Cystatin C: Analysis and Utility in Monitoring GFR Mary Lou Gantzer, Phd Dade Behring, Newark, DE

Home , Cystatin C

CE update [molecular diagnostics] Cystatin C: Analysis and Utility in Monitoring GFR Mary Lou Gantzer, PhD Dade Behring, Newark, DE

DOI: 10.1309/P3BCHUJ4JB0HDRC2

After reading this article, the reader should be able to list the characteristics of an ideal marker of GFR, list the major clinical Downloaded from https://academic.oup.com/labmed/article/34/2/118/2504281 by guest on 02 October 2021 conditions in which monitoring GFR is important, and describe the utility of cystatin C as a marker of GFR. Molecular diagnostic exam 0301 questions and corresponding answer form are located after the “Your Lab Focus” section on p. 141.

̈ Characteristics of an ideal marker of due to the following: serum levels vary with and rapidly broken down by the proximal GFR age and muscle mass of the individual, as tubular cells without reentering the circula- ̈ Clinical conditions in which well as protein intake; creatinine is tion. Thus, it possesses many of the charac- determining GFR is important secreted by the tubules in addition to being teristics of an ideal marker of GFR listed in ̈ Principle of analysis of cystatin C filtered by the glomerulus; and there are a T1. Since no convenient, automated assays ̈ Utility of cystatin C as a marker of GFR number of interferences in the analytical were available at that time, cystatin C did determination of creatinine. not receive much attention for several Glomerular filtration rate (GFR) is Recently, the National Kidney Foun- years; this has now changed, and there is a used to assess kidney function, however, dation1 has issued guidelines suggesting growing body of evidence that indicates the direct measurement of GFR is difficult that laboratories report a calculated GFR utility of cystatin C as a marker of GFR. As and therefore GFR is often estimated by based on serum creatinine, age, gender, is observed for serum creatinine, serum cys- determining the clearance of a substance and race, and eliminate doing 24 hour tatin C values increase as GFR decreases. from the blood by the kidneys. Clearance urine collections to estimate GFR. The T2 summarizes data from several studies in is defined as the quantity of blood, or number of individuals suffering from kid- which both serum creatinine and serum cys- plasma, that is completely cleared of the ney disease continues to increase, as does tatin C were compared to a clearance substance per unit time, and is calculated the prevalence of kidney failure; this leads method for estimating GFR; various assays according to the following equation: to poorer outcomes for the patients, as were used for both markers. As indicated well as high health care costs. It has been in the table, cystatin C measurement corre- Clearance = U x V well demonstrated that detection of kidney lates more closely with GFR than does P disease in the early stages can delay, or in serum creatinine measurement. where U = measured urine concentration some cases prevent, progression of the Cystatin C has additional advantages as of the substance disease. Early detection is of great impor- a marker of GFR. A number of studies9-12 V= urine flow rate tance in diabetic patients, as well as trans- have shown that cystatin C values are inde- P = measured serum or plasma plant recipients. Laboratory testing plays a pendent of gender and age. Both creatinine concentration of the substance. key role in the early detection, and hence and cystatin C values start out high at birth, Ideally, a substance used as a marker there continues to be great interest in and then rapidly fall. After the age of 1, cys- for GFR would have the characteristics identifying markers that can be used for tatin C values remain constant until approxi- listed in T1. this purpose. mately age 70, when there is a gradual age-related decline in GFR and a correspon- Creatinine Levels and GFR Cystatin C and GFR ding increase in cystatin C. In contrast, crea- Through the years, a number of The use of cystatin C in the serum tinine values increase gradually throughout endogenous and exogenous substances have (or plasma) as a marker of GFR was first childhood as body mass increases, and there 118 been used to estimate GFR, although no proposed in 1985.2 Cystatin C is a single is a wide interindividual range for creatinine. substance has been identified previously that chain, non-glycosylated basic protein Since creatinine is related to lean body has all of the characteristics listed in T1. with a molecular weight of approximately mass, creatinine values also vary with gen- These substances include creatinine, in- 13 kDa. It is synthesized in the body by all der; this has not been observed with cystatin ulin, 51Cr-EDTA, iohexol, and iothalamate. nucleated cells that have been examined, C. Due to this relation to lean muscle mass, The most commonly used of these, of and appears to be produced at a constant the use of creatinine measurements for esti- course, is creatinine. Creatinine determina- rate. It is cleared from the blood by mating GFR is problematic in patients suf- tion provides only an approximation of GFR glomerular filtration, and is then reabsorbed fering from muscle-wasting disorders and

laboratorymedicine> february 2003> number 2> volume 34 © Characteristics of an Ideal Marker of GFR T1 Inert substance that circulates freely in the blood, not bound to cells or proteins. Substance that is completely filtered through the glomeruli. Substance is naturally occurring in the body, and is produced at a constant rate. Substance has no external sources of elimination from the body.

Correlation Between 1/Cystatin C and 1/Creatinine and Various Clearance Techniques T2 Downloaded from https://academic.oup.com/labmed/article/34/2/118/2504281 by guest on 02 October 2021 Author Clearance Correlation Coefficient (r) Reference Technique Cystatin C Creatinine

Helin I et al. 51Cr EDTA 0.83 0.67 (3) Kilpatrick et al. 51Cr EDTA 0.81 0.44 (4) Bokenkamp et al. Inulin 0.88 0.72 (5) Ylinen et al. 51Cr EDTA 0.89 0.80 (6) Risch et al. 125Iothalamate 0.83 0.25 (7) Fliser et al. Inulin 0.65 0.3 (8)

patients of small body mass. Since cystatin 2. Simonsen O, Grubb A, Thysell H. The blood serum concentration of cystatin C (g-trace) as a C is not related to body mass, it may have measure of the glomerular filtration rate. Scand J increased utility in this population. Clin Lab Invest. 1985:45:97-101. 3. Helin I, Axenram M, Grubb A. Serum cystatin C Summary of Assay as a determinant of glomerular filtration rate in children. Clin Nephrol. 1998;49:221-225. There is currently only 1 assay for cys- 4. Kilpatrick ES, Keevil BG, Addison GM. Does tatin C that has been cleared by the FDA adjustment of GFR to extracellular fluid volume for use in the United States. This assay is a improve the clinical utility of cystatin C? Arch Dis Child. 2000; 82:499-502. fully automated particle-enhanced nephelo- 5. Bokenkamp A, Domanetzki M, Zinck R, et al. metric immunoassay that can be run on Cystatin C – a new marker for glomerular Dade Behring BNTM Systems (Dade filtration rate in children independent of age and height. Pediatrics. 1998;101:875-881. Behring M, Deerfield, IL). Polystyrene par- 6. Ylinen EA, Ala-Houhala M, Harmoinen APT, et ticles coated with antibodies to cystatin C al. Cystatin C as a marker for glomerular filtration are agglutinated when mixed with samples rate in pediatric patients. Pediatr Nephrol. 1999;13:506-509. containing cystatin C. The intensity of the 7. Risch L, Blumberg A, Huber AR. Assessment of scattered light in the nephelometer depends renal function in renal transplant patients using on the concentration of the cystatin C in the cystatin C. A comparison to other renal function markers and estimates. Renal Failure. sample. The concentration can be 2001;23:439-448. determined by comparison with dilutions of 8. Fliser D, Ritz E. Serum cystatin C concentration a standard of a known concentration. No as a marker of renal dysfunction in the elderly. Am substances that have been examined have J Kid Dis. 2001; 37: 79-83. 9. Finney H, Newman DJ, Thakkar H, et al. Reference been shown to interfere with the analytical ranges for plasma cystatin C and creatinine determination of cystatin C. measurements in premature infants, neonates, and older children. Arch Dis Child. 2000;82:71-75. 10. Bokenkamp A, Domanetzki M, Zinck R; et al. Note on Manufacturer Reference values for cystatin C serum The author is an employee of Dade concentrations in children. Pediatr Nephrol. 1998; Behring, which makes the products de- 12: 125-129. 123 11. Harmoinen E, Ylinen M, Ala-Houlala M, et al. scribed in this article. Reference intervals for cystatin C in pre-and full- term infants and children. Pediatr Nephrol. 1. National Kidney Foundation. K/DOQI Clinical 2000;15:105-108. practice guidelines for chronic kidney disease: 12. Randers E, Krue S, Erlandsen EJ, et al. Reference evaluation, classification, and stratification. Am J interval for serum cystatin C in children. Clin Kid Dis. 2002;39:S1-S266. Chem. 1999;45:1856-1858.