title: Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD.
abstract: BACKGROUND
  Hyperhomocysteinemia is seen in most hemodialysis (HD) patients and is an independent risk factor for cardiovascular disease. Homocysteine metabolism via remethylation requires activated folate and vitamin B12 and metabolism via transsulfuration requires serine and vitamin B6. Prior studies have shown highly variable effects of supplemental B vitamin and folate therapy for hyperhomocysteinemia. We undertook a fully controlled trial with abnormally high doses of folic acid alone or with supplemental vitamin B6 and B12 compared with active folate alone or with serine.
  
  
  METHODS
  Two prospective studies were undertaken in hemodialysis patients. In the first study (protocol A), hyperhomocysteinemia was treated in 77 patients with 30 or 60 mg folic acid with or without vitamins B6 and B12 for eight weeks and compared with matching placebos. In the second study (protocol B), hyperhomocysteinemia was treated in 37 patients with intravenous folinic acid given alone or with serine and compared with matching placebos. All patients received the standard of care treatment with a multivitamin tablet before and throughout the protocol to test the hypothesis that additional therapy is required over and above the routine therapy for maximum reduction in total homocysteine (tHcy).
  
  
  RESULTS
  Normal volunteers; The mean (SD) tHcy of 128 normal subjects was 6.5 (4) micromol/L. Protocol A; Plasma folate increased significantly in the groups given folic acid at both four and eight weeks (P = 0.0001 at both time points). Plasma vitamin B12 was significantly increased at four weeks (P = 0.0018) but not at eight weeks (P = 0.064) in those given Vitamin B12. However, tHcy did not differ between treatment groups at baseline (P = 0.63), four weeks (P = 0.79) or eight weeks (P = 0.74). Protocol B: Plasma folate increased significantly at four weeks in those receiving folinic acid (P = 0.0001) but tHcy was not significantly different between groups (P = 0.92). In neither study was there any significant change in tHcy comparing before and during any treatment intervention.
  
  
  CONCLUSIONS
  In our studies high dose oral folic acid, intravenous folinic acid, vitamins B6 and B12 and oral serine were ineffective at lowering tHcy in patients on hemodialysis when given folic acid, folinic acid serine or B vitamins in addition to routine folic acid and B vitamin supplements.
authors.affiliation: Division of Nephrology and Hypertension, Georgetown University Hospital, Washington, DC 20007, USA. goninj@gunet.georgetown.edu
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Gonin
authors.forename: Hien
authors.initials: H
authors.lastname: Nguyen
authors.forename: René
authors.initials: R
authors.lastname: Gonin
authors.forename: Avina
authors.initials: A
authors.lastname: Sarna
authors.forename: Anne
authors.initials: A
authors.lastname: Michels
authors.forename: Faye
authors.initials: F
authors.lastname: Masri-Imad
authors.forename: Geeta
authors.initials: G
authors.lastname: Bommareddy
authors.forename: Christophe
authors.initials: C
authors.lastname: Chassaing
authors.forename: Irving
authors.initials: I
authors.lastname: Wainer
authors.forename: Asif
authors.initials: A
authors.lastname: Loya
authors.forename: Douglas
authors.initials: D
authors.lastname: Cary
authors.forename: Lew F
authors.initials: LF
authors.lastname: Barker
authors.forename: Ali
authors.initials: A
authors.lastname: Assefi
authors.forename: Robert
authors.initials: R
authors.lastname: Greenspan
authors.forename: David
authors.initials: D
authors.lastname: Mahoney
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018849:Controlled Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D005500:Follow-Up Studies; D006801:Humans; D020138:Hyperhomocysteinemia / Q000188:drug therapy* / Q000209:etiology; D007262:Infusions, Intravenous; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000175:diagnosis / Q000628:therapy; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012016:Reference Values; D006435:Renal Dialysis / Q000009:adverse effects / Q000379:methods; D018570:Risk Assessment; D012694:Serine / Q000008:administration & dosage*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000008:administration & dosage*; D025101:Vitamin B 6 / Q000008:administration & dosage*
chemical_list: D012694:Serine; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12; D002955:Leucovorin