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Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence.

ABSTRACT: To investigate whether inflammation, oxidation, and tubular injury are present in children with stones (RS) compared with healthy controls (HC) by measuring urinary proteins involved in these processes.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) P-value ?.05 for Fisher's exact test.Of the 1813 proteins identified, 230 met the above criteria, with 163 proteins upregulated in the RS group and 67 upregulated in HC. Functional analysis revealed 19 inflammatory proteins, 5 proteins involved in oxidative stress, and 5 involved in tubular injury. Of those proteins, NADPH-oxidase, a major source of reactive oxygen species, was only found in the RS group, whereas 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.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.

SUBMITTER: Kovacevic L

PROVIDER: S-EPMC4891186 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence.

Kovacevic Larisa L Lu Hong H Caruso Joseph A JA Lakshmanan Yegappan Y

Urology 20160215

<h4>Objective</h4>To investigate whether inflammation, oxidation, and tubular injury are present in children with stones (RS) compared with healthy controls (HC) by measuring urinary proteins involved in these processes.<h4>Methods</h4>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. ...[more]

PMID: 26892647

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Project description:Simple Summary We studied survivors of childhood cancer who received cancer treatment that might affect the kidneys and compared them to controls from the general population. We investigated if there was a difference in the occurrence of tubular dysfunction. The tubules are the part of the kidney responsible for reabsorption of needed substances to the blood and the removal of wastes. After around 25 years since their cancer diagnosis, we found that in general there were no differences between survivors and controls, but survivors more often had losses of small proteins in the urine. Yet, some survivors of childhood cancer were found to have an increased risk of tubular dysfunction. Namely, survivors treated with the chemotherapeutic agents ifosfamide, cisplatin or carboplatin. Therefore, these patients should be monitored during their follow-up. Abstract The aim of this nationwide cross-sectional cohort study was to determine the prevalence of and risk factors for tubular dysfunction in childhood cancer survivors (CCS). In the DCCSS-LATER 2 Renal study, 1024 CCS (≥5 years after diagnosis), aged ≥ 18 years at study, treated between 1963 and 2001 with potentially nephrotoxic therapy (i.e., nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or hematopoietic stem cell transplantation) participated, and 500 age- and sex-matched participants from Lifelines acted as controls. Tubular electrolyte loss was defined as low serum levels (magnesium < 0.7 mmol/L, phosphate < 0.7 mmol/L and potassium < 3.6 mmol/L) with increased renal excretion or supplementation. A α1-microglobulin:creatinine ratio > 1.7 mg/mmol was considered as low-molecular weight proteinuria (LMWP). Multivariable risk analyses were performed. After median 25.5 years follow-up, overall prevalence of electrolyte losses in CCS (magnesium 5.6%, potassium 4.5%, phosphate 5.5%) was not higher compared to controls. LMWP was more prevalent (CCS 20.1% versus controls 0.4%). LMWP and magnesium loss were associated with glomerular dysfunction. Ifosfamide was associated with potassium loss, phosphate loss (with cumulative dose > 42 g/m2) and LMWP. Cisplatin was associated with magnesium loss and a cumulative dose > 500 mg/m2 with potassium and phosphate loss. Carboplatin cumulative dose > 2800 mg/m2 was associated with potassium loss. In conclusion, long-term tubular dysfunction is infrequent. Yet, ifosfamide, cisplatin and carboplatin are risk factors.

Dataset Information

Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence.

Publications

Renal Tubular Dysfunction in Pediatric Urolithiasis: Proteomic Evidence.

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