5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients

Study Overview
=================
Brief Summary
-----------------
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.

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).

Official Title
-----------------
5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients

Conditions
-----------------
Mortality, Hyperhomocysteinemia, Inflammation

Intervention / Treatment
-----------------
* Drug: 5-MTHF (5-methyltetrahydrofolate)
* Drug: folic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>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)<br>* 50 mg intravenous at the end of each hemodialysis session<br>|
| Active Comparator: B<br>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<br>* 5 mg per day of oral folic acid<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival |  | 55 months | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ESRD patients, C-reactive protein, homocysteine, 5-MTHF, survival, Hemodialysis patients