In support of hydroxycitrate being clinically investigated as a potential therapy of calcium nephrolithiasis: Theoretical modelling and in vitro investigation of thermodynamic effects

Abstract Hydroxycitrate (HCA), has been mooted as a potentially equivalent, if not superior therapy to citrate for calcium urolithiasis. However, past studies were mainly mechanistic while thermodynamic experiments were limited. We determined stability constants for HCA protonation and metal ion complexation, and measured HCA speciation by potentiometric titration. We modelled the effect of HCA, citrate and pH on calcium oxalate (CaOx) and calcium phosphate (CaP) supersaturation (SS) using the program JESS to which we had added our determined thermodynamic constants. Finally, we measured the effects of HCA on CaOx metastable limit (MSL) in artificial urine using turbidimetry. Our experiments showed that fully dissociated HCA is the dominant species at urinary pH 6. Modelling predicted that HCA decreases SS CaOx and CaP to a greater extent than citrate. In vitro experiments showed increases in the MSLs of CaOx and CaP thereby confirming favorable thermodynamic effects of HCA on SS. Clinical trials are warranted to investigate the promise of HCA for reducing this important risk factor for calcium nephrolithiasis