The role of Tamm-Horsfall glycoprotein and Nephrocalcin in calcium oxalate monohydrate crystallization processes

Abstract

Theoretical considerations as well as clinical observations suggest that the aggregation of nucleated crystals is the most dangerous step in the formation of calcium oxalate (CaOx) renal stones. The effects of 2 major urinary glycoproteins, Tamm-Horsfall glycoprotein (THP) and Nephrocalcin (NC), on calcium oxalate monohydrate (COM) crystal aggregation in vitro are studied. At low ionic strength (IS) and high pH (within urinary limits), THP is a powerful crystal aggregation inhibitor (90% inhibition at 40 mg/l). Decreasing pH to 5.7 and raising IS to 0.21 increases TRP viscosity, thereby lowering THP crystal aggregation inhibition. Upon addition of calcium (5 mmol/l), some THPs are no more soluble and promote crystal aggregation (up to 70%). In the presence of citrate (5 mmol/l), which is only slightly inhibitory (14%), the promoting effect of THP is reversed into aggregation inhibition (up to 55%). There is evidence for a molecular abnormality in THPs from severe recurrent CaOx stone formers, since they exhibit increased polymerization and reduced solubility. The 14 kD (kilodalton), Gla-containing glycoprotein NC also strongly inhibits crystal aggregation. However, NC isolated from urines of recurrent CaOx stone formers and from CaOx renal stones are 10 times less inhibitory. Both are structurally abnormal in that they lack Gla and are less amphophilic.