NDT Advance Access originally published online on October 25, 2005
Nephrology Dialysis Transplantation 2006 21(2):361-369; doi:10.1093/ndt/gfi211
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Clinical Nephrology
Therapeutic action of citrate in urolithiasis explained by chemical speciation: increase in pH is the determinant factor
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Correspondence and offprint requests to: Prof. Allen Rodgers, Department of Chemistry, University of Cape Town, Rondebosch, South Africa 7701. Email: allenr{at}science.uct.ac.za
Background. The therapeutic action of citrate in the management of calcium oxalate urolithiasis has been attributed to the depletion of free calcium ions by complexation of the latter by citrate itself. However, little attention has been given to the nature of such complexes and the chemical conditions which control their formation because it is very difficult to measure them in solution. We therefore modelled the theoretical formation of these complexes in urine following administration of a citrate-containing preparation, using a powerful speciation program, JESS (Joint Expert Speciation System), which has been widely used to model metal–ligand equilibria in biological systems but which has hitherto not been applied in urolithiasis research. This program has an extensive database of thermodynamic constants and is able to calculate mixed ligand speciation.
Methods. Urine data obtained before and after citrate administration in four groups of subjects (male and female normals and stone formers) were used as input for JESS to calculate the speciation of calcium, citrate and oxalate. The program was also used to examine the effects of varying different urinary components on the nature and concentration of the various species.
Results. The speciation predicted the formation of a key calcium–citrate–phosphate species (previously unreported in urolithiasis research), which accounts for a significant percentage of the complexation of the free calcium. Moreover, the formation of this complex was found to be dependent on an increase in urinary pH rather than on an increase in urinary citrate concentration per se.
Conclusion. The therapeutic action of citrate in the management of calcium oxalate urolithiasis is due to the formation of a pH dependent calcium–citrate–phosphate complex which reduces the concentration of the free calcium ion species, thereby reducing the risk of stone formation.
Keywords: chemical speciation in urine; urinary calcium–citrate complexes; urinary pH; urolithiasis management
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