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.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The effects of synbiotics on the liver steatosis, inflammation, and gut microbiome of metabolic dysfunction-associated liver disease patients-randomized trial.

INTRODUCTION: Metabolic Dysfunction-associated Liver Disease (MASLD) represents a spectrum of conditions from simple fat accumulation to non-alcoholic steatohepatitis. The possible role of the intestinal microbiome on MASLD development has been in focus. Our study aimed to examine the effects of synbiotics on the liver steatosis, inflammation, and stool microbiome. METHODS: A double-blind, placebo-controlled study was conducted involving 84 MASLD patients, defined by an elastometric attenuation coefficient (ATT) greater than 0.63 dB/cm/MHz with an alanine aminotransferase level above 40 U/L for men and 35 U/L for women. The patients were divided into an intervention group treated with a synbiotic with 64x109 CFU of Lactobacillus and Bifidobacterium and 6.4g of inulin and a control group treated with a placebo. RESULTS: Using synbiotics for 12 weeks significantly decreased liver steatosis (ΔATT -0.006±0.023 vs -0.016±0.021 dB/cm/MHz, p=0.046). The group of patients treated with synbiotics showed a significant decrease in the level of high-sensitive C-reactive protein (Δhs-CRP 0 vs -0.7 mg/L, p≤0.001). Synbiotics enriched the microbiome of patients in the intervention group with the genera Lactobacillus, Bifidobacterium, Faecalibacterium, and Streptococcus, by 81%, 55%, 51%, and 40%, respectively, with a reduction of Ruminococcus and Enterobacterium by 35% and 40%. Synbiotic treatment significantly shortened the gut transition time (ΔGTT -5h vs. -10h, p=0.031). CONCLUSION: Synbiotics could be an effective and safe option that could have place in MASLD treatment.

Increased Peritoneal Protein Loss and Diabetes: Is There a Link?

Increased peritoneal protein loss has been associated with the fast transport of small molecules, diabetes mellitus (DM), and a reduced survival in patients on peritoneal dialysis (PD), although some studies did not confirm the association with survival. In this single-center retrospective study, we investigated the relationship of baseline peritoneal albumin and protein loss with transport status, comorbidities including DM, and survival in 106 incident PD patients during the period of July 2005-June 2014. Five-year survival rate was determined using Cox-regression analysis. There were not significant differences in D/Pcr or peritoneal protein and albumin loss between diabetics and non-diabetics. In the group of 66 non-diabetics, high and high-average transporters for creatinine had higher values for both peritoneal protein (11.85 ± 6.77 vs. 7.85 ± 4.36 g/day; p = 0.002) and albumin (5.03 ± 2.32 vs. 3.72 ± 1.54 g/day; p = 0.016) loss as compared to slow transporters. However, in the group of 40 diabetics, this association was not observed. Upon multivariable regression analysis, the independent association of D/PCr with peritoneal albumin (ß = 0.313; p = 0.008) and protein (ß = 0.441; p = 0.001) loss was found only in non-diabetics in whom ultrafiltration also appeared as a significant predictor of peritoneal protein loss (ß = 0.330; p = 0.000). A high comorbidity grade, older age, and low serum albumin were associated with mortality, but both peritoneal protein and albumin loss as well as D/Pcr were not determinants of survival. Baseline peritoneal protein and albumin loss was not associated with DM and did not predict survival. The clinical significance of the absence of association between fast peritoneal transport status and peritoneal protein flux in diabetics should be evaluated in a prospective study comprising a greater number of diabetics with evaluation of overhydration as a main inducing variable of protein leak.

Systemic and intraperitoneal proinflammatory cytokine profiles in patients on continuous ambulatory peritoneal dialysis.

Our cross-sectional study included 44 patients (27 men, 17 women; mean age: 57.12 +/- 16.66 years; mean dialysis treatment period: 3.59 +/- 2.67 years) on continuous ambulatory peritoneal dialysis (CAPD). Of the 44 patients, 21 were using standard solutions (Stay*Safe, ANDY-disc: Fresenius Medical Care, Bad Homburg, Germany), and 23 were using biocompatible solutions (Gambrosol Trio: Gambro Lundia AB, Lund, Sweden; Stay*Safe Balance: Fresenius Medical Care). In all CAPD patients dialyzed longer than 6 months, we analyzed levels of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and interleukin 6 (IL-6) in serum and dialysis effluent when patients were free of acute infection-related (CAPD peritonitis, exit-site infection, other acute infections) complications. In a control group of 20 patients with chronic renal failure [CRF (stages IV and V)], we also determined serum levels of the same cytokines. Levels of the inflammatory cytokines were measured using specific commercial ELISA kits (BioSource, Camarillo, CA, U.S.A.). Statistical analysis of the results was performed using commercial statistics software for the PC (Statistica for Windows, rev. 4.5: StatSoft, Tulsa, OK, U.S.A.). Serum levels of LL-1beta and IL-6 were not statistically significantly different between the patients on CAPD, regardless of the type of dialysis the used, and between the patients and the control group with CRF. Serum levels of TNFalpha, unlike those for IL-1beta and IL-6, were statistically significantly higher in patients on CAPD than in the control group with CRF (13.20 +/- 3.23 pg/mL vs. 5.59 +/- 4.54 pg/mL, p < 0.001, Mann-Whitney test). Serum and effluent IL-1beta levels in patients on CAPD for less than 1 year and more than 1 year did not significantly differ, but effluent IL-6 levels were significantly higher than serum IL-6 levels in both groups of patients, and effluent IL-6 levels were significantly higher in CAPD patients dialyzed for more than 1 year than in patients dialyzed for less than 1 year. Serum and intraperitoneal (IP) levels of the examined cytokines did not significantly differ in patients on standard and biocompatible solutions, but a trend toward lower IP levels of IL-6 was seen in patients on biocompatible solutions. Residual renal function and number of episodes of CAPD peritonitis had no important effect on serum and IP levels of the examined cytokines. Elevated serum levels of TNFalpha and significant local IL-6 production in our CAPD patients indirectly confirmed the importance of peritoneal dialysis (PD) in amplifying the chronic inflammation that substantially depends on duration of dialysis treatment.

Onset of Microscopic Polyangiitis in Binephrectomied Patient on Chronic Hemodialysis-Case Report.

INTRODUCTION: Microscopic polyangiitis (MPA) is one of the causes of the pulmonary-renal syndrome associated with elevated non-specific markers of inflammation and antineutrophil cytoplasmic autoantibody (ANCA) positivity in 50-75%. De novo occurrence of the disease in patients on chronic hemodialysis (HD) has not been described. CASE PRESENTATION: We presented patient who developed MPO-ANCA-associated MPA with lung and musculoskeletal involvement after 4 years on regular HD due to bilateral nephrectomy. After excluding the other causes of MPO-ANCA positivity, diagnosis was confirmed even without renal biopsy. Patient received standard immunosuppression therapy and he is still in remission after 27 months. CONCLUSION: The onset of immune-mediated disease could be observed even after introduction of renal replacement therapy, which may be a diagnostic problem. Early recognition and traditional immunosuppressive regiment may provide successful outcome.

Influence of peritoneal dialysis solution biocompatibility on long-term survival of patients on continuous ambulatory peritoneal dialysis and the technique itself.

BACKGROUND/AIM: Morbidity and mortality of continous ambulatory peritoneal dialysis (CAPD) patients is still very high. The aim of the study was to evaluate the effects of peritoneal dialysis (PD) solutions (standard vs biocompatible) on long-term patients' and the techique survival. METHODS: A total of 42 stable patients on CAPD participated in this cross-sectional study. They were prospectively followed-up during the twelve years. Patients with severe anemia (Hb < 10 g/L) and malignant disease ware excluded. Twenty one (50%/0) patients were treated with the standard PD solutions (CAPDP-1) while the other 21 (500/0) were treated with biocompatible PD solutions [(lower level of glucose degradation products, lower concentration of Ca(2+) and neutral pH (CAPDP-2)]. All patients were analyzed for a presence of vascular calcification, nutrition status, and parameters of inflammation after 2.5 +/- 0.6 years of starting CAPD, and these variables considered in the analysis as risk factors. RESULTS: The patients from the group CAPDP-2 compared to those from the group CAPDP-1 had lower level of high-sensitivity C-reactive protein (hs-CRP) (p = 0.003), and better nutritional status as confirmed by the mid-arm circumference (p = 0.015), and mid-arm muscle circumference (p = 0.002) and subjective global assessment (p = 0.000). Also, they had lower vascular calcifications as confirmed by intima media thickness (IMT) (p = 0.003), degree of carotid narrowing (p = 0.001) and calcified plaques of common carotid arteries (CCA) (p = 0.008). Kaplan-Meier analysis confirmed better survival of patients from the group CAPDP-2 than those from the group CAPDP-1 (1-, 5-, and 10-year patients survival rate was: 100%, 61.9% and 14.3% for the group CAPDP-1, and 100%, 85.7%, and 52.4% for the group CAPDP-2, respectively; p = 0.0345). The 1-, 5-, and 10-year technique survival rate was: 100%, 71.4%, and 38.1% for the group CAPDP-1, and 100%, 85.7%, and 76.2% for the group CAPDP-2, respectively; (p = 0.0719). Duration of dialysis, serum triglyceride and cardiovascular score (quantitative scoring system consisting of: ejection fraction (EF) of left ventricle < 50%; IMT > 1 mm; carotid narrowing degree > 50%, presence of carotid plaques in both common carotide, ischaemic heart disease, cerebrovascular event and peripheral vascular disease with or without amputation) were independent predictors of overall patient survival. Duration of dialysis was only independent predictor of overall technique survival. CONCLUSION: Although patients treated with biocompatible solutions showed significantly better survival, the role of biocompatibility of CAPD solutions in patients and technique survival have to be confirmed. Namely, multivariate analysis confirmed that duration of dialysis, serum triglyceride and cardiovascular score significantly predicted overall CAPD patients survival, while only duration of dialysis was found to be independent predictor of overall techique survival.

[Correlation between dialysis solution type and cardiovascular morbidity rate in patients undergoing continuous ambulatory peritoneal dialysis].

BACKGROUND/AIM: Peritoneal dialysis (PD) patients have an increased risk for cardiovascular diseases. The aim of the study was to evaluate the cardiovascular changes in patients undergoing chronic PD and the eventual existing differences depending on biocompatibility of dialysis solutions. METHODS: After 3 +/- 2 years of starting PD, 21 PD patients on the treatment with bioincompatible dialysis solutions (conventional glucose- based solutions: PDP-1), average age 47.43 +/- 12.87 years, and 21 PD patients on the treatment with biocompatible dialysis solutions (neutral solutions with lower level of glucose degradation products, lower concentration of Ca2+ and neutral pH: PDP-2), average age 68.62 +/- 13.98 years, participated in the longitudinal study. The average number of episodes of peritonitis was similar in both groups: 1 episode per 36 months of the treatment. The control group included 21 patients with preterminal phase of chronic renal failure (Glomerular Filtration Rate: 22.19 +/- 10.73 ml/min), average age 65.29 +/- 13.74 years. All the patients underwent transthoracal echocardiography (in order to detect: eject fraction (EF), left ventricular hypertrophy (LVH), and valvular calcification (VC) and B-mode ultrasonography of common carotid artery (CCA): IMT, lumen narrowing, and plaque detection. RESULTS: The values of EF were: in PDP-1 group 62.05 +/- 5.65%, in PDP-2 group 53.43 +/- 7.47%, and in the control group 56.71 +/- 8.12% (Bonferroni test, p = 0.001). The recorded LVH was: in PDP-1 group in 47.6% of the patients; in PDP-2 group in 61.9% of the patients; and in control the group in 52.4% (chi2 test; p = 0.639). The detected VC was: in PDP-1 in 52.4% of the patients, in PDP-2 group in 42.9% of the patients, and in the control group in 23.8% of the patients (chi2 test; p = 0.776). The IMT was: in PDP-1 group 1.26 +/- 0.54 mm, in PDP-2 group 1.23 +/- 0.32, and in the control group 1.25 +/- 0.27 mm (Bonferroni test; p = 0.981). An average lumen narrowing was: in PDP-1 group 13.78 +/- 18.26%, in PDP-2 group 18.57 +/- 22.98%, and in the control group 25.00 +/- 28.02% (Kruskal Wallis test; p = 0.413). Calcified plaques of CCA were detected in PDP-1 group in 61.9% of the patients, in PDP-2 group in 85.7%, of the patients and p = 0.159). CONCLUSION: Generally, PD had a significant influence on cardiovascular morbidity in the treated patients, especially on the left ventricular function and peripheral atherosclerosis. The age of the patients had more influence on acceleration of atherosclerosis than the length of dialysis or biocompatibility of dialysis solutions.

Systemic and intraperitoneal proinflammatory cytokines profiles in patients on chronic peritoneal dialysis.

Cytokines are essential mediators of immune response and inflammatory reactions. Patients with chronic renal failure and on Continuous Ambulatory Peritoneal Dialysis commonly present abnormalities of immune function related to impaired kidney function, accumulation of uremic toxins and bioincompatibility of peritoneal dialysis solutions. Aim of this study was to examine effects of the CAPD solutions (standard v.s. biocompatible), as well as dialysis duration upon the local and systemic profile of the pro-inflammatory cytokines (IL-1, TNF and IL-6) in patients on CAPD. The cross-sectional study included 44 CAPD patients (27 M and 17 F, average mean age 57.12+/-16.66), of whom 21 patients were on the standard solutions (A.N.D.Y.Disc) for peritoneal dialysis and 23 on the biocompatible solutions (Gambrosol bio trio, Stay Safe balance). The average dialysis treatment period was 3.59+/-2.67 years. In all CAPD patients dialysed longer than 6 months, levels of IL-1. TNF and IL-6 in the serum and dialysis effluent were analysed in the phase without acute infection-related complications (CAPD peritonitis, infection of the catheter exit-site, other acute infections). The control group included 20 patients with the CRF (stage IV and V) whose serum levels of the examined cytokines were also determined. Levels of the inflammatory cytokines were measured by commercial specific ELISA kits (BioSource, Camarillo, California, USA). Statistical analysis of the obtained results was performed by commercial statistics PC software (Stat for Windows, R.4.5. SAD). The serum IL-1 and IL-6 levels were not statistically significantly different in patients on CAPD, irrespective of the type of the used dialysis solutions and in the control group of patients with CRF. The serum TNF levels, unlike IL-1 and IL-6, were statistically significantly higher in patients on CAPD in comparison with the control group of patients (13.203.23 v.s. 5.594.54, p< 0.001, Mann Whitney test). The serum and effluent IL-1 levels in patients on CAPD within one and longer than one year of dialysation did not significantly differ, but the effluent IL-6 levels were significantly higher than in the serum of both groups of patients, that is, effluent IL-6 levels in CAPD patients dialysed more than one year was significantly higher in comparison with those in patients dialysed within a year. Both serum and intraperitoneal levels of the examined cytokines did not significantly differ in patients on the standard and biocompatible solutions, regardless of the present trend toward decrease of intraperitoneal IL-6 levels in patients on biocompatible solutions. Residual renal funcion and number of CAPD peritonitis did not have any important impact upon the serum and IP levels of the examined ctokynes. Elevated serum TNF levels and significant local IL-6 production in our CAPD patients indirectly confirm importance of peritoneal dialysis in amplification of the chronic inflammation substantially depend on the duration of dialysis treatment.