Download PDF
Semin Vasc Med 2005; 5(2): 201-208
DOI: 10.1055/s-2005-872405
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Homocysteine and Methionine Metabolism in Renal Failure

Coen van Guldener1 , Coen D. A. Stehouwer2 , 3
  • 1Department of Internal Medicine, Amphia Hospital, Breda, Maastricht, The Netherlands
  • 2Department of Internal Medicine, University Hospital Maastricht, The Netherlands
  • 3Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Further Information

Publication History

Publication Date:
27 July 2005 (online)

    Permissions and Reprints

ABSTRACT

Renal insufficiency is invariably accompanied by elevated plasma concentrations of the sulfur-containing and potentially vasculotoxic amino acid homocysteine. There is a strong relationship between glomerular filtration rate and plasma homocysteine concentration. Unlike creatinine, however, homocysteine is avidly reabsorbed in the renal tubules, and its urinary excretion is minimal. There is no evidence that homocysteine is actively removed by the human kidney. In renal insufficiency, plasma concentrations of S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, and sulfate are elevated, pointing to a remethylation or distal transsulfuration/oxidation block as the cause of hyperhomocysteinemia in renal failure. Stable isotope techniques have shown that both whole-body homocysteine remethylation and methionine transmethylation are decreased in renal failure, whereas homocysteine transsulfuration seems intact. Metabolic homocysteine clearance (i.e., transsulfuration relative to plasma homocysteine) is decreased to a major extent. These metabolic disturbances in renal failure can only be partially restored with current treatments. Folic acid treatment lowers plasma homocysteine concentration and increases remethylation and transmethylation rates. Plasma homocysteine, however, is not normalized, and metabolic homocysteine clearance by transsulfuration remains impaired. According to the currently available data, effective normalization of plasma homocysteine can only be obtained when its metabolic clearance through transsulfuration is restored.

KEYWORDS

Homocysteine - amino acid metabolism - chronic renal failure - renal metabolism

REFERENCES

  • 1 Cheung A K, Sarnak M J, Yan G et al.. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.  Kidney Int. 2000;  58 353-362
    CrossrefPubMedGoogle Scholar
  • 2 Longenecker J C, Coresh J, Powe N R et al.. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study.  J Am Soc Nephrol. 2002;  13 1918-1927
    CrossrefPubMedGoogle Scholar
  • 3 Sarnak M J, Coronado B E, Greene T et al.. Cardiovascular disease risk factors in chronic renal insufficiency.  Clin Nephrol. 2002;  57 327-335
    PubMedGoogle Scholar
  • 4 Henry R MA, Kostense P J, Bos G et al.. Mild renal insufficiency is associated with increased cardiovascular mortality: the Hoorn study.  Kidney Int. 2002;  62 1402-1407
    CrossrefPubMedGoogle Scholar
  • 5 Muntner P, He J, Hamm L, Loria C, Whelton P K. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States.  J Am Soc Nephrol. 2002;  13 745-753
    PubMedGoogle Scholar
  • 6 Cohen B D, Patel H, Kornhauser R S. Alternate reasons for atherogenesis in uremia.  Proc Clin Dial Transplant Forum. 1977;  7 178-180
    PubMedGoogle Scholar
  • 7 Wilcken D EL, Gupta V J. Sulphur containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide.  Eur J Clin Invest. 1979;  9 301-307
    Google Scholar
  • 8 McCully K S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.  Am J Pathol. 1969;  56 111-128
    Google Scholar
  • 9 Bostom A G, Shemin D, Verhoef P et al.. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients.  Arterioscler Thromb Vasc Biol. 1997;  17 2554-2558
    PubMedGoogle Scholar
  • 10 Ducloux D, Motte G, Challier B, Gibey R, Chalopin J M. Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study.  J Am Soc Nephrol. 2000;  11 134-137
    PubMedGoogle Scholar
  • 11 Mallamaci F, Zoccali C, Tripepi G et al.. Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients.  Kidney Int. 2002;  61 609-614
    CrossrefPubMedGoogle Scholar
  • 12 Suliman M E, Qureshi R, Barany P et al.. Hyperhomocysteinemia, nutritional status, and cardiovascular disease in hemodialysis patients.  Kidney Int. 2000;  57 1727-1735
    CrossrefPubMedGoogle Scholar
  • 13 Kalantar-Zadeh K, Block G, Humphreys M H, McAllister C J, Kopple J D. A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients.  J Am Soc Nephrol. 2004;  15 442-453
    CrossrefPubMedGoogle Scholar
  • 14 Suliman M E, Stenvinkel P, Qureshi R et al.. Hyperhomocysteinemia in relation to plasma free amino acids, biomarkers of inflammation and mortality in patients with chronic kidney disease starting dialysis therapy.  Am J Kidney Dis. 2004;  44 455-465
    PubMedGoogle Scholar
  • 15 Finkelstein J D. The metabolism of homocysteine: pathways and regulation.  Eur J Pediatr. 1998;  157(Suppl 2) S40-S44
    PubMedGoogle Scholar
  • 16 Refsum H, Helland S, Ueland P M. Radioenzymic determination of homocysteine in plasma and urine.  Clin Chem. 1985;  31 624-628
    PubMedGoogle Scholar
  • 17 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
  • 18 Cusworth D C, Gattereau A. Inhibition of renal tubular reabsorption of homocystine by lysine and arginine.  Lancet. 1968;  2 916-917
    PubMedGoogle Scholar
  • 19 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
  • 20 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
  • 21 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
  • 22 Gaull G E, von Berg W, Raiha N CR, Sturman J A. Development of methyltransferase activities of human fetal tissues.  Pediatr Res. 1973;  7 527-533
    PubMedGoogle Scholar
  • 23 McKeever M P. Weir D G. Mol1oy 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
  • 24 Hultberg B, Andersson A, Masson P, Larson M, Tunek A. Plasma homocysteine and thiol compound fractions after oral administration of N-acetylcysteine.  Scand J Clin Lab Invest. 1994;  54 417-422
    CrossrefPubMedGoogle Scholar
  • 25 Ventura P, Panini R, Abbati G, Marchetti G, Salvioli G. Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy.  Pharmacology. 2003;  68 105-114
    CrossrefPubMedGoogle Scholar
  • 26 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
  • 27 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
  • 28 van Guldener C, Donker A JM, Jakobs C, Teerlink T, de Meer K, Stehouwer C DA. No net renal extraction of homocysteine in fasting humans.  Kidney Int. 1998;  54 166-169
    CrossrefPubMedGoogle Scholar
  • 29 Garibotto G, Sofia A, Saffioti S et al.. Interorgan exchange of aminothiols in humans.  Am J Physiol Endocrinol Metab. 2003;  284 E757-E763
    PubMedGoogle Scholar
  • 30 Tsai M Y, Aras O, Sozen H et al.. Plasma homocysteine levels in living kidney donors before and after uninephrectomy.  J Lab Clin Med. 2004;  143 340-343
    CrossrefPubMedGoogle Scholar
  • 31 van Guldener C, Janssen M JFM, Stehouwer C DA et al.. 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
  • 32 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
  • 33 Francis M E, Eggers P W, Hostetter T H, Briggs J P. Association between serum homocysteine and markers of impaired kidney function in adults in the United States.  Kidney Int. 2004;  66 303-312
    CrossrefPubMedGoogle Scholar
  • 34 Wollesen F, Brattstrom L, Refsum H, Ueland P M, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus.  Kidney Int. 1999;  55 1028-1035
    CrossrefPubMedGoogle Scholar
  • 35 Ganji V, Kafai M R. Demographic, health, lifestyle, and blood vitamin determinants of serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey, 1988-1994.  Am J Clin Nutr. 2003;  77 826-833
    PubMedGoogle Scholar
  • 36 Bostom A G. Homocysteine: “expensive creatinine” or important modifiable risk factor for arteriosclerotic outcomes in renal transplant recipients?.  J Am Soc Nephrol. 2000;  11 149-151
    PubMedGoogle Scholar
  • 37 Samuelsson O, Lee D M, Attman P O et al.. The plasma levels of homocysteine are elevated in moderate renal insufficiency but do not predict the rate of progression.  Nephron. 1999;  82 306-311
    CrossrefPubMedGoogle Scholar
  • 38 Sarnak M J, Wang S R, Beck G J et al.. Homocysteine, cysteine, and B vitamins as predictors of kidney disease progression.  Am J Kidney Dis. 2002;  40 932-939
    CrossrefPubMedGoogle Scholar
  • 39 Hovind P, Tarnow L, Rossing P et al.. Progression of diabetic nephropathy: role of plasma homocysteine and plasminogen activator inhibitor-1.  Am J Kidney Dis. 2001;  38 1376-1380
    PubMedGoogle Scholar
  • 40 Ninomiya T, Kiyohara Y, Kubo M et al.. Hyperhomocysteinemia and the development of chronic kidney disease in a general population: the Hisayama study.  Am J Kidney Dis. 2004;  44 437-445
    PubMedGoogle Scholar
  • 41 Laidlaw S A, Berg R L, Kopple J D, Naito H, Walker W G, Walser M. Patterns of fasting plasma amino acid levels in chronic renal insufficiency: results from the feasibility phase of the modification of diet in renal disease study.  Am J Kidney Dis. 1994;  23 504-513
    PubMedGoogle Scholar
  • 42 Allen R H, Stabler S P, Lindenbaum J. Serum betaine, N,N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism.  Metabolism. 1993;  42 1448-1460
    CrossrefPubMedGoogle Scholar
  • 43 Loehrer F MT, Angst C P, Brunner F P, Haefeli W E, Fowler B. Evidence for disturbed S-adenosylmethionine: S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions?.  Nephrol Dial Transplant. 1998;  13 656-661
    PubMedGoogle Scholar
  • 44 Herrmann W, Schorr H, Geisel J, Riegel W. Homocysteine, cystathionine, methylmalonic acid and B-vitamins in patients with renal disease.  Clin Chem Lab Med. 2001;  39 739-746
    CrossrefPubMedGoogle Scholar
  • 45 Suliman M E, Anderstam B, Lindholm B, Bergstrom J. Total, free, and protein-bound sulphur amino acids in uraemic patients.  Nephrol Dial Transplant. 1997;  12 2332-2338
    PubMedGoogle Scholar
  • 46 Nakanishi T, Otaki Y, Hasuike Y et al.. Association of hyperhomocysteinemia with plasma sulphate and urine excretion in patients with progressive renal disease.  Am J Kidney Dis. 2002;  40 909-915
    CrossrefPubMedGoogle Scholar
  • 47 Ducloux D, Aboubakr A, Motte G et al.. Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12.  Nephrol Dial Transplant. 2002;  17 865-870
    PubMedGoogle Scholar
  • 48 Ghandour H, Bagley P J, Shemin D et al.. Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of l-folinic or folic acid.  Kidney Int. 2002;  62 2246-2249
    CrossrefPubMedGoogle Scholar
  • 49 Suliman M E, Divino Filho J C, Barany P, Anderstam B, Lindholm B, Bergstrom J. Effects of high-dose folic acid and pyridoxine on plasma and erythrocyte sulfur amino acids in hemodialysis patients.  J Am Soc Nephrol. 1999;  10 1287-1296
    PubMedGoogle Scholar
  • 50 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
  • 51 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
  • 52 van Guldener C, Kulik W, Berger R et al.. Homocysteine and methionine metabolism in ESRD: a stable isotope study.  Kidney Int. 1999;  56 1064-1071
    CrossrefPubMedGoogle Scholar
  • 53 Stam F, van Guldener C, ter Wee P M et al.. Homocysteine clearance and methylation flux rates in health and end-stage renal disease: association with S-adenosylhomocysteine.  Am J Physiol Renal Physiol. 2004;  287 F215-F223
    CrossrefPubMedGoogle Scholar
  • 54 Perna A F, Ingrosso D, Galletti P, Zappia V, De Santo N G. Membrane protein damage and methylation reactions in chronic renal failure.  Kidney Int. 1996;  50 358-366
    PubMedGoogle Scholar
  • 55 Ingrosso D, Cimmioni A, Perna A F et al.. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia.  Lancet. 2003;  361 1693-1699
    CrossrefPubMedGoogle Scholar
  • 56 Stam F, van Guldener C, ter Wee P M, Jakobs C, de Meer K, Stehouwer C DA. Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease.  Kidney Int. 2005;  67 259-264
    CrossrefPubMedGoogle Scholar

Coen van GuldenerM.D. 

Department of Internal Medicine, Amphia Hospital

PO Box 9157, 4800 RL Breda, The Netherlands