Abstract: FR-PO249
Raising Serum Uric Acid With a Uricase Inhibitor Worsens Polycystic Kidney Disease in Rat and Mouse Models
Session Information
- Genetic Diseases of the Kidneys: Cystic - II
November 04, 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
- Atwood, Daniel, Istanbul Universitesi Istanbul Tip Fakultesi, Istanbul, Istanbul, Turkey
- Oto, Ozgur Akin, Istanbul Universitesi Istanbul Tip Fakultesi, Istanbul, Istanbul, Turkey
- Chaudhary, Anjana, Istanbul Universitesi Istanbul Tip Fakultesi, Istanbul, Istanbul, Turkey
- Edelstein, Charles L., Istanbul Universitesi Istanbul Tip Fakultesi, Istanbul, Istanbul, Turkey
Background
Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. In rodents uricase converts uric acid to allantoin and uricase inhibition raises serum uric acid. The aim of the study was to determine whether raising serum uric acid with the uricase inhibitor oxonic acid (OXO) was associated with worse PKD.
Methods
Orthologous models of human PKD were used. PCK rats, a Pkhd1 gene model of ARPKD and Pkd1RC/RC (RC) mice, a hypomorphic Pkd1 gene model. OXO 750 mg/kg by mouth in rats from day 21-84 of age and 300 mg/kg IP in mice from day 50-120 of age was used. Uric acid and allantoin were measured by LC/MS-MS. Creatinine was measured by HPLC. Males and females were analyzed together. 12 pro-inflammatory cytokines were measured by MesoScale technology.
Results
On IHC staining, xanthine oxidase (that converts xanthine to uric acid) was strongly present in normal tubules in PCK rats. In pharmacokinetic studies in rats, there was a 5 -fold increase in serum uric acid 2 hrs after OXO 100 mg/kg (IP or orally), that returned to normal in 8 hrs. OXO resulted in decreased allantoin in PCK rats. In PCK rats and RC mice, OXO resulted in a significant increase in serum uric acid, 2 kidney/body weight ratio (2K/BW) (%), cyst index (% of kidney that was cystic on cross sections) and creatinine (Table). OXO resulted in an increase in pro-inflammatory cytokines in the serum in RC mice.
Conclusion
Increasing serum uric acid by inhibiting uricase with OXO results in an increase in kidney weight, cyst index, creatinine in PCK rats and RC mice Potential mechanisms of increased cyst growth that will be investigated include crystal deposition causing tubular dilatation, increased reactive oxygen radicals and pro-inflammatory cytokines/chemokines causing tubular cell proliferation and endothelial injury.
| PCK VEH | PCK OXO | P Value | RC VEH | RC OXO | P Value | |
| Uric acid (µM) | 22 | 27 | <0.05 | 20.1 | 30.7 | 0.17 |
| Allantoin (µM) | 4.3 | 3.1 | <0.05 | N/A | N/A | N/A |
| 2K/BW (%) | 0.86 | 0.96 | <0.05 | 1.8 | 2.1 | <0.05 |
| Cyst index (%) | 8 | 14 | <0.05 | 6 | 10 | <0.05 |
| Creatinine (mg/dL) | 1.1 | 1.3 | 0.07 | 0.07 | 1.0 | <0.05 |
| IFN-γ/IL-5/TNF-α (mg/dL) | N/A | N/A | N/A | 0.1/1.6/2.8 | 0.4/5.6/4.1 | 0.06 |
Funding
- Veterans Affairs Support – XORTX Therapeutics Inc