The clinical application of a novel biomarker of DKD and the clarification of gut-microbiota axis in DKD

• Project/Area Number: 21K16178
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tohoku University
• Principal Investigator: Kikuchi Koichi 東北大学, 大学病院, 助教 (10845259)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糖尿病性腎臓病 / 尿毒素 / 腸腎連関 / フェニル硫酸 / UCARE study / 腸内細菌 / バイマーカー / 腸内細菌叢

Outline of Research at the Start

糖尿病性腎臓病（DKD）は末期腎不全に至る最多原疾患である。従ってDKD発症や進行リスクの高い患者の早期発見と積極的治療介入が肝要だが既存マーカーでは十分ではない。腎臓病と腸内環境が密接に関係するという腸腎連関の概念が知られて　いる。申請者はDKDの原因物質かつ予後予測マーカーとして腸内細菌由来のフェニル硫酸（PS）を同定しDKDでも腸内環境が病態に影響することを明らかにした。
本研究では長期予後解析や尿検体、新たな大規模コホートを用いた解析による新規DKDバイオマーカーの確立、糖尿病下での腸内細菌叢変化および　血中PS濃度上昇メカニズムの解明、腸内環境への介入による新規DKD治療法の探索する。

Outline of Final Research Achievements

We focused on phenyl sulfate (PS) as a novel marker of diabetic kidney disease (DKD) and demonstrated its clinical utility in two diabetic cohorts.
First, in the UCARE cohort (Nat. Commun. 2019), where blood PS levels and albuminuria (ACR) exacerbation in DKD patients have been shown, multiple regression analysis showed that urinary PS and Cr corrected values significantly correlated with ACR, and in the group of patients in the microalbuminuria phase, urinary PS and Cr corrected values significantly correlated with ACR exacerbation after 2 years The urinary PS and Cr corrected values were significantly correlated with worsening of ACR at 2 years in patients with trace albuminuria. Next, the 2nd Joslin Kidney Study explored risk factors for the onset and progression of nephropathy in patients with type 2 diabetes. Comparing two groups, one with slow progression of nephropathy and the other with onset of renal failure, PS was significantly higher in the group with onset of renal failure.

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎臓病（DKD）は末期腎不全に至る最も多い原疾患だが、アルブミン尿（ACR）やeGFRといった既存の指標だけでは、どの糖尿病患者がDKDを発症し腎不全に至るリスクが高いかを予測するには不十分である。我々はDKDの新規マーカーとして腸内細菌由来の尿毒素であるフェニル硫酸（PS）に着目し先行研究で血清PSは糖尿病患者のACR増悪を予測することを示しているが、今回の研究で尿中PSもACRの増悪を予測する因子であることを明らかにした。更に別の糖尿病患者コホートでの解析で血中PSが早期にeGFRが低下群で有意に高いことを示した。これらの成果はPSの新規DKDマーカーとしての有用性を示唆する。

Research Products

• [Journal Article] (+)-Sesamin, a sesame lignan, is a potent inhibitor of gut bacterial tryptophan indole-lyase that is a key enzyme in chronic kidney disease pathogenesis. (2022)
  • Author(s): 16.Oikawa D, Yamashita S, Takahashi S, Waki T, Kikuchi K, Abe T, Katayama T, Nakayama T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 590 Pages: 158-162
  • DOI: 10.1016/j.bbrc.2021.12.088
  • Peer Reviewed
• [Journal Article] SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure (2021)
  • Author(s): Ho Hsin‐Jung、Kikuchi Koichi、Oikawa Daiki、Watanabe Shun、Kanemitsu Yoshitomi、Kagawa Yoshiteru、その他19名
  • Journal Title: Physiological Reports Volume: 9 Issue: 24 Pages: 15092-15092
  • DOI: 10.14814/phy2.15092
  • Peer Reviewed / Open Access
• [Journal Article] Fibromuscular dysplasia with recurrence after "long-term" following percutaneous transcatheter renal angioplasty: two case reports with a review of 26 patients (2021)
  • Author(s): Oribe S, Toyohara T, Mishima E, Suzuki T, Kikuchi K, Watanabe S, Morita Y, Ota H, Seiji K, Miyazaki M, Takase K, Abe T
  • Journal Title: BMC Nephrol Volume: 22 Issue: 1 Pages: 187-187
  • DOI: 10.1186/s12882-021-02342-w
  • Peer Reviewed / Open Access
• [Journal Article] CE-MS-Based Identification of Uremic Solutes Specific to Hemodialysis Patients (2021)
  • Author(s): Akiyama Yasutoshi、Kikuchi Koichi、Toyohara Takafumi、Mishima Eikan、Suzuki Chitose、Suzuki Takehiro、Nakayama Masaaki、Tomioka Yoshihisa、Soga Tomoyoshi、Abe Takaaki
  • Journal Title: Toxins Volume: 13 Issue: 5 Pages: 324-324
  • DOI: 10.3390/toxins13050324
  • Peer Reviewed / Open Access
• [Presentation] 12.Urinary phenyl sulfate predict the 2-year ACR deterioration in a DKD cohort. (2022)
  • Author(s): Koichi Kikuchi, Ryota Kujirai, Yotaro Matsumoto, Koki Mise, Tomohiro Nakamura, Jun Wada, Yoshihisa Tomioka and Takaaki Abe
  • Organizer: The 11th Scientific Meeting of the Chronic Kidney Disease Frontier.
  • Int'l Joint Research
• [Presentation] he gut microbiome-derived phenyl sulfate is a novel predictive marker and cause of albuminuria in diabetic kidney disease. (2021)
  • Author(s): Koichi Kikuchi, Takaaki Abe.
  • Organizer: American Society of Nephrology Kidney Week 2021
  • Int'l Joint Research