Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD

Xun Liu; Meredith C. Foster; Hocine Tighiouart; Amanda H. Anderson; Gerald J. Beck; Gabriel Contreras; Josef Coresh; John H. Eckfeldt; Harold I. Feldman; Tom Greene; L. Lee Hamm; Jiang He; Edward Horwitz; Julia Lewis; Ana C. Ricardo; Haochang Shou; Raymond R. Townsend; Matthew R. Weir; Lesley A. Inker; Andrew S. Levey; Lawrence J. Appel; Alan S. Go; Jiang He; John W. Kusek; James P. Lash; Akinlolu Ojo; Mahboob Rahman

doi:10.1053/j.ajkd.2016.07.021

Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD

Xun Liu, Meredith C. Foster, Hocine Tighiouart, Amanda H. Anderson, Gerald J. Beck, Gabriel Contreras, Josef Coresh, John H. Eckfeldt, Harold I. Feldman, Tom Greene, L. Lee Hamm, Jiang He, Edward Horwitz, Julia Lewis, Ana C. Ricardo, Haochang Shou, Raymond R. Townsend, Matthew R. Weir, Lesley A. Inker, Andrew S. LeveyLawrence J. Appel, Alan S. Go, Jiang He, John W. Kusek, James P. Lash, Akinlolu Ojo, Mahboob Rahman

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	892-900
Number of pages	9
Journal	American Journal of Kidney Diseases
Volume	68
Issue number	6
DOIs	https://doi.org/10.1053/j.ajkd.2016.07.021
State	Published - Dec 1 2016

Bibliographical note

Funding Information:
Support: Dr Liu was funded by the National Natural Science Foundation of China (grant 813770866 ) and the China Scholarship Council (grant 201308440060 ). Drs Levey and Inker were supported in part by Estimating GFR from a Panel of Endogenous Filtration Markers (Continuation of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) ( NIH R01DK097020 ). Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases ( U01DK060990 , U01DK060984 , U01DK061022 , U01DK061021 , U01DK061028 , U01DK060980 , U01DK060963 , and U01DK060902 ). In addition, CRIC-related work was supported in part by the following: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award (National Institutes of Health [NIH]/National Center for Advancing Translational Sciences [NCATS] UL1TR000003), Johns Hopkins University ( UL1 TR-000424 ), University of Maryland ( GCRC M01 RR-16500 ), Clinical and Translational Science Collaborative of Cleveland, from the NIH/NCATS and NIH roadmap for Medical Research ( UL1TR000439 ), Michigan Institute for Clinical and Health Research ( UL1TR000433 ), University of Illinois at Chicago Clinical and Translational Science Award ( UL1RR029879 ), Tulane University Translational Research in Hypertension and Renal Biology ( P30GM103337 ), and the Kaiser Permanente NIH/National Center for Research Resources University of California San Francisco–Clinical and Translational Science Institute ( UL1 RR-024131 ). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

Publisher Copyright:
© 2016 National Kidney Foundation, Inc.

Keywords

Glomerular filtration rate (GFR)
beta trace protein (BTP)
beta-2 microglobulin (B2M)
biomarker
creatinine
cystatin C
determinants of kidney function
estimation of kidney function
filtration marker
kidney disease

Publisher link

10.1053/j.ajkd.2016.07.021

http://europepmc.org/articles/pmc5123901

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Liu, X., Foster, M. C., Tighiouart, H., Anderson, A. H., Beck, G. J., Contreras, G., Coresh, J., Eckfeldt, J. H., Feldman, H. I., Greene, T., Hamm, L. L., He, J., Horwitz, E., Lewis, J., Ricardo, A. C., Shou, H., Townsend, R. R., Weir, M. R., Inker, L. A., ... Rahman, M. (2016). Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD. American Journal of Kidney Diseases, 68(6), 892-900. https://doi.org/10.1053/j.ajkd.2016.07.021

Liu, X, Foster, MC, Tighiouart, H, Anderson, AH, Beck, GJ, Contreras, G, Coresh, J, Eckfeldt, JH, Feldman, HI, Greene, T, Hamm, LL, He, J, Horwitz, E, Lewis, J, Ricardo, AC, Shou, H, Townsend, RR, Weir, MR, Inker, LA, Levey, AS, Appel, LJ, Go, AS, He, J, Kusek, JW, Lash, JP, Ojo, A & Rahman, M 2016, 'Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD', American Journal of Kidney Diseases, vol. 68, no. 6, pp. 892-900. https://doi.org/10.1053/j.ajkd.2016.07.021

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title = "Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD",

abstract = "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.",

keywords = "Glomerular filtration rate (GFR), beta trace protein (BTP), beta-2 microglobulin (B2M), biomarker, creatinine, cystatin C, determinants of kidney function, estimation of kidney function, filtration marker, kidney disease",

author = "Xun Liu and Foster, {Meredith C.} and Hocine Tighiouart and Anderson, {Amanda H.} and Beck, {Gerald J.} and Gabriel Contreras and Josef Coresh and Eckfeldt, {John H.} and Feldman, {Harold I.} and Tom Greene and Hamm, {L. Lee} and Jiang He and Edward Horwitz and Julia Lewis and Ricardo, {Ana C.} and Haochang Shou and Townsend, {Raymond R.} and Weir, {Matthew R.} and Inker, {Lesley A.} and Levey, {Andrew S.} and Appel, {Lawrence J.} and Go, {Alan S.} and Jiang He and Kusek, {John W.} and Lash, {James P.} and Akinlolu Ojo and Mahboob Rahman",

note = "Funding Information: Support: Dr Liu was funded by the National Natural Science Foundation of China (grant 813770866 ) and the China Scholarship Council (grant 201308440060 ). Drs Levey and Inker were supported in part by Estimating GFR from a Panel of Endogenous Filtration Markers (Continuation of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) ( NIH R01DK097020 ). Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases ( U01DK060990 , U01DK060984 , U01DK061022 , U01DK061021 , U01DK061028 , U01DK060980 , U01DK060963 , and U01DK060902 ). In addition, CRIC-related work was supported in part by the following: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award (National Institutes of Health [NIH]/National Center for Advancing Translational Sciences [NCATS] UL1TR000003), Johns Hopkins University ( UL1 TR-000424 ), University of Maryland ( GCRC M01 RR-16500 ), Clinical and Translational Science Collaborative of Cleveland, from the NIH/NCATS and NIH roadmap for Medical Research ( UL1TR000439 ), Michigan Institute for Clinical and Health Research ( UL1TR000433 ), University of Illinois at Chicago Clinical and Translational Science Award ( UL1RR029879 ), Tulane University Translational Research in Hypertension and Renal Biology ( P30GM103337 ), and the Kaiser Permanente NIH/National Center for Research Resources University of California San Francisco–Clinical and Translational Science Institute ( UL1 RR-024131 ). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Publisher Copyright: {\textcopyright} 2016 National Kidney Foundation, Inc.",

year = "2016",

month = dec,

day = "1",

doi = "10.1053/j.ajkd.2016.07.021",

language = "English (US)",

volume = "68",

pages = "892--900",

journal = "American Journal of Kidney Diseases",

issn = "0272-6386",

publisher = "W.B. Saunders Ltd",

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}

TY - JOUR

T1 - Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD

AU - Liu, Xun

AU - Foster, Meredith C.

AU - Tighiouart, Hocine

AU - Anderson, Amanda H.

AU - Beck, Gerald J.

AU - Contreras, Gabriel

AU - Coresh, Josef

AU - Eckfeldt, John H.

AU - Feldman, Harold I.

AU - Greene, Tom

AU - Hamm, L. Lee

AU - He, Jiang

AU - Horwitz, Edward

AU - Lewis, Julia

AU - Ricardo, Ana C.

AU - Shou, Haochang

AU - Townsend, Raymond R.

AU - Weir, Matthew R.

AU - Inker, Lesley A.

AU - Levey, Andrew S.

AU - Appel, Lawrence J.

AU - Go, Alan S.

AU - He, Jiang

AU - Kusek, John W.

AU - Lash, James P.

AU - Ojo, Akinlolu

AU - Rahman, Mahboob

N1 - Funding Information: Support: Dr Liu was funded by the National Natural Science Foundation of China (grant 813770866 ) and the China Scholarship Council (grant 201308440060 ). Drs Levey and Inker were supported in part by Estimating GFR from a Panel of Endogenous Filtration Markers (Continuation of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) ( NIH R01DK097020 ). Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases ( U01DK060990 , U01DK060984 , U01DK061022 , U01DK061021 , U01DK061028 , U01DK060980 , U01DK060963 , and U01DK060902 ). In addition, CRIC-related work was supported in part by the following: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award (National Institutes of Health [NIH]/National Center for Advancing Translational Sciences [NCATS] UL1TR000003), Johns Hopkins University ( UL1 TR-000424 ), University of Maryland ( GCRC M01 RR-16500 ), Clinical and Translational Science Collaborative of Cleveland, from the NIH/NCATS and NIH roadmap for Medical Research ( UL1TR000439 ), Michigan Institute for Clinical and Health Research ( UL1TR000433 ), University of Illinois at Chicago Clinical and Translational Science Award ( UL1RR029879 ), Tulane University Translational Research in Hypertension and Renal Biology ( P30GM103337 ), and the Kaiser Permanente NIH/National Center for Research Resources University of California San Francisco–Clinical and Translational Science Institute ( UL1 RR-024131 ). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Publisher Copyright: © 2016 National Kidney Foundation, Inc.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

KW - Glomerular filtration rate (GFR)

KW - beta trace protein (BTP)

KW - beta-2 microglobulin (B2M)

KW - biomarker

KW - creatinine

KW - cystatin C

KW - determinants of kidney function

KW - estimation of kidney function

KW - filtration marker

KW - kidney disease

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