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Abstract: SA-PO365

Urine Proteomic Profiling and Insights into CKD Progression in Children

Session Information

  • Pediatric Nephrology - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1900 Pediatric Nephrology

Authors

  • Greenberg, Jason Henry, Yale University, New Haven, Connecticut, United States
  • Lee, Arthur, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Coresh, Josef, Johns Hopkins University, Baltimore, Maryland, United States
  • Warady, Bradley A., Children's Mercy Kansas City, Kansas City, Missouri, United States
  • Ix, Joachim H., University of California San Diego, La Jolla, California, United States
  • Furth, Susan L., The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Denburg, Michelle, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Background

Chronic kidney disease (CKD) progresses to end stage kidney disease (ESKD) and is associated with mortality rates that are 30-150 times higher than in the general pediatric population. We hypothesized that large scale proteomic measurements may provide insights to the molecular basis of CKD progression in children and may identify therapeutic protein targets.

Methods

In the CKiD Cohort Study, children with CKD were enrolled and eGFR was assessed annually. Among participants with an eGFR of 60-90 ml/min/1.73m2 at baseline, 22 CKiD participants with CKD progression were matched by subtype of kidney disease to 22 CKiD participants without CKD progression. The primary outcome of CKD progression was defined as a composite of 50% decline in eGFR or ESKD. We measured 2904 urine proteins collected at the 6 month visit after enrollment using the Olink Proteomics Explore Assay.

Results

Of the 44 children included, the median age was 12 years, 66% were male, 68% had a glomerular cause of CKD, and baseline eGFR was 68 [IQR, 63, 81] ml/min/1.73m2. In the full cohort, 38/2904 proteins were statistically significantly different (p-value cutoff of 0.000017 using the Bonferroni correction) when comparing those with CKD progression to those without CKD progression (Table). B-cell activating factor, Complement 2 (C2), and C5, all druggable targets, were more than 10-fold higher in children with CKD progression relative to those without progression. Pathway analyses demonstrated that TGF-β1, TNF, IL-1β, IL-4, IFN-γ, and angiotensinogen were key pathways activated in children with CKD progression.

Conclusion

Many urine proteins were elevated, and pro-inflammatory and pro-fibrotic pathways were upregulated in children with CKD progression. The application of large-scale proteomics to the study of CKD in children may inform pathomechanisms and identify new therapeutic targets.

Top proteins of CKD progression by adjusted p-value using the Olink Proteomic Assay

Funding

  • NIDDK Support