Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in the Elderly: AGES-Kidney and MESA-Kidney

Abstract

Background: Studies in chronic kidney disease populations suggest that the non-glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β₂-microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine.

Study design: Cross-sectional study.

Setting & participants: Predominantly elderly participants selected from the Age, Gene/Environment Susceptibility Kidney Study (AGES-Kidney; N=683; mean [SD] age, 79 [4] years; GFR, 62 [17]mL/min/1.73 m²) and from the Multi-Ethnic Study of Atherosclerosis Kidney Study (MESA-Kidney; N=273; mean [SD] age, 70.5 [9] years; GFR, 73 [19]mL/min/1.73 m²).

Predictors: Demographic and clinical factors hypothesized to be associated with conditions affecting non-GFR determinants of the filtration markers.

Outcomes: Measured GFRs and estimated GFRs (eGFRs) based on creatinine, cystatin C, B2M, and BTP levels (eGFR_cr, eGFR_cys, eGFR_B2M, and eGFR_BTP, respectively). Residual associations of factors with eGFR after accounting for measured GFR as the parameter of interest.

Results: eGFR_cys, eGFR_B2M, and eGFR_BTP had significantly less strong residual associations with age and sex than eGFR_cr in both AGES-Kidney and MESA-Kidney and were not associated with ethnicity (black vs white) in MESA-Kidney. After adjusting for age, sex, and ethnicity, residual associations with most clinical factors were smaller than observed with age and sex. eGFR_cys and eGFR_B2M, but not eGFR_BTP, had significant residual associations with C-reactive protein levels in both studies.

Limitations: Small sample size may limit power to detect associations. Participants may be healthier than the general population.

Conclusions: Similar to previous studies in chronic kidney disease, in community-dwelling elders, cystatin C, B2M, and BTP levels are less affected than creatinine level by age and sex and are not affected by ethnicity. Both cystatin C and B2M levels may be affected by inflammation. These findings are important for the development and use of GFR estimating equations based on low-molecular-weight serum proteins throughout the range in GFRs.

Keywords: Filtration markers; GFR estimation; beta-trace protein (BTP); biomarker; creatinine; cystatin C; elderly; glomerular filtration rate (GFR); kidney function; β(2)-microglobulin (B2M).

Figure 1. Unadjusted, study-specific associations of age, sex, and ethnicity with mGFR and eGFR in (A) AGES-Kidney and (B) MESA-Kidney

Ethnicity estimates not reported in AGES because all participants are white and of Icelandic descent. The difference in the height of the bars for eGFR in comparison to mGFR reflects the residual association with eGFR accounting for mGFR. * p<0.05 vs. mGFR

Figure 2. Study-specific age, sex, and ethnicity-adjusted associations with mGFR and eGFR in (A) AGES-Kidney and (B) MESA-Kidney

AGES results are age- and sex-adjusted because all participants are white and of Icelandic descent. The difference in the height of the bars for eGFR in comparison to mGFR reflects the residual association with eGFR accounting for mGFR. * p<0.05 vs. mGFR

Figure 2. Study-specific age, sex, and ethnicity-adjusted associations with mGFR and eGFR in (A) AGES-Kidney and (B) MESA-Kidney

AGES results are age- and sex-adjusted because all participants are white and of Icelandic descent. The difference in the height of the bars for eGFR in comparison to mGFR reflects the residual association with eGFR accounting for mGFR. * p<0.05 vs. mGFR