Oral Nutritional Supplement on Nutritional and Functional Status, and Biomarkers in Malnourished Hemodialysis Patients.

Study Overview
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Brief Summary
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Malnutrition in hemodialysis patients is frequent and it is associated with a reduction in muscular mass, strength, functional capacity and quality of life, with an increment in inflammatory and oxidative markers, and with a dysregulation of circulating miRNAs and its target genes. Animal and human studies have reported that some dietary components (macronutrients, micronutrients and other bioactive substances) might restore these altered features. Thus, we hypothesized that the intake of an oral nutritional supplement (ONS) specifically developed for malnourished hemodialysis patients enriched with functional nutrients (extra virgin olive oil, omega 3 fatty acids, whey protein, antioxidants, carnitine, and with or without probiotics) vs. individualized diet recommendations might: Improve nutritional status (visceral proteins, muscular mass), functional capacity and quality of life. Reduce inflammatory and oxidative markers, and modulate the circulating levels of some miRNAs and the expression of its target genes on cells. miRNAs may be useful biomarkers to check the response to a nutritional intervention in malnourished hemodialysis patients. The present study is a randomized, multicenter, parallel-group trial with 3 groups, open to the intake of ONS or individualized diet recommendations, but double-blind to the intake of probiotics. Inclusion criteria comprised adult subjects (>18 y/o) undergoing hemodialysis more than 6 months previous at inclusion and at least one of these caloric malnutrition criteria: a) involuntary weight loss >5% in 3 months or >10% in 6 months; b) serum albumin < 3.5 g/dl or prealbumin <28 mg/dl; c) body mass index (BMI) < 23 kg/m2; d) muscular mass loss >5% in 3 months or >10% in 6 months. The study duration is 6 months, and comprises 4 visits (screening, basal, 3 months and 6 months). A nutritional examination that included anthropometric measurements, handgrip strength measured by a hand dynamometer, body composition assessed by bioelectrical impedance analysis (BIA) and a 5 days dietary record; quality of life evaluation by the 12-item short form health survey; the presence of symptoms of depression and anxiety (Hospital Anxiety and Depression Scale); assessment of functional status by the Barthel test, the Short Physical Performance Battery and the International Physical Activity Questionnaire; and blood and stool samples will be obtained for each participant in each study visit (except screening visit).

Detailed Description
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Hypothesis: The intake of an oral nutritional supplement (ONS) specifically developed for malnourished hemodialysis patients enriched with functional nutrients (extra virgin olive oil, omega 3 fatty acids, whey protein, antioxidants, carnitine, and with or without probiotics) vs. individualized diet recommendations might: Improve nutritional status (visceral proteins, muscular mass), functional capacity and quality of life. Reduce inflammatory and oxidative markers, and modulate the circulating levels of some miRNAs and the expression of its target genes on cells. miRNAs may be useful biomarkers to check the response to a nutritional intervention in undernourished hemodialysis patients. Aims: To evaluate: The clinical response after the nutritional intervention: Nutritional status: anthropometric measurements, handgrip strength measured by a jamar hand dynamometer, body composition assessed by bioelectrical impedance analysis (BIA), and a 5 days dietary record. Functional status assessed by the Barthel test, the Short Physical Performance Battery and the International Physical Activity Questionnaire. Quality of life assessed by the 12-item short form health survey, and the presence of symptoms of depression and anxiety by the Hospital Anxiety and Depression Scale. The physiological response after the nutritional intervention: Inflammatory markers. Oxidative markers. Gut microbiota. Circulating miRNAs and the expression of its target genes on cells. Study design: Randomized, multicenter, parallel-group trial with 3 groups, open to the intake of ONS or diet, but double-blind to the intake of probiotics. Study centers: Hospital Regional Universitario de Málaga (Spain). Hospital San Cecilio. Granada (Spain). Hospital Rey Juan Carlos. Móstoles, Madrid (Spain). One-hundred and twenty patients will be included. Eligible subjects will be invited to participate, and written informed consent will be obtained before the inclusion. Participants will be randomly assigned to one of these three groups: ONS with probiotics. Dietary and physical activity recommendations. ONS without probiotics. Dietary and physical activity recommendations. Dietary and physical activity recommendations. The study duration is 6 months, and comprises 4 visits (screening, basal, 3 months and 6 months). Recruitment period: 12 months. Inclusion criteria: adult subjects (>18 y/o) undergoing hemodialysis more than 6 months previous at inclusion and at least one of these caloric malnutrition criteria: a) involuntary weight loss >5% in 3 months or >10% in 6 months; b) serum albumin < 3.5 g/dl or prealbumin <28 mg/dl; c) body mass index (BMI) < 23 kg/m2; d) muscular mass loss >5% in 3 months or >10% in 6 months. A nutritional examination that included anthropometric measurements, handgrip strength measured by a jamar hand dynamometer, body composition assessed by bioelectrical impedance analysis (BIA) and a 5 days dietary record; quality of life evaluation by the 12-item short form health survey; the presence of symptoms of depression and anxiety (Hospital Anxiety and Depression Scale); assessment of functional status by the Barthel test, the Short Physical Performance Battery and the International Physical Activity Questionnaire; and blood and stool samples will be obtained for each participant in each study visit (except screening visit).

Official Title
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Effect of an Oral Nutritional Supplement on Nutritional and Functional Status, Biological Markers (Inflammation and Oxidative Stress, Intestinal Microbiota, Circulating microRNA and Its Target Genes) in Malnourished Hemodialysis Patients.

Conditions
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Malnutrition, End Stage Renal Disease

Intervention / Treatment
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* Dietary Supplement: Oral nutritional supplement with probiotics
* Dietary Supplement: Oral nutritional supplement without probiotics
* Other: Dietary recommendations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects (>18 y/o) undergoing hemodialysis more than 6 months previous at inclusion. At least one of these caloric malnutrition criteria: a) involuntary weight loss >5% in 3 months or >10% in 6 months; b) serum albumin < 3.5 g/dl or prealbumin <28 mg/dl; c) body mass index (BMI) < 23 kg/m2; d) muscular mass loss >5% in 3 months or >10% in 6 months. Standard hemodialysis therapy (3 days/week, 240 min, high permeability dialyzer, blood flow >250 ml/min and dialysate flow 500 ml/min) or on-line hemodialysis therapy that was not modified in the last 3 months previous to the inclusion. Written informed consent obtained. Exclusion Criteria: Type 1 diabetes mellitus or type 2 diabetes mellitus with HbA1c>9%. Unstable dry weight. Limb amputation. Significant edema. Active malignancy. Hospital admissions in the last 3 months. Acute gastrointestinal disease in the 2 weeks before the inclusion. Gastrectomy, gastroparesis or abnormal gastric emptying. Acute heart failure grade IV. Severe hepatic insufficiency (men gamma glutamyl transferase -GGT- >150 U/l, women >120 U/l). Alcohol or other drugs abuse. Participants enrolled in other research study at inclusion. Pregnant women. No informed consent obtained. Patients who received any oral nutritional supplement (specific for hemodialysis patients or not) in the 4 weeks before the inclusion. Patients receiving enteral tube feeding. Galactosemia, fructosemia, or requirement of a no fiber diet. Allergy or hypersensitivity to any ingredient of the oral nutritional supplement. Ongoing treatment with glucocorticoids. Patients who received any oral fatty acids omega-3 supplement in the 4 weeks before the inclusion. Patients who received intradialytic parenteral nutrition in the 3 months before the inclusion. Patients who received any probiotics or prebiotics (not as part of the diet) in the 3 months before the inclusion. Anemia (Hemoglobin < 10 g/dl) or Epoetin resistance.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, multicenter, parallel-group trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral nutritional supplement with probiotics<br>Oral nutritional supplement specifically developed for undernourished hemodialysis patients enriched with functional nutrients (extra virgin olive oil, omega 3 fatty acids, whey protein, antioxidants, carnitine), with probiotics. Physical activity recommendations. | Dietary Supplement: Oral nutritional supplement with probiotics<br>* Oral nutritional supplement specifically developed for undernourished hemodialysis patients enriched with functional nutrients (extra virgin olive oil, omega 3 fatty acids, whey protein, antioxidants and carnitine), with probiotics.<br>* Other names: Physical activity recommendations.;|
| Experimental: Oral nutritional supplement without probiotics<br>Oral nutritional supplement specifically developed for undernourished hemodialysis patients enriched with functional nutrients (extra virgin olive oil, omega 3 fatty acids, whey protein, antioxidants, carnitine), without probiotics. Physical activity recommendations. | Dietary Supplement: Oral nutritional supplement without probiotics<br>* Oral nutritional supplement specifically developed for undernourished hemodialysis patients enriched with functional nutrients (extra virgin olive oil, omega 3 fatty acids, whey protein, antioxidants and carnitine), without probiotics.<br>* Other names: Physical activity recommendations.;|
| Active Comparator: Individualized dietary recommendations<br>Individualized dietary recommendations. Physical activity recommendations. | Other: Dietary recommendations<br>* Dietary recommendations<br>* Other names: Physical activity recommendations.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in weight | Weight in kg | Baseline and 6 months | 
| Change in fat free body mass | Fat free body mass in kg assessed by bioelectrical impedance analysis | Baseline and 6 months | 
| Change in serum albumin concentration | Serum albumin in g/dl | Baseline and 6 months | 
| Change in serum prealbumin concentration | Serum prealbumin in mg/dl | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in handgrip strength | Handgrip strength in kg, measured by the jamar hydraulic hand dynamometer. | Baseline and 6 months | 
| Change in the score of the Barthel test. | The Barthel is a 10-item ordinal scale that measures functional independence in the domains of personal care and mobility. Specifically, it measures self-care, sphincter management, transfers and locomotion. The score ranges between 0 and 100 points. Scores of 0-20 indicate total dependency, 21-60 indicate severe dependency, 61-90 indicate moderate dependency, 91-99 indicates slight dependency, and 100 indicates independency. | Baseline and 6 months | 
| Change in the score of the Hospital Anxiety and Depression Scale (HADS). | Symptoms of depression and anxiety assessed by the Hospital Anxiety and Depression Scale (HADS). This questionnaire comprises two sub-scales, each one range from 0 to 21 points; one assesses the symptoms of depression, and the other one the symptoms of anxiety. At each sub-scale, a score below 7 is considered normal range, between 8 and 10 means probable presence of depression or anxiety respectively, and more than 11 suggests the presence of depression or anxiety respectively. | Baseline and 6 months | 
| Changes in plasma levels of high sensitivity C reactive protein (hs-CRP) | Plasma levels of high sensitivity C reactive protein (hs-CRP) in mg/dl | Baseline and 6 months | 
| Changes in plasma levels of 8-iso-prostaglandina F2 α (8-iso-PGF2-α) | Plasma levels of 8-iso-prostaglandina F2 α (8-iso-PGF2-α) in pg/ml | Baseline and 6 months |