5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients
5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients
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.
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).
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