End-stage renal disease (ESRD) is a world public health problem, with high morbidity and mortality. Cardiovascular disease is the main cause of mortality in ESRD; uremic toxin retention and inflammation are considered non-traditional risk factors, as they have an active role in atherosclerosis and vascular calcification pathogenesis in dialysis patients.

Uremic toxins may be generated by internal protein metabolism, however, some toxins that can't be efficiently eliminated by dialysis such as indoxyl sulphate and p-cresyl sulphate (protein bound toxins), are generated by the microbial metabolism in the large intestine by proteolytic bacteria, and may diffuse easily through the intestinal lumen, as a leaky gut characterizes kidney disease.

The gut has been recognized as a potential source of inflammation in ESRD patients; accumulation of nitrogen compounds, presence of gastrointestinal symptoms, dietary changes and multiple drugs and supplements use, stimulates microbiota alterations as bacterial overgrowth and translocation. These phenomena, may active the immune system, promoting local and systemic inflammation, which in turn has negative effects increasing endothelial dysfunction, muscle catabolism, insulin and erythropoietin resistance, and decreases appetite.

Some methods have been proposed to decrease inflammation and uremic toxin accumulation, as more efficient dialysis and anti-inflammatory drugs; however, some of them have limited efficacy and high cost. Nutritional treatments focused on modifying intestinal environment, as pre- and probiotics have promising effects by altering production and absorption of uremic toxins and decreasing inflammation; nevertheless, there is scarce information regarding its use and their role in ESRD, particularly in peritoneal dialysis, which is a widely used therapy in México. Furthermore, there is no clinical study comparing the effectiveness of prebiotics, probiotics, and symbiotics on serum concentrations of uremic toxins and inflammation in ESRD patients. It is possible that the administration of a nutritional supplement of probiotics and/or prebiotics decreases the serum concentrations of uremic toxins and inflammation markers in ESRD patients on automated peritoneal dialysis compared to placebo.

Objective:

The aim of the present study is to evaluate and to compare the effect of a nutritional supplement of probiotics and/or prebiotics on serum concentrations of uremic toxins and inflammatory markers compared to placebo, in automated peritoneal dialysis patients.

Sample size:

For the sample size calculation a mean differences formula was used, with a 95% confidence level, a 80% sample power and accuracy of 0.05. As a reference, the study of Salmean YA, 2015 was considered; in this study, the administration of pea fiber + inulin during 12 weeks in chronic kidney disease patients, significantly decreased (p<0.05) serum concentrations of p-cresol (5.82 ± 1.72 mg/L) in comparison to placebo (7.25 ± 1.74 mg/L). After substituting formula values and adding 20% of possible losses during follow-up, the sample size is: 28 patients.

Additionally, sample size calculation was made considering other outcomes. In the study of Xie LN, 2015, the administration of high-fermentable soluble fiber in ESRD patients on hemodialysis during 6 weeks, significantly decreased (p<0.05) inflammation markers: C-reactive protein (CRP), tumour necrosis factor alpha (TNFa) and interleukin 6 (IL-6) (4.8 ± 4.5 pg/mL, 10.1 ± 1.4 pg/mL, 31.8 ± 5.3 mg/L, respectively) compared to control group (9.5 ± 5.6 pg/mL, 13.1 ± 2.4 pg/mL, 51.5 ± 14.6 mg/L). After substituting the formula, sample size was 19, 7, and 5 for CRP, TNFa and IL-6, respectively.

Thus, the highest value was finally used: 28 patients for intervention group.

Statistical analysis:

Quantitative variables will be shown as mean and standard deviation or median (25-75 percentiles) according to their parametric or non-parametric distribution; Qualitative variables will be shown as frequency and percentage. Intergroup comparisons will be performed with χ2 or Fisher test for qualitative variables and one-way ANOVA or Kruskal-Wallis test for quantitative variables as appropriate. For intra-group comparisons Mc Nemar test will be used for qualitative variables and paired T-test, Wilcoxon, repeated-measures or Friedman ANOVA for quantitative variables as appropriate. An intention to treat analysis will be performed.

Inclusion Criteria:

• >3 months on automated peritoneal dialysis treatment
• Signed informed consent

Exclusion Criteria:

• ESRD of inflammatory cause (lupus, vasculitis, collagenopathies)
• Intake of probiotics, prebiotics or fiber in the last 3 months
• Use of anti-inflammatory drugs or nutritional supplements (immunossuppresants, pentoxifylline, NSAIDs, omega-3)
• Treated with antibiotics or sevelamer
• Treated with research drugs or participants in any clinical trial
• Peritonitis or active infection 2 weeks prior the study
• Any medical condition affecting intestinal absorption (inflammatory bowel disease, short bowel syndrome, bariatric surgery) or severe dysmotility
• Severe malnutrition
• Previous kidney transplantation
• Serious diseases altering the fina outcomes of the study: decompensated heart failure, chronic liver disease, cancer, AIDS.

Patient Blinding: Patients in automated peritoneal dialysis will be blinded to the intervention they will receive. Evaluator Blinding: The principal investigator and the Doctorate program student will be blinded to the intervention that patients will receive (probiotic, prebiotic, symbiotic or placebo).

Care providers will be blinded to the intervention groups.