Editorials Recent Developments in the Evaluation of Glomerular Filtration Rate: Is There a Place for -Trace? The National Kidney Foundation’s “K/DOQI clinical practice guidelines for chronic kidney disease” and the recent European recommendations now provide consensus guidelines on the use of laboratory methods in estimating and measuring glomerular filtration rate (GFR) (1, 2 ). Professionals in clinical chemistry will need to be well acquainted with these 2 guidelines because the clinical chemistry laboratory is concerned in several ways. As a sum of the filtration rate of all functioning nephrons, GFR represents the best overall index of the extent of renal function (1 ). GFR can be measured only indirectly. The determination should use an ideal filtration marker that, after having reached a stable plasma concentration, is physiologically inert; is freely filtered in the glomerulus; is not secreted, metabolized, synthesized, or reabsorbed in the tubulus; is not extrarenally eliminated; is stable; and is easily measurable. A gold standard measure of GFR uses inulin as a filtration marker. Other exogenously administered substances (e.g., 125Iiothalamate, 99mTc-diethylenetriaminepentaacetic acid, 51 Cr-EDTA, and iohexol) can also provide a surrogate measure of GFR. Because these methods are labor-intensive, costly, and cumbersome for patients and staff, they are predominantly used in research settings and make up only a very small proportion of renal function determinations in routine clinical settings. The most commonly used indicator for estimation of GFR is serum (or plasma) creatinine. Measurement of creatinine is inexpensive and convenient, but it has several drawbacks. The first drawback is that it is a crude marker, detecting changes in renal function only when GFR is decreased by at least 50%. In addition, a variety of nonrenal physiologic (e.g., muscle mass, gender, and diet) and pathologic factors affect the circulating concentration of creatinine, and measurement of creatinine by the common Jaffe method is subject to numerous analytical influences (e.g., certain antibiotics, bilirubin, and ketones) (3 ). Moreover, creatinine is not only filtered at the glomerulus, but is excreted in the tubules and thus does not behave as an ideal marker of GFR. Finally, calibration of serum creatinine assays still awaits standardization, despite the fact that this analyte is among those with the longest history in clinical chemistry. Important for the laboratory, the new guidelines recommend that clinical laboratories do not report a serum creatinine concentration alone but also an estimate of GFR, taking into account demographic and anthropomorphic variables (1, 2 ). It has been recommended that these GFR estimates be calculated by those equations that have been shown to possess the best agreement with measured GFR [i.e., simplified Modification of Diet in Renal Disease (MDRD) and Cockcroft–Gault for adults; Schwartz and Counahan– Barratt for children] (1, 2 ). The precision and accuracy of GFR calculated by use of these equations were found to be as reliable as measured creatinine clearance. Thus, mea-
surements of creatinine clearance should be reserved for exceptions in favor of prediction equations in the clinical arena (1 ). The equations for prediction of GFR from serum creatinine have limitations. For example, the simplified MDRD estimate has not yet been evaluated in non-white populations other than blacks and was derived for patients with decreased GFR (4 ). Furthermore, as a consequence of the lack of standardization of creatinine methods, GFR estimates are likely to be biased if a creatinine method other than the one used to develop or evaluate the equation is used. This problem has been addressed by some studies, but further work from clinical laboratories and the diagnostic industry is needed (5, 6 ). Creatininebased estimates of GFR give good estimates in patients with reduced GFR but underestimate GFR in people with normal renal function (7 ). At present there is a controversy on the attempts to resolve this issue by means of equations that were also derived from patients with normal renal function (8 –10 ). Finally, GFR estimates are unreliable in patients with rapidly changing kidney function and in patients with extreme age, body size, or body composition (e.g., with obesity or severe malnutrition); in patients with abnormal muscle mass (e.g., after limb amputation or muscle wasting); and in patients with abnormal creatine intake (e.g., vegetarian diet). In these patients, alternative determinations of GFR such as clearance measurements should be done (1 ). Cystatin C has been proposed as a valuable alternative marker, particularly in situations in which creatininebased estimates of GFR fail to provide an accurate estimate (such as muscle wasting or liver cirrhosis) (11, 12 ). It has also been advocated for use in patients with a need for early and sensitive detection of renal function impairment, such as kidney transplant recipients (13 ). Published prediction equations for cystatin C– based estimation of GFR have made use of cystatin C practical (14 –16 ). However, the use of cystatin C is hampered by the fact that glucocorticoid administration and thyroid disorders have been described as nonrenal factors influencing serum cystatin C concentrations (17–22 ). Because kidney transplant recipients often receive glucocorticoids, cystatin C may not be an optimal marker in these patients. In this issue of Clinical Chemistry, Po¨ge et al. (23 ) present interesting data from a study investigating -trace protein as an alternative marker of renal function in kidney transplant recipients. -Trace protein (also known as prostaglandin D synthase) is a low–molecular-mass protein belonging to the lipocalin protein family. With its 168 amino acids, the protein has a molecular mass between 23 and 29 kDa depending on the degree of glycosylation (24 ). In the clinical laboratory, -trace protein has been established as an accurate marker of cerebrospinal fluid leakage (25 ). It has also been described recently as a more sensitive marker than serum creatinine in detecting Clinical Chemistry 51, No. 8, 2005
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impaired renal function, although not more sensitive than cystatin C (26 –30 ). The data presented by Po¨ge et al. (23 ) are confirmative in this respect. However, similar to our findings in neurosurgical patients, the authors showed that -trace protein concentrations, in contrast to cystatin C concentrations, are not influenced by glucocorticoid therapy (31 ). This makes -trace protein appealing in the transplantation setting. The findings of Po¨ge et al. (23 ) represent a starting point to stimulate further study. To be of use in monitoring renal function, a marker is expected to have low intraindividual variation. In addition, possible influencing factors other than glucocorticoids must be investigated. Furthermore, equations to convert a -trace protein concentration to a GFR are needed. With this it may be possible to translate the better sensitivity of -trace protein measurements into more accurate GFR estimates than are obtained from creatinine-based equations. All of these issues, as well as cost, must be addressed before this marker can proceed to use in routine clinical practice. In situations in which creatinine-based estimates can only be applied with caution and cystatin C is influenced by a nonrenal factor, such as the one addressed by Po¨ge et al. (23 ) but also, e.g., in thyroid disorders, -trace protein might thus serve as a valuable alternative marker of renal function. With the experience of creatinine in mind, efforts for standardization of assays should be initiated sooner rather than later. References 1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(Suppl 1):S1–246. 2. European best practice guidelines for haemodialysis (part 1). Measurement of renal function. Nephrol Dial Transplant 2002;17(Suppl 7):7–9. 3. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:1933–53. 4. Risch L, Sagmeister M, Huber AR. Renal function impairment and cardiovascular morbidity. N Engl J Med 2005;352:199 –200. 5. Hallan S, Asberg A, Lindberg M, Johnsen H. Validation of the modification of diet in renal disease formula for estimating GFR with special emphasis on calibration of the serum creatinine assay. Am J Kidney Dis 2004;44:84 –93. 6. Risch L, Huber AR. Assessing glomerular filtration rate in renal transplant recipients by estimates derived from serum measurements of creatinine and cystatin C. Clin Chim Acta 2005;356:204 –11. 7. Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2002;13:2140 – 4. 8. Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141:929 –37. 9. Froissart MC, Rosert J, Houillier P. The new Mayo Clinic equation for estimating glomerular filtration rate [Letter]. Ann Intern Med 2005;142:679. 10. Maaravi Y, Bursztyn M, Stressman J. The new Mayo Clinic equation for estimating glomerular filtration rate [Letter]. Ann Intern Med 2005;142: 680 –1. 11. Lamb EJ, O’Riordan SE, Delaney MP. Kidney function in older people: pathology, assessment and management. Clin Chim Acta 2003;334:25– 40. 12. Orlando R, Mussap M, Plebani M, Piccoli P, De Martin S, Floreani M, Padrini R, et al. Diagnostic value of cystatin C as a glomerular filtration rate marker in decompensated liver cirrhosis. Clin Chem 2002;48:850 – 8. 13. Risch L, Blumberg A, Huber A. Rapid and accurate assessment of glomerular filtration rate in patients with renal transplants using cystatin C. Nephrol Dial Transplant 1999;14:1991– 6. 14. Hoek FJ, Kemperman FAW, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024 –31.
15. Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtration rate expressed in ml/min from plasma cystatin C values in mg/L. Scand J Clin Lab Invest 2004;64:25–30. 16. Grubb A, Bjork J, Lindstrom V, Sterner G, Bondesson P, Nyman U. A cystatin C-based formula without anthropometric variables estimates glomerular filtration rate better than the creatinine clearance using the Cockcroft-Gault formula. Scand J Clin Lab Invest 2005;65:153– 62. 17. Bjarnadottir J, Grubb A, Olafsson I. Promoter-mediated, dexamethasoneinduced increase in cystatin C production in HeLa cells. Scand J Clin Lab Invest 1995;55:617–23. 18. Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J. Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients. Clin Chim Acta 2000;300:83–95. 19. Risch L, Herklotz R, Blumberg A, Huber A. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 2001;47:2055–9. 20. Poge U, Gerhardt T, Bokenkamp A, Stoffel-Wagner B, Klehr HU, Sauerbruch T, et al. Time course of low molecular weight proteins in the early transplantation period—influence of corticoids. Nephrol Dial Transplant 2004;19:2858 – 63. 21. Manetti L, Genovesi M, Pardini E, Grasso L, Lupi I, Morselli LL, et al. Early effects of methylprednisolone infusion on cystatin C in patients with severe Graves’ ophthalmopathy. Clin Chim Acta 2005;356:227– 8. 22. Wiesli P, Schwegler B, Spinas GA, Schmid C. Serum cystatin C is sensitive to small changes in thyroid function. Clin Chim Acta 2003;338:87–90. 23. Po¨ge U, Gerhardt TM, Stoffel-Wagner B, Palmedo H, Klehr H-U, Sauerbruch T, et al. -Trace protein is an alternative marker for glomerular filtration rate in renal transplantation patients. Clin Chem 2005;51:1531–3. 24. Hoffmann A, Nimtz M, Conradt HS. Molecular characterization of -trace protein in human serum and urine: a potential diagnostic marker for renal diseases. Glycobiology 1997;7:499 –506. 25. Risch L, Lisec I, Jutzi M, Podvinec M, Landolt H, Huber AR. Rapid, accurate and non-invasive detection of cerebrospinal fluid leakage using combined determination of -trace protein in secretion and serum. Clin Chim Acta 2005;351:169 –76. 26. Priem F, Althaus H, Birnbaum M, Sinha P, Conradt HS, Jung K. Beta-trace protein in serum: a new marker of glomerular filtration rate in the creatinineblind range. Clin Chem 1999;45:567– 8. 27. Woitas RP, Stoffel-Wagner B, Poege U, Schiedermaier P, Spengler U, Sauerbruch T. Low-molecular weight proteins as markers for glomerular filtration rate. Clin Chem 2001;47:2179 – 80. 28. Priem F, Althaus H, Jung K, Sinha P. Beta-trace protein is not better than cystatin C as an indicator of reduced glomerular filtration rate. Clin Chem 2001;47:2181. 29. Filler G, Priem F, Lepage N, Sinha P, Vollmer I, Clark H, et al. Beta-trace protein, cystatin C, (2)-microglobulin, and creatinine compared for detecting impaired glomerular filtration rates in children. Clin Chem 2002;48: 729 –36. 30. Donadio C, Luchesi A, Ardini M, Donadio E, Giordani R. Serum levels of -trace protein and glomerular filtration rate—preliminary results. J Pharm Biomed Anal 2003;32:1099 –104. 31. Risch L, Reist U, Hefti M, Reist K, Saely C, Huber AR. Course of glomerular filtration rate markers in patients receiving high dose glucocorticoids following subarachnoidal hemorrhage. Clin Chim Acta;in press.
Andreas R. Huber1* Lorenz Risch2 1
Department of Laboratory Medicine Kantonsspital Aarau, Switzerland 2
Department of Internal Medicine Academic Teaching Hospital Feldkirch, Austria
*Address correspondence to this author at: Department of Laboratory Medicine, Kantonsspital, 5001 Aarau, Switzerland. Fax 41-62-838-5399; e-mail
[email protected]. DOI: 10.1373/clinchem.2005.053389
