Prebiotic Therapy to Improve Outcomes of Renal Transplant

Kidney Transplant; Complications Clinical Trial

Official title:

Prebiotic Therapy to Improve Outcomes of Renal Transplant

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04428190
• Other study ID #: PRT01
• Status: Recruiting
• Phase: Early Phase 1
• Start date: February 23, 2022
• Est. completion date: December 15, 2024

Study information

• Verified date: October 2023
• Source: Lawson Health Research Institute
• Contact: Mounirah May
• Phone: 519-685-8500
• Email: mounirah.may[@]lhsc.on.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

An investigator initiated pilot study: two arm, double blind, placebo controlled, randomized, group of approximately 60 patients undergoing a kidney transplant. Participants will be treated with human milk oligosaccharide (HMO) prebiotic versus placebo over 12 weeks from start of the investigational medication date (approximately 3 months) to test whether HMO can improve renal transplant outcomes. Participants will be followed up for 3 months after after they complete the treatment portion of the study. HMO sachets will be administered to determine the safety and efficacy of HMO relative to placebo in improving renal transplant outcomes in patients by reducing delayed graft function and side effects from post transplant therapy.

Description:

Nearly three million people worldwide suffer from end stage renal disease (ESRD), which has debilitating consequences on the quality of life of patients There is a discrepancy between the availability of organs and the increasing number of patients placed on the waiting list. Canadians with ESRD requiring kidney transplantation has increased by 38% from 2005-2014, whereas the number of transplantable organs has not met this growing need.

As clinicians use more marginal donors, the effects of ischemic injury from the procurement process become more pronounced. This ischemia reperfusion injury (IRI) has been linked to increased delayed graft function, rejection and decreased long-term function. Approximately 20% of transplanted patients subsequently return to dialysis due to poor graft function. Therefore, one of the major goals of the transplant community has now shifted to ensuring the longevity of transplanted organs. Research priorities need to shift towards developing ways to ensure the longevity of grafts through modification of recipient factors.

Patients are also required to remain on immunosuppressive drugs following transplant in order to maintain the graft. These have a variety of side effects, including diarrhea and intestinal malabsorption, which can lead to a lack of patient compliance with post transplant therapy and a reduced quality of life.

Patients with ESRD also have an expansion of bacteria that produce urease and uric acid and produce fewer short-chained fatty acids and vitamins.

This is important as it is theorized that the production of short-chained fatty acids by microorganisms in the GI tract are crucial as both the energy source, and to the maintenance of intestinal permeability, which contribute to a healthy gastrointestinal tract.

The expansion of bacteria that produce urease and uric acid contribute to toxicity and inflammation in the GI tract that can cause complications in these patients.

In order to reduce both delayed graft function and side effects from post transplant therapy, novel support options are required. One option is the use of prebiotics.

Non-digestible sugar prebiotics have potential for use in these patients. The Principal Investigator/Sponsor will test this potential in a pilot clinical study with a Human milk oligosaccharides (HMO) prebiotic mix that have been shown to stimulate the production of short chain fatty acids, especially propionate. Propionate has been shown to be important in attenuating hypertrophy, fibrosis, vascular dysfunction and hypertension and is extremely important for the gut kidney axis. Prebiotics offer a safe and well-tolerated therapy, which could have a positive impact by improving systemic inflammatory responses, improving gut barrier function, helping to reduce immunosuppressive drug side effects and stabilizing its dosing.

This study will assess blood, and urine samples collected as part of the participant's post-transplant follow up at eight time points to determine graft function.

Urine and a faecal sample will be collected at 6 time points for microbiome analyses at baseline, day 7, 30, 60, 120 and 180 from the date of starting the study product. Prior to commencing their treatment, and at days 60,90,150, and 180, the research coordinator (blinded to the randomisation) will assess patients using the SF-36 and GI Health questionnaires during clinic visits, or by telephone interview.

Protocol compliance will be tested through product count and interviews at each follow-up visit. Side effects will be assessed using standardized case report forms at each visit. Participants will be encouraged to report any events they may experience directly to the coordinator.

Participants who withdraw consent to continue treatments, will be encouraged to undergo the planned assessments. Withdrawal at the request of investigators or medical personnel may include, but are not limited to:

1. Symptoms are deemed to be potentially related to the study product

2. New diagnosis of exclusion criteria;

3. Unacceptable side effects;

4. Death

Estimated time to complete recruitment: Averaging 86 weeks, approximately 20 months

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 15, 2024
• Est. primary completion date: October 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years of age and over receiving a kidney transplant.

Exclusion Criteria:

• Under 18 years of age

• Inability to give consent

• Usage of probiotics or other prebiotics.

• Have had carcinomas during the last 5 years

• Bowel surgery

• Crohn ´s disease and other conditions.

Related Conditions & MeSH terms

• Kidney Transplant; Complications

Intervention

Dietary Supplement:
• Human Milk Oligosaccharides (HMO)
Sachet containing 10 grams of HMO

Other:
• Placebo
Sachet manufactured to mimic 10g of HMO

Locations

Country	Name	City	State
Canada	London Health Sciences Centre	London	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
Lawson Health Research Institute	London Health Sciences Centre, St. Joseph's Health Care London, The W. Garfield Weston Foundation

Country where clinical trial is conducted

Canada, 

References & Publications (14)

Al KF, Bisanz JE, Gloor GB, Reid G, Burton JP. Evaluation of sampling and storage procedures on preserving the community structure of stool microbiota: A simple at-home toilet-paper collection method. J Microbiol Methods. 2018 Jan;144:117-121. doi: 10.1016/j.mimet.2017.11.014. Epub 2017 Nov 16. — View Citation

Bao Y, Al KF, Chanyi RM, Whiteside S, Dewar M, Razvi H, Reid G, Burton JP. Questions and challenges associated with studying the microbiome of the urinary tract. Ann Transl Med. 2017 Jan;5(2):33. doi: 10.21037/atm.2016.12.14. — View Citation

Bartolomaeus H, Balogh A, Yakoub M, Homann S, Marko L, Hoges S, Tsvetkov D, Krannich A, Wundersitz S, Avery EG, Haase N, Kraker K, Hering L, Maase M, Kusche-Vihrog K, Grandoch M, Fielitz J, Kempa S, Gollasch M, Zhumadilov Z, Kozhakhmetov S, Kushugulova A, — View Citation

Dubberke ER, Riddle DJ; AST Infectious Diseases Community of Practice. Clostridium difficile in solid organ transplant recipients. Am J Transplant. 2009 Dec;9 Suppl 4(0 4):S35-40. doi: 10.1111/j.1600-6143.2009.02891.x. — View Citation

Elison E, Vigsnaes LK, Rindom Krogsgaard L, Rasmussen J, Sorensen N, McConnell B, Hennet T, Sommer MO, Bytzer P. Oral supplementation of healthy adults with 2'-O-fucosyllactose and lacto-N-neotetraose is well tolerated and shifts the intestinal microbiota. Br J Nutr. 2016 Oct;116(8):1356-1368. doi: 10.1017/S0007114516003354. Epub 2016 Oct 10. — View Citation

Harvie RM, Chisholm AW, Bisanz JE, Burton JP, Herbison P, Schultz K, Schultz M. Long-term irritable bowel syndrome symptom control with reintroduction of selected FODMAPs. World J Gastroenterol. 2017 Jul 7;23(25):4632-4643. doi: 10.3748/wjg.v23.i25.4632. — View Citation

Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One. 2015 Mar 27;10(3):e0122399. doi: 10.1371/journal.pone.0122399. eCollection 2015. — View Citation

Li L, Ma L, Fu P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug Des Devel Ther. 2017 Dec 11;11:3531-3542. doi: 10.2147/DDDT.S150825. eCollection 2017. — View Citation

Lobb I, Jiang J, Lian D, Liu W, Haig A, Saha MN, Torregrossa R, Wood ME, Whiteman M, Sener A. Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia-Reperfusion Injury via Specific Mitochondrial Actions. Am J Transplant. 2017 Feb;17(2):341-352. doi: 10.1111/ajt.14080. Epub 2016 Nov 29. — View Citation

Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004 Nov 13-19;364(9447):1814-27. doi: 10.1016/S0140-6736(04)17406-0. — View Citation

Pluznick JL. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 2016 Dec;90(6):1191-1198. doi: 10.1016/j.kint.2016.06.033. Epub 2016 Aug 26. — View Citation

Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant. 2005 Jan;5(1):125-30. doi: 10.1111/j.1600-6143.2004.00649.x. — View Citation

Sawas T, Al Halabi S, Hernaez R, Carey WD, Cho WK. Patients Receiving Prebiotics and Probiotics Before Liver Transplantation Develop Fewer Infections Than Controls: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2015 Sep;13(9):1567-74.e3; quiz e143-4. doi: 10.1016/j.cgh.2015.05.027. Epub 2015 Jun 2. — View Citation

Wong J, Piceno YM, DeSantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 2014;39(3):230-237. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of participants who experience kidney rejection	A kidney rejection will be recorded in the adverse event form for the study.	24 weeks
Other	Immunosuppression suppressive drug dose	will be assessed by the clinic on post-operative day 1, 7, 30, 60, 90, 120, 150 and 180	post-operative day 1, 7, 30, 60, 90, 120, 150 and 180
Other	Infectious complications	Cytomegalovirus will be tested by the clinic, typically reported in IU/mL	post-operative day 30, 60, 90, 120, 150 and 180.
Other	Serum creatinine	Will be used to determine graft function, and is reported in µmol/L.	24 weeks.
Other	Cystatin-c levels	Will be used to determine graft function, and is reported in mg/l.	24 weeks.
Other	Estimated glomerular filtration rate (eGFR)	Will be used to determine graft function, and is reported in mL/min/1.73m**2.	24 weeks.
Other	Urine output	Will be used to determine graft function, and is reported in mL/day.	24 weeks.
Other	Urine protein/creatinine ratio	Will be used to determine graft function, and is reported in g/L	24 weeks.
Other	Dialysis episodes	Will be used to determine graft function, and will be measured by the amount of times a participant required dialysis.	24 weeks.
Other	Renal micro-perfusion using Doppler ultrasound	Will be used to determine graft function by providing an assessment of vascular changes.	24 weeks.
Other	Search Results Web results Kidney Injury Molecule-1 (Kim-1)	Will be used to determine graft function, and is reported in ng/ml	24 weeks.
Other	Neutrophil gelatinase-associated lipocalin (NGAL)	Will be used to determine graft function, and is reported in ng/ml	24 weeks.
Other	Immunosuppression drug serum levels (MMF and FK-506)	will be assessed by the clinic, typically reported in mg/ml.	post-operative day 1, 7, 30, 60, 90, 120, 150 and 180
Other	Serial viral serologies	Polyomavirus will be tested by the clinic post-op, typically reported in IU/mL.	post-operative day 30, 60, 90, 120, 150 and 180.
Primary	Short Form Health Survey (SF-36)	The Short Form Health Survey will measure participant satisfaction using a scale from 1 - 5, 1 being the best outcome, and 5 being the worst outcome.	24 weeks
Primary	Adverse Events	Adverse events will be recorded through case report forms and reported to the principal investigator. Side effects will be assessed using standardized case report forms at each visit. Participants are encouraged to contact the coordinator to report any concerns.	24 weeks
Secondary	Microbiome changes from baseline to end of treatment	Changes in the entire bacterial community from baseline to end of study will be assessed in the lab from faecal and urine samples collected by the participant. The microbes may vary by participant and the study will be looking at which ones present themselves in each case. Units of measure via culture are colony forming units per g (cfu/g).	12 weeks
Secondary	Microbiome changes post intervention	Changes in the entire bacterial community after study intervention will be assessed in the lab from faecal and urine samples collected by the participant. The microbes may vary by participant and this outcome measure will be looking at which ones present themselves in each case.	12 weeks