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Abstract: TH-PO171

Circulating Proteins Protect Against Fast Kidney Function Decline and ESKD in Early Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 702 Diabetic Kidney Disease: Clinical

Authors

  • Md Dom, Zaipul, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Looker, Helen C., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
  • Satake, Eiichiro, Joslin Diabetes Center, Boston, Massachusetts, United States
  • Nelson, Robert G., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
Background

We recently identified circulating protective proteins against ESKD and kidney function decline in advanced diabetic kidney disease (DKD) (Md Dom et al. Sci Transl Med 2021). Proteins that protect against kidney failure/decline in early stages of DKD will further complement and offer valuable insights into underlying mechanisms.

Methods

We followed 294 subjects (45% female) with T1D from Joslin Proteinuria Cohort (median uACR 491 mg/g) with normal baseline kidney function (median eGFR 100 ml/min). We conducted a replication study in an independent cohort of 162 Pima Indians with T2D and very early stage of DKD (median GFR 149 ml/min); 105 subjects had research kidney biopsies obtained in close proximity to baseline examination. We quantified 550 proteins in baseline plasma samples using the SOMAscan platform.

Results

In the Joslin cohort, 39% subjects reached the composite outcome of ESKD or 40% GFR loss within 10 years. Sixty-two (38%) of Pima subjects developed the composite outcome. In univariable logistic model, 54 proteins were significantly associated (Bonferroni-corrected) with protection against kidney failure/decline in the Joslin T1D cohort. Ten proteins were replicated in the Pima T2D cohort. Odds ratios remained significant after adjustment for key confounders. Proteins were clustered into 3 groups. A three-marker panel (FGF17, BMP10, PRLR) was derived and this panel, with added clinical parameters, significantly improved prediction of the composite outcome (c=0.852, p=0.026). BMP10 had significant positive correlations with podocyte density (r=0.30) and filtration slit frequency (r=0.21), and inverse correlations with global glomerular sclerosis (r=-0.28), mesangial fractional volume (r=-0.21) and podocyte foot process width (r=-0.20). Kidney transcriptomic profiles suggest a non-kidney source of circulating protective proteins.

Conclusion

In two independent cohorts with different types of diabetes and racial groups, we identified ten plasma proteins in early DKD associated with no/slow progression to ESKD, which may be therapeutic targets for delaying or preventing the onset of ESKD.

Funding

  • NIDDK Support