Description: Objectives To assess the feasibility and acceptability of facilitated advance care planning (ACP) discussions in elderly Italian and Greek-speaking inpatients compared to English-speaking inpatients. Design, setting and participants This cross-sectional study with convenience sampling was conducted in Melbourne, Australia, and recruited hospital inpatients with medical decision-making capacity, aged 65 years or above, who spoke Greek (25 patients), Italian (24 patients) or English (63 patients). Intervention Facilitated ACP was offered, aiming to assists patients to consider and discuss their goals, values, beliefs and future treatment wishes with their family and doctor; to help them consider how they would like healthcare decisions made in the future if they become unable to do this for themselves; and to complete advance care directives. Main outcome measures The completion of ACP discussions, their duration, advance care directive completion and utilisation of interpreters. Results Of 112 patients, 109 (97%) had at least one discussion, 63 (54%) completed advance care directives, either nominating a substitute decision-maker, documenting their wishes or both, and 76 (68%) included family in discussions. The median duration of discussions for all patients was slightly more than 1 h, over two visits. There were no differences between the Greek-speaking and the Italian-speaking patients, or between the Non-English speaking and the English-speaking patients in any of these measures. Only 14 non-English speaking patients, (30%) utilised interpreters, but when utilised, patients were much more likely (p〈0.005) to complete advance care directives. Conclusions Facilitated ACP in elderly Italian and Greek-speaking patients is feasible, acceptable and is similar to that for English-speaking patients.

Description: Objectives To determine whether the prevalence of chronic kidney disease (CKD) in England has changed over time. Design Cross-sectional analysis of nationally representative Health Survey for England (HSE) random samples. Setting England 2003 and 2009/2010. Survey participants 13 896 adults aged 16+ participating in HSE, adjusted for sampling and non-response, 2009/2010 surveys combined. Main outcome measure Change in prevalence of estimated glomerular filtration rate (eGFR) 〈60 mL/min/1.73 m 2 (as proxy for stage 3–5 CKD), from 2003 to 2009/2010 based on a single serum creatinine measure using an isotope dilution mass spectrometry traceable enzymatic assay in a single laboratory; eGFR derived using Modified Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) eGFR formulae. Analysis Multivariate logistic regression modelling to adjust time changes for sociodemographic and clinical factors (body mass index, hypertension, diabetes, lipids). A correction factor was applied to the 2003 HSE serum creatinine to account for a storage effect. Results National prevalence of low eGFR (〈60) decreased within each age and gender group for both formulae except in men aged 65–74. Prevalence of obesity and diabetes increased in this period, while there was a decrease in hypertension. Adjustment for demographic and clinical factors led to a significant decrease in CKD between the surveyed periods. The fully adjusted OR for eGFR 〈60 mL/min/1.73 m 2 was 0.75 (0.61 to 0.92) comparing 2009/2010 with 2003 using the MDRD equation, and was similar using the CKDEPI equation 0.73 (0.57 to 0.93). Conclusions The prevalence of a low eGFR indicative of CKD in England appeared to decrease over this 7-year period, despite the rising prevalence of obesity and diabetes, two key causes of CKD. Hypertension prevalence declined and blood pressure control improved but this did not appear to explain the fall. Periodic assessment of eGFR and albuminuria in future HSEs is needed to evaluate trends in CKD.

Description: Albuminuria is associated with the additional loss in the urine of small molecular weight proteins normally degraded by the proximal convoluted tubule (PCT), and competition for binding to the megalin/cubilin reuptake system has been considered the likely cause. We have previously reported that deficiency of the intrinsic lysosomal protein Limp-2 causes tubular proteinuria due to reduced fusion of endosomes with lysosomes in the PCT leading to inadequate proteolysis. To determine whether this mechanism also contributes to the tubular proteinuria induced by albumin overload in normal mice, wild-type (WT) mice received daily BSA injections intraperitoneally for 10 days, using untreated Limp-2 –/– mice as positive controls for inadequate proteolysis. BSA overload induced significant urinary loss of megalin and cubilin ligands in WT mice. Tubular uptake of Alexa-conjugated BSA, administered by intravenous injection, was not reduced in the PCT of mice receiving intraperitoneal BSA. Expression of the tubular protein receptor megalin was also unchanged. There was a delay in proteolysis of reabsorbed proteins in WT mice receiving BSA, evidenced by an increased quantity of retinol-binding protein (RBP) in the kidney cortex, increased basal distribution of endocytosed RBP in cells of the PCT, and persistence of exogenous Alexa-conjugated BSA and RBP after injection. Upregulation of cathepsin L and normal fusion of lysosomes with endosomes were apparently not sufficient to maintain normal clearance of endocytosed proteins. The data suggest that in the presence of competition from albumin overload, reabsorption of filtered proteins is limited by the capacity of lysosomal degradation rather than receptor-mediated endocytosis.

Description: Salt reabsorption is the major energy-requiring process in the kidney, and AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism. Mice with targeted deletion of the β1-subunit of AMPK (AMPK-β1 –/– mice) had significantly increased urinary Na + excretion on a normal salt diet. This was associated with reduced expression of the β-subunit of the epithelial Na + channel (ENaC) and increased subapical tubular expression of kidney-specific Na + -K + -2Cl – cotransporter 2 (NKCC2) in the medullary thick ascending limb of Henle. AMPK-β1 –/– mice fed a salt-deficient diet were able to conserve Na + , but renin secretion increased 180% compared with control mice. Cyclooxygenase-2 mRNA also increased in the kidney cortex, indicating greater signaling through the macula densa tubular salt-sensing pathway. To determine whether the increase in renin secretion was due to a change in regulation of fatty acid metabolism by AMPK, mice with a mutation of the inhibitory AMPK phosphosite in acetyl-CoA carboxylase 1 [ACC1-knockin (KI) S79A mice] were examined. ACC1-KI S79A mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na + -Cl – cotransporter, and ENaC-β were similar to those in control mice. When mice were placed on a salt-deficient diet, however, renin secretion and cortical expression of cyclooxygenase-2 mRNA increased significantly in ACC1-KI S79A mice compared with control mice. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1.

Description: Enhanced tubular reabsorption of salt is important in the pathogenesis of obesity-related hypertension, but the mechanisms remain poorly defined. To identify changes in the regulation of salt transporters in the kidney, C57BL/6 mice were fed a 40% fat diet [high-fat diet (HFD)] or a 12% fat diet (control diet) for 14 wk. Compared with control diet-fed mice, HFD-fed mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. When we examined Na + transporter expression, Na + -K + -2Cl – cotransporter (NKCC2) was unchanged in whole kidney and reduced in the cortex, Na + -Cl – cotransporter (NCC) and α-epithelial Na + channel (ENaC) and -ENaC were unchanged, and β-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of STE-20/SPS1-related proline-alanine-rich protein kinase (SPAK)/oxidative stress responsive 1 kinase (OSR1) was increased in kidneys from HFD-fed mice, and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic experiments. HFD-fed mice had reduced activating phosphorylation of AMP-activated protein kinase (AMPK) in the renal cortex. In vitro, activation of AMPK led to a reduction in phospho-SPAK/phospho-OSR1 in AMPK +/+ murine embryonic fibroblasts (MEFs), but no effect was seen in AMPK –/– MEFs, indicating an AMPK-mediated effect. Activation of the with no lysine kinase/SPAK/OSR1 pathway with low-NaCl solution invoked a greater elevation in phospho-SPAK/phospho-OSR1 in AMPK –/– MEFs than in AMPK +/+ MEFs, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto-unrecognized mediator of enhanced Na + reabsorption in obesity and identifies a new role for AMPK in regulating the activity of SPAK/OSR1.

Description: Introduction Although Aboriginal and Torres Strait Islander children in Australia have higher risk of burns compared with non-Aboriginal children, their access to burn care, particularly postdischarge care, is poorly understood, including the impact of care on functional outcomes. The objective of this study is to describe the burden of burns, access to care and functional outcomes in Aboriginal and Torres Strait Islander children in Australia, and develop appropriate models of care. Methods and analysis All Aboriginal and Torres Strait Islander children aged under 16 years of age (and their families) presenting with a burn to a tertiary paediatric burn unit in 4 Australian States (New South Wales (NSW), Queensland, Northern Territory (NT), South Australia (SA)) will be invited to participate. Participants and carers will complete a baseline questionnaire; follow-ups will be completed at 3, 6, 12 and 24 months. Data collected will include sociodemographic information; out of pocket costs; functional outcome; and measures of pain, itch and scarring. Health-related quality of life will be measured using the PedsQL, and impact of injury using the family impact scale. Clinical data and treatment will also be recorded. Around 225 participants will be recruited allowing complete data on around 130 children. Qualitative data collected by in-depth interviews with families, healthcare providers and policymakers will explore the impact of burn injury and outcomes on family life, needs of patients and barriers to healthcare; interviews with families will be conducted by experienced Aboriginal research staff using Indigenous methodologies. Health systems mapping will describe the provision of care. Ethics and dissemination The study has been approved by ethics committees in NSW, SA, NT and Queensland. Study results will be distributed to community members by study newsletters, meetings and via the website; to policymakers and clinicians via policy fora, presentations and publication in peer-reviewed journals.