Abstract: SA-PO132

Systems Biology Identified Molecular Pathways and Biomarkers Associated with Diabetic Kidney Disease Progression

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Mulder, Skander, University Medical Center Groningen, Groningen, Netherlands
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Sas, Kelli M., University of Michigan, Ann Arbor, Michigan, United States
  • Lambers Heerspink, Hiddo Jan, University Medical Center Groningen, Groningen, Netherlands
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Understanding of molecular pathways involved in the initiation and progression of DKD facilitates biomarker development and drug target identification. We aim to identify molecular pathways associated with progressive loss of kidney function in both early and advanced stages of DKD.

Methods

We included 810 patients with early DKD from the DIRECT-2 trial (eGFR 69 ±11ml/min/1.73m2 and normoalbuminuria) and 911 patients with advanced DKD from SUN-Macro (eGFR 33 ±10 and macroalbuminuria). Baseline urine proteomics, serum metabolomics and proteins were mapped to intra-renal transcriptional profiles of DKD biopsies from the European Renal cDNA Biobank (ERCB, n=19). All molecular features were associated with the primary end point of 30% eGFR decline or ESKD (n= 288), and subsequently with the secondary endpoint of eGFR slope < -3ml/year (n=704). Ingenuity pathway analysis identified significantly enriched canonical pathways and disease networks in associated features.

Results

The systems biology integration identified canonical pathways significantly enriched in molecular features associated with renal end points in early (3 pathways), advanced (1) and both stages (5) of DKD, respectively (Figure 1). These pathways include novel (Intrinsic Prothrombin Activation) and known DKD associated pathways (NAD biosynthesis and LXR/RXR activation). Antibody based assay results confirmed 11 (10 serum, 1 urine) biomarkers to be predictive for endpoints, including MMP7, TNFR1 and Endostatin representing the 5 enriched pathways in both early and late DKD.

Conclusion

By integrating intra-renal transcriptomic data with unbiased proteomics and metabolomics we identified stage-specific and shared molecular pathways, as well as their representing biomarkers, that are associated with DKD progression in early and late stages of DKD. Our work sets the stage for investigations of these biomarkers and molecular pathways for prognostic and interventional purposes.

Figure 1:Pathways associated with disease progression in early and advanced stage DKD

Funding

  • Government Support - Non-U.S.