The effects of freeze–thaw on β-trace protein and β2-microglobulin assays after long-term sample storage

Juraschek, Stephen P.; Coresh, Josef; Inker, Lesley A.; Rynders, Gregory P.; Eckfeldt, John H.; Selvin, Elizabeth

doi:10.1016/j.clinbiochem.2012.02.027

Cited by 14 publications

(14 citation statements)

References 8 publications

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“…36 Equally, serum b2-microglobulin measurements were robust to a single freeze-thaw cycle in long-term stored samples from the National Health and Nutrition Examination Survey. 37 More importantly, biomarker degradation would not explain our findings, because degradation would not be expected to occur differentially with regard to outcomes. If significant degradation did occur, it would be expected to bias our results to the null and potentially explain attenuated results for individual biomarkers.…”

Section: Strengths and Limitationscontrasting

confidence: 41%

Analysis of a Urinary Biomarker Panel for Incident Kidney Disease and Clinical Outcomes

O’Seaghdha

Hwang

Larson

et al. 2013

Journal of the American Society of Nephrology

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Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; a1-microglobulin, Kim-1, and TFF-3 predicted allcause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to ,0.001), whereas a1-microglobulin, b2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72-2.25; 95% CI, 1.17 to 3.24; P values,0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of a1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation.

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Section: Strengths and Limitationscontrasting

confidence: 41%

Analysis of a Urinary Biomarker Panel for Incident Kidney Disease and Clinical Outcomes

O’Seaghdha

Hwang

Larson

et al. 2013

Journal of the American Society of Nephrology

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“…Prior work in NHANES indicates that both B2M and BTP are robust to a single freeze-thaw cycle after long-term storage. 27 While it is not clear how an additional freeze-thaw cycle would affect marker stability, we anticipate that results would be biased towards the null if this resulted in non-differential exposure misclassification with respect to the outcomes. Finally, our continuous NRI estimates may be unstable due to instability in our small sample size.…”

Section: Discussionmentioning

confidence: 99%

Filtration Markers as Predictors of ESRD and Mortality in Southwestern American Indians With Type 2 Diabetes

Foster

Inker

Hsu

et al. 2015

American Journal of Kidney Diseases

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Background A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β2-microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known. Study Design Longitudinal cohort study. Setting & Participants 250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). Predictors Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr) or cystatin C (eGFRcys). Outcomes & Measurements Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C-statistics, continuous net reclassification improvement (NRI), and relative integrated discrimination improvement (rIDI). Results During median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M to established markers increased the C statistic for mortality but only weakly when assessed by either continuous NRI or rIDI; none were improved for ESRD by the addition of these markers. Limitations Small sample size, single measures of markers. Conclusions In Pima Indians with type 2 diabetes, BTP, and to a lesser extent B2M, was associated with ESRD. B2M was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M in a multi-marker approach leads to improved risk prediction for mortality in this population..

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“…Both bTP and b2M are reported to be robust to freeze-thaw cycles (22). Interassay coefficients of variation (CVs) for the bTP assay and the b2M assay were 5.7% (mean 0.594 mg/L) and 2.7% (mean 1.757 mg/L), respectively.…”

Section: Primary Outcome Measurementsmentioning

confidence: 89%

Comparison of Serum Concentrations of β-Trace Protein, β2-Microglobulin, Cystatin C, and Creatinine in the US Population

Juraschek

Coresh

Inker

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives b-trace protein (bTP), b2-microglobulin (b2M), and cystatin C (CysC) have advantages over creatinine for estimating GFR and prognosis. This study compares the distribution of all four markers in the general population and their associations with possible determinants of GFR.Design, setting, participants, & measurements bTP and b2M were measured in 7596 participants (aged $12 years) of the Third National Health and Nutrition Examination Survey (1988)(1989)(1990)(1991)(1992)(1993)(1994). bTP and b2M concentrations and the proportion of persons with elevated ($99th percentile for young healthy participants) bTP ($0.81 mg/L), b2M ($2.80 mg/L), standardized CysC ($1.03 mg/L), and creatinine ($1.2 mg/dl for men and $1.0 mg/dl for women) were compared across demographic and clinical factors.Results Elevated bTP, b2M, and CysC showed stronger associations with age than elevated serum creatinine, the prevalence of elevated levels reaching 47%, 44%, 58%, and 26%, respectively, by age 80 years. bTP, CysC, and creatinine were higher in men but b2M was not associated with sex. Mexican Americans had lower bTP, b2M, CysC, and creatinine compared with non-Hispanic whites. Hypertension and higher C-reactive protein were associated with elevations in all markers, whereas non-Hispanic black race, body mass index, diabetes, smoking status, triglycerides, HDL cholesterol, and education were not associated in a consistent manner across the different markers.Conclusions bTP, b2M, CysC, and creatinine differ in their associations with demographic and clinical factors, suggesting variation in their non-GFR determinants. Future studies should examine these markers with measured GFR to determine their diagnostic and prognostic utility.

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The effects of freeze–thaw on β-trace protein and β2-microglobulin assays after long-term sample storage

Cited by 14 publications

References 8 publications

Analysis of a Urinary Biomarker Panel for Incident Kidney Disease and Clinical Outcomes

Analysis of a Urinary Biomarker Panel for Incident Kidney Disease and Clinical Outcomes

Filtration Markers as Predictors of ESRD and Mortality in Southwestern American Indians With Type 2 Diabetes

Comparison of Serum Concentrations of β-Trace Protein, β2-Microglobulin, Cystatin C, and Creatinine in the US Population

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