Clinical trial NCT00626223: 5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients
Official title: 5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Mortality
Hyperhomocysteinemia
Inflammation
Keywords: ESRD patients
C-reactive protein
homocysteine
5-MTHF
survival
Hemodialysis patients
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
Collaborators: name: University of Bologna
First posted: 2008-02-29
Enrollment: 341
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: survival
timeFrame: 55 months
Secondary outcomes:
measure: Risk factors for cardiovascular disease in ESRD patients
timeFrame: 55 months
measure: Homocysteine levels after 6, 12, 24 and 55 months
timeFrame: 55 months
measure: CRP levels after 6, 12, 24 and 55 months
timeFrame: 55 months
measure: Gene polymorphisms analysis on C677T and A1298C loci and differences in polymorphisms distribution in both groups
timeFrame: basal
measure: Differences at baseline between the groups concerning age, dialysis age, CRP, albumin, haemoglobin, Lp(a), homocysteine, folate, B6 and B12 baseline levels
timeFrame: basal
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital
Study officials:
affiliation: Nephrology Dialysis and Renal Trasnplantation Unit S.Orsola University Hospital Bologna Italy
name: Sergio Stefoni, Professor
role: STUDY_CHAIR
References:
citation: Cheung AK, Sarnak MJ, Yan G, Berkoben M, Heyka R, Kaufman A, Lewis J, Rocco M, Toto R, Windus D, Ornt D, Levey AS; HEMO Study Group. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int. 2004 Jun;65(6):2380-9. doi: 10.1111/j.1523-1755.2004.00657.x.
citation: Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvale G. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA. 1995 Nov 15;274(19):1526-33. doi: 10.1001/jama.1995.03530190040032.
citation: Buccianti G, Baragetti I, Bamonti F, Furiani S, Dorighet V, Patrosso C. Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease. J Nephrol. 2004 May-Jun;17(3):405-10.
citation: Mallamaci F, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Candela V, Scudo P, Spoto B, Testa A, Tripepi G, Tech S, Zoccali C. Hyperhomocysteinemia and arteriovenous fistula thrombosis in hemodialysis patients. Am J Kidney Dis. 2005 Apr;45(4):702-7. doi: 10.1053/j.ajkd.2005.01.004.
citation: Perna AF, De Santo NG, Ingrosso D. Adverse effects of hyperhomocysteinemia and their management by folic acid. Miner Electrolyte Metab. 1997;23(3-6):174-8.
citation: Kalantar-Zadeh K, Block G, Humphreys MH, McAllister CJ, Kopple JD. A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients. J Am Soc Nephrol. 2004 Feb;15(2):442-53. doi: 10.1097/01.asn.0000107564.60018.51.
citation: Nair AP, Nemirovsky D, Kim M, Geer EB, Farkouh ME, Winston J, Halperin JL, Robbins MJ. Elevated homocysteine levels in patients with end-stage renal disease. Mt Sinai J Med. 2005 Nov;72(6):365-73.
citation: Bayes B, Pastor MC, Bonal J, Junca J, Hernandez JM, Riutort N, Foraster A, Romero R. Homocysteine, C-reactive protein, lipid peroxidation and mortality in haemodialysis patients. Nephrol Dial Transplant. 2003 Jan;18(1):106-12. doi: 10.1093/ndt/18.1.106.
citation: Bowden RG, Wyatt FB, Wilson R, Wilborn C, Gentile M. Homocysteine and vascular access thrombosis in a cohort of end-stage renal disease patients. Ren Fail. 2004 Nov;26(6):709-14. doi: 10.1081/jdi-200037117.
citation: Chen TC, Wang IK, Lee CH, Chang HW, Chiou TT, Lee CT, Fang JT, Wu MS, Hsu KT, Yang CC, Wang PH, Chuang FR. Hyperhomocysteinaemia and vascular access thrombosis among chronic hemodialysis patients in Taiwan: a retrospective study. Int J Clin Pract. 2006 Dec;60(12):1596-9. doi: 10.1111/j.1742-1241.2006.00848.x. Epub 2006 May 16.
citation: Chuang FR, Fang JT, Chen JB, Lin CL, Chen HY, Lee CN, Wang PH, Lee CH. Hyperhomocystinemia and the prevalence of symptomatic atherosclerotic vascular disease in Taiwanese chronic hemodialysis patients: a retrospective study. Ren Fail. 2003 Sep;25(5):765-74. doi: 10.1081/jdi-120024292.
citation: Dennis VW, Robinson K. Homocysteinemia and vascular disease in end-stage renal disease. Kidney Int Suppl. 1996 Dec;57:S11-7.
citation: Suliman ME, Stenvinkel P, Heimburger O, Barany P, Lindholm B, Bergstrom J. Plasma sulfur amino acids in relation to cardiovascular disease, nutritional status, and diabetes mellitus in patients with chronic renal failure at start of dialysis therapy. Am J Kidney Dis. 2002 Sep;40(3):480-8. doi: 10.1053/ajkd.2002.34887.
citation: Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006 Apr 13;354(15):1578-88. doi: 10.1056/NEJMoa055227. Epub 2006 Mar 12.
citation: Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77. doi: 10.1056/NEJMoa060900. Epub 2006 Mar 12.
citation: Touam M, Zingraff J, Jungers P, Chadefaux-Vekemans B, Drueke T, Massy ZA. Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. Kidney Int. 1999 Dec;56(6):2292-6. doi: 10.1046/j.1523-1755.1999.00792.x.