Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY)

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-1b, IL-6, IL-10, and TNF-a), serum oxidative stress biomarkers (F 2 -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 =69610 years old; 57% men; eGFR=2468 ml/min per 1.73 m 2 ), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (22 mmol/L; 95% confidence interval [95% CI], 25 to 1 mmol/L) but did significantly reduce serum PCS (214 mmol/L; 95% CI, 227 to 22 mmol/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, 225 mmol/L; 95% CI, 238 to 212 mmol/L; serum IS, 25 mmol/L; 95% CI, 28 to 21 mmol/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. ConclusionIn 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.

Effect of Synbiotic Therapy on Gut–Derived Uremic Toxins and the Intestinal Microbiome in Patients with CKD

“…In this issue of the Clinical Journal of American Society of Nephrology, Rossi et al (20) report the results of a randomized, double-blind, crossover trial of coadministration of a prebiotic and a probiotic for 6 weeks separated by a 4-week washout period and changes in serum IS and PCS in patients with CKD (eGFR between 10 and 30 ml/min per 1.73 m 2 ). The prebiotic component consisted of a mixture of high molecular weight inulin, fructooligosaccharides, and galacto-oligosaccharides (7.5 g once daily during the first 3 weeks and twice daily during the final 3 weeks of the trial).…”

Kronik Böbrek Hastalığında Bağırsak Mikrobiyotası ve Diyet Posasının Rolü

“…Kronik böbrek hastalarında disbiyozisin, özellikle proteine bağımlı üremik toksinlerin oluşumunu artırarak üremik durumu daha da kötüleştirdiği bilinmektedir (21). KBH'lı bireylerde ve hayvan modellerinde bozulan simbiyotik ilişkinin düzeltilmesinde fermente edilebilir diyet posasının proteine bağımlı üremik toksin oluşumunu azaltmada etkili olduğu gösterilmiştir (22)(23)(24)(25)(26) KBH'lı hastalarda bağırsak mikrobiyotasının kompozisyonu ve fonksiyonundaki değişikliklerin sebeplerinden biri hastaların hiperkalemiden korunması için diyette potasyumdan zengin meyve ve sebzelerin kısıtlanmasıdır. Beslenme tedavisinde sınırlanan bu besinler aynı zamanda fermente edilebilir diyet posanın da zengin kaynaklarındandır (15, [46][47][48].…”

“…Çalışma süresince hiç antibiyotik tedavisi almayan hastalarda simbiyotik tedavi sonrasında hem serum p-cresol hem de indoxyl sülfat düzeylerinde %22-28 olmak üzere istatistiksel ve klinik öneme sahip azalma gözlenmiştir. Ancak diğer renal, inflamatuvar, oksidatif stres göstergelerinde, gastrointestinal semptom skorlarında ve diyet alımlarında bir değişiklik gözlenmemiştir (25). …”

Regulation of endogenous brakes to kidney fibrosis: turning the view upside down

“…Impaired kidney function goes along with rising levels of uremic toxins, of which there are more than 120 substances that mediate adverse effects on cognition and organ functions, such as digestion in the bowels and muscle weakness, appetite, and bone metabolism. Two uremic toxins have been analyzed in detail, indoxyl sulfate as well as pcresyl sulfate [2]. Both are already elevated at early stages of kidney impairment, importantly, the serum levels of indoxyl sulfate are up to fivefold elevated with chronic kidney disease and highly correlate with tubulointerstitial kidney fibrosis (r > 0.9).…”

“…Alterations in the intestinal microbial flora have been identified in patients with end-stage renal disease and have been induced in animal models of uremia within 8 weeks. Application of probiotics to correct the dysbiosis may prove beneficial [2].…”