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Kidney Week

Abstract: SA-OR27

Urinary Complement Proteome and 10-Year Risk of ESKD in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Moon, Salina, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Md Dom, Zaipul I, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Abedini, Amin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Dillon, Simon T., Harvard Medical School, Boston, Massachusetts, United States
  • Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Niewczas, Monika A., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

Our pilot urinary inflammatory proteomics identified enrichment in the Complement system in subjects with progressive diabetic kidney disease (DKD). Thus, we aimed to comprehensively evaluate the Complement proteome reflected by: i) relationships of urinary profiles with prospective ESKD risk, and ii) kidney tissue expressions in DKD.

Methods

Our prospective cohort study comprised 371 Joslin Kidney Study subjects with Type 1 (T1D) or Type 2 (T2D) Diabetes and an overt DKD (mean eGFR 45 mL/min/1.73m2, ACR 1,075 mg/g). Our main outcome was 10-year ESKD risk. We measured 82 Complement proteins in baseline urine with aptamer proteomics; 8 were validated by quantitative immunoassays. We evaluated kidney tissue expressions of the Complement system with aptamer proteomics in 23 subjects with an overt DKD and 10 controls.

Results

160 (43%) subjects developed ESKD in 10 years. Multiple Complement proteins were associated with ESKD risk in Bonferroni-adjusted Cox models (risk per tertile change of the top protein, C5a: HR 4.2, p<10-23; Fig. A). Cumulative 10-year risk for subjects with low levels of the top proteins built into Principal Component-based tertiles (PC) was 18%, vs. 78% for those with high levels (Fig. B). Accuracy of biostatistical and machine learning models built on the top proteins ranged from c=0.85 to 0.87. Quantitative measurements correlated with proteomics measurements and our outcome (median CFH in ESKD progressors: 214 vs. non-progressors: 8 ng/mg; p<10-14). Of the top 10 urinary Complement proteins, 5 had increased renal expressions in subjects with DKD compared to controls. Renal expression of C3a featured the highest fold change, and CFH had the most significant association (Fig. C).

Conclusion

This study revealed robust associations of the urinary Complement proteome with 10-year risk of ESKD in subjects with T1D and T2D, with select correspondence in kidney protein expressions. These findings strongly suggest that the Complement system is an important driver of DKD progression.

Funding

  • Other NIH Support