Abstract: SA-OR25
Neuroblastoma Suppressor of Tumorigenicity 1 (NBL1) and Risk of Progression to ESKD in Diabetes
Session Information
- Diabetic Kidney Disease: Recent Advances
November 06, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Diabetic Kidney Disease
- 602 Diabetic Kidney Disease: Clinical
Authors
- Kobayashi, Hiroki, Research Division, Joslin Diabetes Center; Department of Medicine, Harvard Medical School, Boston, United States
- Looker, Helen C., Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
- Satake, Eiichiro, Division of Nephrology, hypertension and Endocrinology, Nihon University School of Medicine, Tokyo, Japan
- Nelson, Robert G., Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
- Krolewski, Andrzej S., Research Division, Joslin Diabetes Center; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States
Background
TGF-β-related signaling proteins have been implicated in the development of end-stage kidney disease (ESKD) in diabetes. Most of this evidence has come from cellular and animal studies focusing on individual proteins and, to date, no study has demonstrated the involvement of these proteins in the etiology of ESKD in humans.
Methods
Using aptamer-based SomaScan platform, 25 TGF-β-related circulating proteins including ligands, receptors, and inhibitors were measured in baseline plasma obtained from 4 different cohorts of 754 Caucasian and Pima Indian subjects; including 219 with Type 1 diabetes (T1D) and CKD stage 3 (CKD3) and 144 with T2D and CKD3, and 238 T1D subjects with CKD1,2 and 153 T2D Pima Indian subjects with CKD1,2. All patients were followed for 10 years to ascertain onset of ESKD.
Results
In logistic regression analysis, NBL1, FSTL3, RGMB, and TGF-β RIII were strongly associated with progression to ESKD in all cohorts (Table 1). In multivariable logistic regression analysis for 4 proteins and clinical variables, NBL1, a secreted BMP antagonist never before implicated in kidney diseases, was identified as the only protein very strongly and independently associated with progression to ESKD. Importantly, renal structural parameters, measured quantitatively in research kidney biopsies obtained from Pima Indian subjects, were strongly associated with circulating level of NBL1.
Conclusion
Our study did not find any associations with conventional TGF-β-related proteins but pointed to NBL1 as a very important factor in progression to ESKD. NBL1 is a novel strong biomarker for kidney disease progression, and regulation of this protein may become new therapeutic targets to retard progression to ESKD in diabetes.
Table 1. Logistic regression for each group
| Joslin Cohorts (Caucasian) | Pima Indian Cohort | |||||||
| T1D CKD3 (n=219) | T2D CKD3 (n=144) | T1D CKD1-2 (n=238) | T2D CKD1-2 (n=153) | |||||
| OR | Bonferroni P | OR | P | OR | P | OR | P | |
| NBL1 | 3.39 | 9.3x10-12 | 3.54 | 7.2x10-7 | 2.05 | 1.4x10-5 | 2.92 | 5.2x10-6 |
| FSTL3 | 2.41 | 3.5x10-8 | 2.31 | 6.6x10-5 | 2.24 | 2.6x10-6 | 1.45 | 0.041 |
| RGMB | 2.06 | 3.8x10-6 | 2.12 | 2.1x10-4 | 1.37 | 0.034 | 2.01 | 5.1x10-4 |
| TGF-β R III | 1.64 | 3.3x10-3 | 1.58 | 0.014 | 1.40 | 0.024 | 1.50 | 0.027 |
Funding
- NIDDK Support