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Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial.

ABSTRACT: In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.

SUBMITTER: Weiner DE

PROVIDER: S-EPMC3424309 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial.

Weiner D E DE Carpenter M A MA Levey A S AS Ivanova A A Cole E H EH Hunsicker L L Kasiske B L BL Kim S J SJ Kusek J W JW Bostom A G AG

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20120517 9

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, p ...[more]

PMID: 22594581

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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: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.

Project description: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.

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: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:Background and objectivesIn kidney transplant recipients, elevated circulating advanced glycation endproducts (AGEs) are the result of increased formation and decreased kidney clearance. AGEs trigger several intracellular mechanisms that ultimately yield excess cardiovascular disease. We hypothesized that, in stable kidney transplant recipients, circulating AGEs are associated with long-term risk of cardiovascular mortality, and that such a relationship is mediated by inflammatory, oxidative stress, and endothelial dysfunction biomarkers.Design, setting, participants, & measurementsProspective cohort study of stable kidney transplant recipients recruited between 2001 and 2003 in a university setting. We performed multivariable-adjusted Cox regression analyses to assess the association of AGEs (i.e., Nε -[Carboxymethyl]lysine (CML) and Nε -[Carboxyethyl]lysine (CEL), measured by tandem mass spectrometry) with cardiovascular mortality. Mediation analyses were performed according to Preacher and Hayes's procedure.ResultsWe included 555 kidney transplant recipients (age 51±12 years, 56% men). During a median follow-up of 6.9 years, 122 kidney transplant recipients died (52% deaths were due to cardiovascular causes). CML and CEL concentrations were directly associated with cardiovascular mortality (respectively, hazard ratio, 1.55; 95% confidence interval, 1.24 to 1.95; P<0.001; and hazard ratio, 1.53; 95% confidence interval 1.18 to 1.98; P=0.002), independent of age, diabetes, smoking status, body mass index, eGFR and proteinuria. Further adjustments, including cardiovascular history, did not materially change these findings. In mediation analyses, free thiol groups and soluble vascular cell adhesion molecule-1 consistently explained approximately 35% of the association of CML and CEL with cardiovascular mortality.ConclusionsIn stable kidney transplant recipients, circulating levels of AGEs are independently associated with long-term risk of cardiovascular mortality.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_17_CJN00540119.mp3.

Project description:BackgroundCardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain.Study designPost hoc cohort analysis of FAVORIT, a randomized trial examining the effect of homocysteine-lowering vitamins on CVD in kidney transplant recipients.Setting & participantsPrevalent adult kidney transplant recipients with hyperhomocysteinemia and stable kidney function from the United States, Canada, and Brazil participating in FAVORIT, with no known history of CVD.PredictorAspirin use, with aspirin users matched to nonusers using a propensity score.OutcomesIncident CVD events, kidney failure, all-cause mortality, a composite of CVD events or mortality, and a composite of kidney failure or mortality. Cox proportional hazards models with a robust variance to account for the correlation in outcomes within matched pairs were sequentially adjusted for demographic, clinical, and laboratory characteristics to assess the association between aspirin use and events.Results981 aspirin users were matched to 981 nonusers. During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92-1.58], 0.92 [95% CI, 0.69-1.23], 1.19 [95% CI, 0.81-1.74], 1.03 [0.82-1.31], and 1.11 [95% CI, 0.88-1.38], respectively).LimitationsWe did not examine dose or continued use of aspirin after randomization. CVD history is dependent on participant report at baseline. Aspirin use was non-randomly assigned.ConclusionsAspirin use is not associated with reduced risk for incident CVD, all-cause mortality, or kidney failure in stable kidney transplant recipients with no history of CVD.

Dataset Information

Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial.

Publications

Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial.

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