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B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial.

ABSTRACT: Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients.The study was a longitudinal ancillary of the FAVORIT trial, a randomized, placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinically stable kidney transplant recipients with elevated tHcy.584 participants from 18 sites across North America.The intervention consisted of a daily multivitamin containing high-doses of folate (5.0 mg), vitamin B12 (1.0 mg) and vitamin B6 (50 mg). The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 (0 mg folate; 2.0 µg vitamin B12; 1.4 mg vitamin B6).Annual neuropsychological assessment for up to 5 years (mean 3.3 years) using a standardized test battery. Efficacy was analyzed on an intention-to-treat basis using end-of-trial data. Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations.At baseline, cognitive impairment was common with 61% of participants falling more than one standard deviation below published norms for at least one cognitive test. Fewer than 1% of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However, 44.6% had plasma B6 concentrations < 30 nmol/L. At follow-up, processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls (p?0.05). There was no interaction between baseline tHcy, B-vitamin status and treatment on the cognitive outcomes.High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy. Since nearly all participants were folate and vitamin B12 sufficient at baseline, the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined.

SUBMITTER: Scott TM

PROVIDER: S-EPMC5724781 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial.

Scott T M TM Rogers G G Weiner D E DE Livingston K K Selhub J J Jacques P F PF Rosenberg I H IH Troen A M AM

The journal of prevention of Alzheimer's disease 20170101 3

<h4>Background</h4>Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We t ...[more]

PMID: 29182708

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Project description:BackgroundKidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown.Study designCase-cohort study.Setting & participantsThe FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257).PredictorUsing spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α1-microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide).OutcomeDeath-censored allograft failure.ResultsIn models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure.LimitationsWe lack kidney biopsy data, BK titers, and HLA antibody status.ConclusionsUrine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR.

Project description:Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality.Cohort study.The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs.Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization.During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54).We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites.Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.

Project description:BackgroundTobacco use remains an international health problem with between 10% and 40% of adults currently using tobacco. Given the rising number of patients either awaiting or having received a kidney transplant and the absence of smoking cessation as the criterion for transplantation in guidelines, we explored the association between smoking status and clinical outcomes in kidney transplant recipients.Patients and methodsIn this post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplant trial, the associations between smoking status, defined as never having smoked, formerly or currently smoking, and both all-cause mortality and graft survival were assessed using Cox proportional hazards models. Fatal events were centrally adjudicated into prespecified categories: all-cause, cardiovascular and non-cardiovascular causes. Graft loss was defined as return to dialysis or retransplantation. Clinical Trials URL: http://www.clinicaltrials.gov/show/NCT00064753.ResultsAmong 4110 transplant recipients, there were 451 current smokers and 1611 former smokers. The mortality rate per 100 patient-years was 4.0 (71 deaths) for smokers, 3.5 (226 deaths) for former smokers and 2.4 (116 deaths) for never smokers. Hazard ratio for mortality for current smokers was 1.70 (CI=1.26-2.29, p=0.001) and for former smokers was 1.21 (0.98-1.50, p=0.08) with 1.0 representing never smokers. As the number of cardiovascular deaths was similar in each group (all p>0.3), the differences between groups was driven by non-cardiovascular death rates. Current smokers (2.39; 1.62-3.61, p<0.001) and former smokers (1.50; 1.12-2.01, p=0.007) had increased hazard of non-cardiovascular death. Kidney allograft failure was more likely in current smokers than in either former or never smokers (3.5, 2.1 and 2.0 per 100 patient-years, p<0.001, adjusted hazard ratio 1.49 and 1.05, respectively).ConclusionContinued smoking was associated with >100% increased risk of non-cardiovascular death, 70% greater risk of all-cause mortality and a 50% greater risk of graft loss, a risk not seen in former smokers. These findings confirm previous non-adjudicated observations that smoking is associated with adverse clinical outcomes and suggest that more emphasis should be placed on smoking cessation prior to kidney transplantation.

Project description:BackgroundIn 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.MethodsCox 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.ResultsAmong 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.ConclusionsIn 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.

Dataset Information

B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial.

Publications

B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial.

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