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Abstract: SA-OR111

Complement System and Rapid Renal Function Decline in Type 1 (T1D) and Type 2 Diabetes (T2D) – Application of Novel SOMAscan-Based Proteomic Technology

Session Information

Category: Diabetes

  • 502 Diabetes Mellitus and Obesity: Clinical

Authors

  • Tsay, John J., Joslin Diabetes Center, Boston, Massachusetts, United States
  • Smiles, Adam, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Croall, Stephanie E., Joslin Diabetes Center, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
  • Niewczas, Monika A., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

We aimed to investigate inflammatory protein signatures in the urine associated with rapid renal function loss in subjects with diabetes.

Methods

In a case-control study of 60 subjects nested within the Joslin Kidney Study cohort of subjects with T1D, proteinuria and CKD 3 (discovery panel), we performed urinary baseline measurements of 194 inflammatory proteins using the SOMAscan platform. Subjects with a Rapid Renal Function Decline (eGFR loss >40% within 5 years) were defined as cases (n=29). Eighteen out of 29 subjects developed ESRD within this time period. Further, we performed urinary proteomic measurements in the validation panel of T2D patients. The 2nd nested case-control study group consisted of 26 T2D subjects with eGFR loss >40% within 5 years (cases); 11 of these progressed to ESRD, and 26 controls remained alive with preserved renal function during the follow-up.

Results

Six major inflammatory classes of proteins were measured within the array. We identified 26 proteins that were concordantly associated with rapid eGFR loss in the discovery panel (Bonferroni corrected nominal p value) and in the validation panel (nominal p value < 10-2 ). Candidate inflammatory proteins were particularly enriched for proteins from the complement system (χ2 = 21.5; p<0.0001). Complements C3a, C5a and factor H were among the top proteins associated with an increased renal risk.

Conclusion

In our study we identified a robust inflammatory signature enriched for proteins of the complement system that are associated with rapid renal function decline in both types of diabetes. Our findings suggest that local kidney disturbances of the complement pathway are etiologically linked to the development of kidney complications in diabetes.

Inflammatory ClassesTotal NProteins Associated with Increased Renal Risk
Chemokines416 (14.6%)
Complement System2612 (46.2%)*
Interferons20 (0%)
Interleukins603 (5%)
Tumor Necrosis Factor Family411 (2.4%)
Others244 (16.7%)
Total19426 (13.4%)
   

Funding

  • NIDDK Support