The Impact of Synbiotic Treatment on the Levels of Gut-Derived Uremic Toxins, Inflammation, and Gut Microbiome of Chronic Kidney Disease Patients-A Randomized Trial.
Altering dysbiotic gut flora through synbiotic supplementation has recently been recognized as a potential treatment strategy to reduce the levels of gut-derived uremic toxins and decrease inflammation. Assessing its efficacy and safety has been the main goal of our randomized, double-blind, placebo-controlled study.
A total of 34 nondialyzed chronic kidney disease patients, aged ≥18 years, with an estimated glomerular filtration rate between 15 and 45 mL/minute, were randomized either to an intervention group (n = 17), receiving synbiotic (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium lactis, 32 billion colony forming units per day plus 3.2 g of inulin), or control group (n = 17), receiving placebo during 12 weeks. The impact of treatment on the dynamic of serum levels of gut-derived uremic toxins, total serum indoxyl sulfate, p-cresyl sulfate, and trimethylamine N-oxide, was defined as the primary outcome of the study. Secondary outcomes included changes in the stool microbiome, serum interleukin-6 levels, high-sensitivity C-reactive protein, estimated glomerular filtration rate, albuminuria, diet, gastrointestinal symptom dynamics, and safety. Serum levels of uremic toxins were determined using ultraperformance liquid chromatography. The stool microbiome analysis was performed using the 16S ribosomal ribonucleic acid gene sequencing approach.
Synbiotic treatment significantly modified gut microbiome with Bifidobacteria, Lactobacillus, and Subdoligranulum genera enrichment and consequently reduced serum level of indoxyl sulfate (ΔIS -21.5% vs. 5.3%, P < .001), improved estimated glomerular filtration rate (ΔeGFR 12% vs. 8%, P = .029), and decreased level of high-sensitivity C-reactive protein (-39.5 vs. -8.5%, P < .001) in treated patients. Two patients of the intervention arm complained of increased flatulence. No other safety issues were noted.
Synbiotics could be available, safe, and an effective therapeutic strategy we could use in daily practice in order to decrease levels of uremic toxins and microinflammation in chronic kidney disease patients.
Mitrović M
，Stanković-Popović V
，Tolinački M
，Golić N
，Soković Bajić S
，Veljović K
，Nastasijević B
，Soldatović I
，Svorcan P
，Dimković N
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Protein-bound uremic toxin lowering strategies in chronic kidney disease: a systematic review and meta-analysis.
Accumulation of protein-bound uremic toxins, including indoxyl sulfate and p-cresyl sulfate, are associated with increased cardiovascular disease and mortality in chronic kidney disease (CKD). We performed a systematic review and meta-analysis to synthesize the available strategies for lowering protein-bound uremic toxin levels in CKD patients.
We conducted a meta-analysis by searching the databases of MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials for observational studies and randomized controlled trials (RCTs) that examined the effect of dietary protein restrictions, biotic supplements (including prebiotics, probiotics, and synbiotics), AST-120, dialysis techniques, and the outcome of preservation of residual renal function (RRF) on indoxyl sulfate and p-cresyl sulfate levels. Random-effect model meta-analyses were used to compute changes in the outcomes of interest.
A total of 38 articles (2,492 patients), comprising 28 RCTs, 8 single-arm or prospective cohort studies, and 2 cross-sectional studies were included in this meta-analysis. When compared with placebo, prebiotics, synbiotics, and AST-120 provided significantly lower levels of both serum indoxyl sulfate and p-cresyl sulfate. There were no significant reductions in serum indoxyl sulfate and p-cresyl sulfate levels in patients receiving probiotics. Preservation of RRF in dialysis patients resulted in lower levels of both of the protein-bound uremic toxins. When compared with conventional hemodialysis, hemodiafiltration significantly decreased serum p-cresyl sulfate alone, whereas a significant change in serum indoxyl sulfate levels was observed only in studies with long-term observation periods. Very low protein diet (VLPD) and other oral medications yielded insignificant differences in protein-bound uremic toxins.
The present meta-analysis demonstrated that prebiotics, synbiotics, and AST-120 can effectively reduce both serum indoxyl sulfate and p-cresyl sulfate in CKD patients when compared with placebo. Preservation of RRF was associated with lower serum indoxyl sulfate and p-cresyl sulfate levels. The effect of biotic supplements was detected only in dialysis patients. For non-dialysis CKD patients, the results were limited due to the small number of studies. Further studies are needed to determine the efficacy in these populations.
Takkavatakarn K
，Wuttiputinun T
，Phannajit J
，Praditpornsilpa K
，Eiam-Ong S
，Susantitaphong P
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Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial.
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.
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.
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.
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.
Rossi M
，Johnson DW
，Morrison M
，Pascoe EM
，Coombes JS
，Forbes JM
，Szeto CC
，McWhinney BC
，Ungerer JP
，Campbell KL
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