The significant role of the kidney as a central organ for metabolic organ interrelationship

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H01562
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Keio University
• Principal Investigator: Itoh Hiroshi 慶應義塾大学, 医学部(信濃町), 教授 (40252457)
• Co-Investigator(Kenkyū-buntansha): 長谷川 一宏 慶應義塾大学, 医学部(信濃町), 助教 (30424162) ; 脇野 修 慶應義塾大学, 医学部(信濃町), 准教授 (50265823) ; 徳山 博文 慶應義塾大学, 医学部(信濃町), 講師 (50276250) ; 神田 武志 慶應義塾大学, 医学部(信濃町), 講師 (80317114)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 慢性腎臓病 / MKD / 臓器連関 / SGLT2 / NAD / グレリン / 腸内細菌 / 腎性インスリン抵抗性症候群

Outline of Final Research Achievements

We propose the concept of “Metabolic Kidney Diseases (MKD)”, which is the chronic kidney dysfunction induced by renal metabolic alterations. MKD includes diabetic nephropathy, nephrosclerosis and obesity-related glomerulopathy. In the context of MKD, the kidney can act as the integral organ for energy metabolism. As for kidney-adipose tissue-liver-muscle axis, we elucidated that MKD induces insulin resistance caused by the excessive uremic toxins produced by gut microbiota and translocation to systemic circulation (kidney-gut axis). These metabolic alterations in turn affects the renal structure and function. Nutrients, such as glucose, NAD metabolites or ketone bodies act as signaling molecules to modulate renal functions, such as the expression of SGLT2, ischemia response, or fibrosis. We focused on these abnormalities as therapeutic targets and attempted clinical trials, such as the administrations of ghrelin or NMN into humans for treatment of MKD-associated diseases.

Free Research Field

腎臓病学　内分泌学

Academic Significance and Societal Importance of the Research Achievements

腎臓内の代謝変容に注目するmetabolic Kidney Disease（MKD）が引き起こす病態と腎臓をエネルギー代謝のハブ臓器として捉える新たな概念により、新規治療標的、NAD代謝異常、ケトン体代謝、インスリン抵抗性（腎・脂肪組織・肝臓連関）、腸内細菌の偏倚（腎・腸連関）が明らかとなった。これらを臨床応用する研究、すなわちMKDマーカーとしてのNAD代謝産物、NAD前駆体であるNMN、NNMT活性阻害薬、グレリンのMKDへの治療応用の試みが始まり新規CKD治療薬の開発が始まった。この研究の成果により透析抑制さらにCKD患者のサルコペニア、フレイルの予防が可能になれば社会的にも意義深い。