Kidney Week

Abstract: TH-PO484

Xanthine Oxidase in Rats, Mice, and Humans with Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• He, Zhibin, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Zhibin He, MS

• Wang, Wei, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Wei Wang, MD

• Atwood, Daniel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Daniel Atwood

• Gitomer, Berenice Y., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Berenice Y. Gitomer, PhD

• Chonchol, Michel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol, MD, FASN

• Davidoff, Allen, Xortx Therapeutics Inc, Calgary, Alberta, Canada

Allen Davidoff, PhD

• Edelstein, Charles L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Charles L. Edelstein, MD, PhD, FASN

Background

Raising uric acid (UA) worsens PKD in rodents (Edelstein, AJP, 2024). Xanthine oxidase (XO) results in the formation of uric acid and generates reactive oxygen species like H₂O₂. There is increasing evidence that increased XO in addition to UA plays role in disease.

Methods

To gain insight into whether increased XO is associated with cyst growth, XO activity was measured in PCK rats, Pkd1^RC/RC (RC) mice and 34 patients at HALT-PKD study 24 month visit. XO in rodents (iU/ug): Fluorometric assay kit that detects H₂O₂. XO in humans (ng/mL): ELISA that directly measures XO. Fast progressors (N=17) defined as increase in height corrected total kidney volume (TKV) of >7%/yr. Fast and slow progressors were matched for clinical characteristics including age, gender, Pkd1 mutation. Values=means

Results

Kidney XO was higher in PCK rats vs. RC mice (19 vs. 6, P<0.05). PCK rats: XO was lower in serum (119 vs 145, P<0.01), kidney (19 vs 34, P<0.05) and liver (1505 vs 2173, P<0.01) vs wildtype. Higher cyst index correlated with lower serum (R² 0.66, P=0.09) and kidney (R²=0.47, P=0.02) XO. RC mice: No correlation between cyst index and serum XO (R²=0.06, p=NS) or kidney XO (R²=0.06, NS). Oxypurinol decreased cyst growth (Edelstein et al. AJP, 2024) and decreased both serum UA and serum XO (91 vs. 171, p<0.05). Patients: Serum UA was higher with eGFR<60 vs >60 (8.5 vs. 6, P<0.05). Higher TKV correlated with lower eGFR (R² 0.24, P=0.008). Correlation between higher serum UA and higher total kidney volume (R²=0.02, P=0.003). Fast progressors had higher TKV (1523 vs 583, P=0.003), lower eGFR (65 vs 91, P=0.005) and higher serum UA (8.1 vs 5.5, P<0.01) than slow progressors. Serum XO activity was the same between eGFR>60 vs <60 (8.5 vs 6.3,NS). Correlation between higher serum XO and lower eGFR showed a trend (R²=0.08, P=0.07). No correlation between serum XO and TKV (R²=0.009, NS). XO activity was the same in fast and slow progressors (7.7 vs 9.2, P=NS).

Conclusion

In summary, in rodents with PKD, there was no correlation between increased serum or kidney XO activity and cyst index. In PKD patients there was a trend towards higher serum XO and lower GFR. In conclusion, serum XO needs to be measured in a larger group of patients from the HALT-PKD study.

Funding

• Commercial Support – Xortx Therapeutics inc