Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial

Clin J Am Soc Nephrol. 2016 Feb 5;11(2):223-31. doi: 10.2215/CJN.05240515. Epub 2016 Jan 15.

Abstract

Background and objectives: The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome-generated uremic toxins, IS and PCS, in patients with CKD.

Design, setting, participants, & measurements: Predialysis adult participants with CKD (eGFR=10-30 ml/min per 1.73 m(2)) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double-blind, placebo-controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect.

Results: Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m(2)), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (-2 μmol/L; 95% confidence interval [95% CI], -5 to 1 μmol/L) but did significantly reduce serum PCS (-14 μmol/L; 95% CI, -27 to -2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, -25 μmol/L; 95% CI, -38 to -12 μmol/L; serum IS, -5 μmol/L; 95% CI, -8 to -1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes.

Conclusion: In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large-scale clinical trials are justified.

Keywords: chronic kidney disease; glomerular filtration rate; humans; indoxyl sulphate; microbiota; p-cresyl sulphate; probiotics; renal insufficiency, chronic; synbiotics; uremic toxins.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Bacterial Agents / therapeutic use
  • Bacteria / drug effects
  • Bacteria / metabolism*
  • Cresols / blood
  • Cross-Over Studies
  • Double-Blind Method
  • Feces / microbiology
  • Female
  • Gastrointestinal Microbiome* / drug effects
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / microbiology*
  • Glomerular Filtration Rate
  • Humans
  • Indican / blood
  • Kidney / physiopathology
  • Male
  • Middle Aged
  • Prebiotics* / adverse effects
  • Probiotics / adverse effects
  • Probiotics / therapeutic use*
  • Queensland
  • Renal Insufficiency / blood
  • Renal Insufficiency / diagnosis
  • Renal Insufficiency / microbiology
  • Renal Insufficiency / therapy*
  • Severity of Illness Index
  • Sulfuric Acid Esters / blood
  • Synbiotics* / adverse effects
  • Time Factors
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Cresols
  • Prebiotics
  • Sulfuric Acid Esters
  • 4-cresol sulfate
  • Indican