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Abstract: TH-PO913

Proteomic Study of Circulating Proteins to Identify Novel Surrogate Markers for Progressive Renal Decline

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Skupien, Jan, Jagiellonian University Medical College, Krakow, Poland
  • Ihara, Katsuhito, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • Md Dom, Zaipul I, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • O'Neil, Kristina V., Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
  • Krolewski, Andrzej S., Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
Background

Clinical trials of renoprotection in diabetic nephropathy have been limited to high-risk patients with impaired renal function due to low incidence of clinical and traditional surrogate end-points. End-points based on serum creatinine may be affected by its high variation, especially in patients with normal renal function. No efficient trial design exists to test early interventions in moderate-risk patients with eGFR > 60 ml/min.

Methods

We followed 196 patients (44% female) with type 1 diabetes from Joslin Proteinuria Cohort (median albumin/creatinine ratio 852 mg/g) with normal baseline renal function (median eGFR 100 ml/min). During median 10 years of follow-up there were 110 cases of end-stage renal disease (ESRD) and 15 deaths. We quantified 455 proteins in baseline plasma samples using OLINK (Uppsala, Sweden) Proximity Extension Assay. In 110 patients we measured these proteins in a second sample collected after median 4 years of follow-up. Annualized proteins' increments (DELTAs) were tested as surrogate of ESRD using Cox regression models.

Results

In regression models adjusted for the change in eGFR the DELTAs of 13 proteins were significantly (Bonferroni-corrected) associated with time to ESRD. Also, their baseline concentrations were associated with time to ESRD independently from baseline eGFR (see Table). Prediction of time to ESRD was much more accurate with DELTAs of these proteins than with the change in eGFR (for example C-statistic for LAYN was 0.85 versus 0.78 for eGFR).

Conclusion

Serial measurements of circulating protein markers during a short follow-up are more accurate in ESRD prediction than measurements of creatinine-based eGFR. Surrogate outcomes derived from these candidate proteins may help designing efficient clinical trials. Replication of the findings in independent cohorts is under way.

Candidate surrogate outcome proteins, adjusted for baseline eGFR and DELTA of eGFR

Funding

  • NIDDK Support