Renal Effects of Meditarranean Diet and Low-protein Diet With Ketoacids on Physiological Intestinal Mibrobiota in CKD

Chronic Renal Insufficiency Clinical Trial

— MEDIKA  

Official title:

Gut-kidney Axis: Renal Effects of Meditarranean Diet and Low-protein Diet With Ketoacids to Restore Physiological Intestinal Mibrobiota in Chronic Kidney Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02302287
• Other study ID #: rf 2013-02355394
• Status: Active, not recruiting
• Phase: Phase 4
• First received: November 21, 2014
• Last updated: November 24, 2016
• Start date: January 2015
• Est. completion date: July 2017

Study information

• Verified date: January 2016
• Source: Azienda Sanitaria ASL Avellino 2
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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;

• MD contains 0.7-0.8 g/bw/day of protein, plant protein 40-50 g/day;

• KD contains 0.3-0.5 g/bw/day of protein, animal protein zero g/day, plant protein 30-40 g/day, plus ketoacids of 0.05 g/bw/day.

Specific aim:

1. To evaluate the effects of Mediterranean diet (MD) and low-protein diet supplemented with ketoacids (KD) on microbiota composition

2. To evaluate the effects of KD and MD on microbial-derived VOC (already identified and yet unidentified uremic toxins) levels by metabolomics

3. To evaluate the effects of KD or MD on renal function parameters, uremia, inflammatory and nutritional status

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: July 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• prevalent patients in tertiary nephrology clinic;

• patients over 18 years;

• CKD stage 3b-4 (eGFR between 15 and 45 ml/min/1.73m2, estimated by MDRD formula);

• clinically proven adherence to prescribed therapies;

• informed consent signed.

Exclusion Criteria:

• change of GFR >30% within the last 3 months;

• acute, intercurrent disease during the previous 3 months;

• severe undernutrition as indicated by: BMI < 20 kg/m2 and serum albumin < 3.2 g/dl, or BMI < 17.5 kg/m2 whatever albumin value, or body weight reduction > 5% within the last month or > 10% within the last six months;

• pregnancy or feeding;

• chronic treatment with steroid or cytotoxic drugs; fast progressing glomerulonephritis; active SLE and vasculitis;

• gastrointestinal diseases (Crohn disease, Ulcerative colitis, Celiac Sprue, Stypsis); 7) infectious diseases; 8) cardiac failure stage III-IV NYHA; advanced liver cirrhosis; active cancer diseases; severe encephalopathy associated with lack of spontaneous feeding; chronic obstructive respiratory diseases needing oxygen treatment; 9) use of antibiotics or probiotics until 15 days before the enrolment; 10) psychiatric disease or inability to assess follow-up.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Renal Insufficiency
• Renal Insufficiency
• Renal Insufficiency, Chronic

Intervention

Dietary Supplement:
• Ketoacids 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

Other:
• Mediterranean diet
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
• Free diet
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;

Locations

Country	Name	City	State
Italy	UOC Nefrologia	Solofra	Avellino

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Sanitaria ASL Avellino 2

Country where clinical trial is conducted

Italy, 

References & Publications (8)

Bellizzi V, Chiodini P, Cupisti A, Viola BF, Pezzotta M, De Nicola L, Minutolo R, Barsotti G, Piccoli GB, Di Iorio B. Very low-protein diet plus ketoacids in chronic kidney disease and risk of death during end-stage renal disease: a historical cohort controlled study. Nephrol Dial Transplant. 2015 Jan;30(1):71-7. doi: 10.1093/ndt/gfu251. — View Citation

Bellizzi V, Di Iorio BR, De Nicola L, Minutolo R, Zamboli P, Trucillo P, Catapano F, Cristofano C, Scalfi L, Conte G; ERIKA Study-group.. Very low protein diet supplemented with ketoanalogs improves blood pressure control in chronic kidney disease. Kidney Int. 2007 Feb;71(3):245-51. — View Citation

Brunori G, Viola BF, Parrinello G, De Biase V, Como G, Franco V, Garibotto G, Zubani R, Cancarini GC. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am J Kidney Dis. 2007 May;49(5):569-80. — View Citation

De Angelis M, Montemurno E, Piccolo M, Vannini L, Lauriero G, Maranzano V, Gozzi G, Serrazanetti D, Dalfino G, Gobbetti M, Gesualdo L. Microbiota and metabolome associated with immunoglobulin A nephropathy (IgAN). PLoS One. 2014 Jun 12;9(6):e99006. doi: 10.1371/journal.pone.0099006. — View Citation

Di Iorio BR, Bellizzi V, Bellasi A, Torraca S, D'Arrigo G, Tripepi G, Zoccali C. Phosphate attenuates the anti-proteinuric effect of very low-protein diet in CKD patients. Nephrol Dial Transplant. 2013 Mar;28(3):632-40. doi: 10.1093/ndt/gfs477. — View Citation

Di Iorio BR, Minutolo R, De Nicola L, Bellizzi V, Catapano F, Iodice C, Rubino R, Conte G. Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure. Kidney Int. 2003 Nov;64(5):1822-8. — View Citation

Marzocco S, Dal Piaz F, Di Micco L, Torraca S, Sirico ML, Tartaglia D, Autore G, Di Iorio B. Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease. Blood Purif. 2013;35(1-3):196-201. doi: 10.1159/000346628. — View Citation

Scalone L, Borghetti F, Brunori G, Viola BF, Brancati B, Sottini L, Mantovani LG, Cancarini G. Cost-benefit analysis of supplemented very low-protein diet versus dialysis in elderly CKD5 patients. Nephrol Dial Transplant. 2010 Mar;25(3):907-13. doi: 10.1093/ndt/gfp572. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	0-18 months from the beginning of the study	No
Secondary	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	0-18 months from the beginning of the study	No
Secondary	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	0-18 months from the beginning of the study	No
Secondary	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,	0-18 months from the beginning of the study	No
Secondary	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	0-18 months from the beginning of the study	No
Secondary	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	0-18 months from the beginning of the study	No