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Abstract: PO0444

Novel Fibrosis Biomarker Development and Validation in Human Kidney Disease

Session Information

Category: CKD (Non-Dialysis)

  • 2101 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention

Authors

  • Schmidt, Insa Marie, Boston Univeristy Medical Center, Boston, Massachusetts, United States
  • Colona, Mia, Boston Univeristy Medical Center, Boston, Massachusetts, United States
  • Kestenbaum, Bryan R., University of Washington School of Medicine, Seattle, Washington, United States
  • Alexopoulos, Leonidas G., ProtATonce LTD, Athens, Greece
  • Palsson, Ragnar, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Srivastava, Anand, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Liu, Jing, Boston Univeristy Medical Center, Boston, Massachusetts, United States
  • Stillman, Isaac Ely, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Rennke, Helmut G., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Vaidya, Vishal S., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Wu, Haojia, Washington University in Saint Louis, Saint Louis, Missouri, United States
  • Humphreys, Benjamin D., Washington University in Saint Louis, Saint Louis, Missouri, United States
  • Waikar, Sushrut S., Boston Univeristy Medical Center, Boston, Massachusetts, United States
Background

Biomarkers for non-invasive assessment of kidney fibrosis are not available. This study illustrates the characterization of five novel candidate biomarkers of kidney fibrosis—Cadherin-11 (CDH11), Sparc-related modular calcium binding-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-gla protein (MGP), and Thrombospondin-2 (THBS-2)—which were selected from transcriptomic findings in animal models of fibrosis.

Methods

We developed Luminex-based assays and measured proteins in plasma and urine samples of two independent prospective cohort studies, the Boston Kidney Biopsy Cohort (BKBC, n=801), a cohort of individuals with biopsy-confirmed semi-quantitative assessment of kidney fibrosis, and the Seattle Kidney Study (SKS, n=252). Ordinal logistic regression and Cox proportional hazard models tested associations of biomarkers with interstitial fibrosis and tubular atrophy (IFTA) in the BKBC and progression to end-stage kidney disease (ESKD) in both cohorts, respectively. snRNA datasets of human kidneys assessed cell-specific gene expression profiles.

Results

In the BKBC, higher levels of urinary PEDF and plasma and urinary SMOC2 and CDH11 were independently associated with more severe IFTA (Figure 1). In both cohort studies, higher levels of plasma and urinary SMOC2 and urinary CDH11 associated with progression to ESKD (HR-range 1.27 to 1.89) after adjustment for age, sex, race, proteinuria, and eGFR. Higher levels of urinary PEDF were associated with ESKD in the SKS (HR=1.29, 95% CI 1.14 to 1.45), with consistent signals in the BKBC, although the latter narrowly missed statistical significance. snRNA-sequencing data demonstrated expression of all biomarkers in human fibroblasts.

Conclusion

Novel plasma and urine biomarkers of kidney fibrosis, developed from animal models, are associated with higher levels of human kidney fibrosis and subsequent progression to ESKD.

Funding

  • Private Foundation Support