Probiotics and Low Protein Diet in Advanced Chronic Kidney Disease (ProLowCKD)

Probiotics-addicted Low-protein Diet for Microbiota Modulation in Patients With Advanced Chronic Kidney Disease (ProLowCKD): a Protocol of Placebo-controlled Randomized Trial

Here the investigators will perform a double-blinded randomized placebo-controlled clinical trial to evaluate the synergic effect of low protein diet and prebiotics in reducing the microbial inflammatory uremic toxins.

Study Overview

• Status: Completed
• Conditions: Renal Failure Chronic
• Intervention / Treatment: Dietary supplement: Probiotics

Detailed Description

ProLowCKD is a single-centre, double-blind, placebo-controlled, randomised study. At enrolment (T0) participants were prescribed a LPD in addition to their ongoing pharmacological therapy and according to their comorbidities; after 2 months (T2) they were randomized in accordance to a 1:1 ratio to receive probiotics or placebo for other 3 months (T5) in addition to the continuation of LPD. Enrolled subjects are invited to assume two doses of probiotic/placebo for 1 month and 1 dose for 2 months.

Randomization is 1:1 to receive odd- or even envelopes, according to the odd- or even registration number at enrolment.

Neither the clinician nor the patient knows the content of the odd- and even envelopes.

The evaluations will be performed according to the following schedule: at T0 nephrological evaluation and biochemical analysis, dietary counselling, illustration of protocol and signing of the informed consent, administration of the SF36 questionnaire, body composition evaluation by bioimpedentiometry. At T0, T2, T5: blood biochemical parameters: haemoglobin, urea, creatinine, mean urea and creatinine clearance, CKD and MDRD calculation, sodium, potassium, uric acid, calcium, phosphate, PTH, acid-base balance, CRP, albumin, PC, IS, Lp-PLA2, LPS; 24h-urine biochemical parameters: urea, creatinine, sodium, proteins; microbial stools analysis; clinical nephrological and dietitian evaluation.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Novara, Italy, 28100
    • Nephrology and Dialysis Unit, Azienda Ospedaliero Universitaria Maggiore della Carità

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age 18-80 years
• GFR < 20 ml/min/sqm
• afferent to the outpatient clinic in the Nephrology and Dialysis Unit (Azienda Ospedaliero Universitaria Maggiore della Carità)

Drop out or Exclusion Criteria:

• subject refusing to sign the informed consent
• administration of prolonged antibacterial therapy
• dialysis initiation
• death

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Probiotics; Composition: 5x109 of Bifidobacterium longum (mix DLBL), 1x109 Lactobacillus reuteri LRE02 (DSM 23878) and maltodextrin (total 2 grams)	Dietary supplement: Probiotics; Active composition: 5x109 of Bifidobacterium longum (mix DLBL), 1x 109 Lactobacillus reuteri LRE02 (DSM 23878) and maltodextrin (total 2 grams). The probiotic species employed were granted the Qualified Presumption of Safety (QPS) status by the European Food Safety Authority (EFSA) in 2007. Two envelopes per day and one envelope per day will be recommended for one and two months, respectively. Placebo composition: maltodextrin (2 grams). Two envelopes per day and one envelope per day will be recommended for one and two months, respectively.
Placebo Comparator: Placebo; Composition: maltodextrin (2 grams)	Dietary supplement: Probiotics; Active composition: 5x109 of Bifidobacterium longum (mix DLBL), 1x 109 Lactobacillus reuteri LRE02 (DSM 23878) and maltodextrin (total 2 grams). The probiotic species employed were granted the Qualified Presumption of Safety (QPS) status by the European Food Safety Authority (EFSA) in 2007. Two envelopes per day and one envelope per day will be recommended for one and two months, respectively. Placebo composition: maltodextrin (2 grams). Two envelopes per day and one envelope per day will be recommended for one and two months, respectively.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of the microbial gut populations	Change from baseline of the concentration of proteolytic microbial groups (number of cells/gram of faeces);; Change from baseline of the concentration of saccharolytic microbial groups (number of cells/gram of faeces)	5 months
Change from baseline of the microbial inflammatory uremic toxins	Change from baseline of the serum concentration of PC (mcMOL) and IS (mcMOL), as markers of dysbiotic microbiota	5 months
Change from baseline of the markers of cardiovascular diseases	Change from baseline of the serum concentration of Lp-PLA2 (nmol/ml/min)	5 months
Change from baseline of the markers of intestinal barrier permeability	Change from baseline of the serum concentration of LPS (EU/ml)	5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the renal function	Change from baseline of ΔGFR (mL/min/m2 of body surface)	5 months
Measurement of the urine protein excretion	Change from baseline of 24-hour protein urine excretion (mg/24 hours)	5 months
Evaluation of the anemia	Change from baseline of haemoglobin (g/dL)	5 months
Evaluation of the serum acid-base equilibrium	Change from baseline of bicarbonatemia (mEq/l)	5 months
Quantification of serum inflammatory markers	Change from baseline of the serum concentration of C-reactive protein (CRP) (mg/dL)	5 months
Evaluation of the body composition	Change from baseline of fat-free body mass (kg), fat-body mass (kg), Hand Grip strength (kg), total body water (kg)	5 months
Measurement of vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health (Quality of Life)	Change from baseline of SF36 questionnaire score. The SF36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.	5 months

Collaborators and Investigators

• Sponsor: Probiotical S.p.A.
• Collaborators: Azienda Ospedaliero Universitaria Maggiore della Carita
• Investigators: Principal Investigator: Andreana De Mauri, Azienda Ospedaliero Universitaria Maggiore Della Carità

Publications and helpful links

General Publications

• Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, Quraishi MN, Kinross J, Smidt H, Tuohy KM, Thomas LV, Zoetendal EG, Hart A. The gut microbiota and host health: a new clinical frontier. Gut. 2016 Feb;65(2):330-9. doi: 10.1136/gutjnl-2015-309990. Epub 2015 Sep 2.
• Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj DS. Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target. Am J Kidney Dis. 2016 Mar;67(3):483-98. doi: 10.1053/j.ajkd.2015.09.027. Epub 2015 Nov 15.
• Mafra D, Fouque D. Gut microbiota and inflammation in chronic kidney disease patients. Clin Kidney J. 2015 Jun;8(3):332-4. doi: 10.1093/ckj/sfv026. Epub 2015 May 6.
• Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol. 2014;9(3):399-410. doi: 10.2217/fmb.13.165.
• Rossi M, Klein K, Johnson DW, Campbell KL. Pre-, pro-, and synbiotics: do they have a role in reducing uremic toxins? A systematic review and meta-analysis. Int J Nephrol. 2012;2012:673631. doi: 10.1155/2012/673631. Epub 2012 Dec 19.
• Vaziri ND. Effect of Synbiotic Therapy on Gut-Derived Uremic Toxins and the Intestinal Microbiome in Patients with CKD. Clin J Am Soc Nephrol. 2016 Feb 5;11(2):199-201. doi: 10.2215/CJN.13631215. Epub 2016 Jan 15. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2017
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: November 29, 2019
• First Submitted That Met QC Criteria: December 16, 2019
• First Posted (Actual): December 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 5, 2022
• Last Update Submitted That Met QC Criteria: July 1, 2022
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Chronic kidney disease; Gut microbiota; Probiotic bacteria; Low protein diet; Microbial uremic toxins; Intestinal dysbiosis
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic
• Other Study ID Numbers: 215/CE n.CE 30\17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No