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Published on: August 9, 2019
Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD
Xun Liu1, Meredith C Foster2, Hocine Tighiouart2
1Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guanghzou, China.
Insights
Serum levels of β-trace protein (BTP), β2-microglobulin (B2M), and cystatin C are influenced by factors beyond glomerular filtration rate (GFR). Understanding these influences improves GFR estimation and risk assessment.
Area of Science:
- Nephrology
- Biomarker Discovery
- Renal Physiology
Background:
- Determinants of serum levels for low-molecular-weight proteins like β-trace protein (BTP), β2-microglobulin (B2M), and cystatin C, independent of glomerular filtration rate (GFR), are not well understood.
- Creatinine, a common GFR marker, is affected by non-GFR factors, but similar characterization for other markers is lacking.
Purpose of the Study:
- To investigate and characterize the non-GFR determinants of serum BTP, B2M, and cystatin C levels in individuals with chronic kidney disease.
- To compare the associations of these non-GFR determinants with BTP, B2M, and cystatin C versus serum creatinine.
Main Methods:
- Pooled cross-sectional analysis of 3,156 participants from the Modification of Diet in Renal Disease (MDRD) Study, African American Study of Kidney Disease and Hypertension (AASK), and Chronic Renal Insufficiency Cohort (CRIC) Study.
- Utilized multivariable-adjusted errors-in-variables regression models, accounting for measured GFR (mGFR) and its measurement error.
- Examined demographic (sex, race, age) and clinical factors (urine creatinine excretion, urine protein excretion, weight, smoking) as potential predictors.
Main Results:
- Serum creatinine showed stronger associations with male sex, black race, and higher urine creatinine excretion compared to BTP, B2M, and cystatin C.
- BTP, B2M, and cystatin C exhibited different associations with age, sex, and race compared to creatinine.
- BTP, B2M, and cystatin C levels were more strongly associated with factors like urine protein excretion, weight, and smoking than creatinine.
Conclusions:
- Serum levels of low-molecular-weight proteins (BTP, B2M, cystatin C) are influenced by various non-GFR factors, similar to creatinine.
- Understanding these non-GFR determinants is crucial for accurate interpretation of GFR estimates and risk stratification using these markers.
- Findings may not generalize to populations without chronic kidney disease, and residual confounding with GFR is possible.
Background:
Unlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, β-trace protein (BTP), β2-microglobulin (B2M), and cystatin C, are not well characterized.
Study Design:
Pooled cross-sectional analysis of 3 studies.
Setting & Participants:
3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study.
Predictors:
Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations.
Outcomes:
Serum creatinine, BTP, B2M, and cystatin C levels.
Results:
In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C.
Limitations:
Findings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error.
Conclusions:
Like creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.
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