Kidney Week

Abstract: TH-PO485

Renal Uric Acid Crystals Trigger Cystogenesis and CKD in 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

• Holznecht, Nickolas J., University of California Santa Barbara, Santa Barbara, California, United States

Nickolas J. Holznecht, MS

• Strubl, Sebastian, University of California Santa Barbara, Santa Barbara, California, United States

Sebastian Strubl, MD

• Torres, Jacob A., University of California Santa Barbara, Santa Barbara, California, United States

Jacob A. Torres, PhD

• Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Peter C. Harris, PhD

• Mueller, Roman-Ulrich, Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany

Roman-Ulrich Mueller, MD

• Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States

Thomas Weimbs, PhD

Background

We have reported that renal tubular calcium oxalate crystals trigger transient tubule dilation in normal kidneys facilitating their excretion. In ADPKD kidneys, the same reno-protective mechanism triggers cystogenesis and worsen disease progression. Since hyperuricemia and uric acid (UA) kidneys stones are common in individuals with ADPKD, we investigated the impact of UA crystals on disease progression in a novel, orthologous heterozygous (Pkd1^+/-) rat model that is genetically identical to human ADPKD.

Methods

Pkd1^+/+ and Pkd1^+/- rats were treated with UA and the uricase inhibitor oxonic acid for 14 days followed by a washout period for 56 days. To investigate the preventative and therapeutic potential, respectively, of treatment with beta-hydroxybutyrate (BHB) and citrate, we treated rats with BHB/citrate either concurrently during UA challenge, or for 28 days at the end of the washout period.

Results

Challenging Pkd1^+/- rats with hyperuricemia diet leads to tubular UA crystal deposition which triggers cystogenesis and ongoing, progressive PKD as well as an acute inflammatory response (neutrophils, macrophages) that transitions into chronic inflammation, fibrosis, and cystic progression in Pkd1^+/- rats. In contrast, Pkd1^+/+ rats recover after UA crystal clearance. Concurrent treatment with BHB/citrate prevents UA crystal deposition. Treatment with BHB/citrate after the UA washout leads to regression of inflammation, fibrosis and cystogenesis.

Conclusion

In contrast to all other existing PKD rodent models, our novel, orthologous, heterozygous Pkd1^+/- rat model closely resembles human ADPKD patients (PKD1^+/-). We show that crystal injury triggers de-novo cystogenesis in Pkd1^+/- rats that otherwise do not develop PKD. Therefore, a second-hit genetic mutation is not necessary for cystogenesis. Rather, a specific renal injury controlled by diet, such as hyperuricemia-induced UA crystals, can trigger PKD onset and progression in a heterozygous context. Our results have immediate clinical implications and suggest that avoidance of renal injury triggers is critical for the management of ADPKD. Furthermore, BHB/citrate treatment is promising as a preventative measure and as a disease-modifying therapy.

Funding

• Private Foundation Support