Impact of Propionic Acid on Regulatory T Cell Function in Children With CKD

Study Overview
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Brief Summary
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Pro-Kids is a multi-center, double-blind, randomized and placebo-controlled intervention study in children with chronic kidney disease. The investigators address the effect of a dietary food supplementation of propionic acid on the immune system and the function of the intestinal barrier in CKD patients treated with hemodialysis.

Detailed Description
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Chronic inflammation is a major risk factor of cardiovascular disease progression in CKD, irrespective of confounding comorbidities. Based on current knowledge, microbially-derived metabolites such as short chain fatty acids (SCFA) play an important role in the regulation of chronic inflammatory processes in CKD patients. Children with CKD are known to have reduced serum levels of the SCFA propionic acid (PA), as a consequence of both gut microbial dysbiosis and reduced fiber intake. In animal and human studies the impact of PA on function and abundance of regulatory T cells (Treg) has been demonstrated. Consequently, the investigators aim to normalize the PA serum levels by oral PA food supplementation in hemodialysis patients in order to mitigate chronic inflammation.

Official Title
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Impact of Propionic Acid on Regulatory T Cell Function in Children With Chronic Kidney Disease

Conditions
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CKD (Chronic Kidney Disease) Stage 5D

Intervention / Treatment
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* Dietary Supplement: Sodium propionate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight: > 30kg CKD G5 treated with hemodialysis Continuous hemodialysis treatment for > 3 months Clinical stable condition Manifestation of CKD within childhood (<18 years) Exclusion Criteria: Disease or dysfunctions, which disqualifies the patient Incapacity of contract or any other circumstances, which prohibit the patient or his legal guardians from understanding setup, meaning and entity of the study Acute infections Immunosuppressive therapy within the last 12 weeks before the start of the study Pre-/pro- or postbiotic or antibiotic therapy within the last 4 weeks before the start of the study Planned or unplanned hospitalization within in last 4 weeks before the start of the study or during study Malignant diseases Pregnancy chronic gastrointestinal or hepatic diseases (for example chronic inflammatory bowel disease alcohol- or drug abuse parallel participation on other interventional trials

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, double-blind, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PA Intervention<br>The group which receives the PA as a dietary food supplement. A single capsule contains 500mg of sodiumpropionate, which is taken twice daily for 28 days. | Dietary Supplement: Sodium propionate<br>* The patients will be randomized to PA or placebo intervention (2:1 randomization). After the intervention of 28 days, we conduct an open-label study phase, where all patients are offered a dietary supplement of PA for overall 12 weeks (8 additional weeks for the intervention group and 12 weeks for the placebo group). By doing so we are giving every patient the opportunity to take PA and benefit from the possible positive impact on immunsystem and intestinal barrier function.<br>|
| Placebo Comparator: Placebo Intervention<br>The control-group receives a placebo instead of propionate. The placebo contains maltodextrin and the same amount of sodium chloride as compared to the PA intervention. The placebo is taken twice per day for 28 days. | Other: Placebo<br>* The patients will be randomized to PA or placebo intervention (2:1 randomization). After the intervention of 28 days, we conduct an open-label study phase, where all patients are offered a dietary supplement of PA for overall 12 weeks (8 additional weeks for the intervention group and 12 weeks for the placebo group). By doing so we are giving every patient the opportunity to take PA and benefit from the possible positive impact on immunsystem and intestinal barrier function.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in count of regulatory T-cells from baseline to week 4 | Analysis of Treg counts in whole blood (absolute quantification) and peripheral blood mononuclear cells (PBMC; relative quantification) by flow cytometry. | Baseline visit (week 0) in comparison to week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Propionic acid serum levels and targeted metabolomics | Analysis of PA serum levels and other microbially-derived metabolites by GC-MS and LC-MS | Baseline visit (week 0); Week 2; Week 4; Week 12 | 
| Immune cell phenotyping of peripheral blood mononuclear cells (PBMC) | Patients PBMC will be thawed and immune cells we be analyzed using multicolor flow cytometry and mass cytometry. By using a broad range of different antibodies combined in several panels the investigators will analyse distinct T cell subtypes including markers of activation, but also other immune cells (including B cells, dendritic cells, monocytes, natural killer cells). Data will reported in relation to parent populations (e.g. T heller cells in % of T cells). | Baseline visit (week 0); Week 2; Week 4; Week 12 | 
| T regulatory cell (Treg) suppression assay | The suppressive capacity of patients Treg will be analyzed by co-cultivation with conventional, stimulated T cells (Tconv) in different proportions (Treg:Tconv). The proliferation of Tconv will be reported. | Baseline visit (week 0); Week 4 | 
| Single cell RNA sequencing of immune cells | Analysis of the transcriptome of immune cells using cellular indexing of transcriptomes and epitopes (CITEseq) | Baseline visit (week 0); Week 4 | 
| Intestinal barrier function | Analysis of biomarkers for intestinal barrier function, such as sCD14, zonulin-1 and LPS | Baseline visit (week 0); Week 2; Week 4; Week 12 | 
| Taxonomy of the fecal microbiome | The taxonomy of the fecal microbiome will be anayzed using 16S RNA amplicon sequencing. | Baseline visit (week 0); Week 4 |