Estimating Glomerular Filtration Rate Using Serum Creatinine

Featured Article: Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F, for Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem 2007;53:766–72.3 Chronic kidney disease (CKD4) is now recognized as a global public health problem affecting more than 10% of adults and more than 50% in high-risk subpopulations. Twenty years ago, the rising incidence and prevalence of kidney failure treated by dialysis and transplantation (end-stage renal disease) had been identified as a public health threat, but difficulty in properly relating measured serum creatinine (Scr) values to the level of kidney function had hampered efforts to describe the earlier stages of the disease. The remarkable progress during these 2 decades reflects the strong team work among clinicians, epidemiologists, biostatisticians, laboratory scientists, and in vitro diagnostic (IVD) manufacturers. The 2007 article highlighted here represents a milestone in the development and implementation of equations for estimated glomerular filtration rate (eGFR) for detection, evaluation, and management of CKD. In 1999, the Modification of Diet in Renal Disease (MDRD) Study Group reported a new equation to estimate GFR from serum creatinine (eGFRcr), using more rigorous statistical methods and a more generalizable study population than the previously developed equations (1). The 2002 National Kidney Foundation Kidney Disease Outcomes Quality Initiative clinical practice guidelines included thresholds for GFR to define and classify stages of CKD and recommended that clinical laboratories report estimated GFRcr when Scr is measured, using the MDRD Study equation (2). However, it was soon recognized that accurate GFR estimation required reference measurement procedure–traceable measured Scr values. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases initiated the National Kidney Disease Education Program (NKDEP) Laboratory Working Group and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The NKDEP Laboratory Working Group concluded that a better reference system was needed to enhance accuracy of Scr measurement, encompassing high-level reference measurement procedures based on isotope dilution mass spectrometry (IDMS) combined with gas chromatography or liquid chromatography (LC), and commutable reference materials that could be used directly in clinical laboratory measurement procedures (3). The US National Institute of Standards and Technology, working closely with the NKDEP Laboratory Working Group, developed both a GC-IDMS and an LC-IDMS reference measurement procedure for serum creatinine measurement, as well as a fresh-frozen serum-based reference material that was proven to be commutable with all the clinical measurement procedures, both Jaffe based and enzymatic based, at the time. It became quickly apparent that the new creatinine reference system lowered the reported Scr values from those used to generate the MDRD Study equation originally, thereby leading to the need for adjustment of the equation for use with new IDMS-traceable Scr values. About the same time, the College of American Pathologists (CAP) developed an “accuracy-based” proficiency testing program (CAP LN24 Survey) that could be used to monitor how well clinical laboratories were producing IDMS-traceable Scr values. In the article featured here, the CKD-EPI investigators used the CAP LN24 samples, a calibration panel prepared by the MDRD Study Central Laboratory, and frozen samples from the MDRD Study to develop the regression calibration to relate the original MDRD Study sample assigned Scr concentrations to IDMS-traceable creatinine and to reexpress the MDRD Study equation for use with IDMS-traceable Scr concentrations. In subsequent publications, the CKD-EPI investigators described performance of the original vs modified MDRD Study equation and reported a more accurate eGFR equation using standardized Scr (the CKD-EPI 2009 creatinine equation), which is now recommended for routine use by the 2012 Kidney Disease Improving Global Outcomes clinical practice guideline (4). By 2013, virtually all global IVD manufacturers had transitioned their creatinine measurement procedures to be traceable to the IDMS reference measurement procedure, and more than 85% of clinical laboratories in the US were reporting eGFRcr using either the MDRD Study or CKD-EPI equations whenever Scr was reported (5). Although eGFRcr has become essential to clinical practice, its accuracy remains limited by non-GFR determinants of the Scr concentration, particularly variation in creatinine generation by muscle and diet sources. Cystatin C is an alternative filtration marker that is less affected by muscle than creatinine. With the recent availability of a cystatin C standard reference material, the CKD-EPI investigators developed equations for use with standardized cystatin C alone or in combination with standardized creatinine, which are now recommended as a confirmatory test, but implementation has been narrow due to persistent variation among assays (4). Ongoing efforts to improve GFR estimation include the discovery and evaluation of novel metabolites and serum proteins as filtration markers. If successful, as with creatinine, these efforts will then require development of appropriate reference materials, assay standardization, and expression of GFR estimating equations for standardized values. chronic kidney disease serum creatinine in vitro diagnostic estimated glomerular filtration rate glomerular filtration rate Modification of Diet in Renal Disease National Kidney Disease Education Program Chronic Kidney Disease Epidemiology Collaboration isotope dilution mass spectrometry liquid chromatography College of American Pathologists. We acknowledge Sara Couture for assistance in manuscript preparation.