Phosphaturia in kidney stone formers: Still an enigma

Adv Clin Chem. 2019:90:133-196. doi: 10.1016/bs.acc.2019.01.004. Epub 2019 Apr 19.


Calcium kidney stones are common worldwide. Most are idiopathic and composed of calcium oxalate. Calcium phosphate is present in around 80% and may initiate stone formation. Stone production is multifactorial with a polygenic genetic contribution. Phosphaturia is found frequently among stone formers but until recently received scant attention. This review examines possible mechanisms for the phosphaturia and its relevance to stone formation from a wide angle. There is a striking lack of clinical data. Phosphaturia is associated, but not correlated, with hypercalciuria, increased 1,25 dihydroxy-vitamin D [1,25 (OH)2D], and sometimes evidence of disturbances in proximal renal tubular function. Phosphate reabsorption in the proximal renal tubules requires tightly regulated interaction of many proteins. Paracellular flow through intercellular tight junctions is the major route of phosphate absorption from the intestine and can be reduced therapeutically in hyperphosphatemic patients. In monogenic defects stones develop when phosphaturia is associated with hypercalciuria, generally explained by increased 1,25 (OH)2D production in response to hypophosphatemia. Calcification does not occur in disorders with increased FGF23 when phosphaturia occurs in isolation and 1,25 (OH)2D is suppressed. Candidate gene studies have identified mutations in the phosphate transporters, but in few individuals. One genome-wide study identified a polymorphism of the phosphate transporter gene SLC34A4 associated with stones. Others did not find mutations obviously linked to phosphate reabsorption. Future genetic studies should have a wide trawl and should focus initially on groups of patients with clearly defined phenotypes. The global data should be pooled.

Keywords: 1,25-Dihydroxy vitamin D; Calcium stones; FGF23; Hypophosphatemia; NHE3; NHERF1; Na(+)/K(+)-ATPase; NaPi-2a; NaPi-2b; NaPi-2c; Paracellular diffusion; Renal proximal tubule.

Publication types

  • Review

MeSH terms

  • Fibroblast Growth Factor-23
  • Humans
  • Hydrogen-Ion Concentration
  • Hypophosphatemia, Familial / metabolism*
  • Kidney Calculi / metabolism*