Kidney Week

Abstract: FR-PO1018

Urinary Phosphate Contributes to Kidney Injury, Cyst Formation, and Inflammation

Session Information

• CKD Mechanisms: From Mendel to Mars
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania 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,

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

Timothy A. Fields,

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

Jason R. Stubbs,

Background

High dietary phosphate intake increases urinary phosphate excretion and has been associated with an increased risk for chronic kidney disease (CKD) progression. We hypothesize that high dietary phosphate hastens CKD progression by stimulating tubular nanocrystal formation, epithelial cell injury, microcyst formation, and inflammation when concentrations of phosphate exceed supersaturation in tubular fluid; however, the mechanisms driving this relationship remain poorly defined.

Methods

First, a mouse model of cystic kidney disease, the Pkd1^RC/RC mouse, was fed a high versus low phosphate diet and analyzed for changes in kidney cyst growth, mineral deposition, tubular injury, inflammation, and fibrosis. Second, NaPi2a^-/- mice, a model of primary urinary phosphate wasting, was evaluated to determine the direct effect of urinary phosphate excretion on mechanisms of kidney injury and inflammation.

Results

Pkd1^RC/RC mice fed a high phosphate diet exhibited more rapid cyst growth and increased deposition of phosphate-based crystals in their kidneys compared to mice fed a low phosphate diet. Mineral deposits in these kidneys were spatially colocalized with macrophages and osteopontin, a matricellular protein that is critical for maintaining urinary phosphate solubility. Moreover, gene expression for markers of kidney injury, inflammation, and fibrosis were increased in Pkd1^RC/RC mice on a high phosphate diet. In separate studies utilizing NaPi2a^-/- mice, phosphaturic mutants exhibited extensive kidney crystal deposition, reduced kidney function, as well as increased gene expression for markers of kidney injury, inflammation, and fibrosis compared to wild-type controls. Separate analysis of electron microscopy in wild type mice on a high phosphate diet showed interaction of phagocytic cells with kidney mineral deposits.

Conclusion

Increased urinary phosphate excretion directly contributes to tubular injury, kidney cyst growth, inflammation, and fibrosis in CKD. Current evidence suggests a direct interaction between phosphate-based nanocrystals and local inflammatory cells may be a primary contributor to this relationship.

Funding

• NIDDK Support