Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial

Foster, Meredith C.; Weiner, Daniel E.; Bostom, Andrew G.; Carpenter, Myra A.; Inker, Lesley A.; Jarolím, Petr; Joseph, Alin; Kusek, John W.; Pesavento, Todd E.; Pfeffer, Marc A.; Madhumathi, R; Solomon, Scott D.; Levey, Andrew S.

doi:10.1111/ajt.14258

Cited by 24 publications

(19 citation statements)

References 48 publications

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“…A study by Foster and colleagues demonstrated that estimated GFR (eGFR), calculated from creatinine, cystatin C or β2-microglobulin, is an independent risk factor for cardiovascular events and mortality in RTR [ 49 ]. The highest level of incident cardiovascular disease and all-cause mortality is associated with the lowest eGFR.…”

Section: Non-traditional Cardiovascular Risk Factorsmentioning

confidence: 99%

Cardiovascular risk in renal transplant recipients

2018

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Successful kidney transplantation offers patients with end-stage renal disease the greatest likelihood of survival. However, cardiovascular disease poses a major threat to both graft and patient survival in this cohort. Transplant recipients are unique in their accumulation of a wide range of traditional and non-traditional cardiovascular risk factors. Hypertension, diabetes, dyslipidaemia and obesity are highly prevalent in patients with end-stage renal disease. These risk factors persist following transplantation and are often exacerbated by the drugs used for immunosuppression in organ transplantation. Additional transplant-specific factors such as poor graft function and proteinuria are also associated with increased cardiovascular risk. However, these transplant-related factors remain unaccounted for in current cardiovascular risk prediction models, making it challenging to identify transplant recipients with highest risk. With few interventional trials in this area specific to transplant recipients, strategies to reduce cardiovascular risk are largely extrapolated from other populations. Aggressive management of traditional cardiovascular risk factors remains the cornerstone of prevention, though there is also a potential role for selecting immunosuppression regimens to minimise additional cardiovascular injury. Electronic supplementary material The online version of this article (10.1007/s40620-018-0549-4) contains supplementary material, which is available to authorized users.

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Section: Non-traditional Cardiovascular Risk Factorsmentioning

confidence: 99%

Cardiovascular risk in renal transplant recipients

2018

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“…To evaluate the potential association between serum T50 and the composite CVD outcome, we utilized an efficient, preexisting case-cohort selection scheme employed for prior FAVORIT ancillary studies [11][12][13], especially the report of Park et al [13]. Briefly, a 530-participant subcohort with complete baseline data for key laboratory variables, including serum creatinine and lipid studies, as well as urine albumin to creatinine ratio (UACR), was selected at random from the entire cohort, regardless of whether or not the T50, Fetuin-A, and CVD in Kidney Transplantation participants had experienced a fatal or nonfatal CVD outcome during follow-up [11][12][13].…”

Section: Study Populationmentioning

confidence: 99%

“…Briefly, a 530-participant subcohort with complete baseline data for key laboratory variables, including serum creatinine and lipid studies, as well as urine albumin to creatinine ratio (UACR), was selected at random from the entire cohort, regardless of whether or not the T50, Fetuin-A, and CVD in Kidney Transplantation participants had experienced a fatal or nonfatal CVD outcome during follow-up [11][12][13]. We also selected all participants in the full cohort who were identified as having experienced a CVD event, irrespective of whether they were sampled in the random subcohort.…”

Section: Study Populationmentioning

confidence: 99%

Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

et al. 2018

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Background: “T50,” shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. Methods: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. Results: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20–2.89); fetuin-A, (HR 2.25; 95% CI 1.38–3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. Conclusions: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.

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“…Data are required from large, well-characterized, multicenter KTR cohorts assessing the potential relationships between serum/plasma, or urinary uromodulin concentrations, and the development of graft failure, as well as CVD outcomes, and all-cause mortality, among chronic, stable KTRs. For example, taking advantage of a powerful, efficient case-cohort design scheme previously used, 42 , 43 the completed FAVORIT clinical trial 44 cohort might be ideally suited to evaluate these associations. One of us (A.B.…”

Section: Uromodulin Quantification In Ktrs: Future Directionsmentioning

confidence: 99%

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

Bostom

Steubl

Friedman

2017

Transplantation Direct

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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.

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Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial

Cited by 24 publications

References 48 publications

Cardiovascular risk in renal transplant recipients

Cardiovascular risk in renal transplant recipients

Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients

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

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