Kidney Week

Abstract: FR-OR112

Notch Signaling Proteins as Key Factor in the Progression to ESRD in Diabetes

Session Information

• Translating Discovery to Patients with Diabetic Kidney Disease
  November 08, 2019 | Location: 207, Walter E. Washington Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Kobayashi, Hiroki, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States

Hiroki Kobayashi, MD, PhD

Hiroki Kobayashi (MALE), M.D., Ph.D. PERSONAL INFORMATION Date of Birth: 26/11/1985 Nationality: Japanese Mobile Phone: 617-275-1632 E-mail: hiroki.kobayashi@joslin.harvard.edu (kobayashihiroki2@gmail.com) PRESENT ADDRESS OFFICE: Section on Genetics & Epidemiology, Research Division Joslin Diabetes Center, Harvard Medical School One Joslin Place, Room 462, Boston, MA 02215 Phone 617-275-1632 EDUCATION 2005-2011 Nihon University School of Medicine (Tokyo) 2001-2004 Keio senior high school 1998-2001 Edogawa city seishin-daiichi junior high school 1992-1998 Edogawa city seishin-daisan primary school LICENSURE and CERTIFICATION National Board of Medicine, Registration No. 494726 (Japan) Board Certified Member of the Japanese Society of Internal Medicine Board Certified Nephrologist of the Japanese Society of Nephrology USMLE step1 USMLE step2CK FELLOWSHIP OR STUDY ABROAD 2019/April− ：Overseas Research Fellowships, Japan Society for the Promotion of Science (Japanese government-sponsored), Section on Genetics & Epidemiology, Research Division, Joslin Diabetes Center, Harvard Medical School 2018/March− : Section on Genetics & Epidemiology, Research Division, Joslin Diabetes Center, Harvard Medical School (Research fellow) 2018/April− : Nephrology, Hypertension and Endocrinology in Nihon University (Visiting research fellow) 2017/April to 2018/March: Tokyo Metropolitan Hiroo Hospital (Attending physician) 2014/February to 2018/March: Nephrology, Hypertension and Endocrinology in Nihon University Itabashi Hospital (Senior resident) 2013/April to 2017/March　Nihon University School of Medicine (Postgraduate course) 2013/March to 2014/January： Short-Term Training in Kameda medical center (Department of General Medicine and Infectious Disease) 2011/April–2013/March： Junior resident in Nihon University Itabashi Hospital MEMBERSHIPS The Japanese Society of Internal Medicine, Japanese Society of Nephrology, The Japan Endocrine Society The Japanese Society of Hypertension, Journal of Japanese Society for Dialysis Therapy The Japan Diabetes Society, Endocrine Society MAJOR RESEARCH INTERESTS Nephrology (Diabetic kidney disease), hypertension, primary aldosteronism, epidemiology, genetics HONORS and AWARDS The President's Prize of Nihon University The President's Prize of Nihon University School of Medicine The Prize of 59th Annual Meeting of the Japanese Society of Nephrology The Prize of Ouni-kai The 60th Anniversary Medical Research Grant (Alumini association of Nihon University School of Medicine) Post-doctoral Fellowship, the Uehara Memorial Foundation Overseas Research Fellowships, Japan Society for the Promotion of Science (Japanese government-sponsored) COMMITTEE Guideline Committee member of Primary Aldosteronism (Japan Endocrine Society)

• Satake, Eiichiro, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States

Eiichiro Satake,

• Md Dom, Zaipul I, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States

Zaipul I Md Dom,

• Krolewski, Andrzej S., Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States

Andrzej S. Krolewski,

Background

It has been reported that Notch signaling proteins might regulate interstitial fibrosis development in the kidneys of mice and humans. The objective of this study was to investigate an association of circulating Notch signaling proteins on the development of ESRD in subjects with diabetes during long-term follow-up.

Methods

Using the modified aptamer-based SomaScan platform, 4 proteins including Notch1, delta like protein 1 (DLL1), delta like protein 4 (DLL4), and Jagged 1 protein (JAG1) were measured in baseline plasma specimens obtained from 363 Caucasian subjects with diabetes and CKD stage 3 (CKD3); including 219 with Type 1 diabetes (T1D) and 144 with Type 2 diabetes (T2D). Additionally, the 4 proteins were also measured in 190 T1D patients with CKD stage 1 and 2 (CKD12). All patients were followed for 10 years to ascertain onset of ESRD.

Results

In Cox regression analysis, DLL1, DLL4, and JAG1 were strongly associated with progression to ESRD in T1D patients with CKD3 (P=1.6*10^-10, p=5.1*10^-8, and p=2.0*10^-5, respectively) and in T2D patients with CKD3 (p=3.6*10^-4, p=1.9*10^-4, and p=6.1*10^-4, respectively). Importantly, this significant association with ESRD for DLL1 and JAG1 were also found in T1D patients with CKD12 (p=2.8*10^-6 and p=4.1*10^-2), and DLL1 was the strongest predictor for ESRD in the combined panel, even after adjustment for relevant covariates (Hazard Ratio 1.48, p=8.4*10^-6) (Table 1).

Conclusion

There were few previous reports about the association between circulating Notch signaling proteins and kidney diseases. Our finding is novel in that circulating ligands for Notch receptors, especially DLL1, are strongly associated with progression to future ESRD. Regulation of the specific circulating Notch ligands could become the new therapeutic targets to retard progression to ESRD in diabetes.

Table 1. Cox regression model for each group

Multivariate model was adjusted for baseline eGFR, HbA1c, ACR, and type of diabetes

Funding

• Other NIH Support