Biomarkers of Acute Kidney Injury

Acute kidney injury (AKI) is a common problem in both the inpatient and outpatient setting and often results from drug toxicities. Traditional methods of identifying AKI, through measurement of blood urea nitrogen and serum creatinine, are problematic in that they are slow to detect decreases in glomerular filtration rate (GFR) and are influenced by a variety of factors that are not related to GFR changes. The problems inherent in a creatinine-based diagnosis of AKI have impeded the development of proper therapeutics in AKI and posed problems in evaluating nephrotoxicity of drugs and other chemical exposures. In recent years, a number of new biomarkers of AKI with more favorable test characteristics than creatinine have been identified and studied in a variety of experimental and clinical settings. This review will consider the most well-established biomarkers and appraise the literature, with particular attention given to the use of biomarkers in identifying toxin-mediated AKI

Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid

BACKGROUND: The novel synthetic neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) blocks T-type calcium channels but does not directly modulate neuronal γ-aminobutyric acid type A (GABA METHODS: We used a combination of behavioural loss of righting reflex, neuroendocrine, pharmacokinetic, in vitro patch-clamp electrophysiology, and in vivo electrophysiological approaches in wild-type mice and in genetic knockouts of the Ca RESULTS: Adult male mice were less sensitive to the hypnotic effects of 3β-OH compared with female mice, and these differences appeared during development. Adult males had higher 3β-OH brain concentrations despite being less sensitive to its hypnotic effects. Females metabolised 3β-OH into the active GABA CONCLUSIONS: The sex-specific differences in the hypnotic effect of 3β-OH in mice are attributable to differences in its peripheral metabolism into the more potent hypnotic metabolite 3α-OH

Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism.

Mycophenolate mofetil (MMF) per se is not known to have negative effects on the kidney. MMF alone or in combination with sirolimus, can be the basis of calcineurin inhibitor (CNI)-free, kidney sparing drug protocols. However, long-term outcomes in patients on MMF/SRL seem to be inferior to those treated with regimens that include the CNI tacrolimus (TAC) due to an increased risk of allo-immune reactions. Interestingly, potential enhancement of the negative effects of SRL and TAC on the kidney by MMF has never been considered.It was our aim to study the effects of TAC, SRL and MMF alone and evaluate their interactions when combined on the rat kidney. For this purpose we used a comprehensive molecular marker approach including measurements of urinary 8-isoprostane concentrations (oxidative stress marker) and changes of urinary metabolite patterns ((1)H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology).While MMF alone did not impact GFR, its interaction with SRL and TAC led to a significant decrease of rats' renal function. The decline went in parallel with a significant increase in urinary isoprostane concentrations and an enhancement of negative effects on urinary metabolite patterns.In broad summary, the present study showed that MMF may enhance the negative effects of TAC on kidney function and may even display nephrotoxic properties when combined with SRL

The Fatty Acid Desaturation Index in Human Plasma: Comparison of Different Analytical Methodologies for the Evaluation of Dietary Effects

Abstract (252 words) Background: Stearoyl-CoA Desaturase (SCD1) plays a role in the development of obesity and related conditions, such as insulin resistance, and potentially also in neurological and heart diseases. The activity of SCD1 can be monitored using the desaturation index (DI), the ratio of product (16:1n-7 and 18:1n-9) to precursor (16:0 and 18:0) fatty acids. Here we analyzed the DI in the plasma total triglyceride fraction and very low density lipoproteins (VLDL) in volunteers on a high carbohydrate diet using a dual ultra-high pressure liquid chromatography – mass spectrometry (UHPLC-MS) strategy. Methods: One assay was based on a simple extraction followed by neutral loss triglyceride – fatty acid analysis, the other on saponification of triglycerides followed by fatty acid analysis (specific for the position of the double bond within monosaturated fatty acids (MUFA). Both assays were applied to the isolated VLDL or to the plasma total triglyceride fraction. Assays were compared using plasma from a study in which 8 lean and obese healthy individuals received a high carbohydrate diet for 3 days. Results: All assays showed acceptable accuracies (75-125) and precisions (<20%) for the analysis of fatty acids in VLDL and plasma. Analysis of human plasma samples revealed increased DI (up to 136% of control, p< 0.05 after a high carbohydrate diet of 3 days. Conclusion: Only the specific fatty acid UHPLC-MS analysis of human plasma VLDL samples reflects the complete biological pathway and showed that a significant increase in DI and associated SCD1 activity –in healthy individuals after just 3 days of high carbohydrate diet

Depressed Prostaglandins and Leukotrienes in Veterans with Gulf War Illness

Background: There is need to understand biological markers and mechanisms in Gulf War illness (GWI). Goal: To examine whether and how eicosanoids – prostaglandins and leukotrienes – are altered in veterans with GWI. Methods: Seventy participants including 37 GWI and 33 healthy controls, shared exposure information, and had plasma eicosanoids assessed – prostaglandin F2 alpha (pgf2α), prostaglandin D2 (pgd2), leukotriene B4 (lb4) among others. Values were compared for GWI versus controls. Eicosanoid intercorrelations were compared in cases vs. controls. For the most significantly altered eicosanoid in GWI, exposure and symptom relations were assessed. Results: Prostaglandins and leukotrienes were depressed in GWI, strongest for pgf2α, then lb4. Eicosanoid intercorrelations differed in GWI vs. controls. Fuel-solvent, pesticide, radioactive chemicals and metal exposures related negatively to pgf2α; as, in GWI, did chemical attack and vaccines. Multivariate predictors included fuels-solvents and radioactive chemicals (negative); tetanus vaccine and herbicides (positive). Fuels-solvents and radioactive chemicals predicted lower pgf2α in cases, controls, and all participants controlled for case status. Lower pgf2α related to GWI “Kansas criteria” domains of pain, respiratory, and (borderline significantly) skin symptoms. Conclusion: Multiple eicosanoids are depressed in GWI, particularly pgf2α and lb4. Prior fuel-solvent exposures, radioactive chemicals, and (in GWI cases) vaccines were linked to lower pgf2α.</p