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1.  Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: An interventional cohort study 
BMC Nephrology  2011;12:51.
Nightly extended hours hemodialysis may improve left ventricular hypertrophy and function and endothelial function but presents problems of sustainability and increased cost. The effect of alternate nightly home hemodialysis (NHD) on cardiovascular structure and function is not known.
Sixty-three patients on standard hemodialysis (SHD: 3.5-6 hours/session, 3-5 sessions weekly) converted to NHD (6-10 hours/session overnight for 3-5 sessions weekly). 2Dimensional transthoracic echocardiography and ultrasound measures of brachial artery reactivity (BAR), carotid intima-media thickness (CIMT), total arterial compliance (TAC) and augmentation index (AIX) were performed post dialysis at baseline and 18-24 months following conversion to NHD. In 37 patients, indices of oxidative stress: plasma malonyldialdehyde (MDA) and anti-oxidant enzymes: catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD) activity and total antioxidant status (TAS) were measured at baseline, 3 and 6 months.
Left ventricular mass index (LVMI) remained stable. Despite significant derangement at baseline, there were no changes in diastolic function measures, CIMT, BAR and TAC. AIX increased. Conversion to NHD improved bone mineral metabolism parameters and blood pressure control. Interdialytic weight gains increased. No definite improvements in measures of oxidative stress were demonstrated.
Despite improvement in uremic toxin levels and some cardiovascular risk factors, conversion to an alternate nightly NHD regimen did not improve cardiovascular structure and function. Continuing suboptimal control of uremic toxins and interdialytic weight gains may be a possible explanation. This study adds to the increasing uncertainty about the nature of improvement in cardiovascular parameters with conversion to intensive hemodialysis regimens. Future randomized controlled trials will be important to determine whether increases in dialysis session duration, frequency or both are most beneficial for improving cardiovascular disease whilst minimizing costs and the impact of dialysis on quality of life.
PMCID: PMC3202231  PMID: 21962236
Diastolic Function; Ejection Fraction; Left Ventricular Mass Index; Left Ventricular Hypertrophy; Nocturnal Hemodialysis; Carotid Intima-Media Thickness; Oxidative Stress; Arterial Compliance
2.  Do aluminium-based phosphate binders continue to have a role in contemporary nephrology practice? 
BMC Nephrology  2011;12:20.
Aluminium-containing phosphate binders have long been used for treatment of hyperphosphatemia in dialysis patients. Their safety became controversial in the early 1980's after reports of aluminium related neurological and bone disease began to appear. Available historical evidence however, suggests that neurological toxicity may have primarily been caused by excessive exposure to aluminium in dialysis fluid, rather than aluminium-containing oral phosphate binders. Limited evidence suggests that aluminium bone disease may also be on the decline in the era of aluminium removal from dialysis fluid, even with continued use of aluminium binders.
The K/DOQI and KDIGO guidelines both suggest avoiding aluminium-containing binders. These guidelines will tend to promote the use of the newer, more expensive binders (lanthanum, sevelamer), which have limited evidence for benefit and, like aluminium, limited long-term safety data. Treating hyperphosphatemia in dialysis patients continues to represent a major challenge, and there is a large body of evidence linking serum phosphate concentrations with mortality. Most nephrologists agree that phosphate binders have the potential to meaningfully reduce mortality in dialysis patients. Aluminium is one of the cheapest, most effective and well tolerated of the class, however there are no prospective or randomised trials examining the efficacy and safety of aluminium as a binder. Aluminium continues to be used as a binder in Australia as well as some other countries, despite concern about the potential for toxicity. There are some data from selected case series that aluminium bone disease may be declining in the era of reduced aluminium content in dialysis fluid, due to rigorous water testing.
This paper seeks to revisit the contemporary evidence for the safety record of aluminium-containing binders in dialysis patients. It puts their use into the context of the newer, more expensive binders and increasing concerns about the risks of calcium binders, which continue to be widely used. The paper seeks to answer whether the continued use of aluminium is justifiable in the absence of prospective data establishing its safety, and we call for prospective trials to be conducted comparing the available binders both in terms of efficacy and safety.
PMCID: PMC3107169  PMID: 21569446
3.  Rationale and design of the HEALTHY-CATH trial: A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients 
BMC Nephrology  2009;10:23.
Catheter-related bacteraemias (CRBs) contribute significantly to morbidity, mortality and health care costs in dialysis populations. Despite international guidelines recommending avoidance of catheters for haemodialysis access, hospital admissions for CRBs have doubled in the last decade. The primary aim of the study is to determine whether weekly instillation of 70% ethanol prevents CRBs compared with standard heparin saline.
The study will follow a prospective, open-label, randomized controlled design. Inclusion criteria are adult patients with incident or prevalent tunneled intravenous dialysis catheters on three times weekly haemodialysis, with no current evidence of catheter infection and no personal, cultural or religious objection to ethanol use, who are on adequate contraception and are able to give informed consent. Patients will be randomized 1:1 to receive 3 mL of intravenous-grade 70% ethanol into each lumen of the catheter once a week and standard heparin locks for other dialysis days, or to receive heparin locks only. The primary outcome measure will be time to the first episode of CRB, which will be defined using standard objective criteria. Secondary outcomes will include adverse reactions, incidence of CRB caused by different pathogens, time to infection-related catheter removal, time to exit site infections and costs. Prospective power calculations indicate that the study will have 80% statistical power to detect a clinically significant increase in median infection-free survival from 200 days to 400 days if 56 patients are recruited into each arm.
This investigator-initiated study has been designed to provide evidence to help nephrologists reduce the incidence of CRBs in haemodialysis patients with tunnelled intravenous catheters.
Trial Registration
Australian New Zealand Clinical Trials Registry Number: ACTRN12609000493246
PMCID: PMC2738669  PMID: 19691852
4.  Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial) 
BMC Nephrology  2009;10:20.
The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin® ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet®).
Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp®, Amgen) for ≥ 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events).
This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation.
Trial Registration
Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.
PMCID: PMC2723098  PMID: 19635169
5.  Intravenous versus oral iron supplementation for correction of post-transplant anaemia in renal transplant patients 
BMC Nephrology  2009;10:14.
Post-transplant anaemia remains a common problem after kidney transplantation, with an incidence ranging from nearly 80% at day 0 to about 25% at 1 year. It has been associated with poor graft outcome, and recently has also been shown to be associated with increased mortality.
Our transplant unit routinely administers oral iron supplements to renal transplant recipients but this is frequently accompanied by side effects, mainly gastrointestinal intolerance. Intravenous iron is frequently administered to dialysis patients and we sought to investigate this mode of administration in transplant recipients after noticing less anaemia in several patients who had received intravenous iron just prior to being called in for transplantation.
This study is a single-centre, prospective, open-label, randomised, controlled trial of oral versus intravenous iron supplements in renal transplant recipients and aims to recruit approximately 100 patients over a 12-month period. Patients will be randomised to receive a single dose of 500 mg iron polymaltose (intravenous iron group) or 2 ferrous sulphate slow-release tablets daily (oral iron group). The primary outcome is time to normalisation of haemoglobin post-transplant. Prospective power calculations have indicated that a minimum of 48 patients in each group would have to be followed up for 3 months in order to have a 90% probability of detecting a halving of the time to correction of haemoglobin levels to ≥110 g/l in iron-treated patients, assuming an α of 0.05. All eligible adult patients undergoing renal transplantation at the Princess Alexandra Hospital will be offered participation in the trial. Exclusion criteria will include iron overload (transferrin saturation >50% or ferritin >800 μg/l), or previous intolerance of either oral or intravenous iron supplements.
If the trial shows a reduction in the time to correction of anaemia with intravenous iron or less side effects than oral iron, then intravenous iron may become the standard of treatment in this patient group.
PMCID: PMC2701932  PMID: 19500381
6.  The impact of automated eGFR reporting and education on nephrology service referrals 
Nephrology Dialysis Transplantation  2008;23(12):3845-3850.
Background. Serum creatinine concentration is an unreliable and insensitive marker of chronic kidney disease (CKD). To improve CKD detection, the Australasian Creatinine Consensus Working Committee recommended reporting of estimated glomerular filtration rate (eGFR) using the four-variable Modification of Diet in Renal Disease (MDRD) formula with every request for serum creatinine concentration. The aim of this study was to evaluate the impact of automated laboratory reporting of eGFR on the quantity and quality of referrals to nephrology services in Southeast Queensland, Australia.
Methods. Outpatient referrals to a tertiary and regional renal service, and a single private practice were prospectively audited over 3–12 months prior to and 12 months following the introduction of automated eGFR reporting and concomitant clinician education. The appropriateness of referrals to a nephrologist was assessed according to the Kidney Check Australia Taskforce (KCAT) criteria. Significant changes in the quantity and/or quality of referrals over time were analysed by exponentially weighed moving average (EWMA) charts with control limits based on ±3 standard deviations.
Results. A total of 1019 patients were referred to the centres during the study period. Monthly referrals overall increased by 40% following the introduction of eGFR reporting, and this was most marked for the tertiary renal service (52% above baseline). The appropriateness of nephrologist referrals, as adjudicated by the KCAT criteria, fell significantly from 74.3% in the 3 months pre-eGFR reporting to 65.2% in the 12 months thereafter (P < 0.05). Nevertheless, a greater absolute number of CKD patients were appropriately being referred for nephrologist review in the post-eGFR period (24 versus 15 per month). Patients referred following the introduction of eGFR were significantly more likely to be older (median 63.2 versus 59.3 years, P < 0.05), diabetic (25 versus 18%, P = 0.05) and have stage 3 CKD (48% versus 36%, P < 0.01).
Conclusion. The introduction of automated eGFR calculation has led to an overall increase in referrals with a small but significant decrease in referral quality. The increase in referrals was seen predominantly in older and diabetic patients with stage 3 CKD and appeared to result in net benefit.
PMCID: PMC2639066  PMID: 18632591
chronic kidney disease; Cockcroft–Gault equation; glomerular filtration rate; Modification of Diet in Renal Disease equation; serum creatinine
7.  Clinical Causes of Inflammation in Peritoneal Dialysis Patients 
Inflammation at both systemic and local intraperitoneal levels commonly affects peritoneal dialysis (PD) patients. Interest in inflammatory markers as targets of therapeutic intervention has been considerable as they are recognised as predictors of poor clinical outcomes. However, prior to embarking on strategies to reduce inflammatory burden, it is of paramount importance to define the underlying processes that drive the chronic active inflammatory status. The present review aims to comprehensively describe clinical causes of inflammation in PD patients to which potential future strategies may be targeted.
PMCID: PMC4033334  PMID: 24895536
8.  The Association between Body Mass Index and Mortality in Incident Dialysis Patients 
PLoS ONE  2014;9(12):e114897.
To study the body mass index (BMI) trajectory in patients with incident end-stage kidney disease and its association with all-cause mortality.
This longitudinal cohort study included 17022 adult patients commencing hemodialysis [HD] (n = 10860) or peritoneal dialysis [PD] (n = 6162) between 2001 and 2008 and had ≥6-month follow-up and ≥2 weight measurements, using the Australia and New Zealand Dialysis and Transplant Registry data. The association of time-varying BMI with all-cause mortality was explored using multivariate Cox regression models.
The median follow-up was 2.3 years. There was a non-linear change in the mean BMI (kg/m2) over time, with an initial decrease from 27.6 (95% confidence interval [CI]: 27.5, 27.7) to 26.7 (95% CI: 26.6, 26.9) at 3-month, followed by increments to 27.1 (95% CI: 27, 27.2) at 1-year and 27.2 (95% CI: 26.8, 27.1) at 3-year, and a gradual decrease subsequently. The BMI trajectory was significantly lower in HD patients who died than those who survived, although this pattern was not observed in PD patients. Compared to the reference time-varying BMI category of 25.1–28 kg/m2, the mortality risks of both HD and PD patients were greater in all categories of time-varying BMI <25 kg/m2. The mortality risks were significantly lower in all categories of time-varying BMI >28.1 kg/m2 among HD patients, but only in the category 28.1–31 kg/m2 among PD patients.
BMI changed over time in a non-linear fashion in incident dialysis patients. Time-varying measures of BMI were significantly associated with mortality risk in both HD and PD patients.
PMCID: PMC4267775  PMID: 25513810
9.  Croup in children 
PMCID: PMC3796596  PMID: 23939212
10.  Using technology to revolutionize cooperative learning: an opinion 
Frontiers in Psychology  2014;5:1156.
PMCID: PMC4195269  PMID: 25352815
cooperative learning; technology; social interdependence; cooperation; promotive interaction
11.  Paediatric pain management practice and policies across Alberta emergency departments 
Paediatrics & Child Health  2014;19(4):190-194.
Many children requiring acute care receive suboptimal analgesia.
To describe paediatric pain management practices and policies in emergency departments (EDs) in Alberta.
A descriptive survey was distributed to each of the EDs in Alberta.
A response rate of 67% (72 of 108) was obtained. Seventy-one percent (42 of 59) of EDs reported the use of a pain tool, 29.3% (17 of 58) reported mandatory pain documentation and 16.7% (10 of 60) had nurse-initiated pain protocols. Topical anesthetics were reported to be used for intravenous line insertion by 70.4% of respondents (38 of 54) and for lumbar puncture (LP) by 30.8% (12 of 39). According to respondents, infiltrated anesthetic was used for LP by 69.2% (27 of 39) of respondents, and oral sucrose was used infrequently for urinary catheterization (one of 46 [2.2%]), intravenous line insertion (zero of 54 [0%]) and LP (one of 39 [2.6%]).
Few Alberta EDs use policies and protocols to manage paediatric pain. Noninvasive methods to limit procedural pain are underutilized. Canadian paediatricians must advocate for improved analgesia to narrow this knowledge-to-practice gap.
PMCID: PMC4028644  PMID: 24855415
Analgesia; Emergency; Pain; Paediatrics; Survey
13.  SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial 
BMC Nephrology  2014;15:106.
Emerging evidence suggests modulating the microbiota in the large bowel of patients with chronic kidney disease (CKD) through pre- and/probiotic supplementation may inhibit the development of key nephrovascular toxins. To date, quality intervention trials investigating this novel treatment in CKD are lacking. The aim of SYNERGY is to assess the effectiveness of synbiotics (co-administration of pre- and probiotics) as a potential treatment targeting the synthesis of uremic toxins, specifically, indoxyl sulphate (IS) and p-cresyl sulphate (PCS).
Thirty-seven patients with moderate to severe CKD (Stage IV and V, pre-dialysis) will be recruited to a double-blind, placebo-controlled, randomised cross-over trial. Patients will be provided with synbiotic therapy or placebo for 6 weeks, with a 4 week washout before cross-over. The primary outcome is serum IS, total and free (unbound) concentrations, measured using ultra-performance liquid chromatography. Secondary outcomes include serum PCS, total and free (unbound) concentrations; cardiovascular risk, measured by serum lipopolysaccharides, serum trimethylamine-N-oxide (TMAO) and inflammation and oxidative stress markers; kidney damage, measured by 24 hour proteinuria and albuminuria, estimated glomerular filtration rate and renal tubule damage (urinary kidney injury molecule-1); patients’ self assessed quality of life; and gastrointestinal symptoms. In addition, the effects on the community structure of the stool microbiota will be explored in a subset of patients to validate the mechanistic rationale underpinning the synbiotic therapy.
IS and PCS are two novel uremic toxins implicated in both cardiovascular disease (CVD) and progression of CKD. Preliminary studies indicate that synbiotic therapy maybe a promising strategy when considering a targeted, tolerable and cost-efficient therapy for lowering serum IS and PCS concentrations. This trial will provide high quality ‘proof-of-concept’ data to elucidate both the efficacy of synbiotic therapy for lowering the toxins and whether reductions in serum IS and PCS translate into clinical benefits. Considering the potential of pre- and probiotics to not only shift toxin levels, but to also impede CVD and CKD progression, SYNERGY will provide vital insight into the effectiveness of this innocuous nutritional therapy.
Trial Registration
Universal Trial Number: U1111-1142-4363. Australian New Zealand Clinical Trials Registry Number: ACTRN12613000493741, date registered: 2nd May 2013.
PMCID: PMC4094543  PMID: 24996842
Prebiotics; Probiotics; Synbiotics; Chronic kidney disease; Gut microbiota; Indoxyl sulphate; P-cresyl sulphate; Endotoxins
14.  The HONEYPOT Randomized Controlled Trial Statistical Analysis Plan 
♦ Background: The HONEYPOT study is a multicenter, open-label, blinded-outcome, randomized controlled trial designed to determine whether, compared with standard topical application of mupirocin for nasal staphylococcal carriage, exit-site application of antibacterial honey reduces the rate of catheter-associated infections in peritoneal dialysis patients.
♦ Objective: To make public the pre-specified statistical analysis principles to be adhered to and the procedures to be performed by statisticians who will analyze the data for the HONEYPOT trial.
♦ Methods: Statisticians and clinical investigators who were blinded to treatment allocation and treatment-related study results and who will remain blinded until the central database is locked for final data extraction and analysis determined the statistical methods and procedures to be used for analysis and wrote the statistical analysis plan. The plan describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues, and the specific statistical procedures for analyzing the primary, secondary, and safety outcomes.
♦ Results: A statistical analysis plan containing the pre-specified principles, methods, and procedures to be adhered to in the analysis of the data from the HONEYPOT trial was developed in accordance with international guidelines. The structure and content of the plan provide sufficient detail to meet the guidelines on statistical principles for clinical trials produced by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
♦ Conclusions: Making public the pre-specified statistical analysis plan for the HONEYPOT trial minimizes the potential for bias in the analysis of trial data and the interpretation and reporting of trial results.
PMCID: PMC3707722  PMID: 23843589
Randomized controlled trial; statistical analysis plan; outcome reporting bias; pre-specified statistical analyses; International Conference on Harmonization; intention-to-treat; catheter-associated infections
15.  Impact of emergency department probiotic treatment of pediatric gastroenteritis: study protocol for the PROGUT (Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment) randomized controlled trial 
Trials  2014;15:170.
The burden of acute gastroenteritis on children and their families continues to be enormous. Probiotics, defined as viable microbial preparations that have a beneficial effect on the health of the host, represent a rapidly expanding field. Although clinical trials in children with gastroenteritis have been performed, most have significant flaws, and guidelines do not consistently endorse their use.
PROGUT is a randomized, placebo-controlled, double-blind, five-center, Canadian, emergency department trial. Children aged 3 months to 48 months who present between November 2013 and June 2017 with <72 hours of gastroenteritis symptoms will be assessed for eligibility. A total of 886 children will be randomized (1:1 allocation via an internet based, third party, randomization service) to receive 5 days of a combination probiotic agent (Lactobacillus rhamnosus and L. helveticus) or placebo. All participants, caregivers, and outcome assessors will be blinded to group assignment. The study includes three key outcomes: 1) clinical - the development of moderate to severe disease following an emergency department (ED) evaluation that employs a validated clinical score (Modified Vesikari Scale); 2) safety - side effect; and 3) mechanism - fecal secretory immunoglobulin A levels.
Definitive data are lacking to guide the clinical use of probiotics in children with acute gastroenteritis. Hence, probiotics are rarely prescribed by North American physicians. However, the following current trends obligate an urgent assessment: 1) probiotics are sold as food supplements, and manufacturers can encourage their use while their relevance has yet to be established; 2) North American and European government agencies remain concerned about their value and safety; 3) some institutions are now recommending the routine use of probiotics; and 4) parents of affected children are often providing probiotics. With probiotic consumption increasing in the absence of solid evidence, there is a need to conduct this definitive trial to overcome the limitations of prior work in this field.
Trial registration NCT01853124; first registered 9 May 2013.
PMCID: PMC4037747  PMID: 24885220
Probiotics; Emergencies; Pediatrics; Gastroenteritis; Randomized controlled trial; Adverse effects; Immunoglobulin A
16.  A randomized trial of sodium-restriction on kidney function, fluid volume and adipokines in CKD patients 
BMC Nephrology  2014;15:57.
Dietary sodium restriction is a key management strategy in chronic kidney disease (CKD). Recent evidence has demonstrated short-term reduction in blood pressure (BP) and proteinuria with sodium restriction, however the effect on other cardiovascular-related risk factors requires investigation in CKD.
The LowSALT CKD study involved 20 hypertensive Stage III-IV CKD patients counselled by a dietitian to consume a low-sodium diet (<100 mmol/day). The study was a randomised crossover trial comparing 2 weeks of high-sodium (additional 120 mmol sodium tablets) and low-sodium intake (placebo). Measurements were taken after each crossover arm including BP (peripheral and central), adipokines (inflammation markers and adiponectin), volume markers (extracellular-to-intracellular [E/I] fluid ratio; N-terminal pro-brain natriuretic peptide [NT-proBNP]), kidney function (estimated Glomerular Filtration Rate [eGFR]) and proteinuria (urine protein-creatinine ratio [PCR] and albumin-creatinine ratio [ACR]). Outcomes were compared using paired t-test for each cross-over arm.
BP-lowering benefits of a low-sodium intake (peripheral BP (mean ± SD) 148/82 ± 21/12 mmHg) from high-sodium (159/87 ± 15/10 mmHg) intake were reflected in central BP and a reduction in eGFR, PCR, ACR, NTproBNP and E/I ratio. There was no change in inflammatory markers, total or high molecular weight adiponectin.
Short-term benefits of sodium restriction on BP were reflected in significant change in kidney function and fluid volume parameters. Larger, long-term adequately powered trials in CKD are necessary to confirm these results.
Trial registration
Universal Trial Number U1111-1125-2149 registered on 13/10/2011; Australian New Zealand Clinical Trials Registry Number ACTRN12611001097932 registered on 21/10/2011.
PMCID: PMC3994521  PMID: 24708818
Dietary sodium; Nutrition; Chronic kidney disease; Cardiovascular disease; Blood pressure; Kidney function; Inflammation
17.  The Caenorhabditis elegans Myc-Mondo/Mad Complexes Integrate Diverse Longevity Signals 
PLoS Genetics  2014;10(4):e1004278.
The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the “Myc interaction network” consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging.
Author Summary
Transcription factors are essential proteins that regulate the expression of genes and play an important role in most biological processes. The results of our study presented here demonstrate for the first time a role in aging for a small family of transcription factors in the nematode worm Caenorhabditis elegans. Importantly, these proteins have close relatives in higher organisms, including humans that influence metabolism, cell replication, and have been implicated in the development of cancer. Moreover, the loss of one homologue has also been implicated in Williams-Beuren syndrome, a disease characterized in part by signs of premature aging. Our data demonstrate that these transcription factors function within insulin/IGF-1 signaling and dietary restriction, two highly conserved pathways that link nutrient sensing to longevity. Taken together, our findings provide exciting new insight into a family of proteins that may be essential for linking nutrient sensing to longevity and have implications for the improvement of human healthspan.
PMCID: PMC3974684  PMID: 24699255
18.  Dialysate interleukin-6 predicts increasing peritoneal solute transport rate in incident peritoneal dialysis patients 
BMC Nephrology  2014;15:8.
Repeated exposure to peritoneal dialysis (PD) solutions contributes to cumulative intraperitoneal inflammation and peritoneal injury. The present study aimed to explore the capacity of dialysate interleukin-6(IL-6) to a) predict peritoneal membrane function and peritonitis in incident PD patients, and b) to evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solution on dialysate IL-6 levels.
The study included 88 incident participants from the balANZ trial who had completed 24-months of follow-up. Change in peritoneal solute transport rate (PSTR) and peritonitis were primary outcome measures, and the utility of IL-6 and IL-6 appearance rate (IL-6 AR) in predicting these outcomes was analyzed using multilevel linear regression and Cox proportional hazards models, respectively. Sensitivity analyses were performed by analyzing outcomes in a peritonitis-free cohort (n = 56).
Dialysate IL-6 concentration significantly increased from baseline to 24 months (mean difference 19.07 pg/mL; P < 0.001) but was not affected by the type of PD solution received (P = 0.68). An increase in PSTR from baseline was associated with higher levels of IL-6 (P = 0.004), the use of standard solutions (P = 0.005) and longer PD duration (P < 0.001). Baseline IL-6 level was not associated with a shorter time to first peritonitis (adjusted hazard ratio 1.00, 95% CI 0.99-1.00, P = 0.74). Analysis of IL-6 AR as well as sensitivity analyses in a peritonitis-free cohort yielded comparable results.
Dialysate IL-6 concentration increased with longer PD duration and was a significant, independent predictor of PSTR. The use of biocompatible PD solutions exerted no significant effect on dialysate IL-6 levels but did abrogate the increase in PSTR associated with standard PD solutions. This is the first study to examine the impact of biocompatible solutions on the utility of IL-6 in predicting PSTR and peritonitis.
PMCID: PMC3893539  PMID: 24410736
Biocompatible; Glucose degradation products; Interleukin-6; Peritoneal dialysis; Peritoneal solute transport rate; Peritonitis
19.  Effects of Climatic Region on Peritonitis Risk, Microbiology, Treatment, and Outcomes: a Multicenter Registry Study 
♦ Background: The impact of climatic variations on peritoneal dialysis (PD)-related peritonitis has not been studied in detail. The aim of the current study was to determine whether various climatic zones influenced the probability of occurrence or the clinical outcomes of peritonitis.
♦ Methods: Using ANZDATA registry data, the study in cluded all Australian patients receiving PD between 1 October 2003 and 31 December 2008. Climatic regions were defined according to the Köppen classification.
♦ Results: The overall peritonitis rate was 0.59 episodes per patient-year. Most of the patients lived in Temperate regions (65%), with others residing in Subtropical (26%), Tropical (6%), and Other climatic regions (Desert, 0.6%; Grassland, 2.3%). Compared with patients in Temperate regions, those in Tropical regions demonstrated significantly higher overall peritonitis rates and a shorter time to a first peritonitis episode [adjusted hazard ratio: 1.15; 95% confidence interval (CI): 1.01 to 1.31]. Culture-negative peritonitis was significantly less likely in Tropical regions [adjusted odds ratio (OR): 0.42; 95% CI: 0.25 to 0.73]; its occurrence in Subtropical and Other regions was comparable to that in Temperate regions. Fungal peritonitis was independently associated with Tropical regions (OR: 2.18; 95% CI: 1.22 to 3.90) and Other regions (OR: 3.46; 95% CI: 1.73 to 6.91), where rates of antifungal prophylaxis were also lower. Outcomes after first peritonitis episodes were comparable in all groups.
♦ Conclusions: Tropical regions were associated with a higher overall peritonitis rate (including fungal peritonitis) and a shorter time to a first peritonitis episode. Augmented peritonitis prophylactic measures such as antifungal therapy and exit-site care should be considered in PD patients residing in Tropical climates.
PMCID: PMC3598268  PMID: 22942270
Antibiotics; bacteria; climate; fungus; microbiology; peritonitis; outcomes
20.  Croup in the paediatric emergency department 
Paediatrics & Child Health  2007;12(6):473-477.
Croup is a common childhood illness. The majority of children presenting with an acute onset of barky cough, stridor and indrawing have croup. A careful history and physical examination is necessary to confirm the diagnosis of croup, and to rule out potentially serious alternative causes of upper airway obstruction. Nebulized adrenaline is effective for the temporary relief of airway obstruction. Corticosteroids are the mainstay of treatment in children with croup of all levels of severity.
PMCID: PMC2528757  PMID: 19030411
Child; Corticosteroids; Croup; Inhaled adrenaline
21.  Effect of Timing of Dialysis Commencement on Clinical Outcomes of Patients with Planned Initiation of Peritoneal Dialysis in the Ideal Trial 
♦ Background: Since the mid-1990s, early dialysis initiation has dramatically increased in many countries. The Initiating Dialysis Early and Late (IDEAL) study demonstrated that, compared with late initiation, planned early initiation of dialysis was associated with comparable clinical outcomes and increased health care costs. Because residual renal function is a key determinant of outcome and is better preserved with peritoneal dialysis (PD), the present pre-specified subgroup analysis of the IDEAL trial examined the effects of early-compared with late-start dialysis on clinical outcomes in patients whose planned therapy at the time of randomization was PD.
♦ Methods: Adults with an estimated glomerular filtration rate (eGFR) of 10 - 15 mL/min/1.73 m2 who planned to be treated with PD were randomly allocated to commence dialysis at an eGFR of 10 - 14 mL/min/1.73 m2 (early start) or 5 - 7 mL/min/1.73 m2 (late start). The primary outcome was all-cause mortality.
♦ Results: Of the 828 IDEAL trial participants, 466 (56%) planned to commence PD and were randomized to early start (n = 233) or late start (n = 233). The median times from randomization to dialysis initiation were, respectively, 2.03 months [interquartile range (IQR):1.67 - 2.30 months] and 7.83 months (IQR: 5.83 - 8.83 months). Death occurred in 102 early-start patients and 96 late-start patients [hazard ratio: 1.04; 95% confidence interval (CI): 0.79 - 1.37]. No differences in composite cardiovascular events, composite infectious deaths, or dialysis-associated complications were observed between the groups. Peritonitis rates were 0.73 episodes (95% CI: 0.65 - 0.82 episodes) per patient-year in the early-start group and 0.69 episodes (95% CI: 0.61 - 0.78 episodes) per patient-year in the late-start group (incidence rate ratio: 1.19; 95% CI: 0.86 - 1.65; p = 0.29). The proportion of patients planning to commence PD who actually initiated dialysis with PD was higher in the early-start group (80% vs 70%, p = 0.01).
♦ Conclusion: Early initiation of dialysis in patients with stage 5 chronic kidney disease who planned to be treated with PD was associated with clinical outcomes comparable to those seen with late dialysis initiation. Compared with early-start patients, late-start patients who had chosen PD as their planned dialysis modality were less likely to commence on PD.
PMCID: PMC3524893  PMID: 23212859
Dialysis timing; mortality; outcomes; peritonitis
22.  A Randomized Controlled Trial of Storytelling as a Communication Tool 
PLoS ONE  2013;8(10):e77800.
Stories may be an effective tool to communicate with patients because of their ability to engage the reader. Our objective was to evaluate the effectiveness of story booklets compared to standard information sheets for parents of children attending the emergency department (ED) with a child with croup.
Parents were randomized to receive story booklets (n=208) or standard information sheets (n=205) during their ED visit. The primary outcome was change in anxiety between triage to ED discharge as measured by the State-Trait Anxiety Inventory. Follow-up telephone interviews were conducted at 1 and 3 days after discharge, then every other day until 9 days (or until resolution of symptoms), and at 1 year. Secondary outcomes included: expected future anxiety, event impact, parental knowledge, satisfaction, decision regret, healthcare utilization, time to symptom resolution.
There was no significant difference in the primary outcome of change in parental anxiety between recruitment and ED discharge (change of 5 points for the story group vs. 6 points for the comparison group, p=0.78). The story group showed significantly greater decision regret regarding their decision to go to the ED (p<0.001): 6.7% of the story group vs. 1.5% of the comparison group strongly disagreed with the statement “I would go for the same choice if I had to do it over again”. The story group reported shorter time to resolution of symptoms (mean 3.7 days story group vs. 4.0 days comparison group, median 3 days both groups; log rank test, p=0.04). No other outcomes were different between study groups.
Stories about parent experiences managing a child with croup did not reduce parental anxiety. The story group showed significantly greater decision regret and quicker time to resolution of symptoms. Further research is needed to better understand whether stories can be effective in improving patient-important outcomes.
Trial Registration
Current Controlled Trials, ISRCTN39642997 (
PMCID: PMC3808406  PMID: 24204974
23.  The Effects of Biocompatible Compared with Standard Peritoneal Dialysis Solutions on Peritonitis Microbiology, Treatment, and Outcomes: the balANZ Trial 
♦ Background: A multicenter, multi-country randomized controlled trial (the balANZ study) recently reported that peritonitis rates significantly improved with the use of neutral-pH peritoneal dialysis (PD) solutions low in glucose degradation products (“biocompatible”) compared with standard solutions. The present paper reports a secondary outcome analysis of the balANZ trial with respect to peritonitis microbiology, treatment, and outcomes.
♦ Methods: Adult incident PD patients with residual renal function were randomized to receive either biocompatible or conventional (control) PD solutions for 2 years.
♦ Results: The safety population analysis for peritonitis included 91 patients in each group. The unadjusted geometric mean peritonitis rates in those groups were 0.30 [95% confidence interval (CI): 0.22 to 0.41] episodes per patient-year for the biocompatible group and 0.49 (95% CI: 0.39 to 0.62) episodes per patient-year for the control group [incidence rate ratio (IRR): 0.61; 95% CI: 0.41 to 0.90; p = 0.01]. When specific causative organisms were examined, the rates of culture-negative, gram-positive, gram-negative, and polymicrobial peritonitis episodes were not significantly different between the biocompatible and control groups, although the biocompatible group did experience a significantly lower rate of non-pseudomonal gram-negative peritonitis (IRR: 0.41; 95% CI: 0.18 to 0.92; p = 0.03). Initial empiric antibiotic regimens were comparable between the groups. Biocompatible fluid use did not significantly reduce the risk of peritonitis-associated hospitalization (adjusted odds ratio: 0.80; 95% CI: 0.48 to 1.34), but did result in a shorter median duration of peritonitis-associated hospitalization (6 days vs 11 days, p = 0.05). Peritonitis severity was more likely to be rated as mild in the biocompatible group (37% vs 10%, p = 0.001). Overall peritonitis-associated technique failures and peritonitis-related deaths were comparable in the two groups.
♦ Conclusions: Biocompatible PD fluid use was associated with a broad reduction in gram-positive, gram-negative, and culture-negative peritonitis that reached statistical significance for non-pseudomonal gram-negative organisms. Peritonitis hospitalization duration was shorter, and peritonitis severity was more commonly rated as mild in patients receiving biocompatible PD fluids, although other peritonitis outcomes were comparable between the groups.
PMCID: PMC3524863  PMID: 22991015
Biocompatibility; glucose degradation products; peritonitis; outcomes; randomized controlled trial; technique survival; end-stage renal disease
24.  Weekend Compared with Weekday Presentations of Peritoneal Dialysis-Associated Peritonitis 
♦ Objective: Management of peritoneal dialysis (PD)-associated peritonitis requires timely intervention by experienced staff, which may not be uniformly available throughout the week. The aim of the present study was to examine the effects of weekend compared with weekday presentation on peritonitis outcomes.
♦ Methods: The study, which used data from the Australia and New Zealand Dialysis and Transplant Registry, included all Australian patients receiving PD between 1 October 2003 and 31 December 2008. The independent predictors of weekend presentation and subsequent peritonitis outcomes were assessed by multivariate logistic regression.
♦ Results: Peritonitis presentation rates were significantly lower on Saturdays [0.46 episodes per year; 95% confidence interval (CI): 0.42 to 0.49 episodes per year] and on Sundays (0.43 episodes per year; 95% CI: 0.40 to 0.47 episodes per year) than all other weekdays; they peaked on Mondays (0.76 episodes per year; 95% CI: 0.72 to 0.81 episodes per year). Weekend presentation with a first episode of peritonitis was independently associated with lower body mass index and residence less than 100 km away from the nearest PD unit. Patients presenting with peritonitis on the weekend were significantly more likely to be hospitalized [adjusted odds ratio (OR): 2.32; 95% CI: 1.85 to 2.90], although microbial profiles and empiric antimicrobial treatments were comparable between the weekend and weekday groups. Antimicrobial cure rates were also comparable (79% vs 79%, p = 0.9), with the exception of cure rates for culture-negative peritonitis, which were lower on the weekend (80% vs 88%, p = 0.047). Antifungal prophylaxis was less likely to be co-prescribed for first peritonitis episodes presenting on weekdays (OR: 0.68; 95% CI: 0.05 to 0.89).
♦ Conclusions: Patients on PD are less likely to present with peritonitis on the weekend. Nevertheless, the microbiology, treatment, and outcomes of weekend and weekday PD peritonitis presentations are remarkably similar. Exceptions include the associations of weekend presentation with a higher hospitalization rate and a lower cure rate in culture-negative infection.
PMCID: PMC3524873  PMID: 22302768
After hours; bacteria; fungus; microbiology; peritonitis; outcomes; temporal variation
25.  Use of high-dose erythropoietin for repair after injury: A comparison of outcomes in heart and kidney 
Journal of Nephropathology  2013;2(3):154-165.
Context: There is a need to define the exact benefits and contraindications of use of high-dose recombinant human erythropoietin (EPO) for its non-hematopoietic function as a cytokine that enhances tissue repair after injury. This review compares the outcomes from use of EPO in the injured heart and kidney, two organs that are thought, traditionally, to have intrinsically-different repair mechanisms.
Evidence Acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched.
Results: Ongoing work by us on EPO protection of ischemia-reperfusion-injured kidneys indicated, first, that EPO acutely enhanced kidney repair via anti-apoptotic, pro-regenerative mechanisms, and second, that EPO may promote chronic fibrosis in the long term. Work by others on the ischaemia-injured heart has also indicated that EPO promotes repair. Although myocardial infarcts are made up mostly of necrotic tissue, many publications state EPO is anti-apoptotic in the heart, as well as promoting healing via cell differentiation and stimulation of granulation tissue. In the case of the heart, promotion of fibrosis may be advantageous where an infarct has destroyed a zone of cardiomyocytes, but if EPO stimulates progressive fibrosis in the heart, this may promote cardiac failure.
Conclusions: A major concern in relation to the use of EPO in a cytoprotective role is its stimulation of long-term inflammation and fibrosis. EPO usage for cytoprotection is undoubtedly advantageous, but it may need to be offset with an anti-inflammatory agent in some organs, like kidney and heart, where progression to chronic fibrosis after acute injury is often recorded.
PMCID: PMC3891135  PMID: 24475445
Erythropoietin; Cytokine; Ischemia-reperfusion; Cytoprotection; Heart; Kidney

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