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The role of Tamm-Horsfall glycoprotein and Nephrocalcin in calcium oxalate monohydrate crystallization processes
1Policlinic of Medicine, University Hospital, Berne, Switzerland.
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.
Insights
Tamm-Horsfall glycoprotein and Nephrocalcin inhibit calcium oxalate crystal aggregation, crucial for preventing kidney stones. Abnormalities in these proteins in stone formers reduce their inhibitory effectiveness.
Area of Science:
- Nephrology
- Biochemistry
- Crystallography
Background:
- Calcium oxalate (CaOx) renal stones are a common ailment.
- Crystal aggregation is a critical and dangerous step in kidney stone formation.
- Urinary glycoproteins like Tamm-Horsfall glycoprotein (THP) and Nephrocalcin (NC) are implicated in regulating crystal aggregation.
Purpose of the Study:
- To investigate the in vitro effects of THP and NC on calcium oxalate monohydrate (COM) crystal aggregation.
- To determine how urinary conditions (pH, ionic strength, calcium, citrate) influence glycoprotein activity.
- To examine structural abnormalities in THP and NC from recurrent CaOx stone formers.
Main Methods:
- In vitro studies of COM crystal aggregation.
- Varying ionic strength, pH, and concentrations of calcium and citrate.
- Analysis of THP and NC solubility and polymerization.
- Isolation and characterization of NC from patient samples.
Main Results:
- THP effectively inhibits COM aggregation at low ionic strength and high pH, but its efficacy decreases with lower pH and higher ionic strength.
- Calcium can cause some THPs to promote aggregation, while citrate reverses this effect, enhancing inhibition.
- Abnormal THPs in stone formers show increased polymerization and reduced solubility.
- NC is a potent inhibitor, but NC from stone formers is significantly less inhibitory and structurally altered (lacking Gla, less amphophilic).
Conclusions:
- THP and NC play significant roles in preventing CaOx crystal aggregation.
- Altered physicochemical conditions and molecular abnormalities in THP and NC can impair their protective functions in recurrent CaOx stone formers.
- These findings highlight potential therapeutic targets for kidney stone prevention.