Role of urinary inhibitors of crystallization in uric acid nephrolithiasis: Dalmatian dog model

Abstract

ObjectivesTo study the role of urinary inhibitors on crystallization—nephrocalcin, Tamm-Horsfall protein (THP), and glycosaminoglycans (GAGs)—in hyperuricosuric nephrolithiasis using Dalmatian dogs, a breed well-known for high levels of uric acid excretion, in an in vivo model. MethodsUrine samples were collected from 10 stone-forming Dalmatian dogs and from 5 age-matched Dalmatians without kidney stones. Purine derivatives present in urine were studied by high-performance liquid chromatography. THP, GAGs, and nephrocalcin were isolated and measured. ResultsAs expected, the Dalmatians excreted a large amount of uric acid in urine, but without differences between the two groups (0.42 ± 0.08 mg/mg creatinine versus 0.48 ± 0.11 mg/mg creatinine for stone-forming and healthy Dalmatians, respectively, P = 0.64). No other metabolites were derived from purine in their urine. Stone-forming Dalmatians showed significantly lower urinary excretion of THP than did normal Dalmatians (0.09 ± 0.03 mg/mg creatinine versus 0.21 ± 0.03 mg/mg creatinine, P <0.03). The urinary excretion of GAGs was lower in the stone-forming Dalmatians, although the difference was not statistically significant. Inhibition of calcium oxalate monohydrate crystal growth caused by nephrocalcin isoforms from healthy and stone-forming dogs were in the same order of ∼10−7 M, as calculated from a Langmuir isotherm type plot. ConclusionsThe urinary excretion of THP and GAGs was decreased in stone-forming Dalmatians compared with healthy ones. Our results support the suitability of Dalmatian dogs as an in vivo model to investigate the interrelationship of urine inhibitors of crystallization and hyperuricosuria.