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: HONMA hideki 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: 尿路結石 / オステオポンチン / バイオマーカー / 腎結石 / 重合 / 腎乳頭部

Outline of Final Research Achievements

Osteopontin plays a crucial role in the formation of renal calcium crystals, which are primarily induced by renal tubular cell injury, especially mitochondrial damage. In this study, we analyze the effect of the cryptic OPN epitope generated by thrombin cleavage and by polymeraization on renal crystal formation. We found that a specific anti-OPN antibody contributes to the remarkable inhibition of early stage of renal crystal formation and that thrombin-cleaved OPN contributes to promote the renal crystal formation. As regard to OPN polymerization, the amount of polymerized OPN in the urine of stone formers were higher than that of the healthy human. We speculated that polymerized OPN could be the marker of kidney stone formation.

Academic Significance and Societal Importance of the Research Achievements

切断型OPNや重合OPNなど、OPN構造変化が尿路結石形成と密接に関係していることがわかった。切断型OPNに対する抗体は、腎結石に対する分子標的治療となる可能性があり、尿中における重合OPNは、腎結石形成のバイオマーカとなる可能性がわかった。今後増え続ける腎結石の中で、新しい結石治療薬の開発が求められる。治療薬の効果判定には、結石形成のバイオマーカーが必要となるため、本研究結果は、新しい治療薬開発の礎になると考えられた。

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: Clinical and Experimental Nephrology Volume: 23 Issue: 5 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 Issue: 4 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 Issue: 1 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 Issue: 2 Pages: 314-314
  • 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 Issue: 4 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 Urol. Volume: 18 Issue: 1 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 Issue: 4 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 Rei, Taguchi Kazumi, Okada Atsushi, Ando Ryosuke, Hamamoto Shuzo, Kubota Yasue, Zuo Li, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Journal Title: International Journal of Urology Volume: 24 Issue: 1 Pages: 75-81
  • DOI: 10.1111/iju.13242
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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 Issue: 4 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: EUROPEAN UROLOGY FOCUS Volume: 3 Issue: 1 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 Issue: 2 Pages: 203-210
  • 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: Scientific Reports Volume: 6 Issue: 1 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 T
  • Journal Title: PPAR Res Volume: 2016 Pages: 9605890-9605890
  • DOI: 10.1155/2016/9605890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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