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Novel filtration markers for GFR estimation - IFCC

TF-CKD special issue: The laboratory diagnostics of chronic kidney diseases Novel filtration markers for GFR estimation Amy B. Karger1, Lesley A. Inker2, Josef Coresh3, Andrew S. Levey2, John H. Eckfeldt1. 1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 2. William B. Schwartz Division of Nephrology, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, MA, USA. 3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ARTICLE INFO ABSTRACT. Corresponding author: Creatinine-based glomerular filtration rate estima- Amy B. Karger tion (eGFRcr) has been improved and refined since Department of Laboratory Medicine and Pathology the 1970s through both the Modification of Diet in University of Minnesota Renal Disease (MDRD) Study equation in 1999 and 420 Delaware St SE MMC 609, the CKD Epidemiology Collaboration (CKD-EPI) equa- Minneapolis, MN 55455.

eJIFCC2017Vol28No4pp. 277-288. Page 277. TF-CD special issue The laboratory diagnostics of chronic kidney diseases. Novel filtration markers for GFR estimation

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Transcription of Novel filtration markers for GFR estimation - IFCC

1 TF-CKD special issue: The laboratory diagnostics of chronic kidney diseases Novel filtration markers for GFR estimation Amy B. Karger1, Lesley A. Inker2, Josef Coresh3, Andrew S. Levey2, John H. Eckfeldt1. 1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 2. William B. Schwartz Division of Nephrology, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, MA, USA. 3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ARTICLE INFO ABSTRACT. Corresponding author: Creatinine-based glomerular filtration rate estima- Amy B. Karger tion (eGFRcr) has been improved and refined since Department of Laboratory Medicine and Pathology the 1970s through both the Modification of Diet in University of Minnesota Renal Disease (MDRD) Study equation in 1999 and 420 Delaware St SE MMC 609, the CKD Epidemiology Collaboration (CKD-EPI) equa- Minneapolis, MN 55455.

2 United States of America tion in 2009, with current clinical practice dependent E-mail: primarily on eGFRcr for accurate assessment of GFR. However, researchers and clinicians have recognized Key words: glomerular filtration rate (GFR), limitations of relying on creatinine as the only filtra- estimated GFR, filtration markers , tion marker , which can lead to inaccurate GFR esti- beta-trace protein (BTP), mates in certain populations due to the influence of beta-2-microglobulin (B2M), metabolomics non-GFR determinants of serum or plasma creatinine. Therefore, recent literature has proposed incorpora- tion of multiple serum or plasma filtration markers into GFR estimation to improve precision and accura- cy and decrease the impact of non-GFR determinants for any individual biomarker. To this end, the CKD-EPI. combined creatinine-cystatin C equation (eGFRcr-cys). was developed in 2012 and demonstrated superior accuracy to equations relying on creatinine or cystatin C alone (eGFRcr or eGFRcys).

3 Now, the focus has broad- ened to include additional Novel filtration markers to further refine and improve GFR estimation . Beta- 2-microglobulin (B2M) and beta-trace-protein (BTP). Page 277. eJIFCC2017 Vol28No4pp277-288. Amy B. Karger, Lesley A. Inker, Josef Coresh, Andrew S. Levey, John H. Eckfeldt Novel filtration markers for GFR estimation are two filtration markers with established as- plasma creatinine (eGFRCr) as the first line test, says that have been proposed as candidates for with eGFR based on cystatin C (eGFRcys) or the improving both GFR estimation and risk predic- combination of the two (eGFRcr-cys) as a confir- tion. GFR estimating equations based on B2M matory test, particularly when there is concern and BTP have been developed and validated, for inaccurate eGFRcr results in individuals im- with the CKD-EPI combined BTP-B2M equa- pacted by known non-GFR determinants of tion (eGFRBTP-B2M) demonstrating similar perfor- creatinine, such as extremes of muscle mass, a mance to eGFRcr and eGFRcys.

4 Additionally, sev- high meat-containing diet, or some dietary sup- eral studies have demonstrated that both B2M plements such as creatine4. and BTP are associated with outcomes in CKD. GFR estimating equations were developed as patients, including cardiovascular events, ESRD. early as the 1970s, but it was the 4-variable and mortality. This review will primarily focus Modification of Diet in Renal Disease (MDRD). on these two biomarkers, and will highlight ef- Study equation developed in 2000 and re-ex- forts to identify additional candidate biomark- pressed for use with standardized creatinine5. ers through metabolomics-based approaches. that was the first estimating equation to be- come widely integrated into routine clinical lab- . oratory reports for assessment of kidney func- INTRODUCTION tion, due to its reliance on creatinine and readily available demographic metrics (age, gender and It is currently estimated that 15% of US adults, race)6,7.

5 While this MDRD Study equation was or about 30 million people, have chronic kidney useful for estimating GFR < 60 ml/ m2, disease (CKD)1. CKD is defined as the presence it was found to systematically underestimate of kidney damage, or estimated glomerular fil- GFR at levels > 60 ml/ m2. tration rate (eGFR) < 60 mL/ m2, for a Therefore, the Chronic Kidney Disease duration of at least 3 months2. Once diagnosed, Epidemiology Collaboration (CKD-EPI) was CKD is staged based on cause of disease, level formed in 2003 and set forth to improve the of GFR and albuminuria, to provide guidance accuracy of GFR estimating equations by devel- for disease management and risk stratification2. opment and validation of equations based on GFR is accepted as the best overall measure creatinine or cystatin C in a diverse population of kidney function in health and disease and that included participants across the range of reflects the product of the number of neph- GFR and age3, with and without CKD, diabetes rons and the average single nephron GFR3.

6 And transplants. Cystatin C was selected as a Measured glomerular filtration rate (mGFR). complimentary candidate filtration marker to via quantification of urinary or plasma clear- creatinine because it is less affected by non- ance of an exogenous filtration marker remains the gold standard for assessing GFR in patients GFR determinants that impact creatinine8, and with CKD. However, GFR measurement is bur- several studies have demonstrated that it is a densome for patients as well as clinical labo- better prognostic marker for predicting devel- ratories. Therefore, clinicians instead routinely opment of cardiovascular disease and mortal- use GFR estimates to diagnose and manage ity than creatinine9-11. patients with CKD. The 2012 Kidney Disease The CKD-EPI group developed and validated a Improving Global Outcomes (KDIGO) guidelines new CKD-EPI creatinine-based eGFR equation, recommend GFR estimation based on serum or which was found to have lesser bias compared Page 278.

7 EJIFCC2017 Vol28No4pp277-288. Amy B. Karger, Lesley A. Inker, Josef Coresh, Andrew S. Levey, John H. Eckfeldt Novel filtration markers for GFR estimation to measured GFR at GFR > 60 than the MDRD and the amount eliminated through glomeru- Study equation, and therefore its use was rec- lar filtration and tubular metabolism. Due to its ommended as an improvement over the MDRD ubiquitous presence on the surface of all cells, Study equation12. This work was followed by B2M elevation is seen with diseases associat- publication of two papers which demonstrated ed with high cell turnover, such as many ma- that estimating equations which relied on both lignancies. Therefore, B2M is most commonly creatinine and cystatin C were superior in preci- measured along with serum albumin to risk sion to equations that relied on only one bio- stratify multiple myeloma patients using the marker alone13,14. These studies laid the ground- International Staging System (ISS)16, with high- work for the main hypothesis driving current er levels of B2M associated with higher tumor efforts to improve GFR estimation that incor- burden and more aggressive subtypes, due to poration of additional biomarkers into estima- increased shedding of B2M15.

8 Tion of GFR diminishes the impact of non-GFR B2M was first suggested as a biomarker for glo- determinants for any given biomarker and im- merular filtration in the 1980s17,18, however, as proves overall equation performance. Based an acute phase reactant that increases in a va- on this hypothesis, research in the area of GFR riety of inflammatory and infectious disorders, estimation has moved from fine-tuning current its potential as a candidate for a single- marker creatinine and cystatin C-based equations to equation was limited19,20. Despite this short- identifying new endogenous filtration markers coming a handful of research groups derived that can be incorporated into GFR estimation to GFR estimating equations based on B2M alone, improve precision. but data supporting the performance and va- Beta-2-microglobulin (B2M) and beta-trace pro- lidity of these equations is lacking21-24. tein (BTP) have been identified as two endog- Elevation of B2M in patients with CKD, espe- enous low molecular weight protein filtration cially end stage renal disease (ESRD), has been markers with established assays that have the traditionally attributed to impaired removal potential to improve the accuracy of GFR estima- secondary to decreased glomerular filtration .

9 Tions. Additionally, due to technologic advances However recent literature has put forth the in the field of metabolomics, work is currently hypothesis that an additional source of B2M. in progress to identify and validate the utility of elevation in patients with CKD may be the in- additional, Novel filtration markers , with subse- terference of uremic solutes with the non-co- quent development of validated assays. valent binding of B2M to MHC molecules, lead- ing to an increase in shedding of B2M into the BETA-2-MICROGLOBULIN (B2M) circulation15. B2M is a kD protein which associates with Due to its established use as a prognostic mark- both classical and non-classical MHC Class I er for multiple myeloma, B2M is routinely mea- molecules on the surface of all cells and is criti- sured in many clinical laboratories by a variety cal for antigen presentation15. It is freely filtered of methods nephelometry, turbidimetry, or by the glomerulus, with more than re- immunoassay25.

10 However, studies have demon- absorbed and metabolized in the proximal tu- strated that B2M assays are not harmonized or bule15. Serum/plasma B2M concentrations are standardized leading to discordance between impacted by the amount generated and shed methods25,26. While the WHO 1st International by nucleated cells, body distribution kinetics, Standard for B2M was developed in 1985 27, Page 279. eJIFCC2017 Vol28No4pp277-288. Amy B. Karger, Lesley A. Inker, Josef Coresh, Andrew S. Levey, John H. Eckfeldt Novel filtration markers for GFR estimation and a B2M certified reference value in the se- The first GFR estimating equations based on BTP. rum protein standard ERM-DA470k/IFCC was were derived in 2007 by White and colleagues, assigned in 2015 by the Institute for Reference in a cohort of 163 adult kidney transplant pa- Materials and Measurements (IRMM)28, manu- tients with measured GFR. These equations, facturers have not universally adopted use of known as the White equations, performed ERM-DA470k/IFCC for calibration of their mea- comparably to the MDRD Study equation, with surement procedures25.


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