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Homocysteine, a new crucial element in the pathogenesis of uremic cardiovascular complications
A F Perna1, D Ingrosso, P Castaldo
1Institute of Biochemistry of Macromolecules and Division of Nephrology, School of Medicine, Second University of Naples, Italy.
Insights
High homocysteine levels are a risk factor for cardiovascular disease, especially in kidney patients. High-dose folic acid can effectively lower homocysteine in these individuals, potentially reducing cardiovascular risk.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Biochemistry
Background:
- Moderate hyperhomocysteinemia is an established risk factor for myocardial infarction, stroke, and thromboembolic disease.
- Chronic renal failure patients exhibit a high prevalence (85-100%) of hyperhomocysteinemia, with plasma concentrations significantly elevated (20-40 microM vs. 8-12 microM in controls).
- Post-renal transplant, homocysteine levels decrease but often remain higher than normal.
Purpose of the Study:
- To investigate the role of hyperhomocysteinemia in cardiovascular risk, particularly in chronic renal failure patients.
- To explore the biochemical mechanisms by which homocysteine may increase cardiovascular risk.
- To evaluate the efficacy of vitamin supplementation, specifically folic acid, in managing hyperhomocysteinemia in renal patients.
Main Methods:
- Review of observational studies linking hyperhomocysteinemia to cardiovascular events.
- Analysis of biochemical mechanisms including homocysteine oxidation, hypomethylation, and protein acylation.
- Evaluation of therapeutic interventions using vitamins (B6, B12, betaine, folic acid) in chronic renal failure and post-transplant patients.
Main Results:
- Hyperhomocysteinemia is linked to endothelial damage and increased cardiovascular risk through oxidative stress and hypomethylation.
- High-dose folic acid (5-15 mg) is effective in reducing homocysteine levels in chronic renal failure patients, unlike lower doses.
- Combination therapy with folic acid and vitamin B6 shows promise in transplant patients.
Conclusions:
- Hyperhomocysteinemia significantly contributes to cardiovascular risk in renal failure patients.
- High-dose folic acid is a viable therapeutic strategy for managing hyperhomocysteinemia in this population.
- Further interventional trials are needed to confirm the cardiovascular risk reduction associated with homocysteine-lowering therapies.
Abstract:
Most large observational studies available today establish that moderate hyperhomocysteinemia, either genetically or nutritionally determined, is an independent risk factor for myocardial infarction, stroke, and thromboembolic disease. This is also true for chronic renal failure patients, who exhibit a high prevalence of hyperhomocysteinemia (85-100%), which reaches high plasma concentrations (20-40 microM, while control values range between 8 and 12 microM). After a renal transplant, homocysteine levels decrease, but tend to be higher than normal. The cause of hyperhomocysteinemia in renal failure is still obscure, since recent data have questioned the previous notion that a net homocysteine renal extraction and/or excretion take place in man. No matter the cause of its increase, the sulfur amino acid homocysteine is thought to induce an increment in cardiovascular risk through three basic biochemical mechanisms: (1) homocysteine oxidation, with H2O2 generation; (2) hypomethylation through S-adenosylhomocysteine accumulation, and (3) protein acylation by homocysteine thiolactone. The final result is membrane protein damage, endothelial damage, and endothelial cell growth inhibition, among other effects. Hyperhomocysteinemia, in general, is susceptible of therapeutic intervention with the vitamins involved in its metabolism. Depending on the cause, vitamin B6, vitamin B12, betaine, and/or folic acid can be effectively utilized. Chronic renal failure patients benefit from folic acid in high dosage: 1-2 mg are usually not effective ('relative folate resistance'), while 5-15 mg reduce homocysteine levels to a 'normative' range (<15 microM) in a substantial group of patients. Good results are also obtained in transplant patients, best with a combination of folic and vitamin B6. The results of the interventional trials focusing on the possible reduction in cardiovascular risk after homocysteine-lowering therapy, both in the general population and in end-stage renal disease, are expected soon, as well as the genetic and biochemical studies in suitable models, with the aim to clarify the cause-effect link suggested by the numerous observational and basic science studies.