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ABSTRACT: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD). Our objective is to describe the prevalence of CVD risk factors applying standard criteria and use of CVD risk factor-lowering medications in contemporary KTRs.
The Folic Acid for Vascular Outcome Reduction in Transplantation study enrolled and collected medication data on 4107 KTRs with elevated homocysteine and stable graft function an average of five yr post-transplant.
CVD risk factors were common (hypertension or use of blood pressure (BP) lowering medication in 92%, borderline or elevated low-density lipoprotein (LDL) or use of lipid-lowering agent in 66%, history of diabetes mellitus in 41%, and obesity in 38%); prevalent CVD was reported in 20% of study participants. National Kidney Foundation BP guidelines (BP <130/80 mmHg) were not met by 69% of participants. Uncontrolled hypertension (BP of 140/90 mmHg or higher) was present in 44% of those taking antihypertension medication; 18% of participants had borderline or elevated LDL, of which 60% were untreated, and 31% of the participants with prevalent CVD were not using an antiplatelet agent.
There is opportunity to improve treatment and control of traditional CVD risk factors in kidney transplant recipients.
Clinical Transplantation 07/2012; 26(4):E438-46. · 1.67 Impact Factor
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American Journal of Kidney Diseases 06/2011; 57(6):963-5. · 5.43 Impact Factor
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Andrew G Bostom,
Myra A Carpenter,
John W Kusek,
Andrew S Levey,
Lawrence Hunsicker,
Marc A Pfeffer,
Jacob Selhub,
Paul F Jacques,
Edward Cole,
Lisa Gravens-Mueller,
Andrew A House,
Clifton Kew,
Joyce L McKenney,
Alvaro Pacheco-Silva,
Todd Pesavento,
John Pirsch,
Stephen Smith,
Scott Solomon,
Matthew Weir
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ABSTRACT: Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown.
In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin.
Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level.
Circulation 04/2011; 123(16):1763-70. · 14.74 Impact Factor
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American Journal of Kidney Diseases 09/2010; 57(1):181-2. · 5.43 Impact Factor
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Andrew G Bostom
American Journal of Kidney Diseases 07/2010; 56(1):185. · 5.43 Impact Factor
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Andrew G Bostom
American Journal of Kidney Diseases 04/2010; 55(4):628-30. · 5.43 Impact Factor
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ABSTRACT: Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease.
We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268).
Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of -0.13 mmol/L (-0.15 to -0.13 mmol/L; -0.41 mg/dl [-0.46 to -0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or > or =60 ml/min per 1.73 m(2), a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus < or =1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use.
We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to > or =90 ml/min per 1.73 m(2) (i.e., stages 1 through 3 chronic kidney disease).
Clinical Journal of the American Society of Nephrology 03/2010; 5(4):582-9. · 5.23 Impact Factor
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ABSTRACT: Hyperhomocysteinemia may be a modifiable risk factor for the prevention of arteriosclerotic outcomes in patients with chronic kidney disease (CKD). Few clinical trials of homocysteine lowering have been conducted in persons with CKD before reaching end-stage renal disease. Kidney transplant recipients are considered individuals with CKD.
To describe the baseline characteristics of renal transplant recipients enrolled in a clinical trial of homocysteine lowering with a standard multivitamin containing high doses of folic acid and vitamins B(6) and B(12) aimed at reducing arteriosclerotic outcomes. Factors considered were level of kidney function, total homocysteine concentration, and prevalence of diabetes and previous cardiovascular disease (CVD).
Cross-sectional survey within a randomized controlled trial cohort.
Participants were recruited from kidney transplant clinics in the United States, Canada, and Brazil. Eligible participants had increased levels of homocysteine (> or =12.0 micromol/L in men and > or =11.0 micromol/L in women) and kidney function measured by means of Cockroft-Gault estimated creatinine clearance of 30 mL/min or greater.
Of 4,110 randomly assigned participants, 38.9% had diabetes and 19.5% had previous CVD. Mean total homocysteine concentration was 17.1 +/- 6.3 (SD) micromol/L, whereas mean creatinine clearance was 66.4 +/- 23.2 mL/min. Approximately 90% of the trial cohort had an estimated glomerular filtration rate consistent with stages 2 to 3 CKD (i.e., 30 to 89 mL/min).
Analysis is based on cross-sectional data from a randomized controlled trial, self-report of comorbid illnesses, and level of kidney function was estimated.
A large population of stable renal transplant recipients who are at high risk of the development of CVD (both de novo and recurrent) has been recruited into the Folic Acid for Vascular Outcome Reduction in Transplantation Trial and are likely to experience a sufficient number of events to address the primary hypothesis of the trial.
American Journal of Kidney Diseases 12/2008; 53(1):121-8. · 5.43 Impact Factor
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ABSTRACT: Patients with chronic kidney disease, including kidney transplant recipients, are at high risk for cardiovascular disease (CVD). In addition to the constellation of traditional CVD risk factors in chronic kidney disease, elevated total homocysteine (tHcy) is notably more prevalent among the general population. The Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial is designed to evaluate whether lowering tHcy using vitamin supplementation reduces CVD events in renal transplant recipients.
FAVORIT is a multicenter double-blind randomized controlled clinical trial. Participants are clinically stable renal transplant recipients who are 6 months or longer posttransplant with elevated tHcy. Patients are randomized to a multivitamin that includes either a high-dose or low-dose of folic acid (5 or 0 mg), vitamin B6 (50 or 1.4 mg), and vitamin B12 (1000 or 2 microg). The primary end point is a composite of incident or recurrent CVD outcomes, that is, coronary heart, cerebrovascular, or abdominal aortic/lower extremity arterial events. A sample size of 4000 is estimated to provide 87% power to detect a 20% treatment effect. Recruitment is expected to continue until July 2006, with follow-up through June 2010.
From August 2002 through December 2004, 2234 of the target 4000 patients were enrolled. In accordance with trial design, mean (SD) screening tHcy was elevated (17.4 +/- 6.2 micromol/L), and mean (SD) estimated creatinine clearance was consistent with stable renal function (58.0 +/- 18.6 mL/min). Evaluating baseline results to date, 42% of the randomized participants had a history of diabetes mellitus, and 21% had prevalent CVD.
The FAVORIT trial is designed with sufficient power and follow-up time to detect a clinically relevant change in CVD risk between renal transplant recipients receiving a high or low tHcy-lowering folic acid multivitamin. Preliminary screening and baseline data support the trial's objectives.
American heart journal 10/2006; 152(3):448.e1-7. · 4.65 Impact Factor
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ABSTRACT: Total serum homocysteine (tHcy) has been shown to predict de novo and recurrent cardiovascular events in many studies. However, results in diabetic populations with minimal nephropathy are mixed. The independent relationship between tHcy and arteriosclerotic outcomes and congestive heart failure (CHF) events in a population with high cardiovascular risk and diabetic nephropathy was examined. A total of 1575 individuals were enrolled in the international Irbesartan Diabetic Nephropathy Trial (IDNT) and followed for 2.6 yr. All participants had baseline diabetic nephropathy, overt proteinuria, and hypertension and were recruited between 1996 and 1999. A total of 492 total arteriosclerotic outcomes (primary outcome) and 317 CHF events (secondary outcome) were tallied. Established cardiovascular risk factors were highly prevalent, as were high tHcy levels (quintiles [microM]: first 4.5 to 11; second >11 to 13; third >13 to 15; fourth >15 to 19; fifth >19). No association between tHcy and arteriosclerotic outcomes was observed in a univariate model or after adjustment for study randomization and established cardiovascular risk factors. The strongest outcome predictor was the presence of baseline cardiovascular disease, followed by an inverse relationship to diastolic BP. The significant univariate association between tHcy and CHF events disappeared when serum creatinine alone was added to the model. These findings question the utility of tHcy in predicting de novo or recurrent cardiovascular events in individuals with diabetic nephropathy. Further studies are needed to confirm whether these negative results apply to other populations with heavy cardiovascular risk burdens. Previous positive findings can potentially be explained through tHcy's role as a sensitive surrogate marker for kidney disease, itself a recognized cardiovascular risk factor.
Journal of the American Society of Nephrology 12/2005; 16(11):3397-402. · 9.66 Impact Factor
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ABSTRACT: The inflammatory marker C-reactive protein (CRP) has been found in most, but not all, prospective studies to be associated with future cardiovascular outcomes. However, CRP has not been tested in the high-cardiovascular risk population of type 2 diabetic nephropathy.
We studied the independent relationship between CRP and the subsequent development of incident or recurrent arteriosclerotic outcomes (primary) and congestive heart failure events (secondary) in 1560 individuals with diabetic nephropathy, overt proteinuria, and hypertension enrolled in the prospective Irbesartan Diabetic Nephropathy Trial.
Traditional cardiac risk factors were highly prevalent, CRP levels were high overall [quintiles (mg/L) 1st, 0 to 1.2; 2nd, 1.3 to 2.5; 3rd, 2.6 to 5.0; 4th, 5.1 to 10.0; and 5th, >10), and subsequent cardiovascular events were very common. A univariate relationship existed between CRP and total arteriosclerotic outcomes (P < 0.0001). However, after adjusting for study intervention and traditional risk factors, the relationship no longer remained. In fact, controlling for previous cardiovascular disease alone caused the association to become nonsignificant. The secondary analysis found a significant univariate relationship between CRP and congestive heart failure events (P= 0.007) that persisted in multivariate analyses (P= 0.006). However, this relationship was confined to the highest CRP quintile [RR (95% CI) 2.0 (1.27, 3.16)].
In diabetic patients with nephropathy, CRP does not add predictive information above and beyond that provided by traditional established risk factors. Whether this holds true for other populations with similar risk burdens is an important public health question that should be addressed. A secondary finding of a link between CRP and congestive heart failure requires further confirmation.
Kidney International 09/2005; 68(2):773-8. · 6.61 Impact Factor
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ABSTRACT: Patients with diabetic nephropathy are at elevated cardiovascular risk. C-reactive protein (CRP) has been used to successfully predict cardiovascular events.
We identified clinical and biochemical characteristics that correlate with CRP levels in diabetic nephropathy patients.
Baseline data obtained from 722 patients in the Irbesartan Diabetic Nephropathy Trial included age, sex, body mass index (BMI), systolic blood pressure (BP), serum creatinine, plasma low- and high-density cholesterol, triacylglycerol, serum albumin, hemoglobin A1C, 24h urinary protein excretion, plasma total homocysteine (tHcy), folate, B12, pyridoxal 5'-phosphate (PLP, active form of Vitamin B(6)), and plasma CRP levels.
In univariate analyses CRP was positively associated with female sex (r=0.08; P=0.04), BMI (r=0.34; P<0.01), serum creatinine (r=0.21; P<0.01), hemoglobin A1C (r=0.08; 0.04), and inversely associated with PLP (r=-0.17; P<0.01) and folate (r=-0.09; P=0.02). A stepwise multiple regression model found CRP directly correlated with BMI (P<0.01) and serum creatinine (P<0.01), and inversely correlated with PLP (P<0.01). The final model explained 16% of the total variance of CRP.
These results extend previous findings of an inverse relationship between Vitamin B(6) and CRP. The lack of association between CRP and certain established or emerging cardiovascular risk factors offers novel information regarding cardiovascular risk in this population.
Atherosclerosis 02/2004; 172(1):121-5. · 3.79 Impact Factor
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ABSTRACT: The chronic hemodialysis population has an accelerated rate of cardiovascular morbidity and death. Furthermore, elevated levels of the putative atherothrombotic risk factor homocysteine are almost ubiquitous in this population. Attempts to normalize elevated plasma total homocysteine (tHcy) levels in dialysis patients using pharmacological-dose vitamin therapy or other strategies generally have been unsuccessful. Preliminary uncontrolled evidence suggests that N-acetylcysteine (NAC) may be an effective tHcy-lowering agent. We designed a randomized placebo-controlled study to determine the effect of prolonged oral NAC therapy on lowering tHcy levels in vitamin-replete chronic hemodialysis patients.
Thirty-eight subjects were treated before intervention with a standard dialysis vitamin supplement to ensure a uniform vitamin-replete state. They were then block randomized to treatment with NAC, 1.2 g twice a day, for 4 weeks or matched placebo.
There were no significant baseline differences between the two groups, although differences in pyridoxal 5'-phosphate (active form of vitamin B(6)) levels approached significance (P = 0.06). In a paired analysis, there was no statistically significant difference between the NAC and placebo groups. NAC was very well tolerated in hemodialysis patients.
This randomized placebo-controlled trial found that chronic oral NAC therapy did not significantly reduce tHcy levels in hemodialysis patients. Although a larger sample size theoretically could have increased the statistical significance between groups, implications of the potentially very modest reduction in tHcy levels are not yet known. Finally, based on this limited study, NAC appears to be a safe and well-tolerated therapy in the hemodialysis population.
American Journal of Kidney Diseases 03/2003; 41(2):442-6. · 5.43 Impact Factor
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ABSTRACT: The metabolism of homocysteine requires contributions of several enzymes and vitamin cofactors. Earlier studies identified a common polymorphism of methylenetetrahydrofolate reductase that was associated with mild hyperhomocysteinemia. Common variants of two other enzymes involved in homocysteine metabolism, methionine synthase and methionine synthase reductase, have also been identified. Methionine synthase catalyzes the remethylation of homocysteine to form methionine and methionine synthase reductase is required for the reductive activation of the cobalamin-dependent methionine synthase. The methionine synthase gene (MTR) mutation is an A to G substitution, 2756A-->G, which converts an aspartate to a glycine codon. The methionine synthase reductase gene (MTRR) mutation is an A to G substitution, 66A-->G, that converts an isoleucine to a methionine residue. To determine if these polymorphisms were associated with mild hyperhomocysteinemia, we investigated subjects from two of the NHLBI Family Heart Study field centers, Framingham and Utah. Total plasma homocysteine concentrations were determined after an overnight fast and after a 4-h methionine load test. MTR and MTRR genotype data were available for 677 and 562 subjects, respectively. The geometric mean fasting homocysteine was unrelated to the MTR or MTRR genotype categories (AA, AG, GG). After a methionine load, a weak positive association was observed between change in homocysteine after a methionine load and the number of mutant MTR alleles (P-trend=0.04), but this association was not statistically significant according to the overall F-statistic (P=0.12). There was no significant interaction between MTR and MTRR genotype or between these genotypes and any of the vitamins with respect to homocysteine concentrations. This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine.
Atherosclerosis 01/2003; 166(1):49-55. · 3.79 Impact Factor
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ABSTRACT: We have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid.
Forty-eight chronic and stable hemodialysis patients were block-randomized, based on their screening predialysis tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12. Folate distribution was determined in plasma of 46 participants (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC method, with electrochemical (coulometric) detection.
Both groups had similar baseline geometric means of plasma total folate and similar folate forms distribution. Following treatment, both groups demonstrated similar marked elevation in plasma total folate (geometric mean of the increase: Folinic acid group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid-treated group, practically all of the increase in total folate was due to 5-methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35% of the increase in total folate and the remainder was unmethylated folic acid.
Data from the present findings suggest that defects in folate absorption or impairment in folate interconversion are not the cause of the persistent hyperhomocysteinemia in hemodialysis patients.
Kidney International 01/2003; 62(6):2246-9. · 6.61 Impact Factor
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ABSTRACT: Elevated homocysteine levels increase cardiovascular risk although the mechanism is not well understood. Since thrombosis plays an important role in plaque development and acute coronary syndromes, hyperhomocysteinemia may increase risk by increasing the thrombotic potential.
Hemostatic risk factors were measured in 3,216 individuals (1,451 men and 1,765 women) free of cardiovascular disease who participated in cycle 5 of the Framingham Offspring Study. An increase in homocysteine level was associated with a rise in plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (TPA) antigen, von Willebrand factor and fibrinogen level. After regression analyses adjusting for covariates, there remained significant associations between homocysteine and PAI-1 and TPA antigen.
Increasing homocysteine levels are associated with impaired fibrinolytic potential, as indicated by increased PAI-1 and TPA antigen levels. These data suggest that folic acid and other homocysteine lowering therapies may decrease cardiac events through a reduction in thrombotic tendency.
Thrombosis and Haemostasis 12/2002; 88(5):799-804. · 5.04 Impact Factor
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ABSTRACT: Patients with diabetes who manifest proteinuria are at increased risk for cardiovascular events. Some studies suggest that proteinuria exerts its cardiovascular effects at least partly through a positive association with total plasma homocysteine (tHcy). Modestly sized but better designed contrary studies find no such link through a limited range of serum creatinine and proteinuria. We tested the hypothesis that proteinuria independently predicts tHcy levels in a larger cohort of type 2 diabetic patients with nephropathy throughout a much broader range of kidney disease and proteinuria.
Baseline data for the cross-sectional study were obtained from 717 patients enrolled in the multicenter Irbesartan Diabetic Nephropathy Trial. All subjects had type 2 diabetes, hypertension, and proteinuria and were between 29 and 78 years of age. Data included age, sex, BMI, serum creatinine and albumin, LDL and HDL cholesterol, triglyceride, proteinuria and albuminuria, plasma folate, B12, and pyridoxal 5'-phosphate (PLP) (the active form of B6), HbA(1c), and tHcy levels. Unadjusted and multivariable models were used in the analysis.
Crude analyses revealed significant associations between tHcy and age (r = 0.074; P = 0.008), creatinine (r = 0.414; P < 0.001), PLP (r = -0.105; P = 0.021), B12 (r = -0.216; P < 0.001), folate (r = -0.241; P < 0.001), and HbA(1c) (r = -0.119; P = 0.003), with serum albumin approaching significance (r = 0.055; P = 0.072). Only serum creatinine, plasma folate, B12, serum albumin, sex, HbA(1c), and age were independent predictors of tHcy after controlling for all other variables.
By finding no independent correlation between proteinuria (or albuminuria) and tHcy levels, this study improves the external validity of previous negative findings. Therefore, it is unlikely that the observed positive association between proteinuria and cardiovascular disease is directly related to hyperhomocysteinemia.
Diabetes Care 11/2002; 25(11):2037-41. · 8.09 Impact Factor
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ABSTRACT: Accurate renal function measurements are important for the diagnosis and treatment of kidney disease, proper medication dosing, interpretation of possible uremic symptoms, and decision-making regarding when to initiate renal replacement therapy. Because the use of highly accurate filtration markers to measure renal function has traditionally been limited by cumbersome and costly techniques and the involvement of radioactivity (among other factors), renal function is typically estimated by using specially derived prediction equations. These formulae usually use serum creatinine levels, i.e., a marker of filtration that is insensitive to mild/moderate decreases in GFR. Although attempts have been made to validate certain renal function prediction equations among patients with chronic kidney disease (CKD) with abnormal serum creatinine levels, this is the first study to specifically evaluate the predictive performance of these equations for patients with CKD and serum creatinine levels in the normal range. The results of eight prediction equations for 109 patients with CKD and serum creatinine levels of < or =1.5 mg/dl were compared with standard iohexol GFR values. The most accurate results were obtained with the Cockroft-Gault and Bjornsson equations. The most precise formulae were the Modification of Diet in Renal Disease Study equations, although they were highly biased. Even the most accurate results exhibited levels of error that made them suboptimal for clinical treatment of these patients. These results suggest that measurement of GFR with endogenous or exogenous filtration markers might be the most prudent strategy for the assessment of renal function in the CKD population with normal serum creatinine levels. Further studies are needed to confirm the generalizability of these findings for this patient subgroup.
Journal of the American Society of Nephrology 08/2002; 13(8):2140-4. · 9.66 Impact Factor
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ABSTRACT: Renal transplantation is a commonly performed curative procedure for end-stage renal disease. With the increase in renal allograft half-lives, attention is now being focused on cardiovascular morbidity and death in the renal transplant recipient (RTR) population. Among the more novel cardiovascular disease (CVD) risk factors for which this group is at risk is hyperhomocysteinemia. Hyperhomocysteinemia has been associated with an increased risk of CVD, although prospective randomized trials designed to prove causality are still ongoing. Since plasma total homocysteine levels are inversely related to renal function, RTRs have a greatly increased prevalence of hyperhomocysteinemia. Other determinants of homocysteine include B-vitamins, albumin, age, and genetic polymorphisms. Although RTRs are resistant to the typical B-vitamin doses used to correct hyperhomocysteinemia in the general population, they do respond to supraphysiologic dose therapy. In terms of prevalence, etiology, and treatment of hyperhomocysteinemia, RTRs are very similar to the much larger chronic renal insufficiency population. For this reason, RTRs have been chosen as an ideal study population in investigating the effect of reducing hyperhomocysteinemia on CVD outcomes.
American Journal of Transplantation 05/2002; 2(4):308-13. · 6.39 Impact Factor
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ABSTRACT: The prevalence of deficient plasma folate status and elevated total plasma levels of homocysteine (tHcy), have been dramatically reduced after fortification of all enriched cereal grain flour products with folic acid at 140 microg/100 g flour. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid-based vitamin B supplementation among stable coronary artery disease (CAD) patients. Using a 2x2 factorial design, 131 stable CAD patients (mean age 60.1 years; 29.8% women) were randomly assigned to receive a combination of folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d, or placebo, with or without vitamin B6 50 mg/d, for 12 weeks of treatment. ANCOVA adjusted for baseline fasting tHcy levels revealed only very modest (ie, approximately 1.0 micromol/L), albeit statistically significant (P<0.05), reductions in mean fasting tHcy levels afforded by the folic acid-containing treatments. Additional analyses indicated that none of the treatments provided a statistically significant reduction in the 2-hour post-methionine increase in tHcy levels, relative to placebo treatment. CAD patients exposed to cereal grain flour products fortified with folic acid who receive high-dose, folic acid-containing vitamin B regimens, experience only very modest reductions in their mean fasting plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.
Arteriosclerosis Thrombosis and Vascular Biology 03/2002; 22(3):488-91. · 6.37 Impact Factor
