Kidney Week

Abstract: TH-PO912

Urinary Complement-Enriched Inflammatory Proteome of an Overt Progressive Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Biomarkers, Pathogenesis
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Moon, Salina, Joslin Diabetes Center, Boston, Massachusetts, United States

Salina Moon,

• Donsky, Heather L., Joslin Diabetes Center, Boston, Massachusetts, United States

Heather L. Donsky,

• Tsay, John J., Joslin Diabetes Center, Boston, Massachusetts, United States

John J. Tsay,

• Feener, Edward P., KalVista Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Edward P. Feener,

• Dillon, Simon T., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Simon T. Dillon,

• Niewczas, Monika A., Joslin Diabetes Center, Boston, Massachusetts, United States

Monika A. Niewczas,

Background

We aimed to advance our knowledge of the role of the local kidney inflammation in the progressive diabetic kidney disease (DKD) reflected by the urinary profiles of the inflammatory proteome.

Methods

We conducted a nested case-control study comprising a discovery panel of Joslin subjects with T1D and a validation panel of Joslin subjects with T2D (total n=112). All study subjects had an overt DKD at baseline (CKD stage 3-4 and albuminuria (median GFR: 46 mL/min/1.73m²; median ACR: 653). Subjects experiencing renal function loss of eGFR > 40% within 5 years were defined as progressive DKD cases. 194 inflammatory proteins were measured in baseline urine samples using aptamer proteomics (SOMAscan).

Results

In the multivariate screen we identified a urinary proteomic profile consistently associated with progressive DKD in T1D and T2D. Complement proteins (CPL) accounted for almost half of our profile (twelve out of 26 (46%); enrichment: p<0.001). Chemokines (CHK) comprised the second-most abundant group of our profile (enrichment: p=ns; Fig. A - needle plot). In the adjusted mediation model (ACR - intermediate phenotype), all 26 proteins were associated with the renal slope. The protein effects were mainly independent from albuminuria (median proportion mediated (PM): 25%). One unit change in these proteins resulted in renal function loss between 1.5-7.3 mL/min/1.73m²/yr. These proten effects markedly correlated between the T1D and T2D panels (p <10^-5; Fig. B - β estimates).

Conclusion

We have identified a significant urinary profile of the inflammatory proteome strongly associated with progressive DKD in subjects with an overt disease in both types of diabetes. Our data suggest that the complement system and chemokines seem to be important players of the disease process. Larger studies including subjects with early DKD are needed to evaluate the dynamic of these processes across DKD stages.

Funding

• Private Foundation Support