Reply to K de Meer et al

Department of Medicine, County Hospital, 391 85 Kalmar, Sweden, E-mail: lars.brattstrom{at}ltkalmar.se
Department of Cardiovascular Medicine, University of New South Wales, The Prince of Wales Hospital, Sydney, Australia

Dear Sir:

We appreciate the interesting comments of de Meer et al about the mechanisms mediating the increase in circulating homocysteine concentrations in patients with impaired renal function. We did not discuss the possible mechanisms in our paper, simply noting that there was a much more precise correlation between plasma homocysteine and the glomerular filtration rate (GFR) than between homocysteine and serum creatinine (1). The GFR provides a more accurate estimate of early impairment of renal function than does the serum creatinine concentration. Our point was to stress the association between even modest renal impairment and elevated circulating homocysteine concentrations.

We completely agree with de Meer et al's conclusion that knowledge of the mechanisms responsible for the elevation of homocysteine associated with reduced renal function is incomplete. However, some inferences can be drawn that indicate that both systemic and renal mechanisms are involved. For example, high doses of folic acid lower but do not normalize elevated homocysteine concentrations in patients with chronic renal failure; oral betaine provided no additional lowering effects (2, 3). Thus, mechanisms other than reduced remethylation of homocysteine must contribute to the persistent elevation of homocysteine.

In patients with marked renal impairment, not only is homocysteine elevated but so too is circulating cysteine (2, 4). Because an elevation of both of these sulfur-containing amino acids sensitively reflects impaired renal function, the elevation is consistent with the occurrence of diminished transsulfuration due to impaired renal function or to diminished handling by the kidney of the extrarenal production of these amino acids. Clearly, elucidation and quantitation of our limited knowledge of the mechanisms responsible for the elevated concentrations of homocysteine and cysteine in renal failure warrant further study, as de Meer et al stress.

REFERENCES

1. Brattström L, Wilcken DEL. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000;72:315–23.
2. Wilcken DEL, Dudman NPB, Tyrrell PA, Robertson MR. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease. Metabolism 1988;37:697–701.
3. Guldener CV, Janssen JFM, de Meer K, Donker AJM, Stehouwer CDA. Effect of folic acid and betaine on fasting and postmethionine-loading plasma homocysteine and methionine levels in chronic haemodialysis patients. J Intern Med 1999;245:175–83.
4. Wilcken DEL, Gupta VJ. Sulphur containing amino acids in chronic renal failure with particular reference to homocysteine and cysteine-homocysteine mixed disulphide. Eur J Clin Invest 1979;37:697–701.