Publications by authors named "Brendan Smyth"

36 Publications

Effect of Hemodiafiltration on the Progression of Neuropathy with Kidney Failure.

Clin J Am Soc Nephrol 2021 Jul 7. Epub 2021 Jul 7.

M Jardine, UNSW Sydney, The George Institute for Global Health, Newtown, Australia.

Background And Objectives: Neuropathy is a common complication of kidney disease that lacks proven disease-modifying treatments. Hemodiafiltration improves clearance of uremic toxins and is associated with better nerve function than hemodialysis. We aimed to determine whether hemodiafiltration reduces the progression of neuropathy in people receiving hemodialysis.

Design, Setting, Participants And Measurements: FINESSE was an open-label, blinded endpoint assessment, controlled trial that randomized maintenance hemodialysis recipients to hemodiafiltration or high flux hemodialysis for 48 months, or until death or cessation of dialysis at 4 study centers. The primary outcome was the mean change in the yearly modified Total Neuropathy Score (mTNS) from baseline, with time points weighted equally.

Results: A total of 124 participants were randomized and followed for a mean of 41 months. At baseline, neuropathy was present in 91 (73%) participants (mTNS greater than or equal to 2) and 38 (31%) had moderate to severe neuropathy (mTNS 9-28). Convection volume in the hemodiafiltration arm was median (interquartile range) 24.7 (22.4-26.5)L. The mean mTNS (SE) worsened by 1.7 (0.4)/28 and 1.2 (0.4)/28 in the hemodiafiltration and hemodialysis groups respectively, with a mean difference of 0.5 (95% confidence interval -0.7 to 1.7, p=0.37). There was no difference in survival (HR 1.24 (0.61 to 2.51), log rank p=0.55) or any of the pre-specified adverse events. There was no difference between groups in the number of participants who suffered an adverse event adjusted by follow-up time (Relative risk 1.05 (0.83-1.32) p=0.68).

Conclusions: Neuropathy is still a common complication of kidney disease without disease-altering therapy. Hemodiafiltration did not affect neuropathy progression compared with hemodialysis.

Trial Registration: ACTRN12609000615280.
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http://dx.doi.org/10.2215/CJN.17151120DOI Listing
July 2021

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options.

Kidney Blood Press Res 2021 Jun 15:1-10. Epub 2021 Jun 15.

Department of Renal Medicine, St. George Hospital, Sydney, New South Wales, Australia.

Background: Proteinuria is a key biomarker in nephrology. It is central to diagnosis and risk assessment and the primary target of many important therapies. Etiologies resulting in pathological proteinuria include congenital and acquired disorders, as well as both glomerular (immune/non-immune mediated) and tubular defects.

Summary: Untreated proteinuria is strongly linked to progressive loss of kidney function and kidney failure. Excess protein reaching the renal tubules is ordinarily resorbed by the tubular epithelium. However, when these mechanisms are overwhelmed, a variety of inflammatory and fibrotic pathways are activated, causing both interstitial fibrosis and glomerulosclerosis. Nevertheless, the specific mechanisms underlying this are complex and remain incompletely understood. Recently, a number of treatments, in addition to angiotensin system blockade, have been shown to effectively slow the progression of proteinuric chronic kidney disease. However, additional therapies are clearly needed. Key message: This review provides an update on the pathophysiology of proteinuria, the pathways leading to fibrosis, and an overview of current and emerging therapies.
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http://dx.doi.org/10.1159/000516911DOI Listing
June 2021

Quality of Life in Caregivers of Patients Randomized to Standard- Versus Extended-Hours Hemodialysis.

Kidney Int Rep 2021 Apr 1;6(4):1058-1065. Epub 2021 Feb 1.

Department of Nephrology, Sunshine Coast University Hospital, Birtinya, Australia.

Introduction: Caregivers are essential for the health, safety, and independence of many patients and incur financial and personal cost in this role, including increased burden and lower quality of life (QOL) compared to the general population. Extended-hours hemodialysis may be the preference of some patients, but little is known about its effects on caregivers.

Methods: Forty caregivers of participants of the ACTIVE Dialysis trial, who were randomized to 12 months extended (median 24 hours/wk) or standard (12 hours/wk) hemodialysis, were included. Utility-based QOL was measured by EuroQOL-5 Dimension-3 Level (EQ-5D-3L) and Short Form-6 Dimensions (SF-6D) and health-related QOL (HRQOL) was measured by the 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) and the Personal Wellbeing Index (PWI) at enrolment and then every 3 months until the end of the study.

Results: At baseline, utility-based QOL and HRQOL were similar in both groups. At follow-up, caregivers of people randomized to extended-hours dialysis experienced a greater decrease in utility-based QOL measured by EQ-5D-3L compared with caregivers of people randomized to standard hours (-0.18±0.30 vs. -0.02±0.16,  = 0.04). There were no differences between extended- and standard-hours groups in mean change in SF-6D (0.03±0.12 vs. -0.04±0.1,  = 0.8), PCS (-1.2±9.8 vs. -5.6±9.8,  = 0.2), MCS (-4.1±11.2 vs. -0.5±7.1,  = 0.4), and PWI (2.3±17.6 vs. 0.00±20.4,  = 0.9).

Conclusion: Poorer utility-based QOL, as measured by the EQ-5D-3L, was observed in caregivers of patients receiving extended-hours hemodialysis in this small study. Though the findings are exploratory, the possibility that mode of dialysis delivery negatively impacts on caregivers supports the prioritization of research on burden and impact of service delivery in this population.
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http://dx.doi.org/10.1016/j.ekir.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071646PMC
April 2021

Relationship between measured and prescribed dialysate sodium in haemodialysis: a systematic review and meta-analysis.

Nephrol Dial Transplant 2021 03;36(4):695-703

The George Institute for Global Health, UNSW Sydney, Sydney, Australia.

Background: Dialysate sodium (DNa) prescription policy differs between haemodialysis (HD) units, and the optimal DNa remains uncertain. We sought to summarize the evidence on the agreement between prescribed and delivered DNa, and whether the relationship varied according to prescribed DNa.

Methods: We searched MEDLINE and PubMed from inception to 26 February 2020 for studies reporting measured and prescribed DNa. We analysed results reported in aggregate with random-effects meta-analysis. We analysed results reported by individual sample, using mixed-effects Bland-Altman analysis and linear regression. Pre-specified subgroup analyses included method of sodium measurement, dialysis machine manufacturer and proportioning method.

Results: Seven studies, representing 908 dialysate samples from 10 HD facilities (range 16-133 samples), were identified. All but one were single-centre studies. Studies were of low to moderate quality. Overall, there was no statistically significant difference between measured and prescribed DNa {mean difference = 0.73 mmol/L [95% confidence interval (CI) -1.12 to 2.58; P = 0.44]} but variability across studies was substantial (I2 = 99.3%). Among individually reported samples (n = 295), measured DNa was higher than prescribed DNa by 1.96 mmol/L (95% CI 0.23-3.69) and the 95% limits of agreement ranged from -3.97 to 7.88 mmol/L. Regression analysis confirmed a strong relationship between prescribed and measured DNa, with a slope close to 1:1 (β = 1.16, 95% CI 1.06-1.27; P < 0.0001).

Conclusions: A limited number of studies suggest that, on average, prescribed and measured DNa are similar. However, between- and within-study differences were large. Further consideration of the precision of delivered DNa is required to inform rational prescribing.
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http://dx.doi.org/10.1093/ndt/gfaa287DOI Listing
March 2021

The International Society of Nephrology Advancing Clinical Trials (ISN-ACT) Network: current activities and future goals.

Kidney Int 2021 03 10;99(3):551-554. Epub 2020 Dec 10.

Cambridge Clinical Trials Unit, University of Cambridge, Cambridge, UK; Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1016/j.kint.2020.10.048DOI Listing
March 2021

A retrospective study on the epidemiology of ANCA-associated vasculitis in two Australian health districts.

Intern Med J 2020 Oct 11. Epub 2020 Oct 11.

Department of Renal Medicine, The Wollongong Hospital, Wollongong, NSW, Australia.

Background: ANCA-associated vasculitis (AAV) is more prevalent in rural Australia compared to metropolitan areas suggesting a role of environment in disease pathogenesis. However, the prevalence of environmental risk factors in Australian AAV patients has not been described.

Aims: To compare the incidence of AAV between two health districts (Illawarra Shoalhaven local health district (ISLHD), a mixed rural/metropolitan region, and South Eastern Sydney local health district (SESLHD), a metropolitan region) in Australia and its relationship to environmental exposures.

Methods: Cases of AAV from 2002 to 2017 were retrospectively identified from ISLHD and SESLHD using electronic medical records. Eligible participants were invited to complete a standardised questionnaire examining their exposure to silica, solvents, metal, dust, farming, gardening, and sunlight.

Results: 156 cases of AAV were identified from 2002 to 2017. A higher cumulative incidence of AAV was observed in the ISLHD (184.2 [95% confidence interval (CI) 143.6-232.7] per million) compared to SESLHD (102.6 [95% CI 82.1-126.8] per million). Over 50% of the cohort had high levels of silica and solvents exposure, based on self-reported questionnaires. There was no significant relationship between region and exposure to silica (p=0.96), solvents (p=0.44), metal (p=0.33), dust (p=0.25), farming (p=0.90), gardening (p=0.93), or sunlight (p=0.55).

Conclusions: We found a higher incidence of AAV in ISLHD compared to SESLHD with high levels of exposure to silica and solvents in both regions based on self-reported questionnaires. Prospective systematic collection of data, such as a registry of AAV, is warranted to further explore the relationship between environmental exposures and AAV. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15098DOI Listing
October 2020

Response to: Loutradis et al. Longer Dialysis Sessions Improve Cardiac Systolic Function by Reducing Myocardial Stunning.

J Card Fail 2020 11 3;26(11):1028-1029. Epub 2020 Sep 3.

The George Institute for Global Health and University of New South Wales, Sydney, Australia; Renal Unit, Concord Repatriation General Hospital, Sydney, Australia.

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http://dx.doi.org/10.1016/j.cardfail.2020.09.001DOI Listing
November 2020

RNA-seq analysis of gene expression profiles in isolated stria vascularis from wild-type and Alport mice reveals key pathways underling Alport strial pathogenesis.

PLoS One 2020 21;15(8):e0237907. Epub 2020 Aug 21.

Boys Town National Research Hospital, Omaha, NE, United States of America.

Previous work demonstrates that the hearing loss in Alport mice is caused by defects in the stria vascularis. As the animals age, progressive thickening of strial capillary basement membranes (SCBMs) occurs associated with elevated levels of extracellular matrix expression and hypoxia-related gene and protein expression. These conditions render the animals susceptible to noise-induced hearing loss. In an effort to develop a more comprehensive understanding of how the underlying mutation in the COL4A3 gene influences homeostasis in the stria vascularis, we performed vascular permeability studies combined with RNA-seq analysis using isolated stria vascularis from 7-week old wild-type and Alport mice on the 129 Sv background. Alport SCBMs were found to be less permeable than wild-type littermates. RNA-seq and bioinformatics analysis revealed 68 genes were induced and 61 genes suppressed in the stria from Alport mice relative to wild-type using a cut-off of 2-fold. These included pathways involving transcription factors associated with the regulation of pro-inflammatory responses as well as cytokines, chemokines, and chemokine receptors that are up- or down-regulated. Canonical pathways included modulation of genes associated with glucose and glucose-1-PO4 degradation, NAD biosynthesis, histidine degradation, calcium signaling, and glutamate receptor signaling (among others). In all, the data point to the Alport stria being in an inflammatory state with disruption in numerous metabolic pathways indicative of metabolic stress, a likely cause for the susceptibility of Alport mice to noise-induced hearing loss under conditions that do not cause permanent hearing loss in age/strain-matched wild-type mice. The work lays the foundation for studies aimed at understanding the nature of strial pathology in Alport mice. The modulation of these genes under conditions of therapeutic intervention may provide important pre-clinical data to justify trials in humans afflicted with the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446819PMC
October 2020

Comparative Efficacy and Safety of BP-Lowering Pharmacotherapy in Patients Undergoing Maintenance Dialysis: A Network Meta-Analysis of Randomized, Controlled Trials.

Clin J Am Soc Nephrol 2020 08 16;15(8):1129-1138. Epub 2020 Jul 16.

The George Institute for Global Health, Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia

Background And Objectives: Elevated BP is an important risk factor for cardiovascular disease, with a prevalence of over 80% in patients undergoing maintenance dialysis. We assessed the comparative BP-lowering efficacy and the safety of BP-lowering drugs in patients undergoing maintenance dialysis.

Design, Settings, Participants, & Measurements: We performed a frequentist random effects network meta-analysis of randomized, controlled trials evaluating BP-lowering agents in adult patients undergoing maintenance dialysis. Electronic databases (CENTRAL, MEDLINE, and Embase) were systematically searched (up to August 2018) for relevant trials. The main outcome was systolic BP reduction.

Results: Forty trials (4283 participants) met our inclusion criteria. Angiotensin-converting enzyme inhibitors, -blockers, calcium-channel blockers, and aldosterone antagonists lowered systolic BP to a greater extent than placebo, with effect sizes ranging from -10.8 mm Hg (95% confidence interval, -14.8 to -6.7 mm Hg) for the aldosterone antagonists to -4.3 mm Hg (95% confidence interval, -7.2 to -1.5 mm Hg) for angiotensin-converting enzyme inhibitors. Aldosterone antagonists and -blockers were superior to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers, and renin inhibitors at lowering systolic BP. Compared with angiotensin-converting enzyme inhibitors, aldosterone antagonists and -blockers lowered systolic BP by 6.4 mm Hg (95% confidence interval, -11.4 to -1.4 mm Hg) and 4.4 mm Hg (95% confidence interval, -7.4 to -1.3 mm Hg), respectively. Systolic BP reduction was not different with angiotensin receptor blockers, -blockers, and calcium-channel blockers compared with angiotensin-converting enzyme inhibitors. Renin inhibitors were less effective. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists incurred risks of drug discontinuation due to adverse events and hypotension.

Conclusions: BP-lowering agents significantly reduced systolic BP in patients undergoing maintenance dialysis. -Blockers and aldosterone antagonists may confer larger reductions, although treatment with aldosterone antagonists may be limited by adverse events.
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http://dx.doi.org/10.2215/CJN.12201019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409758PMC
August 2020

No evidence of a legacy effect on survival following randomization to extended hours dialysis in the ACTIVE Dialysis trial.

Nephrology (Carlton) 2020 Oct 2;25(10):792-800. Epub 2020 Jul 2.

Renal and Metabolic Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia.

Aim: Extended hours haemodialysis is associated with superior survival to standard hours. However, residual confounding limits the interpretation of this observation. We aimed to determine the effect of a period of extended hours dialysis on long-term survival among participants in the ACTIVE Dialysis trial.

Methods: Two-hundred maintenance haemodialysis recipients were randomized to extended hours dialysis (median 24 h/wk) or standard hours dialysis (median 12 h/wk) for 12 months. Further pre-specified observational follow up occurred at 24, 36 and 60 months. Vital status and modality of renal replacement therapy were ascertained.

Results: Over the 5 years, 38 participants died, 30 received a renal transplant, and 6 were lost to follow up. Total weekly dialysis hours did not differ between standard and extended groups during the follow-up period (14.1 hours [95%CI 13.4-14.8] vs 14.8 hours [95%CI 14.1-15.6]; P = .16). There was no difference in all-cause mortality (hazard ratio for extended hours 0.91 [95%CI 0.48-1.72]; P = .77). Similar results were obtained after censoring participants at transplantation, and after adjusting for potential confounding variables. Subgroup analysis did not reveal differences in treatment effect by region, dialysis setting or vintage (P-interaction .51, .54, .12, respectively).

Conclusion: Twelve months of extended hours dialysis did not improve long-term survival nor affect dialysis hours after the intervention period. An urgent need remains to further define the optimal dialysis intensity across the broad range of dialysis recipients.
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http://dx.doi.org/10.1111/nep.13737DOI Listing
October 2020

Predictors of Change in Left-Ventricular Structure and Function in a Trial of Extended Hours Hemodialysis.

J Card Fail 2020 Jun 14;26(6):482-491. Epub 2020 Apr 14.

The George Institute for Global Health and University of New South Wales, Sydney, Australia; Renal Unit, Concord Repatriation General Hospital, Sydney, Australia.

Background: Myocardial pathology is common in patients undergoing hemodialysis. To explore the effects of differing aspects of dialysis treatment on its evolution, we examined the impact of change in markers of volume status, hemodynamics and solute clearance on left ventricular (LV) parameters in a randomized trial of extended hours dialysis.

Methods And Results: A Clinical Trial of IntensiVE (ACTIVE) Dialysis randomized 200 patients undergoing hemodialysis to extended dialysis hours (≥ 24 hours/week) or standard hours (12-18 hours/week) for 12 months. In a prespecified substudy, 95 participants underwent cardiac magnetic resonance imaging (CMR) at baseline and at the study's end. Generalized linear regression was used to model the relationship between changes in LV parameters and markers of volume status (normalized ultrafiltration rate and total weekly interdialytic weight gain), hemodynamic changes (systolic and diastolic blood pressure) and solute control (urea clearance, dialysis hours and phosphate). Randomization to extended hours dialysis was not associated with change in any CMR parameter. Reduction in ultrafiltration rate was associated with reduction in LV mass index (P = 0.049) and improved ejection fraction (P = 0.024); reduction in systolic blood pressure was also associated with improvement in ejection fraction (P = 0.045); reduction in interdialytic weight gain was associated with reduced stroke volume (P = 0.038). There were no associations between change in urea clearance, phosphate or total hours per week and CMR parameters.

Conclusions: Reduction in ultrafiltration rate and blood pressure are associated with improved myocardial parameters in hemodialysis recipients independently of solute clearance or dialysis time. These findings underscore the importance of fluid status and related parameters as potential treatment targets in this population.
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http://dx.doi.org/10.1016/j.cardfail.2020.03.010DOI Listing
June 2020

Dialysis funding, eligibility, procurement, and protocols in low- and middle-income settings: results from the International Society of Nephrology collection survey.

Kidney Int Suppl (2011) 2020 Mar 19;10(1):e10-e18. Epub 2020 Feb 19.

School of Medicine, Pontificia Universidade Catolica do Paraná, Curitiba, Brazil.

Dialysis provisions and end-stage kidney disease (ESKD) care represents an important challenge, particularly in low-resource settings. The purpose of this project was to survey nephrologists from low- and lower middle-income countries about their experiences in the following domains: (i) ; (ii) ; (iii) ; (iv) ; and (v) One hundred and twenty responses from 31 low- and middle-income countries, from 8 ISN regions, were included in the analysis. When stratified by World Bank country income status, responses were received from 7 low-income countries, 12 lower middle-income countries, and 12 upper middle-income countries. Eighty-eight documents from 18 countries were uploaded, including country or institutional guidelines, protocols, and standard operating procedures. The International Society of Nephrology aims to develop a set of guidance documents that put forward a considered approach to dialysis provisions and ESKD care within resource limitations. As an initial step in this project, local practitioners from low-resource settings were surveyed about their experiences with dialysis funding, eligibility, procurement and their use of guidance documents, and how practices and procedures may have been developed with adaptations to the local circumstances. In this manuscript we describe the methodology and the main findings from the survey using an integrated quantitative and qualitative approach.
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http://dx.doi.org/10.1016/j.kisu.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031691PMC
March 2020

Inequities in the global representation of sites participating in large, multicentre dialysis trials: a systematic review.

BMJ Glob Health 2019 12;4(6):e001940. Epub 2019 Nov 12.

Renal and Metabolic Division, The George Institute for Global Health and University of New South Wales, Sydney, New South Wales, Australia.

Background: The number of dialysis recipients is growing worldwide, making it important that the full range of patient populations are represented in randomised trials. As trial recruitment has not previously been examined at a global level, we compared the location of trial sites recruiting to large multicentre randomised controlled trials (RCTs) in dialysis to the global distribution of dialysis recipients.

Methods: A systematic review (2007-2016) was conducted to identify RCTs enrolling ≥100 dialysis patients from ≥2 sites. The number and location of sites were extracted from manuscripts and trial registration. The proportion of sites from each International Society of Nephrology global region was divided by the proportion of the global dialysis population in that region to determine a 'representation index' (RI), where 1.0 indicated that the number of sites was proportionate to the number of dialysis recipients in that region.

Results: We identified 180 RCTs, recruiting from 6172 sites in 54 countries. Eastern and Central Europe had the highest RI at 2.45. Other well-represented regions were Western Europe (2.20), North America (2.06), and Russia and newly independent states (1.36). Africa had the lowest RI at 0.05, followed by South Asia (0.08), Latin America (0.15), Middle East (0.27), North-East Asia (0.41), and South-East Asia and Oceania (0.62).

Conclusions: Regions of the world with growing numbers of dialysis patients are poorly represented in large, multicentre RCTs. Efforts to boost trial participation in these regions are required to ensure that generalisable and relevant information is available to local healthcare providers.
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http://dx.doi.org/10.1136/bmjgh-2019-001940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861095PMC
November 2019

Varying Association of Extended Hours Dialysis with Quality of Life.

Clin J Am Soc Nephrol 2019 12 31;14(12):1751-1762. Epub 2019 Oct 31.

The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia;

Background And Objectives: Little is known about the effect of changes in dialysis hours on patient-reported outcome measures. We report the effect of doubling dialysis hours on a range of patient-reported outcome measures in a randomized trial, overall and separately for important subgroups.

Design, Setting, Participants, & Measurements: The A Clinical Trial of IntensiVE Dialysis trial randomized 200 participants to extended or standard weekly hours hemodialysis for 12 months. Patient-reported outcome measures included two health utility scores (EuroQOL-5 Dimensions-3 Level, Short Form-6 Dimension) and their derived quality-adjusted life year estimates, two generic health scores (Short Form-36 Physical Component Summary, Mental Component Summary), and a disease-specific score (Kidney Disease Component Score). Outcomes were assessed as the mean difference from baseline using linear mixed effects models adjusted for time point and baseline score, with interaction terms added for subgroup analyses. Prespecified subgroups were dialysis location (home- versus institution-based), dialysis vintage (≤6 months versus >6 months), region (China versus Australia, New Zealand, Canada), and baseline score (lowest, middle, highest tertile). Multiplicity-adjusted values (Holm-Bonferroni) were calculated for the main analyses.

Results: Extended dialysis hours was associated with improvement in Short Form-6 Dimension (mean difference, 0.027; 95% confidence interval [95% CI], 0.00 to 0.05; =0.03) which was not significant after adjustment for multiple comparisons ( =0.05). There were no significant differences in EuroQOL-5 Dimensions-3 Level health utility (mean difference, 0.036; 95% CI, -0.02 to 0.09; =0.2; =0.2) or in quality-adjusted life years. There were small positive differences in generic and disease-specific quality of life: Physical Component Summary (mean difference, 2.3; 95% CI, 0.6 to 4.1; =0.01; =0.04), Mental Component Summary (mean difference, 2.5; 95% CI, 0.5 to 4.6; =0.02; =0.05) and Kidney Disease Component Score (mean difference, 3.5; 95% CI, 1.5 to 5.5; =0.001; =0.005). The results did not differ among predefined subgroups or by baseline score.

Conclusions: The effect of extended hours hemodialysis on patient-reported outcome measures reached statistical significance in some but not all measures. Within each measure the effect was consistent across predefined subgroups. The clinical importance of these differences is unclear.
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http://dx.doi.org/10.2215/CJN.06800619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895496PMC
December 2019

Studies Making Use of the Same Randomized Clinical Trial Cohorts-Reply.

Authors:
Brendan Smyth

JAMA Intern Med 2019 10;179(10):1447

The George Institute for Global Health, University of New South Wales, Newtown, New South Wales, Australia.

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http://dx.doi.org/10.1001/jamainternmed.2019.4624DOI Listing
October 2019

Effect of extended hours dialysis on markers of chronic kidney disease-mineral and bone disorder in the ACTIVE Dialysis study.

BMC Nephrol 2019 07 12;20(1):258. Epub 2019 Jul 12.

Department of Nephrology, China-Japan Friendship Hospital, 2 Yinghuayuan E St, Chaoyang Qu, Beijing Shi, 100096, China.

Background: Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD) is a significant cause of morbidity among haemodialysis patients and is associated with pathological changes in phosphate, calcium and parathyroid hormone (PTH). In the ACTIVE Dialysis study, extended hours dialysis reduced serum phosphate but did not cause important changes in PTH or serum calcium. This secondary analysis aimed to determine if changes in associated therapies may have influenced these findings and to identify differences between patient subgroups.

Methods: The ACTIVE Dialysis study randomised 200 participants to extended hours haemodialysis (≥24 h/week) or conventional haemodialysis (≤18 h/week) for 12 months. Mean differences between treatment arms in serum phosphate, calcium and PTH; and among key subgroups (high vs. low baseline phosphate/PTH, region, time on dialysis, dialysis setting and frequency) were examined using mixed linear regression.

Results: Phosphate binder use was reduced with extended hours (- 0.83 tablets per day [95% CI -1.61, - 0.04; p = 0.04]), but no differences in type of phosphate binder, use of vitamin D, dose of cinacalcet or dialysate calcium were observed. In adjusted analysis, extended hours were associated with lower phosphate (- 0.219 mmol/L [- 0.314, - 0.124; P < 0.001]), higher calcium (0.046 mmol/L [0.007, 0.086; P = 0.021]) and no change in PTH (0.025 pmol/L [- 0.107, 0.157; P = 0.713]). The reduction in phosphate with extended hours was greater in those with higher baseline PTH and dialysing at home.

Conclusion: Extended hours haemodialysis independently reduced serum phosphate levels with minimal change in serum calcium and PTH levels. With a few exceptions, these results were consistent across patient subgroups.

Trial Registration: Clinicaltrials.gov NCT00649298 . Registered 1 April 2008.
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http://dx.doi.org/10.1186/s12882-019-1438-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624904PMC
July 2019

Representativeness of Randomized Clinical Trial Cohorts in End-stage Kidney Disease: A Meta-analysis.

JAMA Intern Med 2019 Oct;179(10):1316-1324

The George Institute for Global Health and University of New South Wales, Sydney, Australia.

Importance: Systematic differences between patients included in randomized clinical trials (RCTs) and the general patient population may influence the generalizability of RCT findings. Comprehensive national registries of patients with end-stage kidney disease who are undergoing dialysis provide a unique opportunity to compare trial and real-world patient cohorts.

Objective: To determine if participants in large, multicenter dialysis trials were similar to the general population undergoing dialysis in terms of age, comorbidities, and mortality rate.

Data Sources: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials were systematically searched on January 6, 2017, for studies published from January 1, 2007, to December 31, 2016. Data sources were published manuscripts, supplementary material, and trial registration information. Data on the general population undergoing dialysis were derived from the US Renal Data System (USRDS). Data were analyzed from March 17 to July 22, 2018.

Study Selection: Randomized clinical trials enrolling only participants undergoing dialysis for end-stage kidney disease with 100 or more adult participants from 2 or more sites.

Data Extraction And Synthesis: Abstract screening and data extraction were performed independently by 2 researchers. Data were pooled using a random-effects model.

Main Outcomes And Measures: The primary outcome was difference in mean age between the RCT and USRDS populations. Secondary outcomes included differences in mortality rate and comorbidities.

Results: The search identified 186 RCTs, enrolling 79 104 participants. Compared with the 2011 USRDS population, RCT participants were younger (mean age, 58.9 years; 95% CI, 58.3-59.5 years vs 61.2 years; P < .001), more likely to be male (58.9%; 95% CI, 57.6%-60.1% vs 55.7%; P < .001), and have coronary artery disease (26.9%; 95% CI, 22.2%-31.7% vs 17.7%; P < .001) and less likely to have diabetes (40.2%; 95% CI, 36.7%-43.6% vs 44.2%; P = .03) or heart failure (19.6%; 95% CI, 15.1%-24.0% vs 29.8%; P < .001). The mortality rate per 100 patient-years during trial participation was less than half that of the USRDS population (8.9; 95% CI, 7.8-10.0 vs 18.6; P < .001). The differences in age, mortality, and coronary artery disease remained when studies recruiting only from the United States were considered. Diabetes was more common in RCT participants from the United States than in the registry population.

Conclusions And Relevance: Participants in large, multicenter RCTs of patients with end-stage kidney disease undergoing dialysis are younger, have a different pattern of comorbidities, and have a lower mortality rate than the general population of patients undergoing dialysis. This finding has implications for the generalization of trial results to the broader patient population and for future trial design.
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http://dx.doi.org/10.1001/jamainternmed.2019.1501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618769PMC
October 2019

Arteriovenous access practices in Australian and New Zealand dialysis units.

J Vasc Access 2019 Nov 30;20(6):740-745. Epub 2019 May 30.

Department of Epidemiology and Preventive Medicine, Monash University, Prahran, VIC, Australia.

Background: The creation and maintenance of dialysis vascular access is associated with significant morbidity. Structured management pathways can reduce this morbidity, yet practice patterns in Australia and New Zealand are not known. We aimed to describe the arteriovenous access practices in dialysis units in Australia and New Zealand.

Methods: An online survey comprising 51 questions was completed by representatives from dialysis units from both countries. In addition to descriptive analysis, responses were compared between units inside and outside of major cities.

Results: Of 64 contacted units, 48 (75%) responded (Australia 43, New Zealand 5), representing 38% of dialysis units in Australia and New Zealand. While 94% of units provided pre-dialysis education, only 60% reported a structured pre-dialysis pathway and 69% had a dedicated vascular access nurse. Most units routinely monitored fistula/graft function using flow rate measurement (73%) or recirculation studies (63%). A minority used routine ultrasound (35%). Thrombectomy, fistuloplasty and peritoneal dialysis catheter insertion were rarely performed by nephrologists (4%, 4% and 17% of units, respectively). Units outside of a major city were less likely to have access to a local vascular access surgeon (6/13 (46%) vs 35/35 (100%), P < 0.001). There were no other significant differences between units on the basis of location.

Conclusion: Much variation exists in unit management of arteriovenous access. Structured pre-dialysis pathways and dedicated vascular access nurses may be underutilised in Australia and New Zealand. The use of regular access blood flow measurement and ultrasound is common in both countries despite a lack of data supporting its effectiveness. There is room for both practice improvement and a need for further evidence to ensure optimal arteriovenous access care.
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http://dx.doi.org/10.1177/1129729819851061DOI Listing
November 2019

Effects of intravenous hydration on risk of contrast induced nephropathy and in-hospital mortality in STEMI patients undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis of randomized controlled trials.

BMC Cardiovasc Disord 2019 04 8;19(1):87. Epub 2019 Apr 8.

The George Institute for Global Health, the University of Sydney, Camperdown, Australia.

Background: The role of intravenous hydration at the time of primary percutaneous intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) remains unclear. Guidelines are vague, supported by low level evidence, and hydration is used less often than other clinical settings.To perform a systematic review and meta-analysis of all randomized controlled trials assessing intravenous hydration compared with non-hydration for prevention of contrast induced nephropathy (CIN) and In-hospital mortality in patients with STEMI undergoing primary PCI.

Methods: Medline, EMBASE and the Cochrane Register were searched to September 2018. Included studies reported the incidence of CIN, In-hospital mortality, requirement for dialysis and heart failure. Relative risks with 95% confidence intervals (CIs) for individual trials were pooled using a random effects model.

Results: Three moderate quality trials were identified including 1074 patients. Overall, compared with no hydration, intravenous hydration significantly reduced the incidence of CIN by 42% (RR 0.58; 95% CI: 0.45 to 0.74, p < 0.001). The estimated effects upon all-cause mortality (RR 0.56; 95% CI: 0.30 to 1.02, p = 0.057) and the requirement for dialysis (RR 0.52, 95% CI 0.14-1.88, p = 0.462) were not statistically significant. The outcome of heart failure was not consistently reported.

Conclusions: Intravenous hydration likely reduces the incidence of CIN in patients with STEMI undergoing primary PCI. However, for key clinical outcomes such as mortality, heart failure and dialysis the effect estimates were imprecise. Further high quality studies are needed to clarify the appropriate volume of fluid and effects on outcomes.
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http://dx.doi.org/10.1186/s12872-019-1054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454772PMC
April 2019

Randomised controlled trial of the impact of haemodiafiltration on uraemic neuropathy: FINESSE study protocol.

BMJ Open 2019 01 15;9(1):e023736. Epub 2019 Jan 15.

Renal and Metabolic, The George Institute for Global Health, UNSW, Newtown, New South Wales, Australia.

Introduction: The majority of patients undergoing haemodialysis (HD) show evidence of uraemic neuropathy, a condition with no known disease-modifying treatments. The pathogenesis of uraemic neuropathy is poorly understood, but may be related to cumulative exposure to middle molecules or other solutes such as potassium. It is not known whether haemodiafiltration (HDF) reduces the progression of uraemic neuropathy.

Methods And Analysis: Filtration In the Neuropathy of End-Stage kidney disease Symptom Evolution (FINESSE) is a multicentre, randomised, open-label, blinded endpoint assessment, controlled trial designed to assess the impact of HDF versus HD on uraemic neuropathy. Maintenance HD patients will be randomised in a 1:1 ratio to receive HDF or HD with high-flux membranes for 4 years. The primary endpoint is the difference in the mean change in Total Neuropathy Score (TNS)-a measure of peripheral neuropathy combining symptoms, signs and nerve conduction velocity-over the study period. Secondary outcomes include change at annual timepoints in the TNS and the Neuropathy Symptom Score; and in morbidity, mortality and safety events.

Ethics And Dissemination: The FINESSE trial has been approved by the Ethics Review Committee of the Sydney South West Area Health Service (HREC/09/RPAH/268) and of Adventist HealthCare Limited (2012-027). When published in a peer-reviewed journal, it will be the largest and longest reported randomised trial aimed at reducing the incidence and severity of uraemic neuropathy. It will advance the understanding of the natural history of uraemic neuropathy and the influence of convective therapies on both neurophysiological and clinical outcomes. It will also allow refinement of current hypotheses surrounding the pathogenesis of uraemic neuropathy and, most importantly, may lead to improvements in the lives of the many patients affected by this debilitating condition.

Trial Registration Number: ACTRN12609000615280.
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http://dx.doi.org/10.1136/bmjopen-2018-023736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340424PMC
January 2019

Quality of life in caregivers compared with dialysis recipients: The Co-ACTIVE sub-study of the ACTIVE dialysis trial.

Nephrology (Carlton) 2019 Oct 29;24(10):1056-1063. Epub 2019 Apr 29.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

Aim: To compare quality of life (QOL) of caregivers of dialysis patients with the cared for patients and population norms.

Methods: The ACTIVE Dialysis study randomized participants to extended (median 24 h/week) or standard (median 12 h/week) haemodialysis hours for 12 months. A subgroup of participants and their nominated caregivers completed QOL questionnaires including the EuroQOL-5 Dimension-3 Level (EQ5D-3 L), short form-36 (SF-36, also allowing estimation of the SF-6D), as well as a bespoke questionnaire and the personal wellbeing index (PWI). Caregiver QOL was compared with dialysis patient QOL and predictors of caregiver QOL were determined using multivariable regression.

Results: There were 54 patients and caregiver pairs, predominantly from China. Caregivers mean (SD) age was 53.4 (11.3) years, 60% were female, 71% cared for their spouse/partner, and 36% were educated to university level. Caregivers had better physical but similar mental QOL compared with dialysis patients (mean SF-36 physical component summary: 46.9 ± 8.7 vs 40.4 ± 10.2, P < 0.001; mental component summary: 47.8 ± 9.7 vs 49.6 ± 12.0, P = 0.84). Health utility measured with EQ5D-3 L was not significantly different between caregivers and dialysis patients (mean 0.869 ± 0.185 vs 0.798 ± 0.227, P = 0.083). Caregiver PWI was 43.7 ± 15.5, significantly lower than the Chinese population norm (68.2 ± 14.2, P < 0.001). Higher physical and mental QOL among caregivers was predicted by university education but not age, gender or daily hours caring.

Conclusion: Caregivers have higher physical and equivalent mental QOL to dialysis patients but poorer personal well-being than the Chinese population. University education predicts better QOL and may be a surrogate for socioeconomic or other factors. (NCT00649298).
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http://dx.doi.org/10.1111/nep.13530DOI Listing
October 2019

New hypoglycemic agents and the kidney: what do the major trials tell us?

F1000Res 2018 23;7. Epub 2018 Nov 23.

The George Institute for Global Health, UNSW, Sydney, Australia.

As the burden of diabetic kidney disease continues to expand, new therapies to preserve renal function or prevent diabetic nephropathy are urgently needed. In the past decade, a number of new hypoglycemic classes have emerged, each with a unique profile of action and benefits. Here we review the impact of glycemic control on renal outcomes and the results of the major clinical trials of glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Both GLP-1 agonists and SGLT2 inhibitors consistently demonstrate renal benefits. Further studies of these new agents in different patient groups and in comparison to (or in combination with) other treatments are required to better define their role in combating the burden of diabetic kidney disease.
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http://dx.doi.org/10.12688/f1000research.16135.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259591PMC
March 2019

Dialysis catheter management practices in Australia and New Zealand.

Nephrology (Carlton) 2019 Aug 29;24(8):827-834. Epub 2019 Apr 29.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Aim: Dialysis catheter-associated infections (CAI) are a serious and costly burden on patients and the health-care system. Many approaches to minimizing catheter use and infection prophylaxis are available and the practice patterns in Australia and New Zealand are not known. We aimed to describe dialysis catheter management practices in dialysis units in Australia and New Zealand.

Methods: Online survey comprising 52 questions, completed by representatives from dialysis units from both countries.

Results: Of 64 contacted units, 48 (75%) responded (Australia 43, New Zealand 5), representing 79% of the dialysis population in both countries. Nephrologists (including trainees) inserted non-tunnelled catheters at 60% and tunnelled catheters at 31% of units. Prophylactic antibiotics were given with catheter insertion at 21% of units. Heparin was the most common locking solution for both non-tunnelled (77%) and tunnelled catheters (69%), with antimicrobial locks being predominant only in New Zealand (80%). Eight different combinations of exit site dressing were in use, with an antibiotic patch being most common (35%). All units in New Zealand and 84% of those in Australia undertook CAI surveillance. However, only 51% of those units were able to provide a figure for their most recent rate of catheter-associated bacteraemia per 1000 catheter days.

Conclusion: There is wide variation in current dialysis catheter management practice and CAI surveillance is suboptimal. Increased attention to the scope and quality of CAI surveillance is warranted and further evidence to guide infection prevention is required.
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http://dx.doi.org/10.1111/nep.13507DOI Listing
August 2019

Clinical Implications of Contrast-Induced Nephropathy in Patients Without Baseline Renal Dysfunction Undergoing Coronary Angiography.

Heart Lung Circ 2019 Jun 16;28(6):866-873. Epub 2018 May 16.

Guangdong General Hospital Zhuhai Hospital, Zhuhai Golden Bay Center Hospital, Zhuhai, 519040, China. Electronic address:

Background: The clinical implications of different definitions of contrast-induced nephropathy (CIN) in patients without baseline renal dysfunction are not well defined.

Methods: Consecutive patients at a single centre without baseline renal dysfunction (estimated glomerular filtration rate, eGFR≥60ml/min/1.73m) undergoing coronary angiography or percutaneous coronary intervention (PCI), were systematically evaluated for long-term risk of mortality following CIN using two broad definitions: an absolute increase from baseline in serum creatinine (SCr) ≥0.3mg/dl (mild to severe absolute CIN) and a relative increase from baseline of 25% (mild to severe relative CIN) within 72hours.

Result: Of 2,823 subjects alive before discharge following coronary angiography there were 320 episodes of mild to severe relative CIN (11.3%) and 125 of mild to severe absolute CIN (4.4%). During a median follow-up of 2.3years, 73 patients (3.2%) died. After adjustment for confounders, mild to severe absolute CIN was associated with an adjusted hazard ratio (HR) (95% confidence interval) for all-cause mortality of 3.31 (1.74-6.30) (p<0.0001) and relative CIN with an adjusted HR of 1.92 (1.09, 3.38) (p=0.024). The risk of mortality rose with severity of CIN. Two commonly used definitions of CIN combining absolute and relative terms (increase ≥ 0.3mg/dl or 50%, and ≥ 0.5mg/dl or 25% from the baseline) confirmed these results.

Conclusion: Among patients without baseline renal dysfunction undergoing coronary angiography, the incidence of CIN can range widely depending on definition. Absolute CIN is less common than relative CIN. Regardless of definition, CIN is associated with a markedly increased risk of long-term mortality. This finding requires confirmation in multicentre studies.
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http://dx.doi.org/10.1016/j.hlc.2018.04.291DOI Listing
June 2019

Effect of extended hours dialysis on sleep quality in a randomized trial.

Nephrology (Carlton) 2019 Apr;24(4):430-437

Renal & Metabolic Division, The George Institute for Global Health, UNSW, Sydney, New South Wales, Australia.

Aim: Poor sleep quality is common in haemodialysis patients and associated with worse outcomes. In this pre-specified analysis, we examined the impact of extended hours haemodialysis on sleep quality.

Methods: The ACTIVE Dialysis trial randomized 200 participants to extended (≥24 h/week) or standard (target 12-15 h) hours haemodialysis over 12 months. Sleep quality was measured in the Kidney Disease Quality of Life Short Form 1.3 (KDQOL-SF) by overall sleep quality score (0-10, 10 = 'very good') and the sleep subscale (0-100, 100 = 'best possible sleep') every 3 months via blinded telephone interview. The average intervention effect was calculated by mixed linear regression adjusted by time point and baseline score. Factors predicting sleep quality were assessed by multivariate regression analysis.

Results: Overall sleep quality score and sleep subscale at baseline were similar in both groups (5.9 [95%CI 5.4-6.4] vs. 6.3 [5.9-6.8]; 65.0 [60.9-69.1] vs. 63.2 [59.1-67.3]; extended and standard hours, respectively). Extended hours haemodialysis led to a non-significant improvement in overall sleep quality score (average intervention effect 0.44 (-0.01 to 0.89), P = 0.053) and sleep subscale (average intervention effect 3.58 (-0.02 to 7.18), P = 0.051). Poor sleep quality was associated with being female and with current smoking. Sleep quality was positively associated with EuroQol-5D (EQ5D) and the SF-36 Physical Component and Mental Component Summary Scores but not with hospitalizations.

Conclusion: Sleep quality was not significantly improved by extended hours dialysis in this study. Sleep quality is positively correlated with quality of life in haemodialysis patients and is poorer in women and current smokers.
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http://dx.doi.org/10.1111/nep.13236DOI Listing
April 2019

A Systematic Review and Pooled Analysis of Select Safety Parameters Among Normal Healthy Volunteers Taking Placebo in Phase 1 Clinical Trials.

J Clin Pharmacol 2017 09 16;57(9):1079-1087. Epub 2017 May 16.

Bristol-Myers Squibb, Princeton, NJ, USA.

A systematic review of the Bristol-Myers Squibb normal healthy volunteers (NHVs) database identified phase 1 trials that included NHVs administered placebo with the aim of characterizing normal inter- and intraindividual safety parameter variability. Twenty-five single and multiple ascending dose studies, median duration 28 (2 to 63) days, were included in the pooled analysis (355 NHVs). Laboratory evaluations, vital signs, electrocardiograms, and adverse events were assessed. The most commonly occurring adverse event was headache (28 [7.9%] NHVs; 519.5 events/100 person-years). During the dosing period (on placebo), evaluations showed 5.1 events/100 measures of alanine aminotransferase and 7.3 events/100 measures of creatine kinase 1× above the upper limit of normal. Alanine aminotransferase and creatine kinase elevations occurred in 28 (7.9%) and 39 (11.0%) NHVs, respectively; 105 (30.3%) NHVs had low and 46 (13.3%) had high diastolic blood pressure. This analysis may inform future study designs and provide a context for interpretation of safety signals in early phase clinical trials.
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http://dx.doi.org/10.1002/jcph.913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573961PMC
September 2017

Association of N-terminal pro-brain natriuretic peptide with contrast-induced acute kidney injury and long-term mortality in patients with heart failure and mid-range ejection fraction: An observation study.

Medicine (Baltimore) 2017 Mar;96(10):e6259

Department of Graduate School, Southern Medical University Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Key Laboratory of Coronary Disease, Guangdong General Hospital, Guangdong Academy of Medical Sciences School of Medicine, South China University of Technology, Guangzhou, Guangdong Department of Cardiology, Longyan First Hospital, Affiliated to Fujian Medical University, Fujian Department of Cardiology, Fujian Cardiovascular Institute, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China The George Institute for Global Health, the University of Sydney, Sydney, NSW, Australia.

The potential value of N-terminal pro-brain natriuretic peptide (NT-proBNP) for contrast-induced acute kidney injury (CI-AKI) in patients with heart failure and mid-range ejection fraction (HFmrEF) is unclear. We investigated whether NT-proBNP is associated with CI-AKI and long-term mortality following elective cardiac catheterization in patients with HFmrEF.A total of 174 consecutive patients with HFmrEF undergoing elective coronary angiography or intervention were enrolled. The primary endpoint was the development of CI-AKI, defined as an absolute increase of ≥0.3 mg/dL or ≥ 50% from baseline serum creatinine with 48 hours after contrast medium exposure. Receiver-operating characteristic curve analysis was conducted, and Youden index was used to determine the best cutoff NT-proBNP value. Multivariable logistic regression and Cox proportional hazards regression analyses were performed to identify the independent risk factors for CI-AKI and long-term mortality, respectively.The incidence of CI-AKI was 12.1%. Patients with CI-AKI had higher NT-proBNP values than those without (4373[1561.9-7470.5] vs 1303[625.2-2482.3], P = 0.003). Receiver-operating characteristic curve revealed that NT-proBNP was not significantly different from the Mehran risk score in predicting CI-AKI (area under the curve [AUC] = 0.723 vs 0.767, P = 0.516). The best cutoff NT-proBNP value for CI-AKI was 3299 pg/mL, with 70.6% sensitivity and 83.1% specificity. Multivariable analysis demonstrated that NT-proBNP ≥3299 pg/mL is significantly related to CI-AKI (odds ratio = 12.79; 95% confidence interval, 3.18-51.49; P < 0.001). Cox regression analysis showed that NT-proBNP ≥3299 pg/mL is associated with long-term mortality (adjusted hazard ratio = 11.91; 95%CI, 2.16-65.70; P = 0.004) during follow-up.In patients with HFmrEF, NT-proBNP ≥3299 pg/mL is associated with CI-AKI and long-term mortality following elective coronary angiography or intervention.
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http://dx.doi.org/10.1097/MD.0000000000006259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348179PMC
March 2017

The rise and rise of randomized clinical evidence in Sub-Saharan Africa.

Clin Kidney J 2016 Dec 9;9(6):814-816. Epub 2016 Sep 9.

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Sub-Saharan Africa is facing a rising tide of chronic disease, including chronic kidney disease, but the current research literature provides little evidence to guide the practice of nephrology in resource-poor settings. In this issue of CKJ, Waziri & Bello present a trial of two formulations of intravenous iron for patients with anaemia of chronic kidney disease in Nigeria. This study typifies a growing body of work from researchers from low-middle income countries addressing the evidence gaps that they meet in their everyday practice. Collaboration with clinical trialists and health economists from the global renal research community is suggested as an important way to expand, at low cost, the randomized evidence-base in this region.
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http://dx.doi.org/10.1093/ckj/sfw084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162410PMC
December 2016

A randomized trial of Plasma-Lyte A and 0.9 % sodium chloride in acute pediatric gastroenteritis.

BMC Pediatr 2016 08 2;16:117. Epub 2016 Aug 2.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl) intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acute gastroenteritis (AGE).

Methods: Prospective, randomized, double-blind study conducted at eight pediatric emergency departments (EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h. Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 % NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged ≥6 months to <11 years with AGE-induced moderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level ≤22 mEq/L formed the modified intent to treat (mITT) group.

Results: At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, the PLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean ± SD at 4 h: 18 ± 3.74 vs 18.0 ± 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groups received similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2 (both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening of laboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatment group developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3).

Conclusion: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score.

Trial Registration: NCT#01234883 (Registration Date: November 3, 2010).
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http://dx.doi.org/10.1186/s12887-016-0652-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969635PMC
August 2016

Prescribing for patients on dialysis.

Aust Prescr 2016 Feb 1;39(1):21-4. Epub 2016 Feb 1.

Royal Prince Alfred Hospital, Sydney.

The pharmacokinetics of a drug may be altered in patients with renal impairment who require dialysis. Some drugs are contraindicated. The drug's clearance and therapeutic index determine if a dose adjustment is needed. A lower dose or less frequent dosing may be required. Consult a reference source or the patient's nephrologist before prescribing. Start at a low dose and increase gradually. If possible give once-daily drugs after dialysis.
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http://dx.doi.org/10.18773/austprescr.2016.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816865PMC
February 2016
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