SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial

Abstract

BackgroundEmerging 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/designThirty-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.DiscussionIS 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 RegistrationUniversal Trial Number: U1111-1142-4363. Australian New Zealand Clinical Trials Registry Number: ACTRN12613000493741, date registered: 2nd May 2013.

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY)

“…More recently, administration of pre-and/or probiotics has emerged as a promising bowel-targeted therapeutic approach for modifying bacterial production of IS and PCS on the basis of a systematic review of clinical studies (11). Nonetheless, the conclusions that can be drawn from the available studies are appreciably limited by poor methodologic quality, clinical heterogeneity (including with respect to pre-and probiotic formulations), limited control for dietary intake, and a lack of exploration of effects on the gut microbiota (12,13).…”

Synbiotic supplementation promotes improvement of chronic diarrhea of unknown etiology in patient with chronic kidney disease and provides better outcomes in dialysis

“…Gastrointestinal (GI) symptoms tend to increase in CKD patients compared to the general population (13). Approximately 76% of HD patients exhibit such symptoms (14).…”

“…This study also observed improvements in other laboratory parameters such as hemoglobin, hematocrit, pre-dialysis urea, phosphorus and potassium, which can be attributed to the regular hemodialysis treatments that were reestablished after the episodes of diarrhea ceased. There are a number of benefits of synbiotic therapy for CKD patients, such as a reduction of uremic toxins and endotoxemia, improvement in GI symptoms and microbiota function providing an improvement in their quality of life (QOL) (13).…”

“…However, research related to CKD patients is scarce and there is no consensus on the adequate dosing or duration of synbiotic supplementation. Factors such as survival rates of the GI probiotic strains and the characteristics of prebiotic varieties differ widely and are crucial for the definition of therapeutic conduct (13,20).…”

Effects of a novel nutritional formula specially developed for chronic kidney disease patients on protein-restricted diets: a randomized controlled trial

“…Therefore, improving intestinal microflora and reducing uremic toxins by prebiotics may be a therapeutic target for CKD patients. Currently, there is an ongoing trial designed to test whether synbiotics that combine both probiotics and prebiotics reduce uremic toxins including indoxyl sulfate in CKD patients [10].…”