Development of the biomaker of kidney stone formation

• Project/Area Number: 16K11053
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Nagoya City University
• Principal Investigator: 本間 秀樹 名古屋市立大学, 大学院医学研究科, 研究員 (20260789)
• Co-Investigator(Kenkyū-buntansha): 郡 健二郎 名古屋市立大学, その他部局等, 学長 (30122047) ; 安井 孝周 名古屋市立大学, 大学院医学研究科, 教授 (40326153) ; 戸澤 啓一 名古屋市立大学, 大学院医学研究科, 教授 (40264733) ; 岡田 淳志 名古屋市立大学, 大学院医学研究科, 准教授 (70444966) ; 濱本 周造 名古屋市立大学, 大学院医学研究科, 講師 (80551267) ; 田口 和己 名古屋市立大学, 大学院医学研究科, 助教 (00595184)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腎結石 / オステオポンチン / 重合 / 尿路結石 / 腎乳頭部 / バイオマーカー

Outline of Annual Research Achievements

本邦における腎結石の発症頻度は、この40年間で約3倍に増加し、5年再発率は約50％と報告ている。また、腎結石の90％を占めるシュウ酸カルシウム結石の再発予防法は、飲水指導と食事指導のみで有効な薬剤はない。私たちは、無機物質からのこれまでの治療に限界を感じ、有機物質としてオステオポンチン（OPN）を同定し、その分子機構を世界に先駆けて解明した。そこで、OPN遺伝子組み換えマウスを作成し、OPNは尿路結石の形成を促進することを証明し、つづいてOPN抗体によるマウス腎結石の抑制にも成功した。今後、ヒトへの臨床応用に向けた研究が必須と考えるが、結石治療の効果判定のためのバイオマーカーがないことが、新しい創薬開発にむけての大きな課題である。OPNは、酵素による切断や重合による翻訳後修飾を受けて活性を変化させる。そこで本研究では、今回尿路結石形成のためのバイオマーカーの探索を目的として、OPNの酵素による切断や重合について着目した。
今回はじめはサルにおける検討を行おうとしたが、サル自体は草食動物であるため、ヒトと同様の尿路結石を作ることができなかった。そのため、尿中、血清中の重合OPNをELISAで定量化することのできるOPN抗体を広島大学インテグリン治療開発フロンティア研究室から供与いただき、実臨床において尿路結石患者、健常人の尿中重合OPNを定量化した。後ろ向きな研究として、尿路結石患者50名、健常人10名の尿中重合OPNを調べたところ、結石形成のリスクと尿中OPNには、相関関係を認めなかったが、健常人と尿路結石患者を比較すると、尿路結石患者の方が尿中重合OPNの量が多くなることがわかった。

Research Products

• [Journal Article] Identification of new urinary risk markers for urinary stones using a logistic model and multinomial logit model. (2019)
  • Author(s): Okada Atsushi、Ando Ryosuke、Taguchi Kazumi、Hamamoto Shuzo、Unno Rei、Sugino Teruaki、Tanaka Yutaro、Mizuno Kentaro、Tozawa Keiichi、Kohri Kenjiro、Yasui Takahiro
  • Journal Title: Clin Exp Nephrol Volume: 23 Pages: 710-716
  • DOI: 10.1007/s10157-019-01693-x
  • Peer Reviewed
• [Journal Article] NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy (2019)
  • Author(s): Etani T, Naiki T, Naiki-Ito A, Suzuki T, Iida K, Nozaki S, Kato H, Yagayasu Y, Suzuki S, Kawai N, Yasui T, Takahashi S.
  • Journal Title: J Clin Med Volume: 8 Pages: 442-442
  • DOI: 10.3390/jcm8040442
  • Peer Reviewed / Open Access
• [Journal Article] Chronological changes in epidemiological characteristics of lower urinary tract urolithiasis in Japan (2018)
  • Author(s): Sakamoto Shinichi、Miyazawa Katsuhito、Yasui Takahiro、Iguchi Taro、Fujita Misuzu、Nishimatsu Hiroaki、Masaki Takuro、Hasegawa Toru、Hibi Hatsuki、Arakawa Takashi、Ando Ryosuke
  • Journal Title: International Journal of Urology Volume: 26 Pages: 96-101
  • DOI: 10.1111/iju.13817
  • Peer Reviewed
• [Journal Article] Impact of ureteric stent removal by string on patient's quality of life and on complications at post-ureteroscopy for urolithiasis: a controlled trial (2018)
  • Author(s): Inoue Takaaki、Okada Shinsuke、Hamamoto Shuzo、Yoshida Takashi、Murota Takashi、Matsuda Tadashi、On behalf of the SMART Study Group
  • Journal Title: BJU International Volume: Epub
  • DOI: 10.1111/bju.14622
  • Peer Reviewed
• [Journal Article] A kit ligand, stem cell factor as a possible mediator inducing overactive bladder (2018)
  • Author(s): Kubota Yasue, Hamakawa Takashi, Osaga Satoshi, Okada Atsushi, Hamamoto Shuzo, Kawai Noriyasu, Kohri Kenjiro, Yasui Takahiro
  • Journal Title: Neurourology and Urodynamics Volume: 37 Pages: 1258-1265
  • DOI: 10.1002/nau.23449
  • Peer Reviewed
• [Journal Article] Kidney stone formers have more renal parenchymal crystals than non-stone formers, particularly in the papilla region (2018)
  • Author(s): Okada A, Hamamoto S, Taguchi K, Unno R, Sugino T, Ando R, Mizuno K, Tozawa K, Kohri K, Yasui T.
  • Journal Title: BMC Urology Volume: 18 Pages: 19-19
  • DOI: 10.1186/s12894-018-0331-x
  • Peer Reviewed / Open Access
• [Journal Article] Chronological changes in the epidemiological characteristics of upper urinary tract urolithiasis in Japan (2018)
  • Author(s): Sakamoto Shinichi、Miyazawa Katsuhito、Yasui Takahiro、Iguchi Taro、Fujita Misuzu、Nishimatsu Hiroaki、Masaki Takuro
  • Journal Title: International Journal of Urology Volume: 25 Pages: 373-378
  • DOI: 10.1111/iju.13552
  • Peer Reviewed
• [Journal Article] Genetic differences in C57BL/6 mouse substrains affect kidney crystal deposition. (2018)
  • Author(s): Usami Masayuki, Okada Atsushi, Hamamoto Shuzo, Kohri Kenjiro, Yasui Takahiro
  • Journal Title: Urolithiasis Volume: 46 Pages: 515-522
  • Peer Reviewed
• [Journal Article] Potassium-sodium citrate prevents the development of renal microcalculi into symptomatic stones in calcium stone-forming patients (2017)
  • Author(s): Unno R, Taguchi K, Okada A, Ando R, Hamamoto S, Kubota Y, Zuo L, Tozawa K,Kohri K, Yasui T.
  • Journal Title: Int J Urol. Volume: 24 Pages: 26-27
  • DOI: 10.1111/iju.13242
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Two-year-old girl with impacted ureteral stone successfully treated with a single session of combined percutaneous nephrostomy and ureteroscopy (2017)
  • Author(s): Sugino Teruaki, Hamamoto Shuzo, Unno Rei, Moritoki Yoshinobu, Hamakawa Takashi, Naiki Taku, Ando Ryosuke, Okada Atsushi, Yasui Takahiro
  • Journal Title: International Journal of Urology Volume: 24 Pages: 326-329
  • DOI: 10.1111/iju.13319
  • Peer Reviewed
• [Journal Article] Genetic Risk Factors for Idiopathic Urolithiasis: A Systematic Review of the Literature and Causal Network Analysis. (2017)
  • Author(s): Taguchi Kazumi, Yasui Takahiro, Milliner Schmautz Dawn, Hoppe Bernd, Chi Thomas
  • Journal Title: Eur Urol Focus. Volume: 3 Pages: 71-81
  • DOI: 10.1016/j.euf.2017.04.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Determinants of health-related quality of life for patients after urinary lithotripsy: ureteroscopic vs. shock wave lithotripsy. (2017)
  • Author(s): Hamamoto S, Unno R, Taguchi K, Naiki T, Ando R, Okada A, Inoue T, Okada S, AbdelRazek M, Kohri K, Yasui T
  • Journal Title: Urolithiasis Volume: 印刷中
  • DOI: 10.1007/s00240-017-0972-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] M1/M2-macrophage phenotypes regulate renal calcium oxalate crystal development. (2017)
  • Author(s): 70.Taguchi Kazumi, Okada Atsushi, Hamamoto Shuzo, Unno Rei, Moritoki Yoshinobu, Ando Ryosuke, Mizuno Kentaro, Tozawa Keiichi, Kohri Kenjiro, Yasui Takaihro
  • Journal Title: Sci Rep. Volume: 6 Pages: 35167-35167
  • DOI: 10.1038/srep35167
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential roles of peroxisome proliferator-activated receptor-α and receptor-γ on renal crystal formation in hyperoxaluric rodents. (2016)
  • Author(s): Taguchi K, Okada A, Hamamoto S, Unno R, Kobayashi T, Ando R, Tozawa K, Gao B, Kohri K, Yasui
  • Journal Title: PPAR Res Volume: 2016 Pages: 9605890-9605890
  • DOI: 10.1155/2016/9605890
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Japanese topics for stone management -epidemiology, endoscopic surgery, and prevention. (2018)
  • Author(s): Yasui Takahito
  • Organizer: 16th Urological Association of Asia Congress 2018
  • Int'l Joint Research / Invited
• [Presentation] Japanese topics for stone management -epidemiology, endoscopic surgery, and prevention. (2018)
  • Author(s): Yasui Takahiro
  • Organizer: 第106回日本泌尿器科学会総会
  • Int'l Joint Research
• [Presentation] 進化を続けるPNL/ECIRS～軌跡をたどり、今後の可能性を考える～ (2018)
  • Author(s): 濵本 周造
  • Organizer: 第106回日本泌尿器科学会総会
• [Presentation] どのような患者に再発予防が必要か？ (2018)
  • Author(s): 濵本 周造、田口 和己、岡田 淳志、安井 孝周
  • Organizer: 第106回日本泌尿器科学会総会
  • Invited
• [Presentation] 尿路結石溶解療法に向けたiPS細胞由来のマクロファージを用いた創薬 (2018)
  • Author(s): 岡田 淳志、青木 啓将、小野里 太智、加藤 大貴、田中 勇太朗、杉野 輝明、海野 怜、田口 和己、濵本 周造、安藤 亮介、坡下 真大、松永 民秀、安井 孝周
  • Organizer: 第106回日本泌尿器科学会総会
• [Presentation] Cyclophilin D participation in the promotion of kidney stone formation via oxidative stress. (2018)
  • Author(s): Ito Yasuhiko, Niimi Kazuhiro, Unno Rei, Tanaka Yutaro, Sugino Teruaki, Taguchi Kazumi, Fujii Yasuhiro, Hamamoto Shuzo, Okada Atsushi, Ando Ryosuke, Tozawa Keiichi, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Establishment of treatment strategies for impacted calculi by analyzing the ureteroscopic findings. (2018)
  • Author(s): Hamamoto Shuzo, Unno Rei, Taguchi Kazumi, Ando Ryosuke, Okada Shinsuke, Inoue Takaaki, Okada Atsushi, Tozawa Keiichi, Miura Hiroyasu, Matsuda Tadashi, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2018
• [Presentation] 尿路結石のベストマネージメントを目指して―形成機序から見た展望― (2018)
  • Author(s): 安井 孝周
  • Organizer: 第114回徳島県泌尿器科疾患研究会
• [Presentation] Osteopontin antibody in the suppression of kindney crystal formation in a mice model of metabolic syndrome. (2018)
  • Author(s): Sugino Teruaki, Taguchi Kazumi, Unno Rei, Tanaka Yutaro, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Mogami Tohru, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: The 33rd Annual EAU Congress
  • Int'l Joint Research
• [Presentation] β3-adrenergic receptor agonist prevents kindney stone formation by suppressing inflammatory adipocytokine expression and improving antioxidant action. (2018)
  • Author(s): Sugino Teruaki, Taguchi Kazumi, Tanaka Yutaro, Unno Rei, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Mogami Tohru, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: The 33rd Annual EAU Congress
  • Int'l Joint Research
• [Presentation] Autophagy maintains cellular homeostasis and inhibits renal crystal formation. (2017)
  • Author(s): Unno Rei, Unno Naoko, Ota Yuya, Sugino Teruaki, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] A new navigation system of renal puncture for endoscopic combined intrarenal surgery: real-time virtual sonography-guided renal access. (2017)
  • Author(s): Hamamoto Shuzo, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Ando Ryosuke, Okada Shinsuke, Inoue Takaaki, Okada Atsushi, Tozawa Keiichi, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Identification of novel urinary risk markers of urolithiasis by using logistic and multi-nominal logit models. (2017)
  • Author(s): Okada Atsushi, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Hamakawa Takashi, Hamamoto Shuzo, Ando Ryosuke, Kubota Yasue, Honma Hideki, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] Nnt gene suppresses oxidative stress and kidney crystal deposition. (2017)
  • Author(s): Usami Masayuki, Ota Yuya, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Honma Hideki, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2017
• [Presentation] 腎結石患者に特異的な尿中マクロファージ関連マーカーの同定 (2016)
  • Author(s): 岡田 淳志、海野 怜、田口 和己、藤井 泰普、濵本 周造、安藤 亮介、戸澤 啓一、郡 健二郎、安井 孝周
  • Organizer: 第59回日本腎臓学会学術集会
  • Place of Presentation: パシフィコ横浜 会議センター(神奈川県横浜市)
  • Year and Date: 2016-06-17
• [Presentation] Identification of urinary macrophage-related factors specific to patients with calcium oxalate stones using multiplex analysis (2016)
  • Author(s): Okada Atsushi, Taguchi Kazumi, Fujii Yasuhiro, Hamamoto Shuzo, Hirose Masahito, Itoh Yasunori, Tozawa Keiichi, Sasaki Shoichi, Hayashi Yutaro, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2016
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] Different roles of M1/M2 macrophage phenotype for renal crystal formation (2016)
  • Author(s): Taguchi Kazumi, Okada Atsushi, Unno Rei, Fujii Yasuhiro, Hirose Yasuhiko, Usami Masayuki, Hamamoto Shuzo, Ando Ryosuke, Itoh Yasunori, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2016
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-05-06
  • Int'l Joint Research