Remnant cholesterol is prospectively associated with cardiovascular disease events and all-cause mortality in kidney transplant recipients: the FAVORIT study.

BACKGROUND: The cholesterol content of circulating triglyceride-rich lipoproteins is characterized as remnant cholesterol, although little is known about its role in the development of cardiovascular disease (CVD) outcomes, all-cause mortality or transplant failure in kidney transplant recipients (KTRs). Our primary aim was to investigate the prospective association of remnant cholesterol and the risk of CVD events in renal transplant recipients with secondary aims evaluating remnant cholesterol and renal graft failure and all-cause mortality among participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial. METHODS: Among 4110 enrolled participants, 98 were excluded for missing baseline remnant cholesterol levels and covariates. Nonfasting remnant cholesterol levels were calculated based on the lipid profiles in 3812 FAVORIT trial participants at randomization. A Wilcoxon-type test for trend was used to compare baseline characteristics across remnant cholesterol quartiles. Cox proportional hazards regression was used to evaluate the association of baseline remnant cholesterol levels with time to primary and secondary study outcomes. RESULTS: During a median follow-up of 4.0 years we documented 548 CVD incident events, 343 transplant failures and 452 all-cause deaths. When comparing the highest quartile (quartile 4) to quartile 1, proportional hazard modeling revealed a significant increase in CVD risk {hazard ratio [HR] 1.32 [95% confidence interval (CI) 1.04-1.67]} and all-cause mortality risk [HR 1.34 (95% CI 1.01-1.69)]. A nonsignificant increase in transplant failure was seen as well [HR 1.20 (95% CI 0.87-1.64)]. CONCLUSIONS: Remnant cholesterol is associated with CVD and all-cause mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of remnant cholesterol-lowering therapy on these outcomes may be warranted.

Physical activity and risk of cardiovascular events and all-cause mortality among kidney transplant recipients.

BACKGROUND: Insufficient physical activity (PA) may increase the risk of all-cause mortality and cardiovascular disease (CVD) morbidity and mortality among kidney transplant recipients (KTRs), but limited research is available. We examine the relationship between PA and the development of CVD events, CVD death and all-cause mortality among KTRs. METHODS: A total of 3050 KTRs enrolled in an international homocysteine-lowering randomized controlled trial were examined (38% female; mean age 51.8 ± 9.4 years; 75% white; 20% with prevalent CVD). PA was measured at baseline using a modified Yale Physical Activity Survey, divided into tertiles (T1, T2 and T3) from lowest to highest PA. Kaplan-Meier survival curves were used to graph the risk of events; Cox proportional hazards regression models examined the association of baseline PA levels with CVD events (e.g. stroke, myocardial infarction), CVD mortality and all-cause mortality over time. RESULTS: Participants were followed up to 2500 days (mean 3.7 ± 1.6 years). The cohort experienced 426 CVD events and 357 deaths. Fully adjusted models revealed that, compared to the lowest tertile of PA, the highest tertile experienced a significantly lower risk of CVD events {hazard ratio [HR] 0.76 [95% confidence interval (CI) 0.59-0.98]}, CVD mortality [HR 0.58 (95% CI 0.35-0.96)] and all-cause mortality [HR 0.76 (95% CI 0.59-0.98)]. Results were similar in unadjusted models. CONCLUSIONS: PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs. These observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among KTRs.

Albuminuria and Allograft Failure, Cardiovascular Disease Events, and All-Cause Death in Stable Kidney Transplant Recipients: A Cohort Analysis of the FAVORIT Trial.

RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain. STUDY DESIGN: Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial. SETTING & PARTICIPANTS: Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil. PREDICTOR: Urine albumin-creatinine ratio (ACR) at randomization. OUTCOMES: Allograft failure, CVD, and all-cause death. ANALYTICAL APPROACH: Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression. RESULTS: Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m2, mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 [95% CI, 2.19-5.30] and 9.96 [95% CI, 6.35-15.62], respectively), CVD events (HRs of 1.25 [95% CI, 0.96-1.61] and 1.55 [95% CI, 1.13-2.11], respectively), and all-cause death (HRs of 1.65 [95% CI, 1.23-2.21] and 2.07 [95% CI, 1.46-2.94], respectively). LIMITATIONS: No data for rejection; single ACR assessment. CONCLUSIONS: In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.

Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study.

BACKGROUND: Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. STUDY DESIGN: Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. SETTING & PARTICIPANTS: Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. PREDICTOR: Uric acid concentration. OUTCOMES: The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. RESULTS: 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models (P=0.5 for CV events; P=0.09 for death, and P=0.1 for transplant failure). LIMITATIONS: Unknown use of uric acid-lowering agents among study participants. CONCLUSIONS: Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation.

Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Inadequacy of cardiovascular risk factor management in chronic kidney transplantation - evidence from the FAVORIT study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: There is opportunity to improve treatment and control of traditional CVD risk factors in kidney transplant recipients.

Baseline characteristics of participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial.

BACKGROUND: 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. OBJECTIVES: 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). STUDY DESIGN: Cross-sectional survey within a randomized controlled trial cohort. SETTING & PARTICIPANTS: 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. RESULTS: 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). LIMITATIONS: Analysis is based on cross-sectional data from a randomized controlled trial, self-report of comorbid illnesses, and level of kidney function was estimated. CONCLUSIONS: 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.

Physical Activity and Cardiovascular Risk among Kidney Transplant Patients.

PURPOSE: Research examining the relationship between physical activity (PA) and cardiovascular disease (CVD) risk factors among kidney transplant recipients (KTR) is limited. Accordingly, we sought to 1) describe the levels of PA in KTR and 2) analyze the associations between PA levels and CVD risk factors in KTR. METHODS: Baseline data from KTR participants in a large multiethnic, multicenter trial (the Folic Acid for Vascular Outcome Reduction in Transplantation) were examined. PA was categorized in tertiles (low, moderate, and high) derived from a modified PA summary score from the Yale Physical Activity Survey. CVD risk factors were examined across levels of PA by ANOVA, Kruskal-Wallis rank test, and hierarchical multiple regression. RESULTS: The 4034 participants were 37% female (mean ± SD = 51.9 ± 9.4 yr of age, 75% White, 97% with stage 2T-4T chronic kidney disease, and 20% with prevalent CVD. Participants in the "high" PA tertile reported more vigorous PA and walking, compared with participants in moderate and low tertiles (both P < 0.001). No differences were observed in daily household, occupational, or sedentary activities across PA tertiles. More participants in the "low" PA tertile were overweight/obese, had a history of prevalent diabetes, and/or had CVD compared with more active participants (all P < 0.001). Hierarchical modeling revealed that younger age (P = 0.002), cadaveric donor source (P = 0.006), shorter transplant vintage (P = 0.025), lower pulse pressure (P < 0.001), and no history of diabetes (P < 0.001) were associated with higher PA scores. CONCLUSION: The most active KTR engaged in more intentional exercise. Lower levels of PA were positively associated with more CVD risk factors. Higher PA levels were associated with younger age and with more positive KTR outcomes.

Blood Pressure, Chronic Kidney Disease Progression, and Kidney Allograft Failure in Kidney Transplant Recipients: A Secondary Analysis of the FAVORIT Trial.

BACKGROUND: In chronic kidney disease, intensive systolic blood pressure (SBP) control reduces mortality at a cost of greater acute kidney injury risk. Kidney transplantation involves implantation of denervated kidneys and immunosuppressive medications that increase acute kidney injury risk. The optimal blood pressure (BP) target in kidney transplant recipients (KTRs) is uncertain. Prior observational studies from the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial demonstrate associations of lower SBP levels and reduced mortality risk, but the relationship of BP with kidney allograft function remains unknown. Thus, in FAVORIT, we investigated the relationship of SBP and diastolic blood pressure (DBP) with risk of kidney allograft failure and estimated glomerular filtration rate (eGFR) slope among stable KTRs. METHODS: Cox proportional hazards and multivariable linear regression models adjusted for demographics, transplant characteristics, comorbidities, baseline eGFR, and urine albumin-to-creatinine ratio were used to determine associations of SBP and DBP with time to a composite kidney outcome of ≥50% eGFR decline or dialysis dependence, and with annualized eGFR change, respectively. Multivariable restricted cubic spline plots were developed to evaluate the functional form of the relationships. RESULTS: Among 3,598 KTRs, mean age was 52 ± 9 years, SBP was 136 ± 20 mm Hg, DBP was 79 ± 12 mm Hg, and eGFR was 49 ± 18 ml/minute/1.73 m2. There were 369 events of ≥50% eGFR decline or dialysis dependence during a mean follow-up of 4.0 ± 1.5 years. There was no association of either SBP (compared with SBP 120 to <130 mm Hg, hazard ratio (HR) for the SBP < 110 was 1.01 (95% confidence interval (CI) 0.60 to 1.70) and 130 to <140 was 0.89 (0.64 to 1.24)) or DBP (compared with DBP 70 to <80 mm Hg, HR for the DBP 60 to <70 was 1.00 (95% CI 0.74 to 1.34) and 80 to <90 was 0.90 (0.68 to 1.18)) with the kidney failure outcome or annualized eGFR slope, and, when examined using restricted cubic splines, there was no evidence of "J"- or "U"-shaped relationships. CONCLUSIONS: In a large sample of stable KTRs, we found no evidence of thresholds at which lower BPs were related to higher risk of allograft failure or eGFR decline. In light of prior findings of mortality benefit at low SBP, these observational findings suggest lower BP may be beneficial in KTRs. This important question requires confirmation in future randomized trials in KTRs.

Hypothesis: Potential Utility of Serum and Urine Uromodulin Measurement in Kidney Transplant Recipients?

Seventy years after its discovery, studies of the myriad properties, and potential disease associations of uromodulin are now burgeoning. Although normative ranges for serum/plasma uromodulin concentrations were established over 30 years ago, their external validation occurred only in very recent, larger studies. As tubular function indices, serum and urinary uromodulin may be more sensitive indicators of kidney graft dysfunction undetected by glomerular filtration markers, or proteinuria. Moreover, 2 sizable, just published longitudinal reports revealed that lower serum uromodulin levels were associated with cardiovascular disease (CVD) outcomes, total mortality, and infectious disease deaths, in patients with known or suspected coronary heart disease. Preliminary longitudinal studies have reported that reduced levels of plasma or serum uromodulin were linked to progression to end-stage renal disease in chronic kidney disease patients, and graft failure in kidney transplant recipients (KTRs). Conflicting data on the associations, or lack thereof, between lower urinary uromodulin concentrations and accelerated loss of renal function, or renal failure, in nontransplant chronic kidney disease patients, are perhaps due, in part, to analytical limitations in determining urine uromodulin. Potential longitudinal associations between serum and urinary uromodulin concentrations, and CVD outcomes, graft failure, and all-cause mortality, await validation in large, diverse cohorts of chronic KTRs. Taking advantage of an efficient case-cohort design scheme, we demonstrate how the completed FAVORIT clinical trial cohort might be ideally suited to evaluate these associations. Using available case-cohort sample data, statistical power simulations are provided to detect relative risk estimates of 1.50 for CVD (n = 309 events), 1.56 for graft failure (n = 223 events) or 1.50 for death from any cause (n = 320 events), comparing values below the median, to values equal to or above the median for serum uromodulin values. Edifying data such as these would advance our understanding of the hypothetical utility of uromodulin measurement in KTRs considerably.

B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients.

BACKGROUND: Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in Transplantation trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. METHODS: Five hundred ten subjects were selected randomly from the 4110 Folic Acid for Vascular Outcome Reduction in Transplantation participants. This cohort was then enriched for all additional subjects with adverse outcomes (death, dialysis-dependent kidney failure (DDKF), and cardiovascular outcomes) for a total of 1131 participants studied. Quartiles of BNP and high-sensitivity cardiac troponin I (hs-cTnI) were included in adjusted models. Combinations of normal and elevated hs-cTnI (>26.2 ng/L) and BNP (>100 pg/mL) were also studied. RESULTS: Median concentrations (interquartile ranges) were 5.6 (3.3-10.5) ng/L for hs-cTnI and 39 (15, 94) pg/mL for BNP. Hazard ratios for each adverse outcome were higher with higher quartiles of BNP after adjustment and remained statistically significant after adding hs-cTnI to the model. The highest quartile hazard ratio for DDKF was 2.47 (95% confidence interval [95% CI], 1.21-5.05). Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with adverse outcomes with hazard ratios 8.8 (95% CI, 3.4-23.1) for DDKF and 6.3 (95% CI, 2.7-15.0) for cardiovascular outcomes. CONCLUSIONS: Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients. Elevated BNP and hs-cTnI identify candidates for targeted risk reduction.

Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

More than skin deep? Potential nicotinamide treatment applications in chronic kidney transplant recipients.

Non-melanoma cutaneous carcinomas, or skin cancers, predominantly squamous cell carcinomas (SCCs), are the most common malignancies occurring in kidney transplant recipients (KTRs). Squamous cell carcinoma risk is dramatically elevated in KTRs, occurring at rates of up 45-250 times those reported in general populations. New non-melanoma skin cancers in KTRs with a prior non-melanoma skin cancer also develop at 3-times the rate reported in non-KTRs with the same clinical history. The unique aggressiveness of SCCs in KTRs increases patient morbidity, due to the high rate of new lesions requiring treatment, frequently surgical excision. Oral nicotinamide shows promise in the chemoprevention of the especially aggressive non-melanoma skin cancers which occur in KTRs. This benefit might be conferred via its inhibition of sirtuin enzymatic pathways. Nicotinamide's concurrent hypophosphatemic effect may also partially ameliorate the disturbed calcium-phosphorus homeostasis in these patients-a putative risk factor for mortality, and graft failure. Conceivably, a phase 3 trial of nicotinamide for the prevention of non-melanoma skin cancers in KTRs, lasting at least 12-mo, could also incorporate imaging and laboratory measures which assess nicotinamide's impact on subclinical cardiovascular and chronic kidney disease risk, and progression.

Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid-fortified cereal grain flour.

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.

Proteinuria as a predictor of total plasma homocysteine levels in type 2 diabetic nephropathy.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Safety events in kidney transplant recipients: results from the folic Acid for vascular outcome reduction in transplant trial.

BACKGROUND: Kidney transplant recipients are at increased risk for adverse safety events related to their reduced renal function and many medications. METHODS: We determined the incidence of adverse safety events based on previously defined Agency for Healthcare and Research Quality (AHRQ) International Classification of Diseases-9 (ICD-9) code-derived patient safety indicators (PSI) in the Folic Acid for Vascular Outcome Reduction in Transplant trial participants who had a hospitalization stratified by tertiles of estimated glomerular filtration rate (GFR). We also examined the frequency of Micromedex defined two precautionary drug-drug interactions, and two medications whose use may be contraindicated because of reduced GFR from the Folic Acid for Vascular Outcome Reduction in Transplant trial medication thesaurus at baseline, and annually among 4,110 participants. Logistic regression was used to examine the relationship between patient safety events and baseline demographic and clinical variables at a participant level. Event rates were estimated at participant and visit levels. RESULTS: Of the 2,514 patients with a hospitalization, 978 (38.9%) experienced an AHRQ PSI. Factors which were associated with more common AHRQ PSI included: U.S. location, history of cardiovascular disease or diabetes, and lower tertile of estimated GFR. At a participant level, 2,524 of the 4,110 participants (61.4%) were taking calcineurin inhibitor and statin, 378 (9.2%) were taking azathioprine and an angiotensin-converting enzyme inhibitor, 171 (12.9%) were taking a sulfonylurea), 45 (3.4%) were taking metformin despite a baseline GFR below 40 mL per min per 1.73 m. CONCLUSION: We conclude that patient safety events are not uncommon in kidney transplant recipients. Careful monitoring is necessary to prevent adverse outcomes.