Novel Filtration Markers as Predictors of All-Cause and Cardiovascular Mortality in US Adults

Foster, Meredith C.; Inker, Lesley A.; Levey, Andrew S.; Selvin, Elizabeth; Eckfeldt, John H.; Juraschek, Stephen P.; Coresh, Josef

doi:10.1053/j.ajkd.2013.01.016

Cited by 68 publications

(76 citation statements)

References 49 publications

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“…These include B2M, cluster of differentiation 14 (CD14), soluble intracellular adhesion molecule 1 (sICAM1), granulin (GRN), AGP1, CD5 molecule‐like (CD5L), serum amyloid A1 (SAA1), monocyte chemoattractant protein 1 (MCP1), soluble glycoprotein 130 (sGP130), interleukin 6 (IL6), and myeloperoxidase (MPO), which predicted all‐cause mortality in our study. B2M is a glomerular filtration marker and acute‐phase reactant that has been associated with CVD events and mortality among patients with chronic kidney disease,20, 29 and was also associated with all‐cause mortality in the National Health and Nutrition Examination Survey 30. In addition to predicting all‐cause mortality, B2M is also a predictor of incident ASCVD, HF, and CVD mortality in our study.…”

Section: Discussionsupporting

confidence: 58%

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Lyass

Courchesne

et al. 2018

JAHA

222

228

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BackgroundThe discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk‐stratification methods and may be informative regarding biological pathways contributing to disease.Methods and ResultsWe used a discovery proteomic platform that targeted high‐value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable‐adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all‐cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P‐value ranges, 9.8×10−34 to 3.6×10−2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin‐like growth factor 1 (IGF1), insulin‐like growth factor binding protein 1 (IGFBP1), insulin‐like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N‐terminal pro‐b‐type natriuretic peptide, C‐reactive protein, and leptin were associated with incident heart failure, and C‐type lectin domain family 3 member B (CLEC3B; tetranectin), N‐terminal pro‐b‐type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin‐C were associated with all‐cause mortality in a multimarker model.ConclusionsWe identified numerous protein biomarkers that predicted cardiovascular outcomes and all‐cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

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Section: Discussionsupporting

confidence: 58%

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Lyass

Courchesne

et al. 2018

JAHA

222

228

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“…Serum creatinine can be influenced by non-GFR determinants, namely muscle mass and dietary protein intake (10). Al-though not yet widely used in clinical practice, cystatin C and b 2 -microglobulin are low molecular weight proteins considered to be filtration markers that are strongly associated with clinical outcomes (11)(12)(13). Use of these alternative filtration markers instead of or in addition to creatinine could improve estimation of GFR and prognosis in CKD (14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Change in Multiple Filtration Markers and Subsequent Risk of Cardiovascular Disease and Mortality

Rebholz

Grams

Matsushita

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Kidney disease progression, assessed by change in eGFR on the basis of creatinine, is an independent risk factor for cardiovascular disease and death. This study aimed to evaluate whether changes in multiple filtration markers, individually and combined, were associated with cardiovascular disease and death.Design, setting, participants, & measurements Creatinine, cystatin C, and b 2 -microglobulin were measured among 9716 Atherosclerosis Risk in Communities Study participants in 1990-1992 and 1996-1998. Percentage change in three filtration markers (eGFR on the basis of creatinine, eGFR on the basis of cystatin C, and 1/b 2 -microglobulin) individually and the average of percentage change across all three filtration markers were calculated. Cardiovascular events and deaths were ascertained from 1996 to 2011. Cox regression models were adjusted for established risk factors for cardiovascular disease and mortality and first measurement of eGFR on the basis of creatinine.Results During a median follow-up of 14 years, there were 1922 cardiovascular events and 2285 deaths from any cause. Decline of .30% in each filtration marker was significantly associated with higher risk of mortality compared with stable kidney function (29.9% to +9.9% change in the filtration marker) with hazard ratios (95% confidence intervals) of 1.91 (1.67 to 2.18) for eGFR on the basis of creatinine, 2.29 (1.99 to 2.63) for eGFR on the basis of cystatin C, and 2.48 (2.15 to 2.86) for 1/b 2 -microglobulin, with similar associations for cardiovascular disease. An average decline of .30% across the three markers was strongly associated with higher risk of all-cause mortality (hazard ratio, 2.82; 95% confidence interval, 2.42 to 3.29).Conclusions Kidney disease progression was assessed using .30% decline in eGFR on the basis of creatinine, eGFR on the basis of cystatin C, and 1/b 2 -microglobulin and average decline of .30% across the three filtration markers is strongly associated with risk of cardiovascular disease and death.

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“…However, cystatin C is produced by all nucleated cells and there was a small difference in cystatin C following a large amputation (p = 0.21) that may have been statistically significant with a larger study group [2]. The filtration markers β-trace protein (BTP) and β 2 -microglobulin (B2M) strongly correlate with measured GFR (mGFR) and subsequent cardiovascular disease and mortality [15,16,17,18,19]. We hypothesized that serum BTP would be a superior filtration marker for GFR estimation after amputation because it is primarily produced in the brain and heart [20,21,22,23] as opposed to muscle (SCr) or all nucleated cells (cystatin C).…”

Section: Introductionmentioning

confidence: 99%

Effects of Traumatic Amputation on β-Trace Protein and β2-Microglobulin Concentrations in Male Soldiers

Little

Yuan²,

Thurlow³

et al. 2015

Am J Nephrol

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Background: Serum creatinine (SCr) levels are decreased following traumatic amputation, leading to the overestimation of glomerular filtration rate (GFR). β-Trace protein (BTP) and β₂-microglobulin (B2M) strongly correlate with measured GFR and have not been studied following amputation. We hypothesized that BTP and B2M would be unaffected by traumatic amputation. Methods: We used the Department of Defense Serum Repository to compare pre- and post-traumatic amputation serum BTP and B2M levels in 33 male soldiers, via the N Latex BTP and B2M nephelometric assays (Siemens Diagnostics, Tarrytown, N.Y., USA). Osterkamp estimation using DEXA scan measurements was used to establish percent estimated body weight loss (%EBWL). Results were analyzed for small (3-5.9% EBWL), medium (6-13.5%), and large (>13.5%) amputation subgroups; and for a control group matched 1:1 to the 12 large amputation subjects. Paired Student's t test was used for comparisons. Results: Mean serum BTP levels were unchanged in controls, all amputees, and the small and medium amputation subgroups. BTP appeared to decrease following large %EBWL amputation (p = 0.05). Mean serum B2M levels were unchanged in controls, all amputees, and the small and medium amputation subgroups. B2M appeared to increase following large %EBWL amputation (p = 0.05). Conclusions: BTP and B2M levels are less affected than SCr by amputation, and should be considered for future study of GFR estimation. BTP and B2M changes following large %EBWL amputation require validation and may offer insight into non-GFR BTP and B2M determinants as well as increased cardiovascular disease and mortality following amputation. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

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Novel Filtration Markers as Predictors of All-Cause and Cardiovascular Mortality in US Adults

Cited by 68 publications

References 49 publications

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Change in Multiple Filtration Markers and Subsequent Risk of Cardiovascular Disease and Mortality

Effects of Traumatic Amputation on β-Trace Protein and β2-Microglobulin Concentrations in Male Soldiers

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