Abstract: TH-PO406
Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Predicts Disease Progression in Polycystic Kidney Disease
Session Information
- Genetic Diseases of the Kidneys: Cystic - I
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1101 Genetic Diseases of the Kidneys: Cystic
Authors
- van Heugten, Martijn H., Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
- Blijdorp, Charles J., Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
- Meijer, Esther, Universiteit Groningen Faculteit Medische Wetenschappen, Groningen, Groningen, Netherlands
- Zietse, Robert, Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
- Salih, Mahdi, Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
- Gansevoort, Ron T., Universiteit Groningen Faculteit Medische Wetenschappen, Groningen, Groningen, Netherlands
- Hoorn, Ewout J., Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
Background
Autosomal dominant polycystic kidney disease (ADPKD) has a highly variable rate of disease progression, and currently available biomarkers are unable to adequately identify high risk patients. Our aim was to identify a protein biomarker in urinary extracellular vesicles (uEVs) which can be non-invasively measured to differentiate rapid from slow disease progression.
Methods
Patients were selected from the clinical DIPAK trial. We created a discovery (n=10) and confirmation cohort (n=10) including patients with rapid and slow disease progression (eGFR decline ≥4 or < 2 mL/min/1.73 m2/year). uEVs were isolated from 50 mL spot urines by a three-step differential ultracentrifuge protocol, and uEV-proteins were quantified by mass tag labeled and tandem mass spectrometry. A third validation cohort (n=24) was created to validate the mass spectrometry findings with immunoblotting. All patients were matched for established risk factors for disease progression, including age, sex, baseline eGFR, and genetic mutation, and had equal height adjusted total kidney volume.
Results
We identified 2,727 and 1,115 unique uEV-proteins with over 60% annotated for the extracellular exosome (Benjamini p < 0.01). In the discovery and confirmation cohort, a significantly different uEV-protein abundance was found for 65 and 36 proteins, respectively. Matrix metalloproteinase 7 (MMP-7), a protein previously implicated in kidney disease progression in ADPKD, was consistently higher by 47% and 64% in patients with rapid disease progression in both cohorts (p < 0.05). Pathway analysis showed enrichment of Wnt-signaling (q-value < 0.05) of which MMP-7 is a downstream mediator. In the validation cohort, MMP-7 was also higher by 120% in uEVs of patients with rapid disease progression (p < 0.05).
Conclusion
uEV-associated MMP-7 distinguishes patients with slow or rapid ADPKD progression independently of established disease progression markers. MMP-7 is a novel and biologically plausible urinary biomarker for ADPKD which we are currently validating in a larger cohort of patients using a high-throughput assay.
Funding
- Private Foundation Support