Aminoglycoside-induced nephrotoxicity in children

Aminoglycoside antibiotics, in particular gentamicin and tobramycin, are still commonly used in paediatric clinical practice. These drugs cause nephrotoxicity, which particularly affects the proximal tubule epithelial cells due to selective endocytosis and accumulation of aminoglycosides via the multi-ligand receptor megalin. Recent epidemiological studies, using more widely accepted definitions of acute kidney injury (AKI), have suggested that AKI may occur in between 20 and 33 % of children exposed to aminoglycosides. A consensus set of phenotypic criteria for aminoglycoside-induced nephrotoxicity have recently been published. These are specifically designed to provide robust phenotyping for pharmacogenomic studies, but they can pave the way for standardisation for all clinical studies. Novel renal biomarkers, in particular kidney injury molecule-1, identify aminoglycoside-induced proximal tubular injury earlier than traditional markers and have shown promise in observational studies. Further studies need to demonstrate a clear association with clinically relevant outcomes to inform translation into clinical practice. Extended interval dosing of aminoglycosides results in a reduction in nephrotoxicity, but its use needs to become more widespread. Inhibition of megalin-mediated endocytosis by statins represents a novel approach to the prevention of aminoglycoside-induced nephrotoxicity which is currently being evaluated in a clinical trial. Recommendations for future directions are provided

Modulation of LAT1 (SLC7A5) transporter activity and stability by membrane cholesterol.

LAT1 (SLC7A5) is a transporter for both the uptake of large neutral amino acids and a number of pharmaceutical drugs. It is expressed in numerous cell types including T-cells, cancer cells and brain endothelial cells. However, mechanistic knowledge of how it functions and its interactions with lipids are unknown or limited due to inability of obtaining stable purified protein in sufficient quantities. Our data show that depleting cellular cholesterol reduced the Vmax but not the Km of the LAT1 mediated uptake of a model substrate into cells (L-DOPA). A soluble cholesterol analogue was required for the stable purification of the LAT1 with its chaperon CD98 (4F2hc,SLC3A2) and that this stabilised complex retained the ability to interact with a substrate. We propose cholesterol interacts with the conserved regions in the LAT1 transporter that have been shown to bind to cholesterol/CHS in Drosophila melanogaster dopamine transporter. In conclusion, LAT1 is modulated by cholesterol impacting on its stability and transporter activity. This novel finding has implications for other SLC7 family members and additional eukaryotic transporters that contain the LeuT fold

Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin

Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p < 0.0001). KIM-1, in particular, may be a useful, non-invasive, biomarker of acute and chronic proximal tubular injury associated with exposure to aminoglycosides in patients with CF, but its clinical utility needs to be further evaluated in prospective studies

Investigating the prevalence, predictors, and prognosis of suboptimal statin use early after a non-ST elevation acute coronary syndrome

BACKGROUND:High-potency statin therapy is recommended in the secondary prevention of car-diovascular disease but discontinuation, dose reduction, statin switching, and/or nonadherence occurin practice.OBJECTIVES:To determine the prevalence and predictors of deviation from high-potency statin useearly after a non-ST elevation acute coronary syndrome (NSTE-ACS) and its association with subse-quent major adverse cardiovascular events (MACE) and all-cause mortality (ACM).METHODS:A total of 1005 patients from a UK-based prospective NSTE-ACS cohort study dis-charged on high-potency statin therapy (atorvastatin 80 mg, rosuvastatin 20 mg, or 40 mg daily)were included. At 1 month, patients were divided into constant high-potency statin users, and subop-timal users incorporating statin discontinuation, dose reduction, switching statin to a lower equivalentpotency, and/or statin nonadherence. Follow-up was a median of 16 months.RESULTS:There were 156 suboptimal (w15.5%) and 849 constant statin users. Factors associatedin multivariable analysis with suboptimal statin occurrence included female sex (odds ratio 1.75, 95%confidence interval [CI] 1.14–2.68) and muscular symptoms (odds ratio 4.28, 95% CI 1.30–14.08).Suboptimal statin use was associated with increased adjusted risks of time to MACE (hazard ratio2.10, 95% CI 1.25–3.53,P5.005) and ACM (hazard ratio 2.46, 95% CI 1.38–4.39,P5.003). Sub-group analysis confirmed that the increased MACE/ACM risks were principally attributable to statindiscontinuation or nonadherence.CONCLUSIONS:Conversion to suboptimal statin use is common early after NSTE-ACS and ispartly related to muscular symptoms. Statin discontinuation or non-adherence carries an adverse prog-nosis. Interventions that preserve and enhance statin utilization could improve post NSTE-ACSoutcomes

Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children

Aim: The aim of this study was to establish reference intervals in healthy children for two novel urinary biomarkers of acute kidney injury, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Materials & Methods: Urinary biomarkers were determined in samples from children in the UK (n = 120) and the USA (n = 171) using both Meso Scale Discovery (MSD) and Luminex-based analytical approaches. Results: 95% reference intervals for each biomarker in each cohort are presented and stratified by sex or ethnicity where necessary, and age-related variability is explored using quantile regression. We identified consistently higher NGAL concentrations in females than males (p < 0.0001), and lower KIM-1 concentrations in African–Americans than Caucasians (p = 0.02). KIM-1 demonstrated diurnal variation, with higher concentrations in the morning (p < 0.001). Conclusion: This is the first report of reference intervals for KIM-1 and NGAL using two analytical methods in a healthy pediatric population in both UK and US-based populations

A Randomized Controlled Trial of Extended Brief Intervention for Alcohol-Dependent Patients in an Acute Hospital Setting

To determine whether alcohol-dependent patients in a hospital setting benefit from extended brief interventions (EBI) delivered by an Alcohol Specialist Nurse. Methods Alcohol-dependent patients recruited via screening at the emergency department (ED) (n = 267), whether or not admitted to hospital, were randomized to EBI (up to six counselling sessions offered) or control. At 6 months, 84.2% of patients were assessed by a researcher blinded to the intervention. The primary outcome was a fall in Severity of Alcohol Dependence Questionnaire. Results There was no difference between groups in the primary outcome [odds ratio (OR) 1.02; 95% confidence interval (CI): 0.38, 2.75, P = 0.97]. Secondary outcomes including alcohol consumption and readiness to change did not show a significant difference between groups. However, all secondary outcome measures improved, on average, in both arms. Conclusions Although EBI can be delivered in an ED or inpatient setting, it was not shown to be an advantage over screening and usual management (which included advice on alternative services), with patients in both groups showing an average improvement

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry