Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression

J Clin Invest. 2021 Aug 16;131(16):e145693. doi: 10.1172/JCI145693.


The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

Keywords: Chronic kidney disease; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Fluids / chemistry
  • Calcium Phosphates / chemistry
  • Calcium Phosphates / metabolism*
  • Cell Line
  • Crystallization
  • Diet, Western / adverse effects
  • Disease Progression
  • Endocytosis
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / blood
  • Homeostasis
  • Humans
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphates / administration & dosage
  • Phosphates / adverse effects
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / metabolism*
  • Renal Insufficiency, Chronic / pathology
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism


  • Calcium Phosphates
  • FGF23 protein, human
  • Fgf23 protein, mouse
  • Phosphates
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • calcium phosphate