PDF herunterladen
Semin Thromb Hemost 2000; Volume 26(Number 03): 313-324
DOI: 10.1055/s-2000-8407
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Homocysteine and Renal Disease

COEN. VAN GULDENER1 , KILLIAN. ROBINSON2
  • 1Department of Internal Medicine, University Hospital and Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
  • 2Department of Medicine/Cardiology, Wake Forest University, Winston Salem, North Carolina
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
31. Dezember 2000 (online)

    Lizenzen und Reprints

ABSTRACT

Hyperhomocysteinemia refers to an elevated circulating level of the sulfur-containing amino acid homocysteine and has been shown to be a risk factor for vascular disease in the general population. In patients with renal failure, hyperhomocysteinemia is a common feature. The underlying pathophysiological mechanism for this phenomenon is unknown. Proposed mechanisms include reduced renal elimination of homocysteine and impaired nonrenal disposal, possibly because of inhibition of crucial enzymes in the methionine-homocysteine metabolism by the uremic milieu. Absolute or relative deficiencies of folate, vitamin B6, or vitamin B12 may also play a role. Several case-control and prospective studies have now indicated that hyperhomocystenemia is an independent risk factor for atherothrombotic disease in patients with predialysis and end-stage renal disease. In renal patients, plasma homocysteine concentration can be reduced by administration of folic acid in doses ranging from 1 to 15 mg per day. In more than 50% of the cases, however, the homocysteine concentration remains above 15 μmol/L. The effects of vitamin B12 or vitamin B6 are unclear. Large intervention trials are now needed to establish whether homocysteine-lowering therapy will reduce athero-thrombotic events in patients with renal failure. These studies are now planned or are ongoing.

KEYWORD

Homocysteine - renal disease - risk factors - hyperhomocysteinemia - dialysis

REFERENCES

  • 1 U.S. Renal Data System: USRDS 1998 Annual Data Report. Bethesda, MD The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases 1998
  • 2 Raine A E, Margreiter R, Brunner F P. Report on management of renal failure in Europe, XXII, 1991.  Nephrol Dial Transplant . 1992;  7-35 (7-35)
    PubMedGoogle Scholar
  • 3 Herzog C A, Ma J Z, Collins A J. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis.  N Engl J Med . 1998;  339 799-805
    CrossrefPubMedGoogle Scholar
  • 4 Kasiske B L, Guijarro C, Massy Z, Wiederkehr M R, Ma J Z. Cardiovascular disease after renal transplantation.  J Am Soc Nephrol . 1996;  7 158-165
    PubMedGoogle Scholar
  • 5 Frosst P, Blom H J, Milos R. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase.  Nat Genet . 1995;  10 111-113
    CrossrefPubMedGoogle Scholar
  • 6 Hultberg B, Andersson A, Arnadottir M. Reduced, free and total fractions of homocysteine and other thiol compounds in plasma from patients with renal failure.  Nephron . 1995;  70 62-67
    PubMedGoogle Scholar
  • 7 Robins A J, Milewczyk B K, Booth E M, Mallick N P. Plasma amino acid abnormalities in chronic renal failure.  Clin Chim Acta . 1972;  42 215-217
    CrossrefPubMedGoogle Scholar
  • 8 Cohen B D, Patel H, Kornhauser R S. Alternate reasons for atherogenesis in uremia.  Proc Clin Dialysis Transplant Forum . 1977;  7 178-180
    PubMedGoogle Scholar
  • 9 Wilcken D E, Gupta V J. Sulphur containing amino acids in chronic renal failure with particular reference to homocysteine and cysteine-homocysteine mixed disulphide.  Eur J Clin Invest . 1979;  9 301-307
    Google Scholar
  • 10 Chauveau P, Chadefaux B, Coude M. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients.  Kidney Int . 1993;  S72-77 (S72-77)
    PubMedGoogle Scholar
  • 11 Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration.  Scand J Clin Lab Invest . 1996;  56 41-46
    PubMedGoogle Scholar
  • 12 Wollesen F, Brattström L, Refsum H. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus.  Kidney Int . 1999;  55 1028-1035
    CrossrefPubMedGoogle Scholar
  • 13 Bostom A G, Shemin D, Lapane K L. Hyperhomocysteinemia, hyperfibrinogenemia, and lipoprotein (a) excess in maintenance dialysis patients: A matched case-control study.  Atherosclerosis . 1996;  125 91-101
    CrossrefPubMedGoogle Scholar
  • 14 Robinson K, Gupta A, Dennis V. Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.  Circulation . 1996;  94 2743-2748
    PubMedGoogle Scholar
  • 15 Bachmann J, Tepel M, Raidt H. Hyperhomocysteinemia and the risk for vascular disease in hemodialysis patients.  J Am Soc Nephrol . 1995;  6 121-125
    PubMedGoogle Scholar
  • 16 van Guldener C, Janssen M J, Lambert J. No change in impaired endothelial function after long-term folic acid therapy of hyperhomocysteinemia in haemodialysis patients.  Nephrol Dial Transplant . 1998;  13 106-112
    PubMedGoogle Scholar
  • 17 Arnadottir M, Berg A L, Hegbrant J, Hultberg B. Influence of haemodialysis on plasma total homocysteine concentration.  Nephrol Dial Transplant . 1999;  14 142-146
    PubMedGoogle Scholar
  • 18 Hultberg B, Andersson A, Sterner G. Plasma homocysteine in renal failure.  Clin Nephrol . 1993;  40 230-235
    PubMedGoogle Scholar
  • 19 Kim S S, Hirose S, Tamura H. Hyperhomocysteinemia as a possible role for atherosclerosis in CAPD patients.  Adv Perit Dial . 1994;  10 282-285
    PubMedGoogle Scholar
  • 20 Janssen M J, van Guldener C, de Jong G M. Folic acid treatment of hyperhomocysteinemia in dialysis patients.  Miner Electrolyte Metab . 1996;  22 110-114
    PubMedGoogle Scholar
  • 21 Suliman M E, Anderstam B, Lindholm B, Bergström J. Total, free, and protein bound sulphur amino acids in uraemic patients.  Nephrol Dial Transplant . 1997;  12 2332-2338
    PubMedGoogle Scholar
  • 22 Dierkes J, Domröse U, Ambrosch A. Response of hyperhomocysteinemia to folic acid supplementation in patients with end-stage renal disease.  Clin Nephrol . 1999;  51 108-115
    PubMedGoogle Scholar
  • 23 Wilcken D E, Gupta V J, Betts A K. Homocysteine in the plasma of renal transplant recipients: Effects of cofactors for methionine metabolism.  Clin Sci . 1981;  61 743-749
    PubMedGoogle Scholar
  • 24 Massy Z A, Chadefaux-Vekemans B, Chevalier A. Hyperhomocysteinemia: A significant risk factor for cardiovascular disease in renal transplant recipients.  Nephrol Dial Transplant . 1994;  9 1103-1118
    PubMedGoogle Scholar
  • 25 Bostom A G, Gohh R Y, Tsai M Y. Excess prevalence of fasting and postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients.  Arterioscler Thromb Vasc Biol . 1997;  17 1894-1900
    PubMedGoogle Scholar
  • 26 Arnadottir M, Hultberg B, Vladov V, Nilsson-Ehle P, Thysell H. Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients.  Transplantation . 1996;  61 509-512
    PubMedGoogle Scholar
  • 27 Ducloux D, Rueden C, Gibey R. Prevalence, determinants, and clinical significance of hyperhomocyst(e)inaemia in renal-transplant recipients.  Nephrol Dial Transplant . 1998;  13 2890-2893
    PubMedGoogle Scholar
  • 28 van Guldener C, Janssen M J, Stehouwer C D. The effect of renal transplantation on hyperhomocysteinaemia in dialysis patients, and the estimation of renal homocysteine extraction in patients with normal renal function.  Neth J Med . 1998;  52 58-64
    PubMedGoogle Scholar
  • 29 Arnadottir M, Hultberg B, Wahlberg J, Fellström B, Dimény E. Serum total homocysteine concentration before and after renal transplantation.  Kidney Int . 1998;  54 1380-1384
    CrossrefPubMedGoogle Scholar
  • 30 Ambrosi P, Barlatier A, Habib G. Hyperhomocysteinaemia in heart transplant recipients.  Eur Heart J . 1994;  15 1191-1195
    PubMedGoogle Scholar
  • 31 Berger P B, Jones J D, Olson L J. Increase in total plasma homocysteine concentration after cardiac transplantation.  Mayo Clin Proc . 1995;  70 125-131
    PubMedGoogle Scholar
  • 32 Gupta A, Moustapha A, Jacobsen D W. High homocysteine, low folate, and low vitamin B6 concentrations: Prevalent risk factors for vascular disease in heart transplant recipients.  Transplantation . 1998;  65 544-550
    PubMedGoogle Scholar
  • 33 van Guldener C, Janssen M J, de Meer K, Donker A J, Stehouwer C D. Effect of folic acid and betaine on fasting and postmethionine-loading plasma homocysteine and methionine levels in chronic haemodialysis patients.  J Intern Med . 1999;  245 175-183
    CrossrefPubMedGoogle Scholar
  • 34 Refsum H, Helland S, Ueland P M. Radioenzymic determination of homocysteine in plasma and urine.  Clin Chem . 1985;  31 624-628
    PubMedGoogle Scholar
  • 35 Stabler S P, Marcell P D, Podell E R, Allen R H. Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry.  Anal Biochem . 1987;  162 185-196
    CrossrefPubMedGoogle Scholar
  • 36 Cusworth D C, Gattereau A. Inhibition of renal tubular reabsorption of homocystine by lysine and arginine.  Lancet . 1968;  II 916-917
    PubMedGoogle Scholar
  • 37 Falchuk Z M, Edwards W A, Laster L. Effects of alpha-aminoisobutyric acid on urinary excretion of homocystine in patients with homocystinuria.  Metabolism . 1973;  22 605-610
    CrossrefPubMedGoogle Scholar
  • 38 Foreman J W, Wald H, Blumberg G, Pepe L M, Segal S. Homocystine uptake in isolated rat renal cortical tubules.  Metabolism . 1982;  31 613-619
    CrossrefPubMedGoogle Scholar
  • 39 Sturman J A, Rassin D K, Gaull G E. Distribution of transsulphuration enzymes in various organs and species.  Int J Biochem . 1970;  1 251-253
    CrossrefPubMedGoogle Scholar
  • 40 Gaull G E, von Berg W, Räihä N CR, Sturman J A. Development of methyltransferase activities of human fetal tissues.  Pediatr Res . 1973;  7 527-533
    PubMedGoogle Scholar
  • 41 McKeever M P, Weir D G, Molloy A, Scott J M. Betaine-homocysteine methyltransferase: Organ distribution in man, pig, and rat and subcellular distribution in the rat.  Clin Sci . 1991;  81 551-556
    PubMedGoogle Scholar
  • 42 Bostom A, Brosnan J T, Hall B, Nadeau M R, Selhub J. Net uptake of plasma homocysteine by the rat kidney in vivo.  Atherosclerosis . 1995;  116 59-62
    CrossrefPubMedGoogle Scholar
  • 43 House J D, Brosnan M E, Brosnan J T. Characterization of homocysteine metabolism in the rat kidney.  Biochem J . 1997;  328 287-292
    PubMedGoogle Scholar
  • 44 House J D, Brosnan M E, Brosnan J T. Renal uptake and excretion of homocysteine in rats with acute hyperhomocysteinemia.  Kidney Int . 1998;  54 1601-1607
    CrossrefPubMedGoogle Scholar
  • 45 van Guldener C, Donker A J, Jakobs C. No net renal extraction of homocysteine in fasting humans.  Kidney Int . 1998;  54 166-169
    CrossrefPubMedGoogle Scholar
  • 46 Mudd S H, Skovby F, Levy H L. The natural history of homocystinuria due to cystathionine β-synthase deficiency.  Am J Hum Genet . 1985;  37 1-31
    PubMedGoogle Scholar
  • 47 Födinger M, Mannhalter C, Wölfl G. Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients.  Kidney Int . 1997;  52 517-523
    PubMedGoogle Scholar
  • 48 Vychytil A, Födinger M, Wölfl G. Major determinants of hyperhomocysteinemia in peritoneal dialysis patients.  Kidney Int . 1998;  53 1775-1782
    CrossrefPubMedGoogle Scholar
  • 49 Bostom A G, Shemin D, Lapane K L. Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients.  Atherosclerosis . 1996;  123 193-202
    CrossrefPubMedGoogle Scholar
  • 50 Födinger M, Wölfl G, Fischer G. Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.  Kidney Int . 1999;  55 1072-1080
    CrossrefPubMedGoogle Scholar
  • 51 Tamura T, Johnston K E, Bergman S M. Homocysteine and folate concentrations in blood from patients treated with hemodialysis.  J Am Soc Nephrol . 1996;  7 2414-2418
    PubMedGoogle Scholar
  • 52 Wilcken D E, Dudman N P, Tyrrell P A, Robertson M R. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: Possible implications for prevention of vascular disease.  Metabolism . 1988;  37 697-701
    CrossrefPubMedGoogle Scholar
  • 53 Chauveau P, Chadefaux B, Coude M. Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure.  Miner Electrolyte Metab . 1996;  22 106-109
    PubMedGoogle Scholar
  • 54 Arnadottir M, Brattstrom L, Simonsen O. The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients.  Clin Nephrol . 1993;  40 236-240
    PubMedGoogle Scholar
  • 55 Bostom A G, Shemin D, Lapane K L. High-dose B-vitamin treatment of hyperhomocysteinemia in dialysis patients.  Kidney Int . 1996;  49 147-152
    PubMedGoogle Scholar
  • 56 Guttormsen A B, Ueland P M, Svarstad E, Refsum H. Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure.  Kidney Int . 1997;  52 495-502
    PubMedGoogle Scholar
  • 57 Ramirez G, Chen M, Boyce Jr H W. Longitudinal follow-up of chronic hemodialysis patients without vitamin supplementation.  Kidney Int . 1986;  30 99-106
    PubMedGoogle Scholar
  • 58 van Guldener C, Janssen M J, Lambert J. Folic acid treatment of hyperhomocysteinemia in peritoneal dialysis patients: No change in endothelial function after long-term therapy.  Perit Dial Int . 1998;  18 282-289
    PubMedGoogle Scholar
  • 59 Brulez H F, van Guldener C, Donker A J, ter Wee P M. The impact of an amino acid-based peritoneal dialysis fluid on plasma total homocysteine levels, lipid profile and body fat mass.  Nephrol Dial Transplant . 1999;  14 154-159
    PubMedGoogle Scholar
  • 60 Ducloux D, Heuzé-Lecornu L, Gibey R. Dialysis adequacy and homocyst(e)ine concentrations in peritoneal dialysis patients.  Nephrol Dial Transplant . 1999;  14 728-731
    PubMedGoogle Scholar
  • 61 Guttormsen A B, Mansoor A M, Fiskerstrand T, Ueland P M, Refsum H. Kinetics of plasma homocysteine in healthy subjects after peroral homocysteine loading.  Clin Chem . 1993;  39 1390-1397
    PubMedGoogle Scholar
  • 62 van Guldener C, Kulik W, Berger R. Homocysteine remethylation and methionine transmethylation are proportionally decreased in end-stage renal disease-a stable isotope study with L-[2H3-methyl-l-1 3C]methionine.  Kidney Int . 1999;  56 1064-1071
    CrossrefPubMedGoogle Scholar
  • 63 Jennette J C, Goldman I D. Inhibition of the membrane transport of folates by anions retained in uremia.  J Lab Clin Med . 1975;  86 834-843
    PubMedGoogle Scholar
  • 64 Livant E J, Tamura T, Johnston K E. Plasma folate conjugase activities and folate concentrations in patients receiving hemodialysis.  J Nutr Biochem . 1994;  5 504-508
    PubMedGoogle Scholar
  • 65 Dobbelstein H, Korner W F, Mempel W, Grosse-Wilde H, Edel H H. Vitamin B6 deficiency in uremia and its implications for the depression of immune responses.  Kidney Int . 1974;  5 233-239
    PubMedGoogle Scholar
  • 66 Wilcken D E, Gupta V J, Reddy S G. Accumulation of sulphur-containing amino acids including cysteine-homocysteine in patients on maintenance haemodialysis.  Clin Sci . 1980;  58 427-430
    PubMedGoogle Scholar
  • 67 Kang S S, Wong P W, Bidani A, Milanez S. Plasma protein-bound homocyst(e)ine in patients requiring chronic haemodialysis.  Clin Sci . 1983;  65 335-336
    PubMedGoogle Scholar
  • 68 Smolin L A, Laidlaw S A, Kopple J D. Altered plasma free and protein-bound sulfur amino acid levels in patients undergoing maintenance hemodialysis.  Am J Clin Nutr . 1987;  45 737-743
    PubMedGoogle Scholar
  • 69 Jungers P, Massy Z A, Khoa T N. Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: A prospective study.  Nephrol Dial Transplant . 1997;  12 2597-2602
    PubMedGoogle Scholar
  • 70 Jungers P, Chauveau P, Bandin O. Hyperhomocysteinemia is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure patients.  Miner Electrolyte Metab . 1997;  23 170-173
    PubMedGoogle Scholar
  • 71 Stehouwer C D, Gall M A, Hougaard P, Jakobs C, Parving H H. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria.  Kidney Int . 1999;  55 308-314
    CrossrefPubMedGoogle Scholar
  • 72 Bostom A G, Shemin D, Verhoef P. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study.  Arterioscler Thromb Vasc Biol . 1997;  17 2554-2558
    PubMedGoogle Scholar
  • 73 Moustapha A, Naso A, Nahlawi M. Prospective study of hyperhomocysteine as an adverse cardiovascular risk factor in end-stage renal disease.  Circulation . 1998;  97 138-141
    CrossrefPubMedGoogle Scholar
  • 74 Ducloux D, Pascal B, Jamali M, Gibey R, Chalopin J M. Is hyperhomocysteinaemia a risk factor for recurrent vascular access thrombosis in haemodialysis patients?.  Nephrol Dial Transplant . 1997;  12 2037-2038
    PubMedGoogle Scholar
  • 75 Tamura T, Bergman S M, Morgan S L. Homocysteine, B vitamins and vascular-access thrombosis in patients treated with hemodialysis.  Am J Kidney Dis . 1998;  32 475-481
    PubMedGoogle Scholar
  • 76 Manns B J, Burgess E D, Parsons H G. Hyperhomocysteinemia, anticardiolipin antibody status, and risk for vascular access thrombosis in hemodialysis patients.  Kidney Int . 1999;  55 315-320
    CrossrefPubMedGoogle Scholar
  • 77 Ambrosi P, Garcon D, Riberi A. Association of mild hyperhomocysteinemia with cardiac graft vascular disease.  Atherosclerosis . 1998;  138 347-350
    CrossrefPubMedGoogle Scholar
  • 78 Nahlawi M, Naso A, Boparai N. Low vitamin B6: An independent predictor of cardiovascular morbidity and mortality in heart transplant recipients.  Circulation . 1998;  690 (690)
    PubMedGoogle Scholar
  • 79 Massy Z A, Mamzer-Bruneel M F, Chevalier A. Carotid atherosclerosis in renal tranpslant recipients.  Nephrol Dial Transplant . 1998;  13 1792-1798
    PubMedGoogle Scholar
  • 80 Dimény E, Hultberg B, Wahlberg J, Fellström B, Arnadottir M. Serum total homocysteine concentration does not predict outcome in renal transplant recipients.  Clin Transplantation . 1998;  12 563-568
    PubMedGoogle Scholar
  • 81 Liangos O, Kreutz R, Beige J. Methylenetetrahydrofolate-reductase gene C677T variant and kidney-transplant survival.  Nephrol Dial Transplant . 1998;  13 2351-2354
    PubMedGoogle Scholar
  • 82 Dennis V W, Robinson K. Homocysteinemia and vascular disease in end-stage renal disease.  Kidney Int . 1996;  S11-17 (S11-17)
    PubMedGoogle Scholar
  • 83 Bostom A G, Lathrop L. Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerotic outcomes.  Kidney Int . 1997;  52 10-20
    PubMedGoogle Scholar
  • 84 Mayer E L, Jacobsen D W, Robinson K. Homocysteine and coronary atherosclerosis.  J Am Coll Cardiol . 1996;  27 517-527
    Google Scholar
  • 85 Ueland P M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease, and drug therapy.  J Lab Clin Med . 1989;  114 473-501
    Google Scholar
  • 86 van Guldener C, Lambert J, Janssen M J, Donker A J, Stehouwer C D. Endothelium-dependent vasodilatation and distensibility of large arteries in chronic haemodialysis patients.  Nephrol Dial Transplant . 1997;  14-18 (14-18)
    PubMedGoogle Scholar
  • 87 van Guldener C, Janssen M J, Lambert J. Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients.  Nephrol Dial Transplant . 1998;  13 1782-1786
    PubMedGoogle Scholar
  • 88 Tawakol A, Omland T, Gerhard M, Wu J T, Craeger M A. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.  Circulation . 1997;  95 1119-1121
    PubMedGoogle Scholar
  • 89 Bostom A G, Shemin D, Yoburn D. Lack of effect of oral N-acetylcysteine on the acute dialysis-related lowering of total plasma homocysteine in hemodialysis patients.  Atherosclerosis . 1996;  120 241-244
    CrossrefPubMedGoogle Scholar
  • 90 Bostom A G, Gohh R Y, Beaulieu A J. Treatment of hyperhomocysteinemia in renal transplant recipients.  Ann Intern Med . 1997;  127 1089-1092
    PubMedGoogle Scholar
  • 91 Perna A F, Ingrosso D, DeSanto N G. Metabolic consequences of folate-induced reduction of hyperhomocysteinemia in uremia.  J Am Soc Nephrol . 1997;  8 1899-1905
    PubMedGoogle Scholar
  • 92 Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials Homocysteine Lowering Trialists' Collaboration. BMJ 1998 316: 894-898
  • 93 Bostom A G, Shemin D, Lapane K L. Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: A case-control study.  Atherosclerosis . 1995;  114 93-103
    CrossrefPubMedGoogle Scholar
  • 94 Bostom A G, Shemin D, Nadeau M R. Short term betaine therapy fails to lower elevated fasting total plasma homocysteine concentrations in hemodialysis patients maintained on chronic folic acid supplementation.  Atherosclerosis . 1995;  113 129-132
    CrossrefPubMedGoogle Scholar
      >