A Phase 4 interventional study of Ketoacids diet and Mediterranean diet in Chronic Renal Insufficiency, sponsored by Azienda Sanitaria ASL Avellino 2. Status unknown at 1 site in Italy. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2016-11-28.
Sponsored by Azienda Sanitaria ASL Avellino 2 · Phase 4, Interventional, and Treatment
Food intake has a deep influence on gut microbiota composition and function, both in health and in disease status. In chronic kidney disease (CKD), a microbiota dysbiosis status is observed. Moreover, many toxic uremic molecules are microbial-derived and their accumulation promotes, in turn, disease progression.
Investigators' hypothesis foresees a beneficial effect of nutritional treatments, able to restore gut microbiota balance, to lower microbial-derived uremic toxins and to improve clinical conditions in CKD patients.
Mediterranean Diet (MD) is supposed to have beneficial effect on microbiota composition, while low-protein diet supplemented with ketoacids (KD) is used in CKD patients for the improvement of clinical conditions, but its effects on gut microbiota are currently unknown. Investigators' project aim is to verify the effects of MD and KD on: microbiota and metabolome composition, microbial-derived uremic toxins level and clinical conditions in a cohort of CKD patients.
Background: In CKD the biochemical milieu of gastrointestinal tract (GI) is altered by several mechanisms, affecting gut microbiota composition and function. Beyond exerting metabolic functions, microbiota influences the general healthy status. It digests food mainly through saccharolytic or proteolytic catabolism, with a prevalence of the former in healthy status. On the contrary, in CKD, dysbiosis with the prevalence of the latter is observed.
In this setting, reduction in glomerular filtration rate and increase in urea levels result in its heavy influx into the GI. Here urea is hydrolyzed spontaneously and/or by microbial urease, releasing ammonia, readily converted into ammonium hydroxide. The latter raises GI pH, causing mucosa irritation, enterocolitis and changes in microbiota composition. This contributes to worsening of inflammation and disease progression: indeed, microbiota has been identified as the primary source of several well known and yet unidentified volatile organic compounds (VOC), including some of the main uremic toxins.
Some beneficial effects observed from studies with low-protein diet supplemented with ketoacids in CKD cannot be solely explained by the reduced protein intake. Investigators' hypothesis is that ketoacids may have direct protective effects on renal damage progression, through induced modifications in gut biochemical milieu and in microbiota composition.
Similarly, the Mediterranean Diet with its fibers supply can contribute to restore gut microbiota balance.
Hypothesis:
The first hypothesis foresees a beneficial effect of KD on microbiota balancing and microbial-derived uremic toxins decrease in CKD patients, through KD-induced urea reduction. The second envisages MD direct effects on gut microbiota composition with an increase in protective species and a decrease in uremic toxins production.
The study will evaluate the effects of three different dietary regimens, composed as follows:
FD contains 1 g/bw/day of protein, plant protein 15-20 g/day;
Specific aim:
Experimental Design Aim 1:
The designed study will be experimental, randomized, cross-over. It will be carried out according to the Declaration of Helsinki (IV Adaptation) and will be submitted to the approval of the local Ethics Committee; written consent will be obtained from all subjects. 60 patients with CKD stages 3b-4 (MDRD formula) will be enrolled, according to the inclusion and exclusion criteria (see below).
Experimental Design Aim 2:
Untarget metabolomic analysis will be carried out on fecal and urine samples collected at the same time points described in Experimental design aim 1 for VOC (GC-MS/MS) and non-VOC profiling (LC-MS/MS). Sera collected at the same time points will be also analyzed by untarget metabolomic for non-VOC profiling and by target metabolomic to quantify the already known uremic toxins, namely indoxyl sulfate and p-cresyl sulfate, and potential metabolite biomarkers found by the untarget experiment.
Experimental Design Aim 3:
Additionally, each patient will undergo medical examination every three months, with evaluation of: blood pressure and nutritional status. Moreover, at the same time points of aim 1 (T0, T3, T9, T12 and T18 months from the beginning of the study) each patient will provide blood and urine samples, both for routine and experimental analysis.
3,224 studies on the registry are indexed under Renal Insufficiency, Chronic; 706 are open to participants now.
This study's planned enrollment of 60 is below the median of 74 across 2,229 interventional studies indexed under Renal Insufficiency, Chronic.
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Exclusion Criteria:
1. Free diet for 3 months: protein 1 g/body weight/day (animal protein 50-70 g/day, plant protein 15-20 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 6 g/day, potassium 2-4 g/day; 2. Ketoacids diet for 6 months: protein 0,3-0,5 g/bw/day (animal protein 0 g/day, plant protein 30-40 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 0,6-0,8 g/day; sodium 6 g/day, potassium 2-4 g/day; mixture of essential aminoacids and ketoacids 0,05 g/kg ideal bw/day 3. Mediterranean diet for 6 months: protein 0,7-0,8 g/bw/day (animal protein 30-40 g/day, plant protein 40-50 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 2,5-3 g/day, potassium 2-4 g/day 4. Mediterranean diet and ketoacids for 6 months
Dietary Supplement: Ketoacids diet · Other: Mediterranean diet · Other: Free diet
1. Free diet for 3 months: protein 1 g/body weight/day (animal protein 50-70 g/day, plant protein 15-20 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 6 g/day, potassium 2-4 g/day; 2. Mediterranean diet for 6 months: protein 0,7-0,8 g/bw/day (animal protein 30-40 g/day, plant protein 40-50 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 2,5-3 g/day, potassium 2-4 g/day; 3. Ketoacids diet for 6 months: protein 0,3-0,5 g/bw/day (animal protein 0 g/day, plant protein 30-40 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 0,6-0,8 g/day; sodium 6 g/day, potassium 2-4 g/day; mixture of essential aminoacids and ketoacids 0,05 g/kg ideal bw/day 4. Mediterranean diet and ketoacids for 6 months
Dietary Supplement: Ketoacids diet · Other: Mediterranean diet · Other: Free diet
Free diet: protein 1 g/body weight/day (animal protein 50-70 g/day, plant protein 15-20 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 6 g/day, potassium 2-4 g/day
Other: Free diet
Ketoacids diet for 6 months: protein 0,3-0,5 g/bw/day (animal protein 0 g/day, plant protein 30-40 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 0,6-0,8 g/day; sodium 6 g/day, potassium 2-4 g/day; mixture of essential aminoacids and ketoacids 0,05 g/kg ideal bw/day
Also known as: KD
Mediterranean diet for 6 months: protein 0,7-0,8 g/bw/day (animal protein 30-40 g/day, plant protein 40-50 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 2,5-3 g/day, potassium 2-4 g/day
Also known as: MD
Free diet for 3 months: protein 1 g/body weight/day (animal protein 50-70 g/day, plant protein 15-20 g/day); energy 30-35 kcal/bw/day; Calcium 1,1-1,3 g, phosphate 1,2-1,5 g/day; sodium 6 g/day, potassium 2-4 g/day;
Also known as: FD
Change from baseline in fecal microbiota by MD and KD at 18 months
Active fecal microbiota will be analyzed a culture-independent methods. Bacterial tag encoded FLX-titanium amplican pyrosequencing (bTEFAP) analyses will be carried out for bacterial RNA directly extracted from feces at months 0, 3, 9, 12 and 18.
Time frame: 0-18 months from the beginning of the study
Change from baseline in microbial-derived uremic toxins level at 18 months
Untarget metabolomic analysis will be carried out on fecal and urine samples collected at months 0,3,9,12 and 18 after the beginning of the study for volatile organic compounds (VOC) (GC-MS/MS) and non-VOC profiling (LC-MS/MS). Sera collected at the same time points will be also analyzed by untarget metabolomic for non-VOC profiling and by target matabolomic to quantify uremic toxins, as indoxyl sulfate and p-cresyl sulfate, and potential metabolite biomarkers found by the untarget experiment
Time frame: 0-18 months from the beginning of the study
Change from baseline in renal function at 18 months
each patient will provide at months 0,3,9,12 and 18 blood and urine samples for routine analyses to measure urea, creatinine, estimated glomerular filtration rate, BUN, blood pressure, proteinuria
Time frame: 0-18 months from the beginning of the study
Change from baseline in nutritional status at 18 months
each patient will provide at months 0,3,9,12 and 18 blood and urine samples for routine analyses to measure acid-basic balance, serum and urine electrolytes, PTH, serum proteins, haemoglobin,
Time frame: 0-18 months from the beginning of the study
Change from baseline in inflammatory status at 18 months
each patient will provide at months 0,3,9,12 and 18 blood and urine samples for routine analyses to measure EGF/MCP-1 ratio, CRP, TNF-a, IL-6
Time frame: 0-18 months from the beginning of the study
Change from baseline in microbial-derived uremic toxins level at 18 months
Sera will be collected at months 0,3,9,12 and 18 after the beginning of the study to quantify uremic toxin Cyanate
Time frame: 0-18 months from the beginning of the study
The record gives a start of Jan 2015, a primary completion of Jan 2017 and a completion of Jul 2017. It does not say whether these dates are actual or estimated.
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Renal Insufficiency, Chronic →
Azienda Sanitaria ASL Avellino 2