Development of a prognostic evaluation method for precision medicine of early-stage CKD patients

• Project/Area Number: 21H02935
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Osaka University
• Principal Investigator: Isaka Yoshitaka 大阪大学, 大学院医学系研究科, 教授 (00379166)
• Co-Investigator(Kenkyū-buntansha): 山本 陵平 大阪大学, キャンパスライフ健康支援・相談センター, 教授 (00533853) ; 木村 友則 大阪大学, 大学院医学系研究科, 招へい准教授 (00631300) ; 井上 和則 大阪大学, 大学院医学系研究科, 助教 (10631301) ; 水井 理之 大阪大学, 大学院医学系研究科, 講師 (30423106) ; 松井 功 大阪大学, 大学院医学系研究科, 講師 (60456986) ; 高畠 義嗣 大阪大学, 医学系研究科, 講師 (30403075)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2022: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2021: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: CKD / 精密医療 / AIによる腎病理診断 / シングルセルRNA解析 / D-アミノ酸 / オートファジー / AIによる腎病理解析 / Single cell RNA seq / AI / シングルセルRNA-seq解析 / エクソソーム解析

Outline of Research at the Start

我が国の透析患者の増加は医療経済的にも重大な問題であり、その対処法開発は喫緊の課題
である。2018年度腎疾患対策報告書の掲げるkey performance indicator (KPI)である、「2028年までに新規透析導入患者数を10%削減すること」を達成するために早期慢性腎臓病
(CKD)患者の精密医療を目指した予後評価法を開発する。

Outline of Final Research Achievements

To develop a prognostic evaluation method for precision medicine of patients with early-stage chronic kidney disease (CKD), we will 1) establish a novel histological evaluation method for renal pathology using artificial intelligence (AI) and super-resolution microscopy, 2) investigate precise gene expression and intercellular communication at the single cell level using single cell RNA sequence (scRNA-seq) analysis of renal biopsy tissue and FACS analysis of peripheral blood cells from CKD patients, 3) develop a non-invasive quantitative method for autophagy, which plays a protective role in renal lesion development, 4) integrate existing electronic medical record information and D-amino acid analysis data as a novel marker of renal pathology, and 5) extract essential features that define renal prognosis by using AI.

Academic Significance and Societal Importance of the Research Achievements

近年提唱された糖尿病関連腎臓病は、従来の「糖尿病性腎症」に加え、非典型的な経過を辿る糖尿病関連腎疾患を包括している。糸球体腎炎にもステロイドに反応良好な患者と反応不良な患者が存在する。このように一つの疾患概念に、病態の異なる複数の異なる病態が混在している場合、その臨床的鑑別が困難であるだけでなく、適切な治療を行う事もできない。2028年までに年間新規透析導入患者数を35,000人以下に減少させるという KPI を設定している。このようなKPIを達成するために、本研究で行った個々のCKD患者の病態を的確に把握したうえで患者を層別化し、病態に応じた精密医療を早期から開始する重要性が確認できた。

Research Products

• [Journal Article] Association between urinary uric acid excretion and kidney outcome in patients with CKD (2024)
  • Author(s): Asahina Yuta、Sakaguchi Yusuke、Oka Tatsufumi、Hattori Koki、Kawaoka Takayuki、Doi Yohei、Yamamoto Ryohei、Matsui Isao、Mizui Masayuki、Kaimori Jun-Ya、Isaka Yoshitaka
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 5119-5119
  • DOI: 10.1038/s41598-024-55809-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of a three-dimensional HPLC system for the determination of serine, threonine and allo-threonine enantiomers in the plasma of patients with chronic kidney disease (2024)
  • Author(s): Oyaide Mai、Ishii Chiharu、Akita Takeyuki、Kimura Tomonori、Sakai Shinsuke、Mizui Masayuki、Mita Masashi、Ide Tomomi、Isaka Yoshitaka、Hamase Kenji
  • Journal Title: Journal of Chromatography A Volume: 1719 Pages: 464739-464739
  • DOI: 10.1016/j.chroma.2024.464739
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of Individual Variation of d-Amino Acids in Human Plasma by a Two-Dimensional LC-MS/MS System and Application to the Early Diagnosis of Chronic Kidney Disease (2024)
  • Author(s): Ishii Chiharu、Akita Takeyuki、Kimura Tomonori、Sakai Shinsuke、Mita Masashi、Ide Tomomi、Isaka Yoshitaka、Hamase Kenji
  • Journal Title: Analytical Chemistry Volume: 96 Issue: 12 Pages: 4876-4883
  • DOI: 10.1021/acs.analchem.3c05309
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence (2024)
  • Author(s): 1.Cui, M., Yamano, K., Yamamoto, K., Yamamoto-Imoto, H., Minami, S., Yamamoto, T., Matsui, S., Kaminishi, T., Shima, T., Ogura, M., Tsuchiya, M., Nishino, K., Layden B., Kato, H., Ogawa, H., Oki, S., Okada, Y., Isaka, Y., Kosako, H., Matsuda, N., *Yoshimori, T., *Nakamura, S.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 121 Issue: 2
  • DOI: 10.1073/pnas.2306454120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] d-Alanine Affects the Circadian Clock to Regulate Glucose Metabolism in the Kidney (2023)
  • Author(s): Sakai Shinsuke、Tanaka Youichi、Tsukamoto Yusuke、Kimura-Ohba Shihoko、Hesaka Atsushi、Hamase Kenji、Hsieh Chin-Ling、Kawakami Eiryo、Ono Hiraku、Yokote Kotaro、Yoshino Mitsuaki、Okuzaki Daisuke、Matsumura Hiroyo、Fukushima Atsuko、Mita Masashi、Nakane Maiko、Doi Masao、Isaka Yoshitaka、Kimura Tomonori
  • Journal Title: Kidney360 Volume: 5 Issue: 2 Pages: 237-251
  • DOI: 10.34067/kid.0000000000000345
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis (2022)
  • Author(s): Yamamoto-Imoto Hitomi et al.,
  • Journal Title: Cell Reports Volume: 38 Issue: 9 Pages: 110444-110444
  • DOI: 10.1016/j.celrep.2022.110444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Diabetic Nephropathy in Patients Undergoing Kidney Biopsy through Blood and Urinary Profiles of d-Serine (2021)
  • Author(s): Iwata Yukimasa、Okushima Hiroki、Hesaka Atsushi、Kawamura Masataka、Imamura Ryoichi、Takahara Shiro、Horio Masaru、Tanaka Youko、Ikeda Tatsuhiko、Nakane Maiko、Mita Masashi、Hayashi Terumasa、Isaka Yoshitaka、Kimura Tomonori
  • Journal Title: Kidney360 Volume: 2 Issue: 11 Pages: 1734-1742
  • DOI: 10.34067/kid.0004282021
  • Peer Reviewed
• [Journal Article] d-Serine Mediates Cellular Proliferation for Kidney Remodeling (2021)
  • Author(s): Hesaka Atsushi、Tsukamoto Yusuke、Nada Shigeyuki、Kawamura Masataka、Ichimaru Naotsugu、Sakai Shinsuke、Nakane Maiko、Mita Masashi、Okuzaki Daisuke、Okada Masato、Isaka Yoshitaka、Kimura Tomonori
  • Journal Title: Kidney360 Volume: 2 Issue: 10 Pages: 1611-1624
  • DOI: 10.34067/kid.0000832021
  • Peer Reviewed
• [Journal Article] Quantitative Analyses of Foot Processes, Mitochondria, and Basement Membranes by Structured Illumination (2021)
  • Author(s): Matsumoto Ayumi、Matsui Isao、Katsuma Yusuke、Yasuda Seiichi、Shimada Karin、Namba-Hamano Tomoko、Sakaguchi Yusuke、Kaimori Jun-ya、Takabatake Yoshitsugu、Inoue Kazunori、Isaka Yoshitaka
  • Journal Title: Kidney International Reports Volume: 6 Issue: 7 Pages: 1923-1938
  • DOI: 10.1016/j.ekir.2021.04.021
  • Peer Reviewed / Open Access
• [Journal Article] Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney (2021)
  • Author(s): Isao Matsui, Ayumi Matsumoto, Kazunori Inoue, Yusuke Katsuma, Seiichi Yasuda, Karin Shimada, Yusuke Sakaguchi, Masayuki Mizui, Jun-Ya Kaimori, Yoshitsugu Takabatake, Yoshitaka Isaka
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 73-73
  • DOI: 10.1038/s41598-020-80154-y
  • Peer Reviewed / Open Access