Homocysteine and B-group vitamins in renal transplant patients
Introduction
Homocysteine is a sulphur-containing amino acid which is an intermediary product in methionine metabolism. Once formed, homocysteine can either be remethylated to methionine, or converted to cystathionine by B-vitamin-dependent reactions (Fig. 1). Greatly elevated plasma levels of homocysteine are found in subjects with homocystinuria and these patients exhibit early arteriosclerosis, arterial and venous thrombosis, occurring in up to 50% by the age of 30 years [1]. Recently, milder increases in plasma homocysteine have been shown to act as an independent risk factor for cardiovascular disease, including peripheral vascular disease, ischaemic heart disease and stroke [2], and this has been confirmed by several prospective studies with clinical endpoints [3], [4], [5], [6], [7], [8].
Cardiovascular disease is the major cause of death in patients on maintenance dialysis [9] and this is only partially accounted for by the high prevalence of other risk factors, for example, hypertension, smoking, hyperlipidemia, and diabetes mellitus [10]. Patients receiving renal-replacement therapy experience a 16–19-fold increased risk of myocardial ischaemia and infarction when compared with age-matched and sex-matched populations without renal failure [11].
Patients with homocystinuria show an increased urinary excretion of the disulphide homocystine (homocysteine–homocysteine). The normal kidney is thought to play a role in homocysteine catabolism, and this removal mechanism has been shown to be impaired in chronic renal failure [12]. Indeed, it has been shown that homocysteine is increased in patients with various degrees of renal failure [13], [14], [15], including those undergoing regular haemodialysis [16], [17], [18], [19], [20].
Renal transplant patients, in common with other patients with varying degrees of renal failure, have an increased incidence of cardiovascular disease which cannot be fully explained by the increased prevalence of classic risk factors [21]. Little information is available, however, about homocysteine levels in renal transplant patients. Wilcken et al. [22] were the first to examine renal transplant recipients, with homocysteine–cysteine mixed disulphide being raised in the transplant patients, and subsequent work from other groups has confirmed that both fasting and post-methionine-load homocysteine levels are increased in renal transplant recipients [23], [24] Arnadottir et al. [25] found renal transplant patients on cyclosporin had significantly higher total homocysteine (tHcy) concentrations than those not on cyclosporin and renal failure patients without a transplant. They also found a lack of correlation between the concentrations of tHcy and red cell folate in patients treated with cyclosporin, suggesting that cyclosporin interferes with the folate-assisted remethylation of homocysteine. However, the possible influence of cyclosporin on homocysteine in transplant recipients has not been confirmed by others [26], and this remains an area of controversy. In view of this, the aim of our study was to further investigate tHcy levels in renal transplant patients and the association between tHcy and other variables, particularly the effect of immunosuppressive regimen.
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Materials and methods
We selected 55 renal transplant recipients, 32 men and 23 women aged between 18 and 69 years, and 32 age- and sex-matched controls (22 men and 10 women) who were healthy volunteers from the hospital workforce with normal renal function. The renal transplant patients all had stable renal function (creatinine clearance 61.3±2.8 ml/min; urea 7.2±1.4 mmol/l; creatinine 119.0±1.3 μmol/l). All were receiving immunosuppressive drugs: 39 were receiving cyclosporin and the other 16 receiving
Results
Homocysteine was increased in transplant recipients in comparison with control subjects (10.9±1.5 vs. 6.7±1.3 μmol/l, P<0.001).
Renal transplant recipients had significantly higher concentrations of creatinine and urea compared with controls. There was no difference in tHcy, urea and creatinine concentrations between those on cyclosporin and those on prednisolone+azathioprine (Table 1). There was also no difference in creatinine clearance between those on cyclosporin and those on
Discussion
At present, renal transplantation is an established method in the treatment of end-stage renal failure. Cardiovascular disease represents a major cause of both morbidity and mortality in these patients [23]. Several groups [22], [23], [24], [25] have shown that significant hyperhomocysteinaemia is present in renal transplant patients, and also in heart transplant patients [28], [29]. We have confirmed this result, showing that patients with transplanted kidneys and stable but reduced renal
Conclusion
Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment, and this may contribute to the increased cardiovascular disease risk in these patients. In this study, the elevation in homocysteine occurs independently of the immunosuppresive regimen used and despite normal concentrations of folate and elevated vitamin B12.
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