Effect of Prebiotics and/or Probiotics on Uremic Toxins and Inflammation Markers in Peritoneal Dialysis Patients

December 6, 2018 updated by: Alfonso Martín Cueto Manzano, Unidad de Investigacion Medica en Enfermedades Renales

Effect of a Nutritional Supplement of Probiotics and/or Prebiotics vs Placebo on Serum Concentrations of Uremic Toxins and Inflammatory Cytokines in Automated Peritoneal Dialysis Patients.

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

112

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Mexico
    • Jalisco
      • Guadalajara, Jalisco, Mexico, 44290
        • Umae Hospital de Especialidades

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Probiotic
Subjects receiving probiotic supplementation: 2x108 CFU probiotic bacteria + prebiotic placebo per day during 3 months
Dietary supplement: Probiotic
The probiotic supplement is composed of the following bacterial strains: Bacillus coagulans, Bacillus subtilis, Bifidobacterium (B) bifidum, B. breve, B. longum, Lactobacillus (L) acidophilus, L. brevis, L. casei, L. helveticus, L. Paracasei, L plantarum, L. rhamnosus, L. salivarus, Lactococcus lactis, Pediococcus acidilactici, Pediococcus parvulus, Weisella confusa, Weisella paramesenteroides
Active Comparator: Prebiotic
Subjects receiving prebiotic supplementation: 20 g of prebiotic fiber + probiotic placebo per day during 3 months
Dietary supplement: Prebiotic
The prebiotic fiber is Agave inulin
Experimental: Symbiotic
Subjects receiving probiotic and prebiotic supplementation: 2x108 CFU probiotic bacteria + 20 g of prebiotic fiber per day during 3 months
Dietary supplement: Symbiotic
The supplement is a combination of the probiotic product + the prebiotic fiber
Placebo Comparator: Placebo
Subjects receiving placebo of probiotic and prebiotic per day during 3 months
Dietary supplement: Placebo
The supplement is a combination of probiotic placebo and prebiotic fiber placebo. Placebo will consist on maltodextrin for both cases.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of uremic toxins from basal to 1 and 3 months
Time Frame: Baseline, 1 month and 3 months
Measurement of serum concentrations of the uremic toxins p-cresyl sulphate (mg/dL) and indoxyl sulphate (mg/dL) by means of liquid chromatography.
Baseline, 1 month and 3 months
Change of uremic toxins from basal to 1 and 3 months
Time Frame: Baseline, 1 month and 3 months
Measurement of serum concentrations of endotoxin (EU/mL) by means of Limulus amebocyte lisate test.
Baseline, 1 month and 3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in gut microbiota composition from basal to 1 and 3 months
Time Frame: Baseline, 1 month and 3 months
Determination of fecal bacterial composition by DNA extraction and pyrosequencing analysis.
Baseline, 1 month and 3 months
Change in gastrointestinal symptoms from basal to 1 and 3 months
Time Frame: Baseline, 1 month and 3 months
Measurement of appetite and frequency and severity of gastrointestinal symptoms (nausea, vomiting, bloating, diarrhea, constipation) by means of a gastrointestinal symptoms questionnaire.
Baseline, 1 month and 3 months
Change of inflammatory cytokines from basal to 1 and 3 months
Time Frame: Baseline, 1 month and 3 months
Measurement of serum concentrations of inflammatory cytokines Interleukin-6 (pg/mL), Interleukin-10 (pg/mL) and Tumor Necrosis Factor alpha (pg/mL) by means of ELISA.
Baseline, 1 month and 3 months
Change of inflammatory cytokines from basal to 1 and 3 months
Time Frame: Baseline, 1 month and 3 months
Measurement of serum concentrations of C-Reactive Protein (mg/L) by means of nephelometry.
Baseline, 1 month and 3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Unidad de Investigacion Medica en Enfermedades Renales

Collaborators

Universidad de Colima
Centro Universitario de Tonalá

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

January 7, 2019

Primary Completion (Anticipated)

December 1, 2019

Study Completion (Anticipated)

August 1, 2020

Study Registration Dates

First Submitted

May 31, 2018

First Submitted That Met QC Criteria

December 6, 2018

First Posted (Actual)

December 10, 2018

Study Record Updates

Last Update Posted (Actual)

December 10, 2018

Last Update Submitted That Met QC Criteria

December 6, 2018

Last Verified

December 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UIMER003

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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