The following sections have been prepared to ensure that the state of the art and science related to CVD includes novel concepts, therapeutic strategies, and emerging areas of pathophysiological and practical importance to the care of dialysis patients.
The reader will notice that the format of this section is different, reflecting its different perspective: namely, the relative lack of evidence on which to base plausible guideline statements. The evidence that does exist, and is cited in this section, is either completely in nondialysis populations, or is purely associative information, with no intervention in any population yet tested. Thus, it would be a problem to include guideline statements or recommendations.
Nonetheless, this section describes the current status of knowledge with respect to risk factors and biomarkers, and represents an overview of key areas for future clinical trials. The reader is encouraged to review this section, and examine his or her current understanding and practice within the context of these highlights.
The literature review has been conducted using the same systematic strategy as for the previous guidelines in this document. The reviews presented here have been thoughtfully constructed so that clinicians can adopt different practices based on them. However, for reasons cited above, the ability to truly recommend or suggest changes in practice would be premature at this time.
Homocysteine is the demethylation product of the amino acid methionine. Once degraded, homocysteine enters the cysteine biosynthetic pathway (transulfuration), or is remethylated to methionine (activated methyl cycle). The controlling enzymes in these two pathways are cystathionine synthase (CBS), methionine synthase (MS) and 5,10-methylene tetrahydrofolate reductase (MTHFR), the latter of which supplies the methyl group required by MS in the methylation of homocysteine. Each enzyme requires a member of the B vitamin family as a co-factor. A secondary pathway for the remethylation of homocysteine is by betaine methyltransferase, a pathway that occurs in the kidney and liver. The kidneys account for approximately 70% of plasma clearance of homocysteine. The majority of plasma homocysteine is in the protein-bound form. The normal plasma concentration of homocysteine is approximately 5–10 μmol/L. Degrees of hyperhomocysteinemia (HHCY) approximately defined as mild are 15 μmol/L, as moderate are 25 μmol/L, as intermediate are 50 μmol/L, and as severe are >50 μmol/L.532–536
In the general population, HHCY has been suggested by many studies to be a risk factor for CVD, including atherosclerosis and arterial and venous thrombosis.537–547 It is not entirely clear whether a mild increase in plasma homocysteine contributes to the pathogenesis of vascular disease or is a marker for increased risk.537–539 Pathogenic mechanisms that have been postulated include activation of the coagulation cascade, damage to endothelial cells either directly or through an oxidative stress response, and lipid peroxidation.540–544 The association between HHCY and CVD has not yet been proven to be causal. Clarification of the interrelationships between HHCY and CVD will require completion of prospective, randomized intervention trials, several of which are in progress.546 Despite the lack of a solid relationship, there is significant research activity exploring interventions for the treatment of HHCY for the prevention of CVD in both the general population and in CKD patients receiving renal replacement therapy.
Association data
Whether the association between HHCY and CVD applies to patients receiving renal replacement therapy is unclear. Several studies have demonstrated that HHCY is an independent risk factor for CVD or a CVD outcome in HD patients.159,327,357,435,548–561 Others have found negative or inconclusive results.562–566 A recent study reports that in 94 HD patients taking a multivitamin, lipid peroxidation and inflammation—but not HHCY—were the main risk factors for mortality.470
Summaries of data pertaining to the association of HHCY and CVD in the general population are available. A literature review of 33 prospective cohort studies evaluated MI, stroke, CV morbidity, CV death, and/or all-cause mortality.537,547 In 73% of the studies, there was a significant association between elevated homocysteine and the aforementioned outcomes; 27% of the studies were inconclusive. In CKD patients receiving maintenance dialysis, 19 studies suggested an association between elevated plasma homocysteine levels and CVD.159,327,357,435,470,552–566 However, a causal relationship between HHCY and CVD has not been established in either the general or CKD population.
Treatment of HHCY in the general population
Intervention studies in the general population have demonstrated that dietary supplementation with folic acid, vitamin B12 and/or vitamin B6, lowers plasma homocysteine levels.546,547,567–570 Ameta-analysis of randomized trials of homocysteine-lowering vitamin supplements concluded that daily supplementation with 0.5–5.0 mg folate and 0.5 mg vitamin B12 would be expected to reduce homocysteine levels by 12 μmol/L to approximately 8–9 μmol/L.567 Interventional studies designed to reduce plasma homocysteine levels and determine if this reduction modifies cardiovascular outcomes need to be completed.
Observations of HHCY in dialysis patients
Hyperhomocysteinemia is a common observation in the CKD population.551 The prevalence of HHCY in HD patients has been reported in the range of 85%-100%, with the higher end observed in patients who were not receiving a standard multivitamin supplement.551 Concentrations of homocysteine range from 20.4–68.0 μmol/L.551 Mildly elevated levels of homocysteine occur in approximately 5%-7% of the general population, while severe HHCY is rare.533,537,567 Patients without kidney failure with mild HHCY are described as asymptomatic until the third or fourth decade, when CAD and recurrent arterial and venous thrombosis develop.533 The severe elevations of homocysteine seen in patients on maintenance dialysis therapy could be one of the nontraditional risk factors for the 50% mortality rate from CVD observed in this patient population.
Plasma homocysteine levels in HD patients have been reported to be lowered by dietary supplementation with folic acid that is given with or without vitamin B12 and B6.571–581 Other therapies that have been examined include intravenous folinic acid and MTHF. Doses of orally administered nutrients in these studies ranged from 1 mg-60 mg folic acid, with or without up to 110 mg vitamin B6 and with or without up to 1 mg vitamin B12. The higher doses of oral folate did not have a better result compared to the lower doses in terms of the post treatment plasma homocysteine levels.
These studies demonstrate that, while plasma homocysteine levels can be reduced by these nutrients, they are not normalized, and remain in the range of 15.9–29.9 μmol/L. Possible reasons for this resistance include impaired folic acid metabolism and impaired folate absorption.551 Supplementation with betaine or serine, and with the addition of betaine to folic acid, has not demonstrated a reduction in elevated plasma homocysteine levels.569 Results from interventional studies designed to determine whether modifying plasma homocysteine levels affect cardiovascular outcomes in dialysis patients are not available at this time.
Existing guidelines for the general population
The Canadian Task Force on Preventive Health Care completed an evidence-based review of the literature regarding both the association of elevated homocysteine levels and CAD, and the effect of lowering homocysteine levels with vitamin supplementation or diet.546 This evaluative process yielded several results showing associations between total homocysteine levels and CAD risk, but there was insufficient evidence to make therapeutic recommendations regarding screening for, or management of, HHCY.
Applicability to the dialysis patient
There is a strong inverse correlation between serum folate levels and plasma homocysteine levels, and a weaker correlation between homocysteine levels and plasma levels of vitamins B6 and B12.532 In the general population, administration of the deficient nutrient will correct the deficiency.568,570,582 In the dialysis patient, the administration of folate, and vitamins B6 and B12 have been reported to lower, but not normalize, plasma homocysteine levels.567–577 It has been observed that patients who are not receiving a multivitamin supplement have higher levels of plasma homocysteine.553 As a result, routine vitamin supplementation for the dialysis patient becomes important not only for adequate nutritional status. B vitamin supplementation is necessary to replace the losses from dialysis, and to prevent an independent, additive elevation in serum homocysteine levels that could be due to deficient or marginal intake of folate, riboflavin (vitamin B2),583 pyridoxine (vitamin B6) and/or cobalamin (vitamin B12).578
Further data are required regarding the effect of vitamin therapy on clinical outcomes.
As in the general population, the literature for dialysis patients is inconclusive regarding HHCY and CVD. Current studies indicate that normalization of the plasma homocysteine levels in the kidney patient population cannot be effectively obtained through folate, B6, or vitamin B12 supplementation. In addition, any lowering of the plasma homocysteine level that has been reported, has not been shown to effect CVD outcomes. However, the evidence does show that vitamin deficiency, particularly that of vitamins B2, B6, B12 and folic acid, contribute to HHCY.
Current opinion and evidence suggests that it is prudent to supplement, rather than risk deficiency, especially when supplementation is safe at the recommended levels. Therefore, dialysis patients are likely to benefit from a daily vitamin supplement that provides the recommended published vitamin profile for dialysis patients, with special attention to the inclusion of folic acid, and vitamins B2, B6 and B12.