Homocysteine metabolism in renal failure Alessandra F. Perna a,c , Diego Ingrosso b,c , Ersilia Satta a,c , Cinzia Lombardi a,c , Filomena Acanfora a,c and Natale G. De Santo a,c Purpose of review This review focuses on recent findings (June 2002–July 2003) on the topic of homocysteine, a sulfur amino acid associated with cardiovascular disease, and its metabolism in renal failure, a condition with a high prevalence of both hyperhomocysteinemia and cardiovascular disease. Recent findings A large meta-analysis of prospective studies in the general population established that hyperhomocysteinemia is a risk factor for cardiovascular disease. The results of intervention trials, once available, will also have to be tested in a meta-analysis, because of predicted problems with their statistical power. In kidney patients, intervention trials, still in the recruiting stage, target transplant patients, because of their unique characteristics related to folate responsiveness. As for the cause of hyperhomocysteinemia, new findings show that in humans, renal metabolic extraction depends on renal plasma flow in the post-absorptive state. Folate absorption or interconversion seems not to be affected. Riboflavin is a determinant of plasma homocysteine levels in uraemia. The consequences of hyperhomocysteinemia in uraemia are DNA hypomethylation and altered gene expression. Summary The causes of hyperhomocysteinemia in renal failure are still not clear. However, the possibilities include defective renal or extrarenal metabolism as a result of uraemic toxicity. Renal plasma flow is important in homocysteine renal metabolism. Among the consequences of hyperhomocysteinemia in renal failure are impaired protein and DNA methylation, with an alteration in the allelic expression of genes regulated through methylation. Intervention trials are under way to test whether hyperhomocysteinemia is causally related to cardiovascular disease in this patient population. Keywords homocysteine, uraemia, chronic renal failure, cardiovascular disease, uraemic toxicity Curr Opin Clin Nutr Metab Care 7:53–57. # 2004 Lippincott Williams & Wilkins. a First Division of Nephrology/Department of Pediatrics, b Department of Biochemistry and Biophysics ‘F. Cedrangolo’, and c Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy Correspondence to Alessandra F. Perna, MD, PhD, Division of Nephrology/ Department of Pediatrics, Second University of Naples, Via Pansini 5, Ed. 17, Naples, Italy 80131 Tel: +39 081 5666651; fax: +39 081 5666655; e-mail: alessandra.perna@unina2.it Current Opinion in Clinical Nutrition and Metabolic Care 2004, 7:53–57 Abbreviations CBS cystathionine-beta-synthase FAD flavin adenine dinucleotide # 2004 Lippincott Williams & Wilkins 1363-1950 Introduction Homocysteine is a sulfhydryl amino acid situated at a branch point of methionine metabolism. Methionine, contained either in the diet or originating from protein breakdown, is condensed with ATP to form S-adeno- sylmethionine. S-adenosylmethionine in turn donates its methyl group in the transmethylation pathway to various methyl acceptors, and its demethylated product is S- adenosylhomocysteine. S-adenosylhomocysteine is hy- drolysed to adenosine and homocysteine in a reversible reaction. Homocysteine is then metabolized to cystathio- nine in the transsulfuration pathway, where cystathio- nine-beta-synthase (CBS) is the rate-limiting enzyme. The remethylation pathway instead leads to methionine formation from homocysteine, which receives a methyl group from methyltetrahydrofolate. Methylenetetrahy- drofolate reductase is the enzyme that catalyses the reduction of methylenetetrahydrofolate to methyltetra- hydrofolate, thereby irreversibly committing one carbon units to methyltetrahydrofolate. Homocysteinuria, in its most common form caused by the inherited defect of CBS, is the first described human model of hyperhomocysteinemia, in which the latter causally induces high mortality levels as a result of premature cardiovascular disease, and therapy leads to a significant increase in survival [1]. In homocysteinuria, affected patients, who display very high homocysteine levels in the blood and a variety of clinically relevant derangements attributable to homocysteine accumula- tion, used to die of premature cardiovascular disease [2]. Stemming from the observations carried out in homo- cysteinuria, studies on the topic of hyperhomocysteine- mia began. It has been indicated in retrospective and prospective studies that hyperhomocysteinemia is an independent risk factor for cardiovascular disease (ischaemic disease, such as stroke and myocardial infarction, and arterial and venous thrombotic events) in the general population [3,4]. In normal individuals, the plasma total homocysteine concentration range is from 5 to 12 mM, and over 97% is in its oxidized form. Hyperhomocysteinemia is defined of mild degree if below 16 mM, of moderate degree between 16 and 30 mM, intermediate between 31 and 100 mM, and severe as greater than 100 mM [5]. In non- treated homocysteinuria, levels are in the severe range, and in chronic renal failure, levels are in the moderate– DOI: 10.1097/01.mco.0000109607.04238.c1 53