5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients

March 17, 2021 updated by: IRCCS Azienda Ospedaliero-Universitaria di Bologna
A randomized prospective study was done to determine whether i.v. 5-methyltetrahydrofolate vs oral folate improved survival in ESRD patients. Homocysteine, CRP, Lp(a), albumin, folates, vitamin B6 and B12 were checked. The 5-MTHF treated group was associated with lowered C reactive protein and higher survival than the folate treated group.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

BACKGROUND Hemodialysis patients show a 20-fold increase in CVD mortality in comparison to the general population.

Although hyperhomocysteinemia has been implicated as an important independent risk factor in both the general population2, as well as for ESRD patients, several studies have questioned the benefit of lowering homocysteine in ESRD patients. Paradoxically, two recent studies showed that patients with very low homocysteine plasma levels had worse outcomes including a higher incidence of hospitalization and mortality. This raises the question as to whether elevated homocysteine in uremic patients is consequential rather than causal in the role of cardiovascular complications.

Despite this uncertainty, many ESRD and pre-ESRD patients receive treatment to lower homocysteine. Elevated homocysteine is frequently reported for ESRD patients with a prevalence ranging from 85 to 100%.

There are two basic strategies that can be used to lower homocysteine. Both attempt to increase levels of biologically active folate which is essential in the remethylation pathway of homocysteine metabolism via its active metabolite 5-methyltetrahydrofolate (5-MTHF), thus lowering homocysteine efflux from tissues into the plasma compartment.

The first, and most common approach, is by oral administration of folic acid. Folic acid is not biologically active, however it is more stable than folate, and is often used in tablets and food fortification. The second approach is to supplement 5-MTHF, the natural circulating form of folate. In addition to folate, both vitamin B6 and vitamin B12 are necessary co-factors in homocysteine metabolism. ESRD patients are often resistant to homocysteine lowering by administration of both folic acid and 5-MTHF.

Although supplementation with folic acid, B6 and B12 usually decreases homocysteine in patients with vascular disease, it often remains elevated in ESRD patients despite supplementation of folic acid, B6 and B12. Several studies have reported only moderate effects, even with very high doses of folic acid (up to 15 mg/daily).

AIM OF THE STUDY The aim of this study is to investigate whether supplementation with 5MTHF vs. folic acid treatment affects patient survival. Homocysteine blood levels and MTHFR genetic polymorphisms will also be evaluated to determine if they can be considered as independent cardiovascular risk factors.

STUDY DESIGN Single center, randomised, prospective study. Two groups of stable ESRD patients treated with intravenous 5-MTHF or with 5 mg per day of oral folic acid.

Patient selection Period of selection : 4 years Start selection : 1 January 1998 End selection: 30 June 2001 Follow-up: 55 months.

STATISTICAL ANALYSIS Statistical analysis will be performed by the Statistical Package for the Social Sciences (SPSS).

Study Type

Interventional

Enrollment (Actual)

341

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Bologna, Italy, 40138
        • Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Hemodialysis patients with age > 18 years on regular bicarbonate hemodialysis or hemodiafiltration treatment three times a week
  • Clinical stability at least three months before the study started

  • Cardiovascular disease assessment as presence/absence of hypertension, ischemic cardiac disease, cerebral and peripheral vascular disease, diabetes.

    • We will investigate coronary artery disease by determination of at least one of the following parameters:

      • previous documentation of acute myocardial infarction (laboratory or ECG modifications);
      • symptomatic CVD events in the clinical history confirmed by a positive treadmill test;
      • coronary artery stenosis more than 50% in one of the three major coronary vessels documented by an angiographic study. All patients with coronary artery disease will be examined by a treadmill test (thallium scan) or coronary angiographic exam before entering the study.

    • We will investigate cerebrovascular disease by one of the following criteria:

      • a previous ictus (ongoing clinical evidence of neurological deficit in the three months before the study beginning, confirmed by a TC scan, a nuclear magnetic resonance or a physician's record of clinical history);
      • carotid vessels stenosis more than 50% documented by a Doppler exam.
    • Peripheral vascular disease will be assessed by the evidence of claudication intermittence, previous vascular surgical procedure (including amputation for ischemic limb or by angiographic/Doppler documentation of atherosclerotic plaques in abdominal, iliac and femoral vessels). The vascular surgical procedure will be carried out at least three months before the study started.

Exclusion Criteria:

  • Diagnosis of one of the following clinical conditions in the last three months:

    • acute infection
    • vascular access thrombosis
    • ictus cerebri
    • myocardial infarction
    • hemorrhage
    • recent relevant surgery
  • Malignancy
  • Participation in other clinical trials

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
patients treated with intravenous 5-MTHF (Prefolic®, Knoll, Milan, Italy) 50 mg at the end of each hemodialysis session; The group will receive supplementation with vitamin B6 300 mg (Benadon®, Roche, Milan, Italy) and vitamin B12 1000 mcg (Dobetin®, A.C.R.A.F, Rome, Italy) administered by intravenous injection at the end of the hemodialysis session three times per week
Drug: 5-MTHF (5-methyltetrahydrofolate)
50 mg intravenous at the end of each hemodialysis session
Active Comparator: B

treated with 5 mg per day of oral folic acid (Folina® Schwarz Pharma, Milan, Italy).

The group will receive supplementation with vitamin B6 300 mg (Benadon®, Roche, Milan, Italy) and vitamin B12 1000 mcg (Dobetin®, A.C.R.A.F, Rome, Italy) administered by intravenous injection at the end of the hemodialysis session three times per week
Drug: folic acid
5 mg per day of oral folic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
survival
Time Frame: 55 months
55 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Risk factors for cardiovascular disease in ESRD patients
Time Frame: 55 months
55 months
Homocysteine levels after 6, 12, 24 and 55 months
Time Frame: 55 months
55 months
CRP levels after 6, 12, 24 and 55 months
Time Frame: 55 months
55 months
Gene polymorphisms analysis on C677T and A1298C loci and differences in polymorphisms distribution in both groups
Time Frame: basal
basal
Differences at baseline between the groups concerning age, dialysis age, CRP, albumin, haemoglobin, Lp(a), homocysteine, folate, B6 and B12 baseline levels
Time Frame: basal
basal

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Collaborators

University of Bologna

Investigators

  • Study Chair: Sergio Stefoni, Professor, Nephrology Dialysis and Renal Trasnplantation Unit S.Orsola University Hospital Bologna Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 1998

Primary Completion (Actual)

July 1, 2001

Study Completion (Actual)

July 1, 2007

Study Registration Dates

First Submitted

February 4, 2008

First Submitted That Met QC Criteria

February 28, 2008

First Posted (Estimate)

February 29, 2008

Study Record Updates

Last Update Posted (Actual)

March 18, 2021

Last Update Submitted That Met QC Criteria

March 17, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FCRB 2007/0234
  • ndtso 00025/2007

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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