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Letters to the Editor |
Departments of Clinical Chemistry and Pediatrics, University Hospital, Free University, Poli K, PO Box 7057, Amsterdam 1007 MB, Netherlands, E-mail: k.demeer{at}azvu.nl
University Hospital and Institute for Cardiovascular Research, Free University, PO Box 7057, Amsterdam 1007 MB, Netherlands
Dear Sir:
In their article on hyperhomocysteinemia and cardiovascular disease, Brattström and Wilcken (1) interpret the increased plasma total homocysteine (tHcy) concentrations found in many cardiovascular disease patients as secondary to affected kidney function due to renal arteriosclerosis. To explain the elevation in plasma tHcy in patients with decreased renal function, Brattström and Wilcken assumed that homocysteine was not cleared from the plasma because of a decreased glomerular filtration rate. In his editorial that accompanies Brattström and Wilcken's article, Scott (2) reiterates the central role of the kidney in their hypotheses and states that "There is no doubt that this organ is quantitatively important in the catabolism of homocysteine...."
We agree with Brattström, Wilcken, and Scott that diminished kidney function is strongly associated with elevated plasma tHcy in humans, even if serum creatinine is not elevated. However, in vivo studies in humans have cast doubt on the presumed mechanism: the loss of the alleged physiologic ability of the human kidney to clear homocysteine from the blood.
First, during heart catheterization in adults with normal renal function, there was no difference between arterial and renal venous homocysteine (either total or free) concentrations (3). This indicates that, in the fasting state, the normal human kidney does not clear homocysteine; however, this finding contrasts with the report by Bostom et al (4), who found a difference between arterial and renal venous homocysteine concentrations in the rat kidney.
Second, an in vivo stable-isotope study showed that whole-body remethylation of homocysteine was diminished significantly in patients with end-stage renal disease and elevated tHcy concentrations compared with healthy control subjects (5). In the same subjects, the whole-body transsulfuration rate (ie, irreversible catabolism of homocysteine) was measured; although there was a trend toward a lower transsulfuration rate in the patients with end-stage renal failure than in the healthy control subjects, the difference was not statistically significant. The results of the latter study are compatible with the results of Guttormsen et al (6), who showed lower decay rates of tHcy in the blood after homocysteine loading in 8 patients with renal failure and hyperhomocysteinemia.
On the basis of current knowledge, it is not beyond a reasonable doubt that a diminished capacity of the kidney to catabolize homocysteine is the mechanism to explain elevated tHcy concentrations in humans with renal failure. Other possible explanations for this phenomenon in renal patients are 1) decreased remethylation, possibly due to impaired folate or S-adenosyl-methionine or homocysteine metabolism; 2) impaired renal betaine production; or 3) impaired postprandial methionine handling within the dysfunctional human kidney. Elucidating the pathophysiologic role of the kidney in hyperhomocysteinemia in humans with and without kidney disease will help researchers correctly interpret epidemiologic evidence and develop effective preventive strategies for premature cardiovascular disease associated with renal disease.
REFERENCES
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