Glomerular filtration rate (GFR) is a measure of how much blood is filtered by the kidneys each minute. It is the best overall indicator for how well an individual’s kidneys are functioning at a given moment.
The gold standard for measuring GFR involves measuring plasma or urinary clearance of an exogeneous marker such as inulin, 99mTc-DPTA, 51Cr-EDTA, 125I-Iothalamate or Iohexol. This method involves a continuous intravenous infusion of the marker accompanied by repeat blood and/or urine collections at carefully timed intervals. Despite the accuracy offered by exogenous markers, measuring their clearance is too labour-intensive and time-consuming for use in ambulatory settings.
The preferred clinical alternative is to calculate an estimated GFR (eGFR) based on the serum or plasma concentration of an endogenous marker such as cystatin C or creatinine. The ideal endogenous marker is one that is produced at a constant rate in the body, is filtered by the glomerulus and not absorbed, metabolised, or secreted into the renal tract.
Paul Brandt Rehberg publishes “The rate of filtration and reabsorption in the human kidney” and in it describes the calculation of glomerular filtration rate through the exogenous administration of creatinine. Rehberg further concludes that tubular secretion of creatinine did not occur under normal physiological conditions1.
James A. Shannon and Homer W. Smith publish “The excretion of inulin, xylose and urea by normal and phlorinized man,” noting a significant difference between inulin and creatinine clearance rates. Based on this finding, the pair conclude that creatinine is also excreted by tubular secretion and that GFR is better estimated by inulin clearance than creatinine clearance2,3.
Donald W. Cockcroft and M. Henry Gault develop the first formula to predict creatinine clearance from serum creatinine in adult males. The formula was derived from observations made on a population of 249 male patients whose ages ranged from 18-92 years4.
H. Löfberg and A. Grubb discover ϒ-trace (cystatin C) in human biological fluids. After observing high plasma concentrations of cystatin C in patients with advanced renal failure, Löfberg and Grubb posit that the protein must be catabolized in renal tubular cells following glomerular filtration5.
The first automated particle-enhanced turbidimetric assay (PETIA) for cystatin C in serum and plasma is developed by Kyhse-Andersen6.
The Modification of Diet in Renal Disease (MDRD) equation for predicting GFR from serum creatinine concentration is developed by Levey, A.S., et al. Researchers recommend routine use of the MDRD equation to predict GFR from serum creatinine concentrations citing more accurate estimates than those provided by creatinine clearance or the Cockcroft-Gault Formula. Of the 1,628 patients enrolled in the MDRD study, 88% were white7.
Gentian Diagnostics AS develops the first platform-agnostic PETIA for quantification of cystatin C in human serum and plasma.
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) established by the National Institutes of Diabetes, Digestive and Kidney Disease develops a new equation for estimating GFR from serum creatinine values. Researchers conclude that the CKD-EPI creatinine equation is “more accurate than the MDRD study equation across a vide variety of populations and clinical conditions.” One of the limitations noted in the study is the limited representation of racial and ethnic minorities across the 10 study populations (8,254 patients) used to develop the formula8.
Inker, L.A., et al. publish the first equations that obviate race-reporting as part of eGFR calculation. The combined creatinine-cystatin C equation was found to perform better than equations that used either creatinine or cystatin c alone. The authors conclude that the combined equation may be “useful as a confirmatory test for chronic kidney disease"9.
The National Institute for Health and Care Excellence (NICE) recommends using cystatin C to either confirm or rule out CKD in patients with a creatinine-based eGFR between 45 – 59 ml/min/1.73m2 that is maintained for at least 90 days without any other signs of kidney disease. The guideline was published in an attempt to reduce overdiagnosis of CKD stage 3a in the UK10,11.
Beth Israel Deaconess Medical Center calls attention to the bias inherent in race-adjusted calculation of eGFR and becomes the first institution to report eGFR as a range between race-adjusted and race-unadjusted values12.
Keyword search on PubMed for “Cystatin C” in combination of “Kidney Disorders” yields 4000+ academic publications
Dr. Anders Grubb highlights the importance of kidney biomarkers in laboratory medicine by mentioning that creatinine is the second most common analyte used in laboratory medicine; hemobglobin being the first13.
The National Kidney Foundation and the American Society of Nephrology announce the formation of a “joint task force to examine the inclusion of race in the estimation of GFR and its implications for the diagnosis and subsequent management of patients with, or at risk for, kidney diseases14”.
Since its discovery in 19795, cystatin C has been widely recognised as a reliable marker for estimating glomerular filtration rate (GFR). GFR calculations performed using cystatin C are independent of protein intake, race, and muscle mass15-18. Equations that include cystatin C also predict GFR more accurately than serum creatinine in children*19, adults20, and older adults21. For these reasons, Clinical use of cystatin C has been recommended in guidelines published by Kidney Disease: Improving Global Outcomes KDIGO15 and NICE16.
GFR can be estimated with greater accuracy if both cystatin C and creatinine are used. However, cystatin C based equations are superior to creatinine-based equations in predicting end-stage renal disease, cardiovascular disease, hospitalisation, and death.
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Tangri N et al. Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate, in Kidney Int 2011;79:471-7.
Grubb A, et al. eJIFCC 2017 Vol 28 NO4
Bjork J et al. Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children, inPediatr Nephrol. 2019;34:1087–1098
Lesly A et al. Estimating glomerular filtration rate from serum creatinine and cystatin C, in N Engl J Med 2012;367:20–29.
Schaeffner ES et al. Two novel equations to estimate kidney function in persons aged 70 years or older, in Ann Intern Med 2012;157:471–481.
Ebert N et al. Curr Opin Nephrol Hy. 2020;29(6):592-598.
*Not validated for children <14 years in the US
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