Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate

Ebert, Natalie; Delanaye, Pierre; Shlipak, Michael G.; Jakob, Olga; Martus, Peter; Bartel, Jan; Gaedeke, Jens; Giet, Markus van der; Schuchardt, Mirjam; Schaeffner, Elke

doi:10.1016/j.cca.2016.03.002

Cited by 36 publications

(26 citation statements)

References 36 publications

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“…Considerable efforts have been made to standardize creatinine [35,207] and cystatin C measurements [114,115]. Since standardization, reproducibility of equations has improved [208][209][210].…”

Section: Standardization Of Measurementsmentioning

confidence: 99%

Endogenous markers for kidney function in children: a review

Bakker

Gemke

Bökenkamp

2018

Critical Reviews in Clinical Laboratory Sciences

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Although glomerular filtration rate (GFR) in children can be measured using a gold-standard technique following injection of an exogenous marker, this invasive and cumbersome technique is not widely available and GFR is commonly estimated using serum levels of endogenous markers. Creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin are well-established endogenous markers of kidney function. These markers differ in site of production and effects of diet and medication, as well as renal-tubular handling and extra-renal elimination. For each marker, different methods are available for measurement. Importantly, the measurements of creatinine and cystatin C have recently been standardized with the introduction of international reference standards. In order to allow estimation of GFR from serum marker concentrations, different equations for estimated GFR (eGFR) have been developed in children, using simple or more complex regression strategies with gold standard GFR measurements as a dependent variable. As a rule, estimation strategies relying on more than one marker - either by calculating the average of single parameter equations or by using more complex equations incorporating several parameters - outperform eGFR estimations using only a single marker. This in-depth review will discuss the physiology, measurement and clinical use of creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin in children. It will also address the generation of eGFR equations in children and provide an overview of currently available eGFR equations for the pediatric age group.

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Section: Standardization Of Measurementsmentioning

confidence: 99%

Endogenous markers for kidney function in children: a review

Bakker

Gemke

Bökenkamp

2018

Critical Reviews in Clinical Laboratory Sciences

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“…7 To this end, the International Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Standardization of Cystatin has been established and has developed an international reference standard in collaboration with the Institute for Reference Materials and Measurements. 59,60 With the recent availability of this cystatin C standard reference material, the CKD-EPI investigators also developed new equations for standardized cystatin C alone or in combination with standardized creatinine, which are now recommended as a confirmatory test for GFR. 61 These efforts to improve assay standardization and cystatin C estimating equations will require further modification of cystatin C eGFR equations for new standardized values.…”

Section: Limitations Of Cystatin C As a Gfr Biomarkermentioning

confidence: 99%

Cystatin C Is a More Reliable Biomarker for Determining eGFR to Support Drug Development Studies

Kar

Paglialunga

Islam

2018

The Journal of Clinical Pharma

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Glomerular filtration rate (GFR) is routinely used as a surrogate endpoint for the development of investigational drugs in clinical trials. GFR and staging of chronic kidney disease are typically assessed by measuring the concentration of endogenous serum biomarkers such as albumin and creatinine. However, creatinine is subject to high biological variability, and levels of creatinine do not rise until nearly 50% of kidney function is damaged, leading to inaccurate chronic kidney disease staging and false negatives. A newer biomarker for GFR, cystatin C, has been shown to be subject to less biological interference and more sensitive to early declines in kidney function. Cystatin C has also been shown to outperform creatinine as an indicator of true GFR and to add information about the occurrence of acute kidney injury. Comparison studies of cystatin C and creatinine continue to demonstrate its increased accuracy and sensitivity for changes in true GFR. While challenges remain for use of cystatin C, international agencies and working groups continue to validate cystatin C as a biomarker and accompanying GFR estimating equations for diagnostic and drug development use. In this review, we summarize these comparison studies, regulatory and industry guidelines, and clinical trial case studies for use of cystatin C in drug development.

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“…The difference between the 2 assays becomes apparent at higher cystatin C concentrations as can be seen in online supplement 1. At low and normal levels, a small change in cystatin C concentration translates to a relevant change in eGFR [35] . Fortunately, this is compensated for by the fact that the change in eGFR per unit of change in cystatin C becomes smaller at higher cystatin C values, coinciding with where the measurement error between Roche 1 and Roche 2 grows larger.…”

Section: Laboratory Methodsmentioning

confidence: 99%

Combining Cystatin C and Creatinine Yields a Reliable Glomerular Filtration Rate Estimation in Older Adults in Contrast to β-Trace Protein and β2-Microglobulin

Werner

Pihlsgård

Elmståhl

et al. 2017

Nephron

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Background: The glomerular filtration rate (GFR) is the most important measure of kidney function and chronic kidney disease (CKD). This study aims to validate commonly used equations for estimated GFR (eGFR) based on creatinine (cr), cystatin C (cys), β-trace protein (BTP), and β2-microglobulin (B2M) in older adults. Method: We conducted a validation study with 126 participants aged between 72 and 98 with a mean measured GFR (mGFR) by iohexol clearance of 54 mL/min/1.73 m². The eGFR equations (CKD-Epidemiology collaboration [CKD-EPI], Berlin Initiative Study [BIS], Full Age Spectrum [FAS], Modification of Diet in Renal Disease [MDRD]_cr, Caucasian-Asian-Pediatric-Adult [CAPA]_cys, Lund-Malmö Revised [LM-REV]_cr, and MEAN-LM-CAPA_cr-cys), were assessed in terms of bias (median difference: eGFR-mGFR), precision (interquartile range of the differences), and accuracy (P30: percentage of estimates ±30% of mGFR). The equations were compared to a benchmark equation: CKD-EPI_cr-cys. Results: All cystatin C-based equations underestimated the GFR compared to mGFR, whereas bias was mixed for the equations based only on creatinine. Accuracy was the highest for CKD-EPI_cr-cys (98%) and lowest for MDRD (82%). Below mGFR 45 mL/min/1.73 m² only equations incorporating cystatin C reached P30 accuracy >90%. CKD-EPI_cr-cys was not significantly more accurate than the other cystatin C-based equations. In contrast, CKD-EPI_cr-cys was significantly more accurate than all creatinine-based equations except LM-REV_cr. Conclusion: This study confirms that it is reasonable to use equations incorporating cystatin C and creatinine in older patients across a wide spectrum of GFR. However, the results call into question the use of creatinine alone below mGFR 45 mL/min/1.73 m². B2M and BTP do not demonstrate additional value in eGFR determination in older adults.

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Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate

Cited by 36 publications

References 36 publications

Endogenous markers for kidney function in children: a review

Endogenous markers for kidney function in children: a review

Cystatin C Is a More Reliable Biomarker for Determining eGFR to Support Drug Development Studies

Combining Cystatin C and Creatinine Yields a Reliable Glomerular Filtration Rate Estimation in Older Adults in Contrast to β-Trace Protein and β2-Microglobulin

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