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Article Comparison of Serum Concentrations of B-Trace Protein, B2-Microglobulin, Cystatin C, and Creatinine in the US Population

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Article Comparison of Serum Concentrations of B-Trace Protein, B2-Microglobulin, Cystatin C, and Creatinine in the US Population Article Comparison of Serum Concentrations of b-Trace Protein, b2-Microglobulin, Cystatin C, and Creatinine in the US Population | | Stephen P. Juraschek,*†‡ Josef Coresh,*†‡§ Lesley A. Inker, Andrew S. Levey, Anna Ko¨ttgen,*¶ Meredith C. Foster,*† Brad C. Astor,**†† John H. Eckfeldt,‡‡ and Elizabeth Selvin*†‡ Summary Departments of b b b b *Epidemiology and Background and objectives -trace protein ( TP), 2-microglobulin ( 2M), and cystatin C (CysC) have advan- §Biostatistics, Johns tages over creatinine for estimating GFR and prognosis. This study compares the distribution of all four markers Hopkins Bloomberg in the general population and their associations with possible determinants of GFR. School of Public Health, Baltimore, † b b $ Maryland; Welch Design, setting, participants, & measurements TP and 2M were measured in 7596 participants (aged 12 years) Center for Prevention, of the Third National Health and Nutrition Examination Survey (1988–1994). bTP and b2M concentrations and Epidemiology, and the proportion of persons with elevated ($99th percentile for young healthy participants) bTP ($0.81 mg/L), Clinical Research, 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 Johns Hopkins Medical Institutions, women) were compared across demographic and clinical factors. Baltimore, Maryland; ‡Department of Results Elevated bTP, b2M, and CysC showed stronger associations with age than elevated serum creatinine, the Medicine, Johns prevalence of elevated levels reaching 47%, 44%, 58%, and 26%, respectively, by age 80 years. bTP, CysC, and Hopkins Hospital, Baltimore, Maryland; b b b | creatinine were higher in men but 2M was not associated with sex. Mexican Americans had lower TP, 2M, Division of CysC, and creatinine compared with non-Hispanic whites. Hypertension and higher C-reactive protein were Nephrology, Tufts associated with elevations in all markers, whereas non-Hispanic black race, body mass index, diabetes, smoking Medical Center, status, triglycerides, HDL cholesterol, and education were not associated in a consistent manner across the Boston, Massachusetts; ¶Renal Division, different markers. University Hospital, Freiburg, Germany; Conclusions bTP, b2M, CysC, and creatinine differ in their associations with demographic and clinical factors, Departments of suggesting variation in their non-GFR determinants. Future studies should examine these markers with mea- **Medicine and ††Population Health sured GFR to determine their diagnostic and prognostic utility. Sciences, University of Clin J Am Soc Nephrol 8: 584–592, 2013. doi: 10.2215/CJN.08700812 Wisconsin School of Medicine and Public Health, Madison, Wisconsin; and Introduction originates from the choroid plexus of the central ner- ‡‡Department of b-trace protein (bTP) and b2-microglobulin (b2M) are vous system (8). b2M, a subunit of the major histo- Laboratory Medicine low molecular mass serum proteins that are increas- compatibility class I molecule, is produced by all and Pathology, ingly viewed as useful for estimating GFR and pre- nucleated cells (9). Like CysC, bTP and b2M are con- University of Minnesota, dicting prognosis in kidney disease, cardiovascular sidered candidates for the assessment of GFR because – Minneapolis, outcomes, and death, independently of GFR (1 3). they are produced at a constant rate, are freely fil- Minnesota Recent studies have shown that bTP and b2M are tered by the glomerulus, and are then reabsorbed better predictors of adverse health outcomes than cre- and almost completely metabolized by the proximal Correspondence: atinine and are potentially as good as cystatin C tubule with no appreciable entry into the circulation Dr. Elizabeth Selvin, (CysC) (4). It is now appreciated that the use of a (10–12).Thereissomeevidencethatcerebrospinal Johns Hopkins fi fl University, 2024 E. combination of ltration markers leads to more accu- uidleaks(13)andcorticosteroiduse(14)affect Monument, Suite 2- rate estimates of GFR than single markers (5), and as bTP, whereas rare inflammatory conditions affect 600, Baltimore, MD in other fields, it is expected that a combination of b2M (15–18). 21205. Email: markers will lead to more accurate predictions of The challenge of measuring GFR in large popula- [email protected] prognosis (6). However, as we have learned from cre- tion studies and the almost complete absence of atinine and CysC, knowledge of their non-GFR deter- urinary excretion of these markers make it difficult minants in the general population will be necessary to study the relative contributions of GFR and non- for optimal use. GFR determinants to their serum concentrations. As Determinants of the serum concentrations in bTP such, examining four filtration markers in the general and b2M have not yet been studied in the general population presents an opportunity to infer demo- population. bTP, a 168 amino acid glycoprotein (7), graphic and clinical factors that may be associated 584 Copyright © 2013 by the American Society of Nephrology www.cjasn.org Vol 8 April, 2013 Clin J Am Soc Nephrol 8: 584–592, April, 2013 b-Trace Protein and b2-Microglobulin in the US Population, Juraschek et al. 585 with variation in underlying GFR. Thus, the objectives of for men and $1.0 mg/dl for women. This is approximately this study were to describe the distributions of bTP and equal to the 99th percentile in either sex in participants aged b2M in the US population, to identify factors associated 20–39 years without diabetes and hypertension. The cutoff with elevations in bTP and b2M, to compare these distri- for decreased estimated GFR using creatinine was ,60 ml/ butions and associations with those of standardized creat- min per 1.73m2, computed from the Chronic Kidney Disease inine and CysC, and to distinguish factors that may be Epidemiology Collaboration (CKD-EPI) equation (24). associated with GFR versus non-GFR determinants of all four filtration markers. Determination of Potential Risk Factors We examined covariates associated with CKD. Race and ethnicity were grouped as non-Hispanic white, non-Hispanic Materials and Methods black, Mexican American, and other, although the “other” Study Population category was not presented due to inherent heterogeneity Data for this study were derived from the Third National and small sample size (25). Education (,12 years, $12 Health and Nutrition Examination Survey (NHANES III), years), current smoking status (yes/no), and obesity (body a large, cross-sectional study conducted by the National mass index [BMI] ,30 kg/m2, $30 kg/m2)weredichoto- Center for Health Statistics (NCHS) using a complex mized. BMI was also analyzed as a continuous variable multistage sampling design. Interviews, physical exami- (scaled to per 5 kg/m2). Hypertensive status (yes/no) was nations, and laboratory measurements were obtained from defined as a physician-diagnosis of hypertension, hyperten- $ 18,722 individuals aged 12 years (19). Stored serum sam- sion medication use, or a mean systolic or diastolic BP $140 ples from a subset of NHANES III participants were used mmHg or $90 mmHg, respectively. Diabetes status (yes/ for the measurement of nontraditional markers of GFR. no) was based on a fasting plasma glucose of $126 mg/dl Details of this study design were previously described ($7.0 mmol/L) or a nonfasting glucose of $200 mg/dl fl (20,21). Brie y, we selected the following: all participants ($11.0 mmol/L) or self-reported diagnosis by a physician $ aged 60 years because decreased GFR is common in this (independent of pregnancy), use of insulin, or use of diabe- n group ( =5248), all participants with elevated creatinine tes medication. HDL cholesterol was defined as a continu- . 1.189 mg/dl in men and 0.997 mg/dl in women ous variable (per 10-mg/dl increase) for logistic regression, n ( =305), and a 25% random sample of participants aged and as a dichotomous variable (,40 mg/dl for men and – n 12 59 years ( =3293). This design minimized costs while ,50 mg/dl for women) to estimate study population prev- retaining power and generalizability. Sample weights alence. Triglycerides were log-transformed to normalize its were re-calculated based on the total number of samples distribution. C-reactive protein (CRP) was divided into three n that were not missing CysC (86%; =7596). Among the categories (,0.22 mg/dl, 0.22–1 mg/dl, .1 mg/dl). The original CysC subsample, there were 7529 (99.1%) partic- lower limit of detection for CRP was 0.22 mg/dl. Urine al- b ipants with a TP measurement and 7534 (99.2%) partic- bumin was measured by a solid-phase fluorescent immuno- b ipants with a 2M measurement. assay, and urine creatinine was measured using the modified kinetic rate Jaffe method. Urinary albumin/creati- Primary Outcome Measurements nine ratio (ACR) was expressed in milligrams per gram In 2009, we measured bTP and b2M in stored serum (26,27). Additional data collection details, including assay samples collected in 1988–1994, using particle-enhanced precision estimates, are available in the NHANES field man- immunonephelometric assays (N Latex b-trace protein as- ual published online (19). say and N Latex b-2 microglobulin assay; Dade Behring, fi b b Deer eld, IL). Both TP and 2M are reported to be robust Statistical Analyses fi to freeze-thaw cycles (22). Interassay coef cients of varia- Themethodusedtogeneratesampleweightswas b b tion (CVs) for the TP assay and the 2M assay were 5.7% described in detail elsewhere (20). Briefly, the original (mean 0.594 mg/L) and 2.7% (mean 1.757 mg/L), respec- sampling weights were modified to account for both miss- fi tively. Creatinine was measured using a modi ed kinetic ing creatinine and CysC using standard methods ap- Jaffe reaction, traceable to higher-order isotope dilution proved by the NCHS. These weights were utilized in all mass spectrometry methods, and the CV ranged from of our analyses and SEMs for estimates were obtained us- 1.2% (mean 1.00 mg/dl) to 1.6% (mean 3.84 mg/dl) (23).
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