Effects of Microbiota-Driven Therapy on Circulating Indoxyl Sulfate and P-Cresyl Sulfate in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), protein-bound uremic toxins, exacerbate the deterioration of renal function and increase the risk of cardiovascular events in chronic kidney disease (CKD) patients. The effects of microbiota-driven therapy (probiotics, prebiotics, or synbiotics) on decreasing circulating IS and PCS concentrations are controversial; thus, we performed the present systematic review and meta-analysis to assess the effects of microbiota-driven therapy on circulating IS and PCS concentrations in CKD patients. PubMed, EMBASE, and Cochrane Library databases were systematically searched from inception to 22 July, 2021, and randomized controlled trials (RCTs) investigating the effects of microbiota-driven therapy on circulating IS and PCS concentrations in CKD patients were included. In all, 14 RCTs with 513 participants were eligible for the meta-analysis. The effects of microbiota-driven therapy on the circulating IS and PCS concentrations were evaluated with weighted mean differences (WMDs) measured by a fixed-effects model or a random-effects model. Compared with placebo, microbiota-driven therapy had no statistically significant effect on the circulating IS concentration (WMD: -1.64 mg/L; 95% CI: -3.46, 0.18 mg/L; P = 0.077) but it decreased the circulating PCS concentration (WMD: -2.42 mg/L; 95% CI: -3.81, -1.04 mg/L; P = 0.001). In the subgroup analyses, prebiotic (n = 6) and synbiotic (n = 3) supplementation significantly decreased the circulating PCS concentration, whereas probiotic (n = 3) supplementation did not. Meta-regression showed that the effects of microbiota-driven therapy were not associated with the supplementation time or the year of publication. Moreover, there was no significant evidence of publication bias. This review found that microbiota-driven therapy decreased the circulating PCS concentration in CKD patients. Additional large, well-designed RCTs with improved methodology and reporting are necessary to assess the effects of microbiota-driven therapy on circulating IS and PCS concentrations in the long term. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42021269146.

Chen L ，Shi J ，Ma X ，Shi D ，Qu H ... -  《-》

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 ... -  《-》

Prebiotic, Probiotic, and Synbiotic Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-analysis.

Gut dysbiosis has been implicated in the pathogenesis of chronic kidney disease (CKD). Restoring gut microbiota with prebiotic, probiotic, and synbiotic supplementation has emerged as a potential therapeutic intervention but has not been systematically evaluated in the CKD population. This is a systematic review. A structured search of MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and the International Clinical Trials Register Search Portal was conducted for articles published since inception until July 2017. Included studies were randomized controlled trials investigating the effects of prebiotic, probiotic, and/or synbiotic supplementation (>1 week) on uremic toxins, microbiota profile, and clinical and patient-centered outcomes in adults and children with CKD. Sixteen studies investigating 645 adults met the inclusion criteria; 5 investigated prebiotics, 6 probiotics, and 5 synbiotics. The quality of the studies (Grades of Recommendation, Assessment, Development and Evaluation) ranged from moderate to very low. Prebiotic, probiotic, and synbiotic supplementation may have led to little or no difference in serum urea (9 studies, 345 participants: mean difference [MD] -0.30 mmol/L, 95% confidence interval [CI] -2.20 to 1.61, P = .76, I2 = 53%), indoxyl sulfate (4 studies, 144 participants: MD -0.02 mg/dL, 95% CI -0.09 to 0.05, P = .61, I2 = 0%), and p-cresyl sulfate (4 studies, 144 participants: MD -0.13 mg/dL, 95% CI -0.41 to 0.15, P = .35, I2 = 0%). Prebiotic supplementation may have slightly reduced serum urea concentration (4 studies, 105 participants: MD -2.23 mmol/L, 95% CI -3.83 to -0.64, P = .006, I2 = 11). Of the 2 studies investigating microbiota changes, synbiotic interventions significantly increased Bifidobacterium. Supplement effects on clinical outcomes were uncertain. There is limited evidence to support the use of prebiotics, probiotics, and/or synbiotics in CKD management.

McFarlane C ，Ramos CI ，Johnson DW ，Campbell KL ... -  《-》

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 ... -  《-》

Probiotics, prebiotics, and synbiotics for the improvement of metabolic profiles in patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials.

Zheng HJ ，Guo J ，Wang Q ，Wang L ，Wang Y ，Zhang F ，Huang WJ ，Zhang W ，Liu WJ ，Wang Y ... -  《-》