A New Panel-Estimated GFR, Including β2-Microglobulin and β-Trace Protein and Not Including Race, Developed in a Diverse Population

CKD-EPI GFR Collaborators

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. β2-Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is. Study Design: Study of diagnostic test accuracy. Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [51Cr]EDTA. Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1 − P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 − P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups. Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe. Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Original languageEnglish (US)
Pages (from-to)673-683.e1
JournalAmerican Journal of Kidney Diseases
Volume77
Issue number5
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
The Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS): Margret B. Andresdottir, Hrefna Gudmundsdottir, Olafur S. Indridason, and Runolfur Palsson; Assessing Long Term Outcomes in Living Kidney Donors (ALTOLD): Paul Kimmel, Matt Weir, Roberto Kalil, Todd Pesavento; Chronic Renal Insufficiency Cohort (CRIC): Anna Porter, Jonathan Taliercio, Chi-yuan Hsu, Jing Chen; Groningen Renal Hemodynamic Cohort Study Group (GRECO): Steef Sinkeler; study of people with HIV: Christina Wyatt, Zipporah Krishnasami, James Hellinger; Multicenter AIDS Cohort Study (MACS), now the MACS/WIHS Combined Cohort Study (MWCCS): Joseph Margolick (Baltimore), Lawrence Kingsley (Pittsburgh), Mallory Witt (Los Angeles), Steven Wolinsky (Chicago Northwestern); Multi Ethnic Study of Atherosclerosis (MESA): Tariq Shafi, Wendy Post; Preventing Early Renal Loss in Diabetes (PERL): Alessandro Doria; Steno Diabetes Center study: Hans-Henrik Parving. Lesley A. Inker, MD, MS, Sara J. Couture, MPH, Hocine Tighiouart, MS, Alison G. Abraham, PhD, MHS, Gerald J. Beck, PhD, Harold I. Feldman, MD, MSCE, Tom Greene, PhD, Vilmundur Gudnason, MD, PhD, Amy B. Karger, MD, PhD, John H. Eckfeldt, MD, PhD, Bertram L. Kasiske, MD, Michael Mauer, MD, Gerjan Navis, MD, PhD, Emilio D. Poggio, MD, Peter Rossing, MD, DMSc, Michael G. Shlipak, MD, MPH, and Andrew S. Levey, MD. Research idea and study design: LAI, ASL; data acquisition: AGA, GJB, HIF, TG, EDP, VG, ABK, JHE, BLK, MM, GN, PR, MGS, LAI; data analysis/interpretation: LAI, ASL, HT, SJC; statistical analysis: HT; supervision or mentorship: LAI, ASL. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. The measurements and analyses were supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK097020 ?Estimating GFR from a Panel of Endogenous Filtration Markers? to Tufts Medical Center (MC). Information on support for the pooled studies follows. The African-American Study of Kidney Disease and Hypertension (AASK): NIDDK U01 DK045388 and the NCMHHD M01 RR00071. AGES-Kidney: NIDDK R01-DK082447 and supplement 01A1S1 to ASL. ALTOLD: funded by NIH under cooperative agreement U01 DK066013. The National Institutes of Health (NIH) participated in the interpretation of data, writing the report, and the decision to submit the report for publication. This study was also supported by the Minneapolis Medical Research Foundation, Minneapolis, MN, which did not participate in any aspect of the study. Cleveland Clinic Foundation Population (CCFP): NIDDK U01 DK053869. CRIC: cooperative agreements from NIDDK (U01 DK060990, U01 DK060984, U01 DK061022, U01 DK061021, U01 DK061028, U01 DK060980, U01 DK060963, and U01 DK060902) and supported in part by the following institutional Clinical Translational Science Awards (CTSA) and other NIH grants: University of Pennsylvania NIH/National Center for Advancing Translational Sciences (NCATS) UL1 TR000003, K01 DK092353, and K24 DK002651; Johns Hopkins University UL1 TR000424; University of Maryland General Clinical Research Center M01 RR16500; Clinical and Translational Science Collaborative of Cleveland; UL1 TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research; Michigan Institute for Clinical and Health Research UL1 TR000433; University of Illinois at Chicago CTSA UL1 RR029879; Tulane University Translational Research in Hypertension and Renal Biology P30GM103337; Kaiser Permanente NIH/National Center for Research Resources (NCRR) University of California San Francisco-Clinical and Translational Science Institute UL1 RR024131; HIV study: supported by Gilead Sciences, Inc, under an investigator-initiated protocol NCRR L1RR025752 and by the NIH/NCATS UL1 RR025752 (Tufts MC), UL1 RR029887 (Mount Sinai School of Medicine), and UL1 RR025777 (University of Alabama at Birmingham). MACS: Baltimore CRS, U01-HL146201; Pittsburgh CRS, U01-HL146208; Chicago-Northwestern CRS, U01-HL146240; Los Angeles CRS, U01-HL146333; Data Analysis and Coordination Center U01-HL146193. Modification of Diet in Renal Disease: NIDDK U01 DK35073. MESA: supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the NCATS. PERL: NIDDK (R03-DK-094484, R34-DK-097808, and UC4-DK-101108) and JDRF (17-2012-377). The iohexol used for GFR measurements was a generous gift of GE Healthcare. Research reported in this publication was supported by the NCATS, the NIDDK, and the National Institute on Aging (Claude Pepper Center grants) under award numbers P30-DK-036836, UL1-TR-002494, P30-DK-020572, UL1-TR-001422, UL1-TR-002556, UL1-TR-002319, UL1-TR-001105, UL1-TR-002319-02, P30-AG-08808, and P30-AG-02482. RASS: research grants from NIDDK (DK51975); Merck & Co, USA; Merck Frosst, Canada; and Canadian Institutes of Health Research (DCT 14281) Canada; supported in part by the University of Minnesota General Clinical Research Center, M01-RR00400 NCRR, NIH. The remaining studies had no funding to report. Except as indicated, the funders had no a role in study design, data collection, analysis, reporting, or the decision to submit for publication. Dr Inker reports research funding to Tufts MC from NIH, National Kidney Foundation, Retrophin, Omeros, Dialysis Clinic, Inc, and Reata Pharmaceuticals; and consulting fees to Tufts MC from Tricida, Goldfinch Bio, and Diamtrix. Dr Abraham reports grant support from NIH. Dr Kasiske reports that all income is from the Hennepin Healthcare Research Institute, including funding from the NIH, Health Resources & Services Administration, and pharmaceutical companies (CSLB, Astellas). Dr Navis reports honoraria from Nutricia/Danone. Dr Rossing reports honoraria to institution from Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Merck, Mundipharma, Sanofi, Gilead, Vifor, and Novo Nordisk. Dr Levey reports grant support from NIH, National Kidney Foundation, and Siemens. The remaining authors declare that they have no relevant financial interests. The authors thank Shiyuan Miao (Tufts MC), for assistance with creating the figures and Juhi Chaudhari (Tufts MC) with administrative aspects of the paper. The MESA authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at www.mesa-nhlbi.org. Received July 27, 2020. Evaluated by 3 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Angela Webster, MBBS, MM[Clin Epid], PhD). Accepted in revised form November 10, 2020. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.

Funding Information:
Dr Inker reports research funding to Tufts MC from NIH, National Kidney Foundation, Retrophin, Omeros, Dialysis Clinic, Inc, and Reata Pharmaceuticals; and consulting fees to Tufts MC from Tricida, Goldfinch Bio, and Diamtrix. Dr Abraham reports grant support from NIH. Dr Kasiske reports that all income is from the Hennepin Healthcare Research Institute, including funding from the NIH, Health Resources & Services Administration, and pharmaceutical companies (CSLB, Astellas). Dr Navis reports honoraria from Nutricia/Danone. Dr Rossing reports honoraria to institution from Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Merck, Mundipharma, Sanofi, Gilead, Vifor, and Novo Nordisk. Dr Levey reports grant support from NIH, National Kidney Foundation, and Siemens. The remaining authors declare that they have no relevant financial interests.

Funding Information:
The measurements and analyses were supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK097020 “Estimating GFR from a Panel of Endogenous Filtration Markers” to Tufts Medical Center (MC). Information on support for the pooled studies follows. The African-American Study of Kidney Disease and Hypertension (AASK): NIDDK U01 DK045388 and the NCMHHD M01 RR00071. AGES-Kidney: NIDDK R01-DK082447 and supplement 01A1S1 to ASL. ALTOLD: funded by NIH under cooperative agreement U01 DK066013. The National Institutes of Health (NIH) participated in the interpretation of data, writing the report, and the decision to submit the report for publication. This study was also supported by the Minneapolis Medical Research Foundation, Minneapolis, MN, which did not participate in any aspect of the study. Cleveland Clinic Foundation Population (CCFP): NIDDK U01 DK053869. CRIC: cooperative agreements from NIDDK (U01 DK060990, U01 DK060984, U01 DK061022, U01 DK061021, U01 DK061028, U01 DK060980, U01 DK060963, and U01 DK060902) and supported in part by the following institutional Clinical Translational Science Awards (CTSA) and other NIH grants: University of Pennsylvania NIH/National Center for Advancing Translational Sciences (NCATS) UL1 TR000003, K01 DK092353, and K24 DK002651; Johns Hopkins University UL1 TR000424; University of Maryland General Clinical Research Center M01 RR16500; Clinical and Translational Science Collaborative of Cleveland; UL1 TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research; Michigan Institute for Clinical and Health Research UL1 TR000433; University of Illinois at Chicago CTSA UL1 RR029879; Tulane University Translational Research in Hypertension and Renal Biology P30GM103337; Kaiser Permanente NIH/National Center for Research Resources (NCRR) University of California San Francisco-Clinical and Translational Science Institute UL1 RR024131; HIV study: supported by Gilead Sciences, Inc, under an investigator-initiated protocol NCRR L1RR025752 and by the NIH/NCATS UL1 RR025752 (Tufts MC), UL1 RR029887 (Mount Sinai School of Medicine), and UL1 RR025777 (University of Alabama at Birmingham). MACS: Baltimore CRS, U01-HL146201; Pittsburgh CRS, U01-HL146208; Chicago-Northwestern CRS, U01-HL146240; Los Angeles CRS, U01-HL146333; Data Analysis and Coordination Center U01-HL146193. Modification of Diet in Renal Disease: NIDDK U01 DK35073. MESA: supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the NCATS. PERL: NIDDK (R03-DK-094484, R34-DK-097808, and UC4-DK-101108) and JDRF (17-2012-377). The iohexol used for GFR measurements was a generous gift of GE Healthcare. Research reported in this publication was supported by the NCATS, the NIDDK, and the National Institute on Aging (Claude Pepper Center grants) under award numbers P30-DK-036836, UL1-TR-002494, P30-DK-020572, UL1-TR-001422, UL1-TR-002556, UL1-TR-002319, UL1-TR-001105, UL1-TR-002319-02, P30-AG-08808, and P30-AG-02482. RASS: research grants from NIDDK (DK51975); Merck & Co, USA; Merck Frosst, Canada; and Canadian Institutes of Health Research (DCT 14281) Canada; supported in part by the University of Minnesota General Clinical Research Center, M01-RR00400 NCRR, NIH. The remaining studies had no funding to report. Except as indicated, the funders had no a role in study design, data collection, analysis, reporting, or the decision to submit for publication.

Publisher Copyright:
© 2020 National Kidney Foundation, Inc.

Keywords

  • African American
  • Black race
  • GFR estimation
  • Glomerular filtration rate (GFR)
  • bias
  • creatinine
  • cystatin C
  • estimating equations
  • filtration marker
  • kidney disease diagnosis
  • laboratory testing
  • race
  • race-based medicine
  • renal function
  • β-microglobulin (B2M)
  • β-trace protein (BTP)

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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