ASSESSING THE DIAGNOSTIC ACCURACY OFCYSTATIN C AS A MARKER OF IMPAIRED

GLOMERULAR FILTRATION RATE

To the Editor:We read with interest the article by Oddoze et al1 investi-

gating the diagnostic validity of cystatin C in patients withdiabetes mellitus. In a collective including more than 50%(26 of 49 patients) patients with a normal glomerular filtra-tion rate (GFR) (.80 mL/min/1.73 m2), the authors assessedserum creatinine and cystatin C by receiver operating charac-teristic (ROC) curves and found that serum cystatin C wasnot superior to creatinine-based methods for detecting earlyrenal failure. In the discussion, they wrongly stated that anearlier paper by our group2 showed the same findings. Thisstatement needs to be corrected. Our study in kidney trans-plant recipients found cystatin C to be of significantly higherdiagnostic accuracy than serum creatinine in detecting animpaired GFR below 60 mL/min/1.73m2.

The authors further claim that ROC analysis in anotherstudy by Seco et al3 showed that serum creatinine andcystatin C did not show a difference between the areas underthe curve (AUC), which is a measure for diagnostic accu-racy. In fact, this paper did not report testing for statisticaldifference of AUC. In addition, the authors suggest that onlythree studies reported cystatin C to exhibit larger AUC thanserum creatinine, one of which did not employ an exogenousclearance study as a reference measurement of GFR. Thisagain does not reflect correctly the literature, because substan-tially more papers reported cystatin C as a significantlybetter parameter than serum creatinine when assessing GFRby a reference method and diagnostic accuracy by ROCanalysis.4-10 With the exception of two papers,1,11 cystatin Calways was reported to be of greater diagnostic accuracythan serum creatinine. In some reports, however, this findingdid not reach a level of significance.

Assessing the diagnostic value of a new parameter in-cludes comparisons with already established parameters.This should be done by applying correct analytical andstatistical methods. The fact that the medical literature iscontroversial, whether cystatin C is a significantly or insig-nificantly better parameter than serum creatinine, can interalia be explained with heterogeneous methods used to assessdiagnostic accuracy and thus represent a cause for limitedcomparability of results. In addition, some papers use meth-ods that are inappropriate or incomplete. This clearly illus-trates the need for guidelines concerning how to assessdiagnostic accuracy of cystatin C. Efforts such as determin-ing GFR by reference method, determining diagnostic accu-racy with ROC analysis at two acknowledged GFR cut-offs,and including glucocorticoid medication into data analysiscan eliminate important sources of bias when assessing thediagnostic accuracy of cystatin C. Implementing these stan-dards in future studies would represent a major step towardsa reliable comparability of study results.

Lorenz Risch, MDAndreas R. Huber, MD

Department of Laboratory MedicineKantonsspital AarauAarau, Switzerland

REFERENCES

1. Oddoze C, Morange S, Portugal H, Berland Y, DussolY: Cystatin C is not more sensitive than creatinine fordetecting renal impairment in patients with diabetes. Am JKidney Dis 38:310-316, 2001

2. Risch L, Blumberg A, Huber A: Rapid and accurateassessment of glomerular filtration rate in patients with renaltransplants using serum cystatin C. Nephrol Dial Transplant14:1991-1996, 1999

3. Seco ML, Rus A, Sierra M, Caballero M, Borque L:Determination of serum cystatin C in patients with essentialhypertension. Nephron 81:446-447, 1999

4. Kyhse-Andersen J, Schmidt C, Nordin G, AnderssonB, Nilsson-Ehle P, Lindstrom V, Grubb A: Serum cystatin C,determined by a rapid, automated particle-enhanced turbidi-metric method, is a better marker than serum creatinine forglomerular filtration rate. Clin Chem 40:1921-1926, 1994

5. Randers E, Erlandsen EJ, Pedersen OL, Hasling C,Danielsen H: Serum cystatin C as an endogenous parameterof the renal function in patients with normal to moderatelyimpaired kidney function. Clin Nephrol 54:203-209, 2000

6. Plebani M, Dall’Amico R, Mussap M, Montini G,Ruzzante N, Marsilio R, Giordano G, Zacchello G: Is serumcystatin C a sensitive marker of glomerular filtration rate(GFR)? A preliminary study on renal transplant patients.Ren Fail 20:303-309, 1998

7. Helin I, Axenram M, Grubb A: Serum cystatin C as adeterminant of glomerular filtration rate in children. ClinNephrol 49:221-225, 1998

8. Ylinen EA, Ala-Houala M, Harmoinen AP, Knip M:Cystatin C as a marker of glomerular filtration rate inpediatric patietns. Ped Nephrol 13:506-509, 1999

9. Hayashi T, Nitta K, Hatano M, Nakauchi M, Nihei H:The serum concentration measured by particle enhancedimmunonephelometry is well correlated with inulin clear-ance in patients with various types of glomerulonephritis.Nephron 82:90-92, 1999

10. Fliser D, Ritz E: Serum cystatin C concentration as amarker of renal dysfunction in elderly. Am J Kidney Dis37:79-83, 2001

11. Donadio C, Lucchesi A, Ardini M, Giordani R: Cysta-tin C, beta-2-microglobulin, and retinol-binding protein asindicators of glomerular filtration rate: Comparison withplasma creatinine. J Pharmaceut Biomed 24:835-842, 2001

© 2002 by the National Kidney Foundation, Inc.doi:10.1053/ajkd.2002.32162

In Reply:We fully agree with Risch and Huber when they state that

the diagnostic value of a new marker of impaired glomerularfiltration rate (GFR) requires GFR measurements by a refer-ence method and receiver operating characteristic (ROC)analysis together with comparison of areas under the curve(AUC). Keeping in mind these prerequisites, we carefullylooked for all the articles dealing with the diagnostic valueof serum cystatin C for renal insufficiency (some of themwere not published at the time we submitted our article). Wefound 6 articles evidencing a better diagnostic value for

CORRESPONDENCE 661