Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 1, 2013

B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes

  • John David Spence EMAIL logo


Therapy to lower homocysteine with B vitamins does reduce the risk of stroke, if not myocardial infarction. The apparent lack of efficacy of vitamin therapy in most of the large clinical trials was probably determined by the failure to take account of the metabolic deficiency of vitamin B12, which is very common and often missed, and by the failure to take account of impaired renal function. Metabolic B12 deficiency is present in 20% of people over 65 years of age, and in 30% of vascular patients above 70 years, so higher doses of B12 are needed in elderly patients. However, high-dose cyanocobalamin leads to accumulation of cyanide in patients with renal failure. B vitamin therapy is beneficial in patients with good renal function, but harmful in patients with significantly impaired renal function (a glomerular filtration rate <50). It seems likely that in patients with renal impairment, methylcobalamin should be used instead cyanocobalamin.

Corresponding author: Dr. John David Spence, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, 1400 Western Road, London, ON, Canada N6G 2V2, Phone: +1 519 9315731, Fax: +1 519 9315737


1. Spence JD, Stampfer MJ. Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses. J Am Med Assoc 2011;306:2610–1.10.1001/jama.2011.1834Search in Google Scholar

2. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578–88.10.1056/NEJMoa055227Search in Google Scholar

3. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567–77.10.1056/NEJMoa060900Search in Google Scholar

4. Robertson J, Iemolo F, Stabler SP, Allen RH, Spence JD. Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products. CMAJ 2005;172:1569–73.10.1503/cmaj.045055Search in Google Scholar

5. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230–6.10.1056/NEJM199707243370403Search in Google Scholar

6. Graham IM, Daly L, Refsum H, Robinson K, Brattstrom LE, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease. J Am Med Assoc 1997;277:1775–81.10.1001/jama.1997.03540460039030Search in Google Scholar

7. Zhou J, Moller J, Ritskes-Hoitinga M, Larsen ML, Austin RC, Falk E. Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atherosclerosis 2003;168:255–62.10.1016/S0021-9150(03)00138-2Search in Google Scholar

8. Colgan SM, Austin RC. Homocysteinylation of metallothionein impairs intracellular redox homeostasis: the enemy within! Arterioscler Thromb Vasc Biol 2007;27:8–11.10.1161/01.ATV.0000254151.00086.26Search in Google Scholar

9. Veeranna V, Zalawadiya SK, Niraj A, Pradhan J, Ference B, Burack RC, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol 2011;58:1025–33.10.1016/j.jacc.2011.05.028Search in Google Scholar

10. Holmes MV, Newcombe P, Hubacek JA, Sofat R, Ricketts SL, Cooper J, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 2011;378:584–94.10.1016/S0140-6736(11)60872-6Search in Google Scholar

11. Rimm EB, Stampfer MJ. Folate and cardiovascular disease: one size does not fit all. Lancet 2011;378:544–6.10.1016/S0140-6736(11)61057-XSearch in Google Scholar

12. Herrmann W, Obeid R, Schorr H, Geisel J. The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings. Curr Drug Metab 2005;6:47–53.10.2174/1389200052997384Search in Google Scholar

13. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004;171:251–9.10.1503/cmaj.1031155Search in Google Scholar

14. Spence JD. Nutrition and stroke prevention. Stroke 2006;37:2430–5.10.1161/01.STR.0000236633.40160.eeSearch in Google Scholar

15. Vogiatzoglou A, Oulhaj A, Smith AD, Nurk E, Drevon CA, Ueland PM, et al. Determinants of plasma methylmalonic acid in a large population: implications for assessment of vitamin B12 status. Clin Chem 2009;55:2198–206.10.1373/clinchem.2009.128678Search in Google Scholar

16. Bang H, Mazumdar M, Spence JD. Tutorial in biostatistics: analyzing associations between total plasma homocysteine and B vitamins using optimal categorization and segmented regression. Neuroepidemiology 2006;27:188–200.10.1159/000096149Search in Google Scholar

17. Rajan S, Wallace JI, Brodkin KI, Beresford SA, Allen RH, Stabler SP. Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults. J Am Geriatr Soc 2002;50:1789–95.10.1046/j.1532-5415.2002.50506.xSearch in Google Scholar

18. Refsum H, Smith AD. Homocysteine, B vitamins, and cardiovascular disease. N Engl J Med 2006;355:207.Search in Google Scholar

19. Spence JD. Homocysteine-lowering therapy: a role in stroke prevention? Lancet Neurol 2007;6:830–8.10.1016/S1474-4422(07)70219-3Search in Google Scholar

20. Poli D, Antonucci E, Cecchi E, Marcucci R, Liotta AA, Cellai AP, et al. Culprit factors for the failure of well-conducted warfarin therapy to prevent ischemic events in patients with atrial fibrillation: the role of homocysteine. Stroke 2005;36: 2159–63.10.1161/01.STR.0000183620.06179.7bSearch in Google Scholar PubMed

21. Spence JD, Tamayo A, Lownie SP, Ng WP, Ferguson GG. Absence of microemboli on transcranial Doppler identifies low-risk patients with asymptomatic carotid stenosis. Stroke 2005;36:2373–8.10.1161/01.STR.0000185922.49809.46Search in Google Scholar PubMed

22. Madani A, Beletsky V, Tamayo A, Munoz C, Spence JD. High-risk asymptomatic carotid stenosis: ulceration on 3D ultrasound versus TCD microemboli. Neurology 2011;77:744–50.10.1212/WNL.0b013e31822b0090Search in Google Scholar

23. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233–40.10.1161/01.CIR.0000163561.90680.1CSearch in Google Scholar

24. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8.10.1161/01.STR.22.8.983Search in Google Scholar

25. Spence JD. Mechanisms of thrombogenesis in atrial fibrillation. Lancet 2009;373:1006.10.1016/S0140-6736(09)60604-8Search in Google Scholar

26. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010;170:1622–31.10.1001/archinternmed.2010.348Search in Google Scholar PubMed

27. Huang T, Chen Y, Yang B, Yang J, Wahlqvist ML, Li D. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr 2012;31:448–54.10.1016/j.clnu.2011.01.003Search in Google Scholar PubMed

28. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. Br Med J 2010;341:c6273.10.1136/bmj.c6273Search in Google Scholar PubMed PubMed Central

29. Alsagaff MY, Thaha M, Aminuddin M, Yogiarto RM, Yogiantoro M, Tomino Y. Asymmetric dimethylarginine: a novel cardiovascular risk factor in end-stage renal disease. J Int Med Res 2012;40:340–9.10.1177/147323001204000135Search in Google Scholar PubMed

30. Stuhlinger MC, Oka RK, Graf EE, Schmolzer I, Upson BM, Kapoor O, et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 2003;108:933–8.10.1161/01.CIR.0000085067.55901.89Search in Google Scholar PubMed

31. Wilcox CS. Asymmetric dimethylarginine and reactive oxygen species: unwelcome twin visitors to the cardiovascular and kidney disease tables. Hypertension 2012;59:375–81.10.1161/HYPERTENSIONAHA.111.187310Search in Google Scholar PubMed PubMed Central

32. van GC, Nanayakkara PW, Stehouwer CD. Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in chronic kidney disease. Clin Chem Lab Med 2007;45:1683–7.Search in Google Scholar

33. Rocha MS, Teerlink T, Janssen MC, Kluijtmans LA, Smulders Y, Jakobs C, et al. Asymmetric dimethylarginine in adults with cystathionine beta-synthase deficiency. Atherosclerosis 2012;222:509–11.10.1016/j.atherosclerosis.2012.03.009Search in Google Scholar PubMed

34. Rueda-Clausen CF, Cordoba-Porras A, Bedoya G, Silva FA, Zarruk JG, Lopez-Jaramillo P, et al. Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC-VI sub-study. Eur J Neurol 2012;19:417–25.10.1111/j.1468-1331.2011.03534.xSearch in Google Scholar PubMed

35. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering plasma total homocysteine to prevent recurrent stroke, myocardial infarction, and death in ischemic stroke patients: results of the Vitamin Intervention for Stroke Prevention (VISP) Randomized Trial. J Am Med Assoc 2004;291:565–75.10.1001/jama.291.5.565Search in Google Scholar PubMed

36. Spence JD, Cordy P, Kortas C, Freeman D. Effect of usual doses of folate supplementation on elevated plasma homocyst(e)ine in hemodialysis patients: no difference between 1 and 5 mg daily. Am J Nephrol 1999;18:405–10.10.1159/000013486Search in Google Scholar PubMed

37. House AA, Eliasziw M, Cattran DC, Churchill DN, Oliver MJ, Fine A, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. J Am Med Assoc 2010;303:1603–9.10.1001/jama.2010.490Search in Google Scholar PubMed

38. Loscalzo J. Homocysteine trials – clear outcomes for complex reasons. N Engl J Med 2006;354:1629–32.10.1056/NEJMe068060Search in Google Scholar PubMed

39. Obeid R, Shannan B, Herrmann W. Advanced glycation end products overload might explain intracellular cobalamin deficiency in renal dysfunction, diabetes and aging. Med Hypotheses 2011;77:884–8.10.1016/j.mehy.2011.08.002Search in Google Scholar PubMed

40. Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant 1997;12:1622–8.10.1093/ndt/12.8.1622Search in Google Scholar PubMed

41. Wang R. Is H2S a stinky remedy for atherosclerosis? Arterioscler Thromb Vasc Biol 2009;29:156–7.10.1161/ATVBAHA.108.180190Search in Google Scholar PubMed

42. Koyama K, Ito A, Yamamoto J, Nishio T, Kajikuri J, Dohi Y, et al. Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis 2010;55: 1069–78.10.1053/j.ajkd.2009.12.035Search in Google Scholar PubMed

43. Hasuike Y, Nakanishi T, Moriguchi R, Otaki Y, Nanami M, Hama Y, et al. Accumulation of cyanide and thiocyanate in haemodialysis patients. Nephrol Dial Transplant 2004;19:1474–9.10.1093/ndt/gfh076Search in Google Scholar PubMed

44. Perna AF, Luciano MG, Ingrosso S, Pulzella P, Sepe I, Lanza D, et al. Hydrogen sulphide-generating pathways in haemodialysis patients: a study on relevant metabolites and transcriptional regulation of genes encoding for key enzymes. Nephrol Dial Transplant 2009;24:3756–63.10.1093/ndt/gfp378Search in Google Scholar PubMed

Received: 2012-7-17
Accepted: 2012-9-27
Published Online: 2013-03-01
Published in Print: 2013-03-01

©2013 by Walter de Gruyter Berlin Boston

Downloaded on 26.2.2024 from
Scroll to top button