title: SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial.
abstract: 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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Universal Trial Number: U1111-1142-4363. Australian New Zealand Clinical Trials Registry Number: ACTRN12613000493741, date registered: 2nd May 2013.
authors.affiliation: School of Medicine, University of Queensland, Brisbane, Australia. megan.rossi@health.qld.gov.au.
authors.forename: Megan
authors.initials: M
authors.lastname: Rossi
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.forename: Mark
authors.initials: M
authors.lastname: Morrison
authors.forename: Elaine
authors.initials: E
authors.lastname: Pascoe
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Coombes
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.forename: Goce
authors.initials: G
authors.lastname: Dimeski
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Campbell
mesh_terms: D015415:Biomarkers / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D064307:Microbiota / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051437:Renal Insufficiency / Q000097:blood / Q000178:diet therapy* / Q000382:microbiology*; D058616:Synbiotics
chemical_list: D015415:Biomarkers