Kidney Week

Abstract: TH-PO1174

Urinary Phosphate Promotes Kidney Injury and Cyst Growth

Session Information

• CKD: Mechanisms, AKI, and Beyond - 1
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Jansson, Kyle, The University of Kansas Medical Center, Kansas City, Kansas, United States

Kyle Jansson, MD, PhD

• Zhang, Shiqin, The University of Kansas Medical Center, Kansas City, Kansas, United States

Shiqin Zhang, PhD

• Fields, Timothy A., The University of Kansas Medical Center, Kansas City, Kansas, United States

Timothy A. Fields, MD, PhD

• Wallace, Darren P., The University of Kansas Medical Center, Kansas City, Kansas, United States

Darren P. Wallace, PhD

• Stubbs, Jason R., The University of Kansas Medical Center, Kansas City, Kansas, United States

Jason R. Stubbs, MD

Background

High dietary phosphate and elevated levels of fibroblast growth factor 23 (FGF23) predict polycystic kidney disease (PKD) progression; however, the mechanisms for these relationships remain undefined. A common feature of these scenarios is high tubular phosphate concentrations that favor toxic calcium-phosphate crystal formation. To date, no studies have examined the direct contribution of phosphaturia to PKD progression.

Methods

First, we analyzed NaPi2a^-/- mice, a model of urinary phosphate wasting, to determine if urinary phosphate can independently stimulate kidney injury, inflammation, and fibrosis. Next, we investigated how dietary phosphate impacted kidney cyst growth in Pkd1^RC/RC mice. Then, to evaluate the specific role of urinary phosphate on PKD progression we bred Pkd1^RC/RC mice to NaPi2a mutant mice to generate Pkd1^RC/RC mice with and without enhanced phosphaturia. Finally, to define the relevance to human disease, we conducted micro-computed tomography (µCT) analysis of human PKD and control kidneys to assess the prevalence of sub-clinical tissue mineral deposition.

Results

NaPi2a^-/- mice exhibited extensive kidney crystal deposition, reduced kidney function, tubular microcyst formation, and increased gene expression for markers of kidney injury, inflammation, and fibrosis compared to wild-type controls. Pkd1^RC/RC mice on high phosphate diet had acceleration of cyst growth and exhibited phosphate-based crystal deposits that colocalized with macrophages. Moreover, gene expression for markers of kidney injury, inflammation, and fibrosis were increased in Pkd1^RC/RC mice fed a high phosphate diet. Induction of phosphaturia by NaPi2a deletion in Pkd1^RC/RC mice led to accelerated cyst growth and reduced kidney function compared to Pkd1^RC/RC non-phosphaturic controls. Finally, µCT analysis of human kidneys showed consistently higher mineral deposition in PKD kidneys compared to non-cystic controls.

Conclusion

Urinary phosphate excretion directly contributes to tubular injury, early cyst growth, inflammation, and kidney fibrosis. Chronic phosphaturia, from either dietary or genetic manipulation, hastens cystic kidney disease progression in PKD mice and leads to kidney mineral retention that may activate local innate immune responses. Human PKD kidneys exhibit consistent microcrystal deposition, suggesting direct relevance of our findings to human disease.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025xr4r2tbw