Identification of factors involved in formation and elimination of urinary stones and development of new risk diagnosis and prevention methods

• Project/Area Number: 16K15692
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Nagoya City University
• Principal Investigator: OKADA atsushi 名古屋市立大学, 大学院医学研究科, 准教授 (70444966)
• Co-Investigator(Kenkyū-buntansha): 田口 和己 名古屋市立大学, 大学院医学研究科, 助教 (00595184) ; 郡 健二郎 名古屋市立大学, その他部局等, 学長 (30122047) ; 安藤 亮介 名古屋市立大学, 大学院医学研究科, 講師 (30381867) ; 藤井 泰普 名古屋市立大学, 大学院医学研究科, 研究員 (30566229) ; 安井 孝周 名古屋市立大学, 大学院医学研究科, 教授 (40326153) ; 海野 怜 名古屋市立大学, 大学院医学研究科, 研究員 (40755683)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 尿路結石 / 結石消失 / マクロファージ / オステオポンチン / マルチプレックス解析 / 多変量解析 / 多項ロジットモデル解析 / IL-4 / シュウ酸カルシウム / 貪食解析 / iPS細胞 / 創薬 / 化合物ライブラリー / オステオポンチン(OPN) / ノックアウトマウス / 結石モデルマウス

Outline of Final Research Achievements

In order to establish a crystal phagocytosis model of macrophage (Mφ), Mφ nuclei were stained with DAPI, cytoplasm with Phalloidin-iFluor 555, COM crystals with Alexa-Fluor 488, and phagocytosis ability was measured by imaging cytometry using Incell Analyzer.
Human spot urine was collected and the related factors of urinary Mφ were measured, and univariate analysis showed high AUC value of IL-4 and IL1a between healthy persons and first-time stone formers. Multinomial logit model analysis among 3 groups of healthy persons, first-time and recurrent stone formers showed that the combination of IL4, IL10, IL1b, GM-CSF and urinary Mg had discriminatory power of more than 87%.

Academic Significance and Societal Importance of the Research Achievements

尿路結石は一度できると排出するか手術するしか体内から除去できないと考えられてきた。私たちは、基礎研究で「結石消失現象」を発見し、その機序がマクロファージ (Mφ)による結晶貪食であることを見いだした。
本研究は、Mφによる結晶貪食の機序を明らかにすることと、健常者と結石患者の尿中Mφ関連因子の差を見いだすことが目的であったが、いずれも仮説通りの成果を得たことは学術的意義が大きい。
また本研究の成果は、尿路結石治療の新たな分子標的を提供するとともに、不確かであった尿生化学のみによるリスク診断に、Mφ関連因子の測定という新たな評価法を示した点で、社会的に大きな意義がある、

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] Genetic differences in C57BL/6 mouse substrains affect kidney crystal deposition. (2018)
  • Author(s): Usami M, Okada A, Taguchi K, Hamamoto S, Kohri K, Yasui T.
  • Journal Title: Urolithiasis Volume: 印刷中 Issue: 6 Pages: 515-522
  • DOI: 10.1007/s00240-018-1040-3
  • 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] Genome-wide gene expression profiling of Randall's plaques in calcium oxalate stone formers (2017)
  • Author(s): Taguchi K, Hamamoto S, Okada A, Unno R, Kamisawa H, Naiki T, Ando R, Mizuno K, Kawai N, Tozawa K, Kohri K, Yasui T
  • Journal Title: J Am Soc Nephrol Volume: 28 Issue: 1 Pages: 333-347
  • DOI: 10.1681/asn.2015111271
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Optimizing RNA Extraction of Renal Papilla Biopsy Tissue in Kidney Stone Formers: A New Methodology for Genomic Study. (2017)
  • Author(s): Taguchi K, Usawachintachit M, Hamamoto S, Unno R, Tzou DT, Sherer BA, Wang Y, Okada A, Stoller ML, Yasui T, Chi T.
  • Journal Title: J Endourol Volume: 31 Issue: 9 Pages: 922-929
  • DOI: 10.1089/end.2017.0320
  • 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] Do teas rich in antioxidants reduce the physicochemical and peroxidative risk factors for calcium oxalate nephrolithiasis in humans? Pilot studies with Rooibos herbal tea and Japanese green tea. Urolithiasis. (2016)
  • Author(s): Rodgers A, Mokoena M, Durbach I, Lazarus J, de Jager S, Ackermann H, Breytenbach I, Okada A, Usami M, Hirose Y, Ando R, Yasui T, Kohri K
  • Journal Title: Urolithiasis Volume: Epub Issue: 4 Pages: 299-310
  • DOI: 10.1007/s00240-015-0855-4
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Helper T cell signaling and inflammatory pathway lead to formation of calcium phosphate, but not calcium oxlate stones on Randall's plaques. (2019)
  • Author(s): Taguchi Kazumi, Hamamoto Shuzo, Sugino Teruaki, Unno Rei, Ando Ryosuke, Okada Atsushi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: Nagoya Immunology Network in NCU The first international symposium
  • Invited
• [Presentation] β3 Stimulant contributes to the prevention of renal crystal formation via differentitation of beige adipocytes. (2019)
  • Author(s): Sugino Teruaki, Okada Atsushi, Tanaka Yutaro, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Mogami Tohru, Kohri Kenjiro, Yamashita Hitoshi, Yaasui Takahiro
  • Organizer: 34th Anuual EAU Congress
  • Int'l Joint Research
• [Presentation] Low bone mineral density is associated with the onset of symptoms during follow-up: The relationship between bone mineral density and clinical outcomes in urolithiasis patients. (2019)
  • Author(s): Taguchi Kazumi, Sugino Teruaki, Okada Atsushi, Hamamoto Shuzo, Tanaka Yutaro, Unno Rei, Ando Ryosuke, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: 34th Anuual EAU Congress
  • Int'l Joint Research
• [Presentation] The effect of alendronate on the urinary stone risk of astronauts flown on expeditions aboad the International Space Station for a long time. (2018)
  • Author(s): Okada Atsushi, Matsumoto Toshio, Ohshima Hiroshi, Adrian Leblac, Jean Sibonga, Elisabeth Spector, Jeff Jones, Linda Shackelford, Scott Smith, Kohri Kenjiro, Yasui Takahiro
  • Organizer: 16th Urological Association of Asia Congress 2018
  • Int'l Joint Research
• [Presentation] The mechanism of prevention of urinary stone by white adipocyte to beige cell transdifferentiation (2018)
  • Author(s): Sugino Teruaki, Taguchi Kazumi, Okada Atsushi, Unno Rei, Hamamoto Shuzo, Ando Ryosuke, Mogami Tohru, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: 第106回日本泌尿器科学会総会
• [Presentation] Selective autophagy via mTORC1 and TFEB signals suppresses kidney stone formation. (2018)
  • Author(s): Unno Rei, Kawabata Tsuyoshi, Takase Hiroshi, Sugino Teruaki, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Tozawa Keiichi, Kohri Kenjiro, Yoshimori Tamotsu, Yasui Takahiro
  • Organizer: 第106回日本泌尿器科学会総会
• [Presentation] Establishment of a new method to evaluate the phagocytic ability of calcium oxalate monohydrate crystals by macrophages. (2018)
  • Author(s): Okada Atsushi, Takase Hiroshi, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Tozawa Keiichi, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Selective autophagy via mTORC1 and TFEB signals in the suppression of kidney stone formation. (2018)
  • Author(s): Unno Rei, Kawabata Tsuyoshi, Takase Hiroshi, Sugino Teruaki, Tanaka Yutaro, Taguchi Kazumi, Unno Naoko, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Kohri Kenjiro, Yoshimori Tamotsu, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2018
  • Int'l Joint Research
• [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] Pro-inflammatory and immune-active responses predominantly leading to Randall's plaque formation on calcium phosphate stone. (2018)
  • Author(s): Taguchi Kazumi, Hamamoto Shuzo, Unno Rei, Tanaka Yutaro, Sugino Teruaki, Ando Ryosuke, Okada Atsushi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Transdifferentiation from white adipocytes to beige cells prevents kidney stone formation. (2018)
  • Author(s): Sugino Teruaki, Taguchi Kazumi, Unno Rei, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Mogami Tohru, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Fatty acid binding protein 4 is an essential molecule associated with the development of kidney stone disease. (2018)
  • Author(s): Taguchi Kazumi, Hamamoto Shuzo, Sugino Teruaki, Unno Rei, Tzou David, Fujii Yasuhiro, Ando Ryosuke, Kamiya Hiroyuki, Okada Atsushi, Stoller Marshall, Chi Thomas, Yasui Takahiro
  • Organizer: 第61回日本腎臓学会学術総会
• [Presentation] Transdifferentiation of white adipocytes into beige cells prevents kidney stone formation (2018)
  • Author(s): Sugino Teruaki, Taguchi Kazumi, Unno Rei, Tanaka Yutaro, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Mogami Tohru, Tozawa Keiichi, Kohri Kenjiro, Yamashita Hitoshi, Yasui Takahiro
  • Organizer: 第61回日本腎臓学会学術総会
• [Presentation] Introduction of NCU Stone-Basic Researches. (2018)
  • Author(s): Okada Atsushi
  • Organizer: Urinary Stone Research Conference 2018
  • Int'l Joint Research / 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
  • Invited
• [Presentation] 尿路結石モデルマウスに始まる私たちがたどった基礎研究の道 (2018)
  • Author(s): 岡田 淳志、田口 和己、田中 勇太朗、杉野 輝明、海野 怜、宇佐美 雅之、新美 和寛、藤井 泰普、廣瀬 泰彦、濵本 周造、広瀬 真仁、戸澤 啓一、郡 健二郎、安井 孝周
  • Organizer: 日本尿路結石学会第28回学術集会
  • Invited
• [Presentation] 尿路結石とは？～臨床と研究の現場からみた課題～ (2018)
  • Author(s): 岡田 淳志
  • Organizer: 第47回結晶成長国内会議（JCCG-47）
  • Invited
• [Presentation] Urolithasis Pannel Discussion: Case management for urinary stones. (2017)
  • Author(s): Okada Atushi
  • Organizer: Advancements in Urology 2017
  • Int'l Joint Research / Invited
• [Presentation] Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss. (2017)
  • Author(s): LeBlanc Adrian, Matsumoto Toshio, Spector E, Jones J, Shapiro J, Lang T, Shackelford L, Smith M S, Evans H, Ploutz-Snyder R, Sibonga J, Keyak J, Nakamura Toshitaka, Kohri Kenjiro, Ohshima Hiroshi, Okada Atsushi, Yasui Takahiro
  • Organizer: 2017 NASA Human Research Program Investigators’ Workshop
  • Int'l Joint Research / Invited
• [Presentation] Stone Cases. (2017)
  • Author(s): Okada Atsushi
  • Organizer: 第105回日本泌尿器科学会総会
  • Invited
• [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
  • Invited
• [Presentation] Identification of new urinary risk markers for urinary stone patients using logistic model and multinomial-logit model. (2017)
  • Author(s): Okada Atsushi, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: American Urological Association Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Identification of the recommended techniques, case selection, and invention to improve extracorporeal shock wave lithotripsy success rates. (2017)
  • Author(s): Okada Atsushi, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Tozawa Keiichi, Yasui Takahir
  • Organizer: American Urological Association Annual Meeting 2017
• [Presentation] Alendronate ameliorates the risk of urinary stone formation of astronauts on the International Space Station for 6 months. (2017)
  • Author(s): Okada Atsushi, Yasui Takahiro, Kohri Kenjiro, Matsumoto Toshio, LeBlanc Adrian, Sibonga Jean, Spector Elisabeth, Jones Jeff, Shapiro Jay, Lang Thomas, Shackelford Linda, Smith Scott, Evans Harlan, Keyak Joyce, Ohshima Hiroshi
  • Organizer: ASBMR 2017 Annual Meeting,
  • Int'l Joint Research
• [Presentation] ロボット支援腎部分切除術の初期症例における温阻血時間に影響する因子の同定。 (2017)
  • Author(s): 岡田 淳志、守時 良演、濱川 隆、内木 拓、濵本 周造、安藤 亮介、水野 健太郎、河合 憲康、戸澤 啓一、安井 孝周
  • Organizer: 第31回日本泌尿器内視鏡学会総会
• [Presentation] ESWLの成功率向上に寄与するトレーニング・患者因子・治療因子の同定 (2017)
  • Author(s): 岡田 淳志、杉野 輝明、海野 怜、田口 和己、濵本 周造、戸澤 啓一、郡 健二郎、安井 孝周
  • Organizer: 第31回日本泌尿器内視鏡学会総会
  • Invited
• [Presentation] Technical training of the SWL to achieve 100% of success rates. (2016)
  • Author(s): Okada Atsushi
  • Organizer: 13th Annual Meeting of the East Asian Society of Endourology
  • Place of Presentation: ナレッジキャピタルコングレコンベンションセンター(大阪府大阪市北区)
  • Year and Date: 2016-11-19
  • Int'l Joint Research / Invited
• [Presentation] JSE上部尿路結石内視鏡治療標準化委員会シンポジウム PNLの標準術式 (2016)
  • Author(s): 岡田 淳志、柿木 寛明、眞﨑 拓朗、吉水 敦、山口 秋人
  • Organizer: 第30回日本泌尿器科内視鏡学会総会
  • Place of Presentation: イベントラボ・グランフロント大阪(大阪府大阪市)
  • Year and Date: 2016-11-17
  • Invited
• [Presentation] 尿路結石症手術の教育 尿路結石症手術の教育：ESWL (2016)
  • Author(s): 岡田 淳志、海野 怜、濵本 周造、安藤 亮介、戸澤 啓一、安井 孝周
  • Organizer: 第30回日本泌尿器科内視鏡学会総会
  • Place of Presentation: イベントラボ・グランフロント大阪(大阪府大阪市)
  • Year and Date: 2016-11-17
  • Invited
• [Presentation] Macrophage-derived cytokines and chemokines may be new markers for calcium oxalate stone formation risk in humans. (2016)
  • Author(s): Okada Atsushi, Unno Rei, Taguchi Kazumi, Fujii Yasuhiro, Hamamoto Shuzo, Ando Ryosuke, Tozawa Keiichi, Kohri Kenjiro, Yasui Takahiro
  • Organizer: 13th International Symposium on Urolithiasis
  • Place of Presentation: 幕張メッセ(千葉県千葉市)
  • Year and Date: 2016-07-19
  • Int'l Joint Research / Invited
• [Presentation] Efficacy of ESWL training using human body-typed stone-targeting phantoms. (2016)
  • Author(s): Okada Atsushi, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Itoh Yasunori, Tozawa Keiichi, Zuo Li, Gao Bing, Kohri Kenjiro, Yasui Takahiro
  • Organizer: 13th International Symposium on Urolithiasis
  • Place of Presentation: 幕張メッセ(千葉県千葉市)
  • Year and Date: 2016-07-19
  • Int'l Joint Research
• [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(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] Printed three-dimensional elastic organ model to increase robot-assisted laparoscopic partial nephrectomy performance. (2016)
  • Author(s): Okada Atsushi, Tozawa Keiichi, Kobayashi Daichi, Mizuno Kentaro, Umemoto Yukihiro, Kawai Noriyasu, Sasaki Shoichi, Hayashi Yutaro, Kunimoto Katsushi, 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] ファントムを使用したESWLトレーニングと、砕石率100%を目指した最新テクニック。 (2016)
  • Author(s): 岡田 淳志
  • Organizer: 第104回日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター他（宮城県仙台市）
  • Year and Date: 2016-04-23
  • Invited