Kidney360 · 2026
Phosphaturia Exacerbates Tubular Injury and Cyst Formation in Polycystic Kidney Disease.
СтатьяНазвание и аннотация: Перевод в очереди
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Jansson Kyle P, Kuluva Jordan, Swanson Taylor, Zhang Shiqin, Fields Timothy A, Swenson-Fields Katherine I, Wallace Darren P, Rowe Peter S, Stubbs Jason R
Аннотация
KEY POINTS: High concentrations of tubular phosphate directly contribute to kidney mineral retention, tubular injury/inflammation, and cyst growth in mice. Human polycystic kidney disease kidneys exhibit subclinical calcium-phosphate microcrystals that may be promoting kidney pathology in this setting. Phosphaturia and kidney mineral deposition may be novel and modifiable therapeutic targets to slow polycystic kidney disease progression.
BACKGROUND: Accumulating evidence supports a direct contribution of abnormalities in phosphate homeostasis to progression of polycystic kidney disease (PKD); however, the mechanisms for these relationships remain undefined. A universal feature of nephron loss in all forms of kidney disease is increased urinary phosphate excretion by residual functional nephrons that helps to maintain systemic phosphate balance. To date, no studies have examined the direct contribution of urinary phosphate to kidney pathology in PKD.
METHODS: We first examined the impact of dietary phosphate on kidney outcomes in Pkd1RC/RC mice, an orthologous murine model of PKD. Next, to more specifically delineate the direct contribution of urinary phosphate to kidney pathology, we characterized kidney phenotypes in phosphaturic Slc34a1-/- mice. We then investigated how increasing urinary phosphate excretion through Slc34a1 deletion affected cystic kidney disease progression in Pkd1RC/RC mice. Finally, to define the relevance of our findings to human PKD, we conducted high-resolution imaging and trace mineral analysis of human PKD and control kidney specimens to assess the prevalence and composition of subclinical mineral deposition.
RESULTS: Pkd1RC/RC mice fed a high phosphate diet exhibited kidney injury with activation of early fibrosis pathways, accelerated cyst growth, and phosphate-based crystal deposition that spatially colocalized with macrophages. Slc34a1-/- mice demonstrated extensive nephrocalcinosis, tubular microcyst formation, and evidence of early kidney injury, inflammation, and fibrosis. Moreover, compound mutant Pkd1RC/RC , Slc34a1-/- mice had increased kidney cyst burden accompanied by reduced kidney function compared with Pkd1RC/RC , Slc34a1+/+ controls. Finally, micro-computed tomography and trace mineral analyses of human kidneys revealed consistent deposition of calcium-phosphate microcrystals in PKD kidneys.
CONCLUSIONS: Increased urinary phosphate excretion directly contributes to kidney injury, cyst formation/growth, inflammation, and fibrosis. Urinary phosphate excretion and tubular mineral solubility may represent novel therapeutic targets for slowing PKD progression in humans.
BACKGROUND: Accumulating evidence supports a direct contribution of abnormalities in phosphate homeostasis to progression of polycystic kidney disease (PKD); however, the mechanisms for these relationships remain undefined. A universal feature of nephron loss in all forms of kidney disease is increased urinary phosphate excretion by residual functional nephrons that helps to maintain systemic phosphate balance. To date, no studies have examined the direct contribution of urinary phosphate to kidney pathology in PKD.
METHODS: We first examined the impact of dietary phosphate on kidney outcomes in Pkd1RC/RC mice, an orthologous murine model of PKD. Next, to more specifically delineate the direct contribution of urinary phosphate to kidney pathology, we characterized kidney phenotypes in phosphaturic Slc34a1-/- mice. We then investigated how increasing urinary phosphate excretion through Slc34a1 deletion affected cystic kidney disease progression in Pkd1RC/RC mice. Finally, to define the relevance of our findings to human PKD, we conducted high-resolution imaging and trace mineral analysis of human PKD and control kidney specimens to assess the prevalence and composition of subclinical mineral deposition.
RESULTS: Pkd1RC/RC mice fed a high phosphate diet exhibited kidney injury with activation of early fibrosis pathways, accelerated cyst growth, and phosphate-based crystal deposition that spatially colocalized with macrophages. Slc34a1-/- mice demonstrated extensive nephrocalcinosis, tubular microcyst formation, and evidence of early kidney injury, inflammation, and fibrosis. Moreover, compound mutant Pkd1RC/RC , Slc34a1-/- mice had increased kidney cyst burden accompanied by reduced kidney function compared with Pkd1RC/RC , Slc34a1+/+ controls. Finally, micro-computed tomography and trace mineral analyses of human kidneys revealed consistent deposition of calcium-phosphate microcrystals in PKD kidneys.
CONCLUSIONS: Increased urinary phosphate excretion directly contributes to kidney injury, cyst formation/growth, inflammation, and fibrosis. Urinary phosphate excretion and tubular mineral solubility may represent novel therapeutic targets for slowing PKD progression in humans.