Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS

Tiffany A. Freed; Josef Coresh; Lesley A. Inker; Douglas R. Toal; Regis Perichon; Jingsha Chen; Kelli D. Goodman; Qibo Zhang; Jessie K. Conner; Deirdre M. Hauser; Kate E.T. Vroom; Maria L. Oyaski; Jacob E. Wulff; Gudný Eiríksdóttir; Vilmundur Gudnason; Vicente E. Torres; Lisa A. Ford; Andrew S. Levey

doi:10.1373/clinchem.2018.288092

Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS

Tiffany A. Freed, Josef Coresh, Lesley A. Inker, Douglas R. Toal, Regis Perichon, Jingsha Chen, Kelli D. Goodman, Qibo Zhang, Jessie K. Conner, Deirdre M. Hauser, Kate E.T. Vroom, Maria L. Oyaski, Jacob E. Wulff, Gudný Eiríksdóttir, Vilmundur Gudnason, Vicente E. Torres, Lisa A. Ford, Andrew S. Levey

Nephrology and Hypertension

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

6 Scopus citations

Abstract

BACKGROUND: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables. METHODS: An ultra-performance liquid chromatography–tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n 1615) and evaluated in the remaining participants (n 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 P ₃₀ ); goal 10%]. RESULTS: The assay had a mean imprecision (10% intraassay, 6.9% interassay), linearity over the quantitative range (r ² 0.98), and analyte recovery (98.5%–113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 P ₃₀ in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups. CONCLUSIONS: The new eGFRmet equation could serve as a confirmatory test for GFR estimation.

Original language	English (US)
Pages (from-to)	406-418
Number of pages	13
Journal	Clinical chemistry
Volume	65
Issue number	3
DOIs	https://doi.org/10.1373/clinchem.2018.288092
State	Published - Mar 2019

ASJC Scopus subject areas

Clinical Biochemistry
Biochemistry, medical

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Freed, T. A., Coresh, J., Inker, L. A., Toal, D. R., Perichon, R., Chen, J., Goodman, K. D., Zhang, Q., Conner, J. K., Hauser, D. M., Vroom, K. E. T., Oyaski, M. L., Wulff, J. E., Eiríksdóttir, G., Gudnason, V., Torres, V. E., Ford, L. A., & Levey, A. S. (2019). Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS. Clinical chemistry, 65(3), 406-418. https://doi.org/10.1373/clinchem.2018.288092

Freed, TA, Coresh, J, Inker, LA, Toal, DR, Perichon, R, Chen, J, Goodman, KD, Zhang, Q, Conner, JK, Hauser, DM, Vroom, KET, Oyaski, ML, Wulff, JE, Eiríksdóttir, G, Gudnason, V, Torres, VE, Ford, LA & Levey, AS 2019, 'Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS', Clinical chemistry, vol. 65, no. 3, pp. 406-418. https://doi.org/10.1373/clinchem.2018.288092

@article{ed9a7c44b27f48d29990699738777a1b,

title = "Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS",

abstract = " BACKGROUND: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables. METHODS: An ultra-performance liquid chromatography–tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n 1615) and evaluated in the remaining participants (n 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 P 30 ); goal 10%]. RESULTS: The assay had a mean imprecision (10% intraassay, 6.9% interassay), linearity over the quantitative range (r 2 0.98), and analyte recovery (98.5%–113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 P 30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups. CONCLUSIONS: The new eGFRmet equation could serve as a confirmatory test for GFR estimation.",

author = "Freed, {Tiffany A.} and Josef Coresh and Inker, {Lesley A.} and Toal, {Douglas R.} and Regis Perichon and Jingsha Chen and Goodman, {Kelli D.} and Qibo Zhang and Conner, {Jessie K.} and Hauser, {Deirdre M.} and Vroom, {Kate E.T.} and Oyaski, {Maria L.} and Wulff, {Jacob E.} and Gudn{\'y} Eir{\'i}ksd{\'o}ttir and Vilmundur Gudnason and Torres, {Vicente E.} and Ford, {Lisa A.} and Levey, {Andrew S.}",

note = "Funding Information: J. Coresh, peGFR R01 grant #5007386-SERV, funding from National Kidney Foundation and National Institute of Health to institution; L.A. Inker, peGFR R01 grant #5007386-SERV; V. Gudnason, Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik) was funded by NIH contracts N01-AG-1–2100 and HHSN27120120022C the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Alth-ingi (the Icelandic Parliament); V.E. Torres, NIH R01DK097020 Estimating GFR from a Panel of Endogenous Filtration Markers to institution; A.S. Levey, peGFR R01 grant #5007386-SERV, NI-DDK to institution. Publisher Copyright: {\textcopyright} 2018 American Association for Clinical Chemistry",

year = "2019",

month = mar,

doi = "10.1373/clinchem.2018.288092",

language = "English (US)",

volume = "65",

pages = "406--418",

journal = "Clinical Chemistry",

issn = "0009-9147",

publisher = "American Association for Clinical Chemistry Inc.",

number = "3",

}

TY - JOUR

T1 - Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS

AU - Freed, Tiffany A.

AU - Coresh, Josef

AU - Inker, Lesley A.

AU - Toal, Douglas R.

AU - Perichon, Regis

AU - Chen, Jingsha

AU - Goodman, Kelli D.

AU - Zhang, Qibo

AU - Conner, Jessie K.

AU - Hauser, Deirdre M.

AU - Vroom, Kate E.T.

AU - Oyaski, Maria L.

AU - Wulff, Jacob E.

AU - Eiríksdóttir, Gudný

AU - Gudnason, Vilmundur

AU - Torres, Vicente E.

AU - Ford, Lisa A.

AU - Levey, Andrew S.

N1 - Funding Information: J. Coresh, peGFR R01 grant #5007386-SERV, funding from National Kidney Foundation and National Institute of Health to institution; L.A. Inker, peGFR R01 grant #5007386-SERV; V. Gudnason, Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik) was funded by NIH contracts N01-AG-1–2100 and HHSN27120120022C the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Alth-ingi (the Icelandic Parliament); V.E. Torres, NIH R01DK097020 Estimating GFR from a Panel of Endogenous Filtration Markers to institution; A.S. Levey, peGFR R01 grant #5007386-SERV, NI-DDK to institution. Publisher Copyright: © 2018 American Association for Clinical Chemistry

PY - 2019/3

Y1 - 2019/3

N2 - BACKGROUND: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables. METHODS: An ultra-performance liquid chromatography–tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n 1615) and evaluated in the remaining participants (n 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 P 30 ); goal 10%]. RESULTS: The assay had a mean imprecision (10% intraassay, 6.9% interassay), linearity over the quantitative range (r 2 0.98), and analyte recovery (98.5%–113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 P 30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups. CONCLUSIONS: The new eGFRmet equation could serve as a confirmatory test for GFR estimation.

AB - BACKGROUND: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables. METHODS: An ultra-performance liquid chromatography–tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n 1615) and evaluated in the remaining participants (n 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 P 30 ); goal 10%]. RESULTS: The assay had a mean imprecision (10% intraassay, 6.9% interassay), linearity over the quantitative range (r 2 0.98), and analyte recovery (98.5%–113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 P 30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups. CONCLUSIONS: The new eGFRmet equation could serve as a confirmatory test for GFR estimation.

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EP - 418

JO - Clinical Chemistry

JF - Clinical Chemistry

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ER -

Validation of a metabolite panel for a more accurate estimation of glomerular filtration rate using quantitative LC-MS/MS

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