Kidney Week

Abstract: TH-PO235

Longitudinal Changes (Deltas) of Circulating Proteins During Fast Progression to ESKD in Diabetes: Results of a Global Proteomics Study

Session Information

• Diabetic Kidney Disease: Clinical - I
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Kobayashi, Hiroki, Research Division, Joslin Diabetes Center, Boston, United States

Hiroki Kobayashi,

• Looker, Helen C., Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phenix, Arizona, United States

Helen C. Looker,

• Satake, Eiichiro, Research Division, Joslin Diabetes Center, Boston, Massachusetts, United States

Eiichiro Satake,

• Nelson, Robert G., Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phenix, Arizona, United States

Robert G. Nelson,

• Krolewski, Andrzej S., Research Division, Joslin Diabetes Center, Boston, Massachusetts, United States

Andrzej S. Krolewski,

Background

We recently showed that approximately 6-10% of patients with diabetes have fast progressive kidney function decline (FPKD) that leads to ESKD from normal kidney function within 2-15 years. However, the disease processes underlying FPKD is not well understood. Similarly, the way to identify patients at risk of FPKD is unknown. This study aims to answer this question by examining longitudinal changes (referred to as DELTAs) in concentration of circulating proteins associated with FPKD.

Methods

Using the OLINK proteomics platform, we measured concentration of 452 proteins at baseline and at follow-up (median interval 3-4 years apart) in two cohorts of patients with diabetes and normal kidney function at baseline. These participants were followed for 7 to 15 years. The Joslin Cohort had 106 T1D patients; 47 developed ESKD. The Pima Indians Cohort had 77 patients with T2D; 37 developed ESKD. We evaluated the association of DELTAs (expressed as % change from baseline value/year) with progression to ESKD using logistic regression model.

Results

In both cohorts, DELTAs for the same 74 circulating proteins were robustly associated with fast progression to ESKD. The set of 74 proteins was significantly enriched for tumor necrosis factor (TNF) receptors (p<0.001) and immunoregulatory receptors (p<0.001) and was depleted of proteins classified as enzymes (p<0.001). DELTAs for four of these proteins CD27 (TNF-R7), TNF-R2, SIRPB1 and LAYN predicted ESKD with power similar to DELTAs for eGFR and UACR. The C-statistics for the clinical model was 0.879 and increased to 0.921 - 0.924 when combined with these proteins.

Conclusion

In conclusion, the disease process underlying fast progression to ESKD in diabetes manifests as increased circulation of multiple TNF and other receptors but no other proteins. Measuring DELTAs of the four proteins can be used to monitor fast progression to ESKD in addition to current clinical markers, such as eGFR.

Funding

• Other NIH Support