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Gender-related effects on urine l-cystine metastability

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Abstract

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.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Gene Expression-Microarrays Laboratory, Bambino Gesù Children’s Hospital - IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy

    Andrea Masotti

  2. Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital - IRCCS, Rome, Italy

    Chiara Laurenzi, Anna Taranta, Francesco Bellomo, Luca Dello Strologo & Francesco Emma

  3. Division of Metabolism, Bambino Gesù Children’s Hospital - IRCCS, Rome, Italy

    Sara Boenzi, Anna Pastore & Carlo Dionisi-Vici

  4. Division of Laboratory Medicine, Bambino Gesù Children’s Hospital - IRCCS, Rome, Italy

    Maurizio Muraca

  5. Department of Clinical Biochemistry, Tor Vergata Hospital, Tor Vergata University, Rome, Italy

    Pierfrancesco Bertucci

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  1. Andrea Masotti
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  2. Chiara Laurenzi
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  4. Anna Pastore
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  10. Luca Dello Strologo
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  11. Francesco Emma
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Correspondence to Andrea Masotti.

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A. Masotti and C. Laurenzi have equally contributed.

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Masotti, A., Laurenzi, C., Boenzi, S. et al. Gender-related effects on urine l-cystine metastability. Amino Acids 46, 415–427 (2014). https://doi.org/10.1007/s00726-013-1631-9

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  • DOI: https://doi.org/10.1007/s00726-013-1631-9

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