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Abstract: TH-PO437

A Serum Proteomic Study Identifies Novel Biomarkers for Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Zhou, Xia, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Li, Xiaoyan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background

ADPKD is a genetic disorder characterized by cyst growth and expansion, and inflammation and renal fibrosis leading to kidney failure. The disease course of ADPKD is highly variable depending on the gene, mutation, and other factors. Better methods to measure disease progression, such as serum biomarkers, are urgently needed in ADPKD to complement total kidney volume data.

Methods

The level of 1500 circulating proteins in serum samples from 45 ADPKD patients with an eGFR ≥ 15 ml/min/1.73m2 (4 subgroups based on eGFR, CKD1-4) and 12 healthy individuals were measured using the SOMAscan proteomics platform. Differentially expressed proteins (DEPs) were analyzed by Go and KEGG enrichment analyses. Differentially expressed genes in kidneys of Pkd1flox/flox:Pkhd1-Cre mice were identified by RNA-seq.

Results

A total of 155 proteins were upregulated and 49 proteins downregulated in patients with ADPKD and CKD3 compared to healthy individuals (p < 0.05). DEPs were associated with several signaling pathways, including cytokine-cytokine receptor interactions, TGF-β signaling, complement and coagulation cascades, TNF signaling, cancer, lipid regulation, and atherosclerosis. Potential individual serum biomarkers were identified by the following criteria: 1) more than >20% increase in CKD2 versus healthy control; 2) more than two-fold increase in CKD4 versus healthy control; and 3) the change of protein level was associated with a decline of eGFR. A total of 31 proteins were identified, including the inflammatory biomarkers (MIC-1, TNFR-I, TNFR-II, TNFRSF21, IGFBP-6, and TGF-bRIII), fibrosis biomarkers (MMP-7, MMP-3, Edostatin, WFDC2), and other biomarkers (Resistin, EPHB4, EFNB2, and CAD17). Specifically, the level of MMP-7 was increased 1.8-, 3.2-, 6-, and 8.2-fold in ADPKD patients with CKD1-4, respectively. Among the 155 upregulated and 49 downregulated proteins, the mRNA levels of 55 and 11 genes were similarly increased or decreased in mouse PKD kidneys. These results suggest that these specific upregulated and downregulated proteins are altered in the kidney and can also be tested as urinary biomarkers.

Conclusion

Our study identified several potential diagnostic biomarkers in ADPKD. The TNFR-I, TNFR-II, MMP-7, and WFDC2 have been reported as prognostic biomarkers in CKD, but the other inflammatory and fibrotic biomarkers are novel for ADPKD.

Funding

  • NIDDK Support