, Volume 47, Issue 1, pp 23–33 | Cite as

Calcium-sensing receptor: evidence and hypothesis for its role in nephrolithiasis

  • Giuseppe VezzoliEmail author
  • Lorenza Macrina
  • Giulia Magni
  • Teresa Arcidiacono
Invited Review


Calcium-sensing receptor (CaSR) is a plasma-membrane G protein-coupled receptor activated by extracellular calcium and expressed in kidney tubular cells. It inhibits calcium reabsorption in the ascending limb and distal convoluted tubule when stimulated by the increase of serum calcium levels; therefore, these tubular segments are enabled by CaSR to play a substantial role in the regulation of serum calcium levels. In addition, CaSR increases water and proton excretion in the collecting duct and promotes phosphate reabsorption and citrate excretion in the proximal tubule. These CaSR activities form a network in which they are integrated to protect the kidney against the negative effects of high calcium concentrations and calcium precipitates in urine. Therefore, the CaSR gene has been considered as a candidate to explain calcium nephrolithiasis. Epidemiological studies observed that calcium nephrolithiasis was associated with polymorphisms of the CaSR gene regulatory region, rs6776158, located within the promoter-1, rs1501899 located in the intron 1, and rs7652589 in the 5′-untranslated region. These polymorphisms were found to reduce the transcriptional activity of promoter-1. Activating rs1042636 polymorphism located in exon 7 was associated with calcium nephrolithiasis and hypercalciuria. Genetic polymorphisms decreasing CaSR expression could predispose individuals to stones because they may impair CaSR protective effects against precipitation of calcium phosphate and oxalate. Activating polymorphisms rs1042636 could predispose to calcium stones by increasing calcium excretion. These findings suggest that CaSR may play a complex role in lithogenesis through different pathways having different relevance under different clinical conditions.


Calcium nephrolithiasis Calcium-sensing receptor Claudin-14 Claudin-16 Randall’s plaque Calcium stones Gene polymorphism Hypercalciuria 



Parathyroid hormone


Calcium-sensing receptor


1,25-dyhydroxyvitamin D


Protein kinase C


G protein-coupled receptor




Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All studies reported in the present article and involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments.


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Nephrology and Dialysis Unit, Postgraduate School of Nephrology, IRCCS San Raffaele Scientific InstituteVita Salute UniversityMilanItaly

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