5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients

Inflammation Clinical Trial

Official title:

5-methyltetrahydrofolate Survival and Inflammation in ESRD Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00626223
• Other study ID #: FCRB 2007/0234
• Secondary ID: ndtso 00025/2007
• Status: Completed
• Phase: N/A
• Start date: January 1998
• Est. completion date: July 2007

Study information

• Verified date: March 2021
• Source: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 341
• Est. completion date: July 2007
• Est. primary completion date: July 2001
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hyperhomocysteinemia
• Inflammation
• Mortality

Intervention

Drug:
• 5-MTHF (5-methyltetrahydrofolate)
50 mg intravenous at the end of each hemodialysis session
• folic acid
5 mg per day of oral folic acid

Locations

Country	Name	City	State
Italy	Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital	Bologna

Sponsors (2)

Lead Sponsor	Collaborator
IRCCS Azienda Ospedaliero-Universitaria di Bologna	University of Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (16)

Bayés B, Pastor MC, Bonal J, Juncà 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. — View Citation

Bønaa KH, Njølstad 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. Epub 2006 Mar 12. — View 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. — View 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. — View 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. Epub 2006 May 16. — View 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. — View 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. — View Citation

Dennis VW, Robinson K. Homocysteinemia and vascular disease in end-stage renal disease. Kidney Int Suppl. 1996 Dec;57:S11-7. Review. — View 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. — View 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. Epub 2006 Mar 12. Erratum in: N Engl J Med. 2006 Aug 17;355(7):746. — View 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. — View 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. — View Citation

Nygård O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvåle G. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA. 1995 Nov 15;274(19):1526-33. — View 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. Review. — View Citation

Suliman ME, Stenvinkel P, Heimbürger O, Bàràny P, Lindholm B, Bergström 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. — View Citation

Touam M, Zingraff J, Jungers P, Chadefaux-Vekemans B, Drüeke 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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

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