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Rationale & objectiveCardiovascular 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 designPost hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial.Setting & participantsStable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil.PredictorUrine albumin-creatinine ratio (ACR) at randomization.OutcomesAllograft failure, CVD, and all-cause death.Analytical approachMultivariable 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.ResultsAmong 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).LimitationsNo data for rejection; single ACR assessment.ConclusionsIn 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.

BackgroundUromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center -European study involving 91 kidney transplant recipients (KTRs).MethodsThe Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome.ResultsThe 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77).ConclusionsLower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs.

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.

Introduction: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD) mortality. We investigated vascular biomarkers, angiopoietin-1, and angiopoietin-2 (angpt-1, -2), in CVD development in KTRs. Methods: This ancillary study from the FAVORIT evaluates the associations of baseline plasma angpt-1, -2 levels in CVD development (primary outcome) and graft failure (GF) and death (secondary outcomes) in 2000 deceased donor KTRs. We used Cox regression to analyze the association of biomarker quartiles with outcomes. We adjusted for demographic; CVD- and transplant-related variables; medications; urine albumin-to-creatinine ratio; and randomization status. We calculated areas under the curves (AUCs) to predict CVD or death, and GF or death by incorporating biomarkers alongside clinical variables. Results: Participants' median age was 52 IQR [45, 59] years: with 37% women and 73% identifying as white. Median time from transplantation was 3.99 IQR [1.58, 7.93] years and to CVD development was 2.54 IQR [1.11–3.80] years. Quartiles of angpt-1 were not associated with outcomes. Whereas higher levels of angpt-2 (quartile 4) were associated with about 2 times the risk of CVD, GF, and death (aHR 1.85 [1.25–2.73], p < 0.01; 2.24 [1.36–3.70)], p < 0.01; 2.30 [1.48–3.58], p < 0.01, respectively) as compared to quartile 1. Adding angiopoietins to preexisting clinical variables improved prediction of CVD or death (AUC improved from 0.70 to 0.72, p = 0.005) and GF or death (AUC improved from 0.68 to 0.70, p = 0.005). Angpt-2 may partially explain the increased risk of future CVD in KTRs. Further research is needed to assess the utility of using angiopoietins in the clinical care of KTRs. Conclusion: Angpt-2 may be a useful prognostic tool for future CVD in KTRs. Combining angiopoietins with clinical markers may tailor follow-up to mitigate CVD risk. Plain Language Summary: We have identified compelling insights into the role of two proteins called angiopoietin 1 and 2, which are needed, in balance, for healthy blood vessels to form. In the case of kidney transplants from deceased donors, we found that high levels of angiopoietin-2, suggest a higher risk of future heart problems, kidney transplant failure, and even death. As such, our study reaffirms that high levels of angiopoietin-2 in the blood is a marker of blood vessel injury and inflammation. Notably, when we included information about these proteins along with the regular medical details, we were better at predicting important clinical outcomes. Understanding these proteins could help us figure out which KTRs are at a higher risk, so we can take better care of them and potentially improve their outcomes. [ABSTRACT FROM AUTHOR]

An FDA regulation requiring all grain products to be fortified with folic acid appears to have been successful. Researchers measured folic acid and homocysteine levels in 756 people in the Framingham Offspring Study who were examined before the regulation took effect in 1996 and 350 who were examined after the regulation took effect. The average folic acid concentration in blood increased from 4.6 nanograms per milliliter to 10 over this time period. Conversely, blood levels of homocysteine fell from an average of 10 micromoles per liter to 9.4. Elevated homocysteine levels are a risk factor for heart disease.

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. [ABSTRACT FROM AUTHOR]

Elevated plasma lipoprotein(a) may be an additional risk factor for coronary heart disease in middle-aged men. This was demonstrated in the Framingham Offspring study, which has followed the children of the original Framingham population since 1971. At the fourth examination between 1987 and 1991, men whose lipoprotein(a) was elevated in the early 1970s were twice as likely to develop coronary heart disease. The risk was as strong as the risk of elevated cholesterol. However, smoking was the strongest risk factor for coronary heart disease in these men., Objective.--To establish whether elevated lipoprotein(a) [Lp(a)], detected as a sinking pre-[Beta]-lipoprotein band on electrophoresis of fresh plasma, is an independent risk factor for the development of premature coronary heart disease (CHD) in men. Design and Setting.--Prospective study of the Framingham offspring cohort. Participants.--A total of 2191 men aged 20 to 54 years old who were free of cardiovascular disease when they were examined between 1971 and 1975. Main Outcome Measures.--Incident CHD (myocardial infarction, coronary insufficiency, angina pectoris, or sudden cardiac death) occurring by age 55 years. Results.--After a median follow-up of 15.4 years, there were 129 CHD events. The relative risk (RR) estimates (with 95% confidence intervals [Cis]) for premature CHD derived from a proportional hazards model that included age, body mass index, and the dichotomized risk factor covariables elevated plasma Lp(a) level, total cholesterol level of 6.2 mmol/L (240 mg/dL) or more, high-density lipoprotein (HDL) level less than 0.9 mmol/L (35 mg/dL), smoking, glucose intolerance, and hypertension were as follows: elevated Lp(a) level, RR, 1.9 (95% Cl, 1.2-2.9), prevalence, 11.3%; total cholesterol level of 6.2 mmol/L or more, RR, 1.8 (95% Cl, 1.2-2.7), prevalence, 14.3%; HDL level of less than 0.9 mmol/L, RR, 1.8 (95% Cl, 1.2-2.6), prevalence, 19.2%; smoking, RR, 3.6 (95% Cl, 2.2-5.5), prevalence, 46.7%; glucose intolerance, RR, 2.7 (95% Cl, 1.4-5.3), prevalence, 2.6%; hypertension, RR, 1.2 (95% Cl, 0.8-1.8), prevalence, 26.3%. Conclusions.--Elevated plasma Lp(a) is an independent risk factor for the development of premature CHD in men, comparable in magnitude and prevalence (ie, attributable risk) to a total cholesterol level of 6.2 mmol/L (240 mg/dL) or more, or an HDL level less than 0.9 mmol/L (35 mg/dL). JAMA. 1996;276:544-548

Recent studies demonstrated associations between occlusive vascular disease and hyperhomocysteinemia of both genetic and nutritional origin. In the present study we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to B vitamins and prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely associated with intakes of folate and vitamin B-6, but not vitamin B-12. Prevalence of high homocysteine (> 14 [micro]mol/l) was 29.3% in this cohort, and inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Prevalence of stenosis [greater than or equal to]25% was 43% in men and 34% in women with an odds ratio of 2.0 for individuals in the highest homocysteine quartile ([greater than or equal to]14.4 [micro]mol/l) compared with those in the lowest quartile ([less than or equal to]9.1 [micro]mol/l), after adjustment for sex, age, high density lipoprotein cholesterol, systolic blood pressure and cigarette smoking ([P.sub.trend] < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and folate intake were inversely associated with extracranial carotid stenosis after adjustment for age, sex and other risk factors. J. Nutr. 126: 1258S-1265S, 1996. INDEXING KEY WORDS: homocysteine, folic acid, pyridoxal phosphate, vitamin B-6, vitamin B-12, arteriosclerosis

Hyperhomocysteinemia and low concentrations of folate and vitamin B6 appear to be associated with an increased risk of carotid artery stenosis in the elderly. Hyperhomocysteinemia is a condition in which plasma levels of homocysteine are higher than normal. Inadequate folate and vitamin B6 concentrations in the blood are associated with the condition. A group of 1,041 people over the age of 66 were divided into two groups based upon the severity of stenosis in two carotid vessels. People with high levels of homocysteine were found to be twice as likely to be in the group with more severe stenosis than those with normal homocysteine concentrations. Higher concentrations of folate and B6 in the plasma were related to less stenosis, while lower concentrations of folate and B6 were found in patients with more severe sclerosis.