Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence

OBJECTIVE - To investigate whether inflammation, oxidation and tubular injury is present in children with stones (RS) compared to healthy controls (HC) by measuring urinary proteins involved in these processes.

METHODS - Quantitative proteomic comparison of pooled urine from RS (N=30, 24 females, mean age 12. 95±4. 03 years) versus age- and gender-matched HC (N=30), using liquid chromatography-mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: 1) ≥5 spectral counts; 2) ≥2-fold difference in spectral counts; and 3) ≤0. 05 p-value for the Fisher's Exact Test.

RESULTS - Of the 1813 proteins identified, 230 met the above criteria, with 163 proteins up-regulated in the RS group and 67 up-regulated in HC. Functional analysis revealed 19 inflammatory proteins, 5 proteins involved in oxidative stress, and 5 involved in tubular injury. Of those, NADPH-oxidase, a major source of reactive oxygen species, was only found in the RS group, while glutathione S-transferase A2, an important antioxidant enzyme, was more abundant in controls. ELISA analysis confirmed statistically significant differences in the urinary excretion of retinol-binding protein 4, a marker of proximal tubular dysfunction, between stone patients with hypercalciuria and controls.

CONCLUSIONS - We provide proteomic evidence of oxidative stress, inflammation, and tubular injury in children with renal stones. We speculate that inflammation and changes in the oxidant-antioxidant balance may cause tubular damage in these patients. Targeting these proteins may have therapeutic benefits.

Urology. 2016 Feb 15 [Epub ahead of print]

Larisa Kovacevic, Hong Lu, Joseph A Caruso, Yegappan Lakshmanan

Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI. Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI. , Institute of Environmental Health Sciences, Wayne State University, Detroit, MI. , Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI.

PubMed

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