5-Methyltetrahydrofolate Survival and Inflammation in ESRD Patients
|ClinicalTrials.gov Identifier: NCT00626223|
Recruitment Status : Completed
First Posted : February 29, 2008
Last Update Posted : February 29, 2008
|Condition or disease||Intervention/treatment||Phase|
|Mortality Hyperhomocysteinemia Inflammation||Drug: 5-MTHF (5-methyltetrahydrofolate) Drug: folic acid||Not Applicable|
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 (Clinical Trial)|
|Actual Enrollment :||341 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||5-Methyltetrahydrofolate Survival and Inflammation in ESRD Patients|
|Study Start Date :||January 1998|
|Actual Primary Completion Date :||July 2001|
|Actual Study Completion Date :||July 2007|
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
- survival [ Time Frame: 55 months ]
- Risk factors for cardiovascular disease in ESRD patients [ Time Frame: 55 months ]
- Homocysteine levels after 6, 12, 24 and 55 months [ Time Frame: 55 months ]
- CRP levels after 6, 12, 24 and 55 months [ Time Frame: 55 months ]
- Gene polymorphisms analysis on C677T and A1298C loci and differences in polymorphisms distribution in both groups [ Time Frame: 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 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00626223
|Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital|
|Bologna, Italy, 40138|
|Study Chair:||Sergio Stefoni, Professor||Nephrology Dialysis and Renal Trasnplantation Unit S.Orsola University Hospital Bologna Italy|