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Abstract: PO0979

Cellular Proteomic Phenotypes Underlying Plasma Signature of 10-Year Risk of Kidney Failure

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Moon, Salina, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Donsky, Heather L., Joslin Diabetes Center, Boston, Massachusetts, United States
  • Rosas, Sylvia E., Joslin Diabetes Center, Boston, Massachusetts, United States
  • Dillon, Simon T., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Niewczas, Monika A., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

A robust circulating proteomic signature of 10-year risk of kidney failure (KRIS) in a large prospective three-diabetes cohort study was recently identified (Niewczas et al, Nat Med 2019), but the source of the KRIS proteins remains unknown. Therefore, we aimed to evaluate potential contributions of the peripheral blood mononuclear cells (PBMC) and its subset, CD14, to the KRIS in a proteome-wide fashion.

Methods

Our study group consisted of a sample of Joslin Kidney Study participants with Type 2 Diabetes (n=16) with an average eGFR of 59±23 mL/min/1.73m2 and median albuminuria of 57 (8, 312) at baseline. Within a median of 12 years, our study group experienced a median annual renal function decline of -1.4 (-2.6, -0.5) mL/min/1.73m2/yr. We obtained PBMC and CD14 lysates using cell density and immunomagnetic separation techniques. Cell lysate samples were subjected to aptamer proteomics (1305 proteins).

Results

In the targeted evaluation, six out of 17 KRIS proteins in PBMC lysates associated significantly with the top KRIS protein in plasma (TNFR1 PBMC:β: 3.4, p=0.003) (Fig. 1A). TNFRSF members and IL17F accounted for most of these associations. TNFR1 PBMC was also associated with the renal slope (TNFR1 PBMC:β: -7.6, p=0.025) (Fig.1B). In the untargeted evaluation, 68 proteins were associated with the renal slope (MAPKAPK3, ILT-2, and IL17R, among others). CD14 cellular KRIS patterns did not robustly associate with the phenotypes of our interest.

Conclusion

Our pilot study suggests potential contributions of the PBMC to the plasma KRIS that requires validation in a larger population. We also demonstrate the potential for biomarker and novel drug target discoveries using an approach that relies on the proteomics in white blood cell subpopulations.