Radiation metabolomics. 3. Biomarker discovery in the urine of gamma-irradiated rats using a simplified metabolomics protocol of gas chromatography-mass spectrometry combined with random forests machine learning algorithm

Abstract Radiation metabolomics employing mass spectral technologies represents a plausible means of high-throughput minimally invasive radiation biodosimetry. A simplified metabolomics protocol is described that employs ubiquitous gas chromatography-mass spectrometry and open source software including random forests machine learning algorithm to uncover latent biomarkers of 3 Gy gamma radiation in rats. Urine was collected from six male Wistar rats and six sham-irradiated controls for 7 days, 4 prior to irradiation and 3 after irradiation. Water and food consumption, urine volume, body weight, and sodium, potassium, calcium, chloride, phosphate and urea excretion showed major effects from exposure to gamma radiation. The metabolomics protocol uncovered several urinary metabolites that were significantly up-regulated (glyoxylate, threonate, thymine, uracil, p-cresol) and down-regulated (citrate, 2-oxoglutarate, adipate, pimelate, suberate, azelaate) as a result of radiation exposure. Thymine and uracil were shown to derive largely from thymidine and 2'-deoxyuridine, which are known radiation biomarkers in the mouse. The radiation metabolomic phenotype in rats appeared to derive from oxidative stress and effects on kidney function. Gas chromatography-mass spectrometry is a promising platform on which to develop the field of radiation metabolomics further and to assist in the design of instrumentation for use in detecting biological consequences of environmental radiation release.

Early and late urodynamic assessment of ileal orthotopic bladder substitutes combined with an afferent tubular segment

PURPOSE: Limited information is available concerning changes in the urodynamic characteristics of orthotopic bladder substitutes with time. Therefore, we compared early and late urodynamic results in patients with an ileal orthotopic bladder substitute combined with an afferent tubular segment. MATERIALS AND METHODS: Of 139 patients surviving at least 5 years after cystoprostatectomy and ileal orthotopic bladder substitution with an afferent tubular segment 119 underwent urodynamic assessment, including 66 at a median of 9 months (early) and 77 at a median of 62 months (late). Of these patients 24 were assessed at each time point. Simultaneously all patients were asked to complete a bladder diary and questionnaire regarding continence for at least 3 days in the week preceding the urodynamic study. RESULTS: Urodynamic parameters were comparable in patients who were evaluated early and late postoperatively. In addition, median values at early and late urodynamic evaluation in the 24 patients with the 2 examinations showed no statistically significant differences for volume at first desire to void (300 vs 333 ml, p = 0.85), pressure at first desire to void (12 vs 13 cm H2O, p = 0.57), maximum cystometric capacity (450 vs 453 ml, p = 0.84), end filling pressure (19 vs 20 cm H2O, p = 0.17), reservoir compliance (25 vs 28 ml/cm H2O, p = 0.58) or post-void residual urine volume (5 vs 15 ml, p = 0.27). CONCLUSIONS: Urodynamic results after 5 years of living with an ileal orthotopic bladder substitute with an afferent tubular segment show grossly unchanged urodynamic characteristics. Patients maintain a reservoir capacity and micturition pattern consistent with a normal life-style. Reservoir pressure remained low, thereby protecting and preserving upper tract function. To achieve these results patients must be regularly followed, and the causes of bacteriuria, increased post-void residual urine and bladder outlet obstruction must be recognized and dealt with accordingly.

Which factors account for renal stone formation in cystic fibrosis?

Studies dealing with the increased tendency to stone formation noted in cystic fibrosis, focus on enteric hyperoxaluria. It is well recognized, however, that low urine volume, hypocitraturia and perhaps even hypercalciuria are further risk factors for stone formation.

Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort.

INTRODUCTION Community acquired pneumonia (CAP) is the most common infectious reason for admission to the Intensive Care Unit (ICU). The GenOSept study was designed to determine genetic influences on sepsis outcome. Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe. METHODS Kaplan-Meier analysis was used to determine mortality rates. A Cox Proportional Hazards (PH) model was used to identify variables independently associated with 28-day and six-month mortality. RESULTS Data from 1166 patients admitted to 102 centres across 17 countries was extracted. Median age was 64 years, 62% were male. Mortality rate at 28 days was 17%, rising to 27% at six months. Streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. Independent risk factors associated with an increased risk of death at six months included APACHE II score (hazard ratio, HR, 1.03; confidence interval, CI, 1.01-1.05), bilateral pulmonary infiltrates (HR1.44; CI 1.11-1.87) and ventilator support (HR 3.04; CI 1.64-5.62). Haematocrit, pH and urine volume on day one were all associated with a worse outcome. CONCLUSIONS The mortality rate in patients with severe CAP admitted to European ICUs was 27% at six months. Streptococcus pneumoniae was the commonest organism isolated. In many cases the infecting organism was not identified. Ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and pH on admission were independent predictors of a worse outcome.

Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population

BACKGROUND AND OBJECTIVES Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age±SD, 45±17 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53±11 years) with fresh spot morning urine samples. We calculated eGFRs using the CKD-Epidemiology Collaboration formula and by 24-hour creatinine clearance. RESULTS In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR<90 ml/min per 1.73 m(2). CONCLUSION Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.

Fluid balance, glomerular filtration rate, and urine output in dogs anesthetized for an orthopedic surgical procedure

OBJECTIVE: To determine fluid retention, glomerular filtration rate, and urine output in dogs anesthetized for a surgical orthopedic procedure. ANIMALS: 23 dogs treated with a tibial plateau leveling osteotomy. PROCEDURES: 12 dogs were used as a control group. Cardiac output was measured in 5 dogs, and 6 dogs received carprofen for at least 14 days. Dogs received oxymorphone, atropine, propofol, and isoflurane for anesthesia (duration, 4 hours). Urine and blood samples were obtained for analysis every 30 minutes. Lactated Ringer's solution was administered at 10 mL/kg/h. Urine output was measured and glomerular filtration rate was estimated. Fluid retention was measured by use of body weight, fluid balance, and bioimpedance spectroscopy. RESULTS: No difference was found among control, cardiac output, or carprofen groups, so data were combined. Median urine output and glomerular filtration rate were 0.46 mL/kg/h and 1.84 mL/kg/min. Dogs retained a large amount of fluids during anesthesia, as indicated by increased body weight, positive fluid balance, increased total body water volume, and increased extracellular fluid volume. The PCV, total protein concentration, and esophageal temperature decreased in a linear manner. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs anesthetized for a tibial plateau leveling osteotomy retained a large amount of fluids, had low urinary output, and had decreased PCV, total protein concentration, and esophageal temperature. Evaluation of urine output alone in anesthetized dogs may not be an adequate indicator of fluid balance.