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1.  SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial 
BMC Nephrology  2014;15:106.
Background
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).
Methods/design
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.
Discussion
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.
doi:10.1186/1471-2369-15-106
PMCID: PMC4094543  PMID: 24996842
Prebiotics; Probiotics; Synbiotics; Chronic kidney disease; Gut microbiota; Indoxyl sulphate; P-cresyl sulphate; Endotoxins
2.  Time course and dose response of alpha tocopherol on oxidative stress in haemodialysis patients 
BMC Nephrology  2009;10:32.
Background
Oxidative stress is associated with increased cardiovascular morbidity and mortality particularly in patients with end stage kidney disease. Although observational data from the general population has shown dietary antioxidant intake is associated with reduced cardiovascular morbidity and mortality, most clinical intervention trials have failed to support this relationship. This may be a consequence of not using an effective antioxidant dose and/or not investigating patients with elevated oxidative stress. The SPACE study, conducted in haemodialysis patients, reported that 800 IU/day of alpha tocopherol significantly reduced cardiovascular disease endpoints. A recent time course and dose response study conducted in hypercholesterolaemic patients that found 1600 IU/day of alpha tocopherol was an optimal dose. There is no such dose response data available for haemodialysis patients. Therefore the aim of this study is to investigate the effect of different doses of oral alpha tocopherol on oxidative stress in haemodialysis patients with elevated oxidative stress and the time taken to achieve this effect.
Methods
The study will consist of a time-course followed by a dose response study. In the time course study 20 haemodialysis patients with elevated oxidative stress will take either 1600 IU/day natural (RRR) alpha tocopherol for 20 weeks or placebo. Blood will be collected every two weeks and analysed for a marker of oxidative stress (plasma F2-isoprostanes) and alpha tocopherol. The optimum time period to significantly decrease plasma F2-isoprostanes will be determined from this study. In the dose response study 60 patients will be randomised to receive either placebo, 100, 200, 400, 800 or 1600 IU/day of natural (RRR) alpha tocopherol for a time period determined from the time course study. Blood will be collected at baseline and every two weeks and analysed for plasma F2-isoprostanes and alpha tocopherol. It is hypothesised that doses ≥ 800 IU of vitamin E will be required to significantly decrease plasma F2-isoprostanes.
Discussion
This study will determine the time and dose required for alpha tocopherol to significantly decrease oxidative stress in haemodialysis patients. Data will be used to plan a large randomised controlled trial to assess the effects of alpha tocopherol on cardiovascular outcomes in haemodialysis patients.
Trial Registration
ACTRN12609000608268
doi:10.1186/1471-2369-10-32
PMCID: PMC2770501  PMID: 19845969
3.  Assessment of arterial stiffness, oxidative stress and inflammation in acute kidney injury 
BMC Nephrology  2009;10:15.
Background
It is well know that arterial stiffness, oxidative stress and inflammation are features of chronic kidney disease. The arterial changes have a multitude of potential interconnected causes including endothelial dysfunction, oxidative stress, inflammation, atherosclerosis and vascular calcification. There is evidence that arterial stiffness becomes progressively worse as CKD progresses. The contribution of the biochemical changes of uremic toxicity to arterial stiffness is less clear. The aim of this study is to elucidate the vascular changes in acute kidney injury. We hypothesise that arterial stiffness will be increased during acute kidney injury and this will return to normal after kidney function recovers.
Methods/Design
One hundred and forty four patients with acute kidney injury defined as an acute increase in serum creatinine to > 133 μmol/l or urea > 14.3 mmol/l or urine output < 410 ml/day will be recruited. Baseline measures of aortic pulse wave velocity, augmentation index, and brachial and central blood pressure will be recorded along with blood measures for oxidative stress and inflammation. Repeat measures will be taken at six and 12 months after the onset of the acute kidney injury.
Discussion
The role and contribution of the biochemical changes to arterial stiffness in the acute phase of kidney disease is not known. This study will primarily assess the time course changes in pulse wave velocity from the onset of acute kidney injury and after recovery. In addition it will assess augmentation index, central blood pressure and oxidative stress and inflammation. This may shed light on the contribution of biochemical kidney toxins on arterial stiffness in both acute kidney injury and chronic kidney disease.
Trial Registration
ACTRN 12609000285257
doi:10.1186/1471-2369-10-15
PMCID: PMC2702366  PMID: 19538714
4.  Comparison of markers of oxidative stress, inflammation and arterial stiffness between incident hemodialysis and peritoneal dialysis patients – an observational study 
BMC Nephrology  2009;10:8.
Background
Patients on peritoneal and hemodialysis have accelerated atherosclerosis associated with an increase in cardiovascular morbidity and mortality. The atherosclerosis is associated with increased arterial stiffness, endothelial dysfunction and elevated oxidative stress and inflammation. The aims of this study are to investigate the effects of peritoneal and hemodialysis on arterial stiffness, vascular function, myocardial structure and function, oxidative stress and inflammation in incident patients with end stage kidney disease.
Methods
This is an observational study. Eighty stage five CKD patients will be enrolled and followed for one-year. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity, 2) oxidative stress assessed by plasma F2 isoprostanes and 3) inflammation measured by plasma pentraxin-3. Secondary outcomes will include additional measures of oxidative stress and inflammation, changes in vascular function assessed using the brachial artery reactivity technique, carotid artery intimal medial thickness, augmentation index and trans thoracic echocardiography to assess left ventricular geometry, and systolic and diastolic function. Patients will undergo these measures at baseline (6–8 weeks prior to starting dialysis therapy), then at six and 12 months after starting dialysis.
Discussion
The results of this study may guide the choice of dialysis modality in the first year of treatment. It may also lead to a larger study prospectively assessing the effect of dialysis modality on cardiovascular morbidity and mortality.
Trial Registration
ACTRN12609000049279
doi:10.1186/1471-2369-10-8
PMCID: PMC2666726  PMID: 19284599
5.  Intradialytic versus home based exercise training in hemodialysis patients: a randomised controlled trial 
BMC Nephrology  2009;10:2.
Background
Exercise training in hemodialysis patients improves fitness, physical function, quality of life and markers of cardiovascular disease such as arterial stiffness. The majority of trials investigating this area have used supervised exercise training during dialysis (intradialytic), which may not be feasible for some renal units. The aim of this trial is to compare the effects of supervised intradialytic with unsupervised home-based exercise training on physical function and arterial stiffness.
Methods and design
This is a randomised, controlled clinical trial. A total of 72 hemodialysis patients will be randomised to receive either six months of intradialytic exercise training, home-based exercise training or usual care. Intradialytic patients will undergo three training sessions per week on a cycle ergometer and home-based patients will be provided with a walking program to achieve the same weekly physical activity. Primary outcome measures are six-minute walk distance (6 MWD) and aortic pulse wave velocity (PWV). Secondary outcome measures include augmentation index, peripheral and central blood pressures, physical activity and self-reported health. Measures will be made at baseline, three and six months.
Discussion
The results of this study will help determine the efficacy of home-based exercise training in hemodialysis patients. This may assist in developing exercise guidelines specific for these patients.
Trial Registration
ACTRN12608000247370
doi:10.1186/1471-2369-10-2
PMCID: PMC2642817  PMID: 19178747
6.  Astaxanthin vs placebo on arterial stiffness, oxidative stress and inflammation in renal transplant patients (Xanthin): a randomised controlled trial 
BMC Nephrology  2008;9:17.
Background
There is evidence that renal transplant recipients have accelerated atherosclerosis manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress and inflammation associated with immunosuppressive therapy. The dietary supplement astaxanthin has shown promise as an antioxidant and anti-inflammatory therapeutic agent in cardiovascular disease. The aim of this trial is to investigate the effects of astaxanthin supplementation on arterial stiffness, oxidative stress and inflammation in renal transplant patients.
Method and Design
This is a randomised, placebo controlled clinical trial. A total of 66 renal transplant recipients will be enrolled and allocated to receive either 12 mg/day of astaxanthin or an identical placebo for one-year. Patients will be stratified into four groups according to the type of immunosuppressant therapy they receive: 1) cyclosporine, 2) sirolimus, 3) tacrolimus or 4) prednisolone+/-azathioprine, mycophenolate mofetil or mycophenolate sodium. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by plasma isoprostanes and 3) inflammation by plasma pentraxin 3. Secondary outcomes will include changes in vascular function assessed using the brachial artery reactivity (BAR) technique, carotid artery intimal medial thickness (CIMT), augmentation index (AIx), left ventricular afterload and additional measures of oxidative stress and inflammation. Patients will undergo these measures at baseline, six and 12 months.
Discussion
The results of this study will help determine the efficacy of astaxanthin on vascular structure, oxidative stress and inflammation in renal transplant patients. This may lead to a larger intervention trial assessing cardiovascular morbidity and mortality.
Trial Registration
ACTRN12608000159358
doi:10.1186/1471-2369-9-17
PMCID: PMC2666668  PMID: 19091127
7.  The Lipid lowering and Onset of Renal Disease (LORD) Trial: A randomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression of kidney disease 
BMC Nephrology  2008;9:4.
Background
There is evidence that dyslipidemia is associated with chronic kidney disease (CKD). Experimental studies have established that lipids are damaging to the kidney and animal intervention studies show statins attenuate this damage. Small clinical trials, meta-analyses, observational studies and post-hoc analyses of cardiovascular intervention studies all support the concept that statins can reduce kidney damage in humans. Based on this background, a double blind randomized placebo controlled trial was designed to assess the effectiveness of atorvastatin 10 mg on slowing the progression of kidney disease in a population of patients with CKD.
Method/Design
The Lipid lowering and Onset of Renal Disease (LORD) trial is a three-year, single center, multi-site, double blind, randomized, placebo controlled trial. The primary outcome measure is kidney function measured by eGFR calculated by both Modification of Diet in Renal Disease (MDRD) and Cockcroft and Gault equations. Secondary outcome measures include kidney function measured by 24-hour urine creatinine clearance and also 24-hour urinary protein excretion, markers of oxidative stress, inflammation and drug safety and tolerability.
Discussion
The results of this study will help determine the effectiveness and safety of atorvastatin and establish its effects on oxidative stress and inflammation in patients with CKD.
Trial Registration
ANZCTRN012605000693628
doi:10.1186/1471-2369-9-4
PMCID: PMC2276485  PMID: 18366658

Results 1-7 (7)