Gender-related effects on urine L-cystine metastability.

[cystinuria]

Cystinuria is an autosomal recessive disease that causes L-cystine precipitation in urine and nephrolithiasis . Disease severity is highly variable ; it is known , however , that cystinuria has a more severe course in males . The aim of this study was to compare L-cystine metastability in first -morning urine collected from 24 normal female and 24 normal male subjects . Samples were buffered at pH 5 and loaded with L-cystine (0 .4 and 4 mM final concentration ) to calculate the amount remaining in solution after overnight incubation at 4 °C ; results were expressed as Z scores reflecting the L-cystine solubility in each sample . In addition , metabolomic analyses were performed to identify candidate compounds that influence L-cystine solubility . L-cystine solubility Z score was +0 .44 ± 1 .1 and -0 .44 ± 0 .70 in female and male samples , respectively (p < 0 .001 ). Further analyses showed that the L-cystine solubility was independent from urine concentration but was significantly associated with low urinary excretion of inosine (p = 0 .010 ), vanillylmandelic acid (VMA ) (p = 0 .015 ), adenosine (p = 0 .029 ), and guanosine (p = 0 .032 ). In vitro L-cystine precipitation assays confirmed that these molecules induce higher rates of L-cystine precipitation in comparison with their corresponding dideoxy molecules , used as controls . In silico computational and modeling analyses confirmed higher binding energy of these compounds . These data indicate that urinary excretion of nucleosides and VMA may represent important factors that modulate L-cystine solubility and may represent new targets for therapy in cystinuria .