Urinary Phosphate Promotes Kidney Injury and Cyst Growth

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 Pkd1RC/RC mice. Then, to evaluate the specific role of urinary phosphate on PKD progression we bred Pkd1RC/RC mice to NaPi2a mutant mice to generate Pkd1RC/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. Pkd1RC/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 Pkd1RC/RC mice fed a high phosphate diet. Induction of phosphaturia by NaPi2a deletion in Pkd1RC/RC mice led to accelerated cyst growth and reduced kidney function compared to Pkd1RC/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