsuji, Akiko Inoue-Torii, Kazuhiko Fukushima, Shinji Kitamura, Jun Wada

International journal of molecular sciences 21 ( 11 ) 2020.6

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

Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.

DOI： 10.3390/ijms21114099

Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice. Reviewed International journal

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

International journal of molecular sciences 21 ( 11 ) 2020.6

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

Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i-HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

DOI： 10.3390/ijms21114054

Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report. Reviewed International journal

Natsumi Matsuoka, Kenji Tsuji, Eiki Ichihara, Takayuki Hara, Kazuhiko Fukushima, Kishio Toma, Shinji Kitamura, Kenichi Inagaki, Hitoshi Sugiyama, Jun Wada

BMC nephrology 21 ( 1 ) 113 - 113 2020.3

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

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. CASE PRESENTATION: A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. CONCLUSION: All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed.

DOI： 10.1186/s12882-020-01775-z

Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases. Reviewed International journal

Kenji Tsuji, Shinji Kitamura, Jun Wada

International journal of molecular sciences 21 ( 3 ) 2020.1

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

Mesenchymal stem cells (MSCs) have immunomodulatory and regenerative effects in many organs, including the kidney. Emerging evidence has shown that the trophic effects from MSCs are mainly mediated by the paracrine mechanism rather than the direct differentiation of MSCs into injured tissues. These secretomes from MSCs include cytokines, growth factors, chemokines and extracellular vesicles (EVs) containing microRNAs, mRNAs, and proteins. Many research studies have revealed that secretomes from MSCs have potential to ameliorate renal injury in renal disease models, including acute kidney injury and chronic kidney disease through a variety of mechanisms. These trophic mechanisms include immunomodulatory and regenerative effects. In addition, accumulating evidence has uncovered the specific factors and therapeutic mechanisms in MSC-derived EVs. In this article, we summarize the recent advances of immunomodulatory and regenerative effects of EVs from MSCs, especially focusing on the microRNAs.

DOI： 10.3390/ijms21030756

Integrin-Linked Kinase Deficiency in Collecting Duct Principal Cell Promotes Necroptosis of Principal Cell and Contributes to Kidney Inflammation and Fibrosis. Reviewed International journal

Ming Huang, Shuai Zhu, Huihui Huang, Jinzhao He, Kenji Tsuji, William W Jin, Dongping Xie, Onju Ham, Diane E Capen, Weining Lu, Teodor G Păunescu, Baoxue Yang, Hua A Jenny Lu

Journal of the American Society of Nephrology : JASN 30 ( 11 ) 2073 - 2090 2019.11

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

BACKGROUND: Necroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied. METHODS: We performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown. RESULTS: Ilk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-β signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals' injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasma membrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, and membrane translocation of MLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice. CONCLUSIONS: The study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.

DOI： 10.1681/ASN.2018111162

Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril. Reviewed International journal

Onju Ham, William Jin, Lei Lei, Hui Hui Huang, Kenji Tsuji, Ming Huang, Jason Roh, Anthony Rosenzweig, Hua A Jenny Lu

Scientific reports 8 ( 1 ) 16087 - 16087 2018.10

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

Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.

DOI： 10.1038/s41598-018-34216-x

Manganese promotes intracellular accumulation of AQP2 via modulating F-actin polymerization and reduces urinary concentration in mice. Reviewed International journal

Lei Lei, Ming Huang, Limin Su, Dongping Xie, Fahmy A Mamuya, Onju Ham, Kenji Tsuji, Teodor G Păunescu, Baoxue Yang, Hua A Jenny Lu

American journal of physiology. Renal physiology 314 ( 2 ) F306-F316 - F316 2018.2

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

Aquaporin-2 (AQP2) is a water channel protein expressed in principal cells (PCs) of the kidney collecting ducts (CDs) and plays a critical role in mediating water reabsorption and urine concentration. AQP2 undergoes both regulated trafficking mediated by vasopressin (VP) and constitutive recycling, which is independent of VP. For both pathways, actin cytoskeletal dynamics is a key determinant of AQP2 trafficking. We report here that manganese chloride (MnCl2) is a novel and potent regulator of AQP2 trafficking in cultured cells and in the kidney. MnCl2 treatment promoted internalization and intracellular accumulation of AQP2. The effect of MnCl2 on the intracellular accumulation of AQP2 was associated with activation of RhoA and actin polymerization without modification of AQP2 phosphorylation. Although the level of total and phosphorylated AQP2 did not change, MnCl2 treatment impeded VP-induced phosphorylation of AQP2 at its serine-256, -264, and -269 residues and dephosphorylation at serine 261. In addition, MnCl2 significantly promoted F-actin polymerization along with downregulation of RhoA activity and prevented VP-induced membrane accumulation of AQP2. Finally, MnCl2 treatment in mice resulted in significant polyuria and reduced urinary concentration, likely due to intracellular relocation of AQP2 in the PCs of kidney CDs. More importantly, the reduced urinary concentration caused by MnCl2 treatment in animals was not corrected by VP. In summary, our study identified a novel effect of MnCl2 on AQP2 trafficking through modifying RhoA activity and actin polymerization and uncovered its potent impact on water diuresis in vivo.

DOI： 10.1152/ajprenal.00391.2017

Secretomes from Mesenchymal Stem Cells against Acute Kidney Injury: Possible Heterogeneity. Reviewed International journal

Kenji Tsuji, Shinji Kitamura, Jun Wada

Stem cells international 2018 8693137 - 8693137 2018

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

A kidney has the ability to regenerate itself after a variety of renal injuries. Mesenchymal stem cells (MSCs) have been shown to ameliorate tissue damages during renal injuries and diseases. The regenerations induced by MSCs are primarily mediated by the paracrine release of soluble factors and extracellular vesicles, including exosomes and microvesicles. Extracellular vesicles contain proteins, microRNAs, and mRNAs that are transferred into recipient cells to induce several repair signaling pathways. Over the past few decades, many studies identified trophic factors from MSCs, which attenuate renal injury in a variety of animal acute kidney injury models, including renal ischemia-reperfusion injury and drug-induced renal injury, using microarray and proteomic analysis. Nevertheless, these studies have revealed the heterogeneity of trophic factors from MSCs that depend on the cell origins and different stimuli including hypoxia, inflammatory stimuli, and aging. In this review article, we summarize the secretomes and regenerative mechanisms induced by MSCs and highlight the possible heterogeneity of trophic factors from different types of MSC and different circumstances for renal regeneration.

DOI： 10.1155/2018/8693137

Deletion of β1-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis. Reviewed International journal

Fahmy A Mamuya, Dongping Xie, Lei Lei, Ming Huang, Kenji Tsuji, Diane E Capen, BaoXue Yang, Ralph Weissleder, Teodor G Păunescu, Hua A Jenny Lu

American journal of physiology. Renal physiology 313 ( 4 ) F1026-F1037 - F1037 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

The renal collecting duct (CD) contains two major cell types, intercalated (ICs) and principal cells (PCs). A previous report showed that deletion of β1-integrin in the entire renal CD causes defective CD morphogenesis resulting in kidney dysfunction. However, subsequent deletion of β1-integrin specifically in ICs and PCs, respectively, did not cause any morphological defects in the CDs. The discrepancy between these studies prompts us to reinvestigate the role of β1-integrin in CD cells, specifically in the PCs. We conditionally deleted β1-integrin in mouse CD PCs using a specific aquaporin-2 (AQP2) promoter Cre-LoxP system. The resulting mutant mice, β-1f/fAQP2-Cre+, had lower body weight, failed to thrive, and died around 8-12 wk. Their CD tubules were dilated, and some of them contained cellular debris. Increased apoptosis and proliferation of PCs were observed in the dilated CDs. Trichrome staining and electron microscopy revealed the presence of peritubular and interstitial fibrosis that is associated with increased production of extracellular matrix proteins including collagen type IV and fibronectin, as detected by immunoblotting. Further analysis revealed a significantly increased expression of transforming growth factor-β (TGF-β)-induced protein, fibronectin, and TGF-β receptor-1 mRNAs and concomitantly increased phosphorylation of SMAD-2 that indicates the activation of the TGF-β signaling pathway. Therefore, our data reveal that normal expression of β1-integrin in PCs is a critical determinant of CD structural and functional integrity and further support the previously reported critical role of β1-integrin in the development and/or maintenance of the CD structure and function.

DOI： 10.1152/ajprenal.00038.2017

Ultrastructural Characterization of the Glomerulopathy in Alport Mice by Helium Ion Scanning Microscopy (HIM). Reviewed International journal

Kenji Tsuji, Hani Suleiman, Jeffrey H Miner, James M Daley, Diane E Capen, Teodor G Păunescu, Hua A Jenny Lu

Scientific reports 7 ( 1 ) 11696 - 11696 2017.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The glomerulus exercises its filtration barrier function by establishing a complex filtration apparatus consisting of podocyte foot processes, glomerular basement membrane and endothelial cells. Disruption of any component of the glomerular filtration barrier leads to glomerular dysfunction, frequently manifested as proteinuria. Ultrastructural studies of the glomerulus by transmission electron microscopy (TEM) and conventional scanning electron microscopy (SEM) have been routinely used to identify and classify various glomerular diseases. Here we report the application of newly developed helium ion scanning microscopy (HIM) to examine the glomerulopathy in a Col4a3 mutant/Alport syndrome mouse model. Our study revealed unprecedented details of glomerular abnormalities in Col4a3 mutants including distorted podocyte cell bodies and disorganized primary processes. Strikingly, we observed abundant filamentous microprojections arising from podocyte cell bodies and processes, and presence of unique bridging processes that connect the primary processes and foot processes in Alport mice. Furthermore, we detected an altered glomerular endothelium with disrupted sub-endothelial integrity. More importantly, we were able to clearly visualize the complex, three-dimensional podocyte and endothelial interface by HIM. Our study demonstrates that HIM provides nanometer resolution to uncover and rediscover critical ultrastructural characteristics of the glomerulopathy in Col4a3 mutant mice.

DOI： 10.1038/s41598-017-12064-5

Ezrin directly interacts with AQP2 and promotes its endocytosis. Reviewed International journal

Wei Li, William W Jin, Kenji Tsuji, Ying Chen, Naohiro Nomura, Limin Su, Naofumi Yui, Julian Arthur, Susanna Cotecchia, Teodor G Paunescu, Dennis Brown, Hua A J Lu

Journal of cell science 130 ( 17 ) 2914 - 2925 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：COMPANY OF BIOLOGISTS LTD

The water channel aquaporin-2 (AQP2) is a major regulator of water homeostasis in response to vasopressin (VP). Dynamic trafficking of AQP2 relies on its close interaction with trafficking machinery proteins and the actin cytoskeleton. Here, we report the identification of ezrin, an actin-binding protein from the ezrin/radixin/moesin (ERM) family as an AQP2-interacting protein. Ezrin was first detected in a co-immunoprecipitation (co-IP) complex using an anti-AQP2 antibody in a proteomic analysis. Immunofluorescence staining revealed the co-expression of ezrin and AQP2 in collecting duct principal cells, and VP treatment caused redistribution of both proteins to the apical membrane. The ezrin-AQP2 interaction was confirmed by co-IP experiments with an anti-ezrin antibody, and by pulldown assays using purified full-length and FERM domain-containing recombinant ezrin. By using purified recombinant proteins, we showed that ezrin directly interacts with AQP2 C-terminus through its N-terminal FERM domain. Knocking down ezrin expression with shRNA resulted in increased membrane accumulation of AQP2 and reduced AQP2 endocytosis. Therefore, through direct interaction with AQP2, ezrin facilitates AQP2 endocytosis, thus linking the dynamic actin cytoskeleton network with AQP2 trafficking.

DOI： 10.1242/jcs.204842

Re-characterization of the Glomerulopathy in CD2AP Deficient Mice by High-Resolution Helium Ion Scanning Microscopy. Reviewed International journal

Kenji Tsuji, Teodor G Păunescu, Hani Suleiman, Dongping Xie, Fahmy A Mamuya, Jeffrey H Miner, Hua A Jenny Lu

Scientific reports 7 ( 1 ) 8321 - 8321 2017.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Helium ion scanning microscopy (HIM) is a novel technology that directly visualizes the cell surface ultrastructure without surface coating. Despite its very high resolution, it has not been applied extensively to study biological or pathology samples. Here we report the application of this powerful technology to examine the three-dimensional ultrastructural characteristics of proteinuric glomerulopathy in mice with CD2-associated protein (CD2AP) deficiency. HIM revealed the serial alteration of glomerular features including effacement and disorganization of the slit diaphragm, followed by foot process disappearance, flattening and fusion of major processes, and eventual transformation into a podocyte sheet as the disease progressed. The number and size of the filtration slit pores decreased. Strikingly, numerous "bleb" shaped microprojections were observed extending from podocyte processes and cell body, indicating significant membrane dynamics accompanying CD2AP deficiency. Visualizing the glomerular endothelium and podocyte-endothelium interface revealed the presence of endothelial damage, and disrupted podocyte and endothelial integrity in 6 week-old Cd2ap-KO mice. We used the HIM technology to investigate at nanometer scale resolution the ultrastructural alterations of the glomerular filtration apparatus in mice lacking the critical slit diaphragm-associated protein CD2AP, highlighting the great potential of HIM to provide new insights into the biology and (patho)physiology of glomerular diseases.

DOI： 10.1038/s41598-017-08304-3

The level of urinary semaphorin3A is associated with disease activity in patients with minimal change nephrotic syndrome. Reviewed International journal

Akiko Inoue-Torii, Shinji Kitamura, Jun Wada, Kenji Tsuji, Hirofumi Makino

International journal of nephrology and renovascular disease 10 167 - 174 2017

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

Semaphorin3A is a secreted protein known to be involved in organogenesis, immune responses and cancer. In the kidney, semaphorin3A is expressed in the glomerular podocytes, distal tubules and collecting tubules, and believed to play a role in the regulation of the kidney development and function. We examined the serum and urinary semaphorin3A levels in 72 patients with renal disease and 5 healthy volunteers. The patients had been diagnosed with thin basement membrane disease (n=4), minimal change nephrotic syndrome (MCNS; n=22), IgA nephritis (n=21), membranous nephropathy (n=16) and focal segmental glomerular sclerosis (n=9). The level of urinary semaphorin3A in MCNS patients tended to be relatively high among all disease groups. We also investigated the urinary semaphorin3A level in 7 patients with MCNS from disease onset to remission during the drug therapy. MCNS patients in pre-remission states had higher urinary semaphorin3A levels than those in post-remission states receiving immunosuppressive therapies. These results suggested that the urinary semaphorin3A level correlates with the MCNS activity. Semaphorin3A has the potential as a biomarker for MCNS to clarify the reactivity for therapy and may be useful in examining other glomerular diseases with proteinuria as well.

DOI： 10.2147/IJNRD.S132980

Trophic Factors from Tissue Stem Cells for Renal Regeneration. Reviewed International journal

Kenji Tsuji, Shinji Kitamura

Stem cells international 2015 537204 - 537204 2015

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

Stem cell therapies against renal injury have been advancing. The many trials for renal regeneration are reported to be effective in many kinds of renal injury models. Regarding the therapeutic mechanism, it is believed that stem cells contribute to make regeneration via not only direct stem cell differentiation in the injured space but also indirect effect via secreted factors from stem cells. Direct differentiation from stem cells to renal composed cells has been reported. They differentiate to renal composed cells and make functions. However, regarding renal regeneration, stem cells are discussed to secrete many kinds of growth factors, cytokines, and chemokines in paracrine or autocrine manner, which protect against renal injury, too. In addition, it is reported that stem cells have the ability to communicate with nearby cells via microvesicle-related RNA and proteins. Taken together from many reports, many secreted factors from stem cells were needed for renal regeneration orchestrally with harmony. In this review, we focused on the effects and insights of stem cells and regenerative factors from stem cells.

DOI： 10.1155/2015/537204

Hypoxia-inducible factor 1α regulates branching morphogenesis during kidney development. Reviewed International journal

Kenji Tsuji, Shinji Kitamura, Hirofumi Makino

Biochemical and biophysical research communications 447 ( 1 ) 108 - 14 2014.4

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

The kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13Ks) and cultured the organs under normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. E13Ks cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-α1), increased under hypoxic conditions in E13Ks. When we cultured E13Ks with the HIF-1α inhibitor digoxin or with siRNA targeting HIF-1α under hypoxic conditions, we did not observe increased UB branching. In addition, the expression of GDNF and GFR-α1 was inhibited under hypoxic conditions when the kidneys were treated with siRNA targeting HIF-1α. We also elucidated that hypoxia inhibited UB cell apoptosis and promoted the expression of FGF7 mRNA levels in metanephric mesenchymal (MM) cells in vitro. These findings suggest that hypoxic condition has important roles in inducing branching morphogenesis during kidney development. Hypoxia might mediate branching morphogenesis via not only GDNF/Ret but also FGF signaling pathway.

DOI： 10.1016/j.bbrc.2014.03.111

The selection of peritoneal mesothelial cells is important for cell therapy to prevent peritoneal fibrosis. Reviewed International journal

Shinji Kitamura, Naoya Horimoto, Kenji Tsuji, Akiko Inoue, Keiichi Takiue, Hitoshi Sugiyama, Hirofumi Makino

Tissue engineering. Part A 20 ( 3-4 ) 529 - 39 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：MARY ANN LIEBERT, INC

Long-term peritoneal dialysis (PD) causes chronic peritoneal damage. Peritoneal mesothelial cells (PMCs) play an important role in peritoneal function. We investigated the possibility of cell therapy using the PMCs to prevent peritoneal damage in PD patients. We harvested human PMCs from the PD effluent of PD patients. The PMCs were separated based on morphological characteristics into epithelial-like (Epi) cells and fibroblast-like (Fib) cells by the limiting dilution method. We transplanted these cells into nude mice whose parietal and visceral peritoneum were scratched by mechanical scraping. The transplanted cells were detected at the parietal and visceral peritoneum. Compared with the positive control, the Epi cell therapy group showed very few adhesions and exhibited no thickening of the parietal and visceral peritoneum. However, the group with Fib cell therapy could not inhibit peritoneal adhesion and thickening. In addition, hepatocyte growth factor was expressed by the grafted Epi cells but not Fib cells. Fib cells expressed vascular endothelial growth factor stronger than Epi cells. These two types of cells from the same patient showed different characteristics and effects for cell therapy. These findings suggest that the PMCs from the PD patient showed different characteristics, such as Epi cells and Fib cells, and the selection of PMCs is important for cell therapy on the point of not only the direct cellular interactions but also cytokine secretion from the grafted cells. Furthermore, the differences in the morphological cell characteristics may influence their role in peritoneal regeneration.

DOI： 10.1089/ten.TEA.2013.0130

Mizoribine inhibits the proliferation of renal stem/progenitor cells by G1/S arrest during renal regeneration. Reviewed

Naoya Horimoto, Shinji Kitamura, Kenji Tsuji, Hirofumi Makino

Acta medica Okayama 68 ( 1 ) 7 - 15 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Immunosuppressive agents are generally administered to treat kidney diseases. However, it is unclear whether renal stem/progenitor cells are directly affected by the immunosuppressive agents. We used normal rat kidney cells, ureteric bud cells and rat kidney stem/progenitor cells in this study. Mizoribine (MZR), cyclophosphamide (CPA) and cyclosporine (CyA) were added to the culture media of these cells. We evaluated the effects of these immunosuppressive agents on cell proliferation using an electrical cell-substrate impedance sensing system (ECIS) and their effects on the process of renal regeneration using the ischemia-reperfusion (I/R) injury rat model. The ECIS data showed that proliferation of each of the 3 types of cells was significantly suppressed by MZR. MZR treatment enhanced renal tubular injury in ischemia-reperfusion (I/R) injured rats, and significantly decreased levels of M-phase cells and Nestin-positive cells. These results suggested that MZR inhibits the cell cycle of renal stem/progenitor cells;thus, physicians should take note that MZR might affect not only inflammation but also renal regeneration.

DOI： 10.18926/AMO/52138

Membranous nephropathy with acquired factor V inhibitor: a case report. Reviewed International journal

Shinji Kitamura, Mahito Misawa, Sayaka Namba, Kenji Tsuji, Rikako Torigoe, Midori Shima, Hirofumi Makino

BMC research notes 6 553 - 553 2013.12

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

BACKGROUND: Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. In contrast, acquired factor V inhibitor is a rare bleeding disorder. CASE PRESENTATION: A 62-year-old Asian man with a history of cerebral hemorrhage, purpura, eosinophilia and hyper immunoglobulin E syndrome developed proteinuria. The bleeding disorder was diagnosed with acquired factor V inhibitors. A renal biopsy revealed that he suffered from membranous nephropathy with glomerular endothelial damage which is reported to be involved in another factor disorder. After the steroid administration, the coagulation test and proteinuria were improved. CONCLUSIONS: The presence of factor V inhibitors may have been involved in the development of membranous nephropathy.

DOI： 10.1186/1756-0500-6-553

A case of focal segmental glomerulosclerosis in an adult patient with hypogammaglobulinemia superimposed on membranoproliferative glomerulonephritis in childhood. Reviewed International journal

Kenji Tsuji, Haruhito Adam Uchida, Tetsuichirou Ono, Tatsuyuki Inoue, Katsuji Shinagawa, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Hirofumi Makino

BMC nephrology 13 46 - 46 2012.6

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

BACKGROUND: Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia without a known predisposing cause. CASE PRESENTATION: We report a 36-year-old man who had suffered membranoproliferative glomerulonephritis (MPGN) in his childhood, later diagnosed with CVID at 35 years of age. He presented at our hospital with signs of proteinuria. A renal biopsy revealed he suffered from focal segmental glomerulosclerosis (FSGS), possibly due to obesity and hypertension, not CVID - associated MPGN. CONCLUSION: This is the first case report of FSGS in a CVID patient. In this case, we have to pay attention not only to the treatment of obesity and hypertension for FSGS but also to the recurrence of immune-complex glomerulonephritis such as MPGN, in case of the restoration of hypogammaglobulinemia.

DOI： 10.1186/1471-2369-13-46

腹膜透析患者における腹膜機能廃絶重症化防止のための新たな腹膜機能検査の開発 Reviewed

辻憲二, 喜多村真治, 杉山斉, 槇野博史

中国腎不全研究会誌 21 2012

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