REVIEW J Am Soc Nephrol 12: 2181–2189, 2001 The Kidney and Homocysteine Metabolism ALLON N. FRIEDMAN,*† ANDREW G. BOSTOM,*‡ JACOB SELHUB,* ANDREW S. LEVEY,† and IRWIN H. ROSENBERG* *Vitamin Metabolism and Aging, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; †Division of Nephrology, Tufts University-New England Medical Center, Boston, Massachusetts; and ‡Division of General Internal Medicine, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island. Abstract. Homocysteine (Hcy) is an intermediate of methio- renal Hcy handling and should be considered when measuring nine metabolism that, at elevated levels, is an independent risk Hcy plasma flux and renal clearance. The underlying cause of factor for vascular disease and atherothrombosis. Patients with hyperhomocysteinemia in renal disease is not entirely under- renal disease, who exhibit unusually high rates of cardiovas- stood but seems to involve reduced clearance of plasma Hcy. cular morbidity and death, tend to be hyperhomocysteinemic, This reduction may be attributable to defective renal clearance particularly as renal function declines. This observation and the and/or extrarenal clearance and metabolism, the latter possibly inverse relationship between Hcy levels and GFR implicate the resulting from retained uremic inhibitory substances. Although kidney as an important participant in Hcy handling. The nor- the currently available evidence is not conclusive, it seems mal kidney plays a major role in plasma amino acid clearance more likely that a reduction in renal Hcy clearance and me- and metabolism. The existence in the kidney of specific Hcy tabolism is the cause of the hyperhomocysteinemic state. Ef- uptake mechanisms and Hcy-metabolizing enzymes suggests forts to resolve this important issue will advance the search for that this role extends to Hcy. Dietary protein intake may affect effective Hcy-lowering therapies in patients with renal disease. Homocysteine (Hcy) is an amino acid metabolite that has been introduces the issues of Hcy plasma flux, protein binding, and implicated, in retrospective and prospective studies, as a potential general metabolism, and reviews amino acid/Hcy metabolism in atherogenic agent and risk factor for cardiovascular disease normal kidneys, including the effects of dietary intake on this (CVD) (1–3). Hyperhomocysteinemia, the state of elevated process. It then reviews the association between Hcy and the plasma Hcy levels, is very common among patients with chronic GFR, amino acid/Hcy metabolism in diseased kidneys, and in- renal insufficiency (defined as the range of kidney function below sights gleaned from Hcy-lowering trials. It concludes with the normal but above that requiring renal replacement therapy) and hypothesis that the hyperhomocysteinemia of renal disease is occurs almost uniformly in the end-stage renal disease (ESRD) primarily attributable to reduced renal clearance and intrarenal population (4). This is of particular importance for the latter group metabolism. of patients, in which CVD is the major cause of death. In fact, these patients may have up to a 30 times higher risk of CVD- related death than the general population (5). Interestingly, tradi- Plasma Hcy Levels, Protein Binding, and Flux tional cardiac risk factors may not be able to account for this high Average fasting plasma total Hcy levels for healthy human mortality rate (6). Despite the abundance of data on Hcy metab- subjects in the current era of flour and grain folic acid fortifi- olism, the pathogenesis of hyperhomocysteinemia in renal disease cation range between 6 and 12 ␮M (Table 1) (7), with “mod- remains unclear. A better understanding of this deranged state erate” hyperhomocysteinemia occurring when levels are be- would advance current knowledge of renal physiologic processes, tween 12 and 30 ␮M, “intermediate” hyperhomocysteinemia as well as efforts to find an effective therapy. Although there is occurring when levels are between 31 and 100 ␮M, and “se- abundant evidence suggesting that the kidney plays a prominent vere” hyperhomocysteinemia occurring when levels are greater role in Hcy metabolism, there is considerable controversy sur- than 100 ␮M (8). In normal subjects, approximately 75% of rounding the extent and mechanisms of this role. This article total plasma Hcy is bound via a disulfide bond, to protein, primarily albumin, [bound Hcy (bHcy)], while the remaining 25% exists in a free unbound form [free Hcy (fHcy)] (Figure 1) Received January 24, 2001. Accepted March 24, 2001. (9,10). fHcy is composed almost entirely of oxidized, disul- Correspondence to Dr. Allon N. Friedman, Vitamin Metabolism and Aging, fide-linked heterodimers (Hcy-cysteine) or homodimers (Hcy- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts Hcy, or homocystine), with perhaps 1 to 2% existing in a University, 711 Washington Street, Room 829, Boston, MA 02111. Phone: 617-556-3007; Fax: 617-556-3166; E-mail: [email protected] reduced sulfhydryl state (11). Unfortunately, fHcy is inherently 1046-6673/1210-2181 unstable, and accurate levels may be difficult to measure. Of Journal of the American Society of Nephrology importance, only the fHcy fraction is thought to be freely Copyright © 2001 by the American Society of Nephrology filtered at the glomerulus. The fHcy/bHcy ratio varies among 2182 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 2181–2189, 2001 Table 1. Comparison of ranges of total Hcy levels in different populationsa Geometric Means 10th to 90th Percentile Group (␮M) Total Hcy Levels (␮M) End-stage renal disease 24 12 to 39 Renal transplantationb 15 9to25 Chronic renal insufficiencyb 15 9to25 Normal renal function (population-based controls)c 9 6 to 12 a Hcy, homocysteine. Modified from reference 7, with permission. b Renal transplant recipients receiving standard immunosuppressive therapy and patients with chronic renal insufficiency receiving no immunosuppressive drugs, with equivalent renal function. c In the current era of folic acid-fortified cereal grain flour. species. For example, in contrast to humans, approximately 65 Hyperhomocysteinemia is a condition in which the regula- to 75% of Hcy in rats is in the free form (12). tion of intracellular Hcy levels is disrupted and Hcy export to Hcy production occurs in all cells as a consequence of the the plasma compartment is accelerated and/or normal Hcy normal methylation process (Figure 2). The Hcy volume of dis- plasma clearance is decreased. Human kinetic studies suggest tribution in healthy subjects was observed to be approximately 0.4 that hyperhomocysteinemia in those with vitamin B12 or folate L/kg, similar to that in subjects with severe renal insufficiency deficiency is caused by enhanced tissue export of Hcy (19). In (13). Intracellular Hcy levels rise with enhanced intracellular Hcy contrast, hyperhomocysteinemia in renal disease is related to production and/or inhibition of intracellular metabolism. To main- reduced plasma Hcy clearance (13). The underlying cause of tain low intracellular levels of this putatively cytotoxic substance, this reduction is unknown but involves a defect in renal and/or Hcy that is not metabolized within the cell is exported to the extrarenal clearance. As noted below, the kidney likely plays plasma compartment (14,15). Calculations based on steady-state an important role in Hcy clearance and metabolism. kinetics in healthy adult humans estimate that 1.2 mmol of Hcy, or approximately 5 to 10% of the total daily cellular production, General Metabolism is delivered daily to the plasma compartment (16,17). Because Hcy is an endogenous sulfur-containing amino acid inter- Hcy is constantly produced and exported by cells, it must also be mediate of the essential amino acid methionine and is not constantly cleared for plasma levels to remain within 10% of obtained from the diet. An overview of the metabolic pathway baseline values, as they do in healthy human subjects (18). Plasma is presented in Figure 2. Methionine enters the one-carbon Hcy levels are not known to be actively regulated. metabolic cycle either through the dietary consumption of Figure 1. Homocysteine (Hcy) and the major related disulfides in normal human plasma. Reprinted from reference 9, with permission. J Am Soc Nephrol 12: 2181–2189, 2001 The Kidney and Hcy Metabolism 2183 Figure 2. Hcy metabolism. Enzyme reactions that are regulated by S-adenosylmethionine (SAM) and 5-methyltetrahydrofolate (MethylTHF) are indicated by large arrows. Open arrows indicate activation, and closed arrows indicate inhibition. Enzymes are as follows: 1, 5,10- methylenetetrahydrofolate reductase; 2, methionine synthase; 3, S-adenosylmethionine synthase; 4, S-adenosylhomocysteine hydrolase; 5, cystathionine ␤-synthase; 6, betaine/Hcy methyltransferase; 7, glycine N-methyltransferase; 8, serine hydroxymethyltransferase; 9, cystathio- nase. THF, tetrahydrofolate; FAD, flavin adenine dinucleotide; PLP, pyridoxal-5-phosphate. Modified from reference 4, with permission. methionine-containing protein or through endogenous protein Folate or B vitamin deficiencies and inborn errors of me- breakdown. It is then converted intracellularly to S-adenosyl- tabolism are well recognized causes of hyperhomocysteinemia methionine, which functions as a universal methyl donor for a (14). Folate and vitamin B12 deficiencies cause fasting Hcy variety of important acceptors, including nucleic acids, neuro-