The initial and subsequent inflammatory events during calcium oxalate lithiasis

Clin Chim Acta. 2010 Aug 5;411(15-16):1018-26. doi: 10.1016/j.cca.2010.03.015. Epub 2010 Mar 27.


Background: Crystallization is believed to be the initiation step of urolithiasis, even though it is unknown where inside the nephron the first crystal nucleation occurs.

Methods: Direct nucleation of calcium oxalate and subsequent events including crystal retention, cellular damage, endocytosis, and hyaluronan (HA) expression, were tested in a two-compartment culture system with intact human proximal tubular HK-2 cell monolayer.

Results: Calcium oxalate dihydrate (COD) was nucleated and bound onto the apical surface of the HK-2 cells under hypercalciuric and hyperoxaluric conditions. These cells displayed mild cellular damage and internalized some of the adhered crystals within 18h post-COD-exposure, as revealed by electron microscopy. Prolonged incubation in complete medium caused significant damage to disrupt the monolayer integrity. Furthermore, hyaluronan disaccharides were detected in the harvested media, and were associated with HAS-3 mRNA expression.

Conclusion: Human proximal cells were able to internalize COD crystals which nucleated directly onto the apical surface, subsequently triggering cellular damage and HAS-3 specific hyaluronan synthesis as an inflammatory response. The proximal tubule cells here demonstrate that it plays an important role in facilitating urolithiasis via endocytosis and creating an inflammatory environment whereby free hyaluronan in tubular fluid can act as crystal-binding molecule at the later segments of distal and collecting tubules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Calcium / pharmacology
  • Calcium Oxalate / chemistry
  • Calcium Oxalate / metabolism*
  • Calcium Oxalate / pharmacology
  • Cell Line
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation / drug effects
  • Glucuronosyltransferase / genetics
  • Humans
  • Hyaluronan Synthases
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kidney Tubules, Proximal / pathology
  • Lithiasis / genetics
  • Lithiasis / metabolism*
  • Lithiasis / pathology


  • Calcium Oxalate
  • Glucuronosyltransferase
  • HAS3 protein, human
  • Hyaluronan Synthases
  • Calcium