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Effect of corticosteroid therapy on low-molecular-weight protein markers of kidney function.

To the Editor:

Serum cystatin C, [[beta].sub.2]-microglobulin, and [beta]-trace protein are endogenous markers of glomerular filtration rate (GFR). Cystatin C, in particular, is a promising alternative to creatinine for the detection of incipient renal failure. However, corticosteroids affect the extrarenal metabolism of cystatin C, which limits the use of cystatin C as a marker of GFR in a variety of clinical settings. Low-molecular-weight (LMW) [beta]-trace protein might be a useful alternative in this respect. The present study set out to compare the effect of corticosteroid therapy on the serum concentrations of cystatin C, [[beta].sub.2]-microglobulin, and [beta]-trace protein.

We studied a group of 108 children being treated or followed for malignancy (n = 41) or renal disease (n = 67). In the former group 14 patients (34%) were treated with glucocorticoids, in the latter 18 (27%). We compared single-injection inulin clearance studies in 76 patients not receiving steroids with 32 in patients receiving corticosteroid treatment (median dose 33.0 mg prednisone-equivalent per [m.sup.2] body surface area per day, range 1.2-70.4). Mean (SD) age was 9.7 (5.8) years, mean (SD) GFR 92.8 (34.6) ml, * [min.sup.-1] * (1.73 [m.sup.2).sup.-1]. Patients included in the study had to be on corticosteroid therapy for at least 5 days or had corticosteroids discontinued for at least 10 days.

In 16 patients, a paired analysis was performed before and during high-dose corticosteroid therapy with a median (range) dose of 36.3 mg/[m.sup.2] (11.5 to 61.4 mg/[m.sup.2]). This analysis included 10 children in the reinduction protocol of acute lymphoblastic leukemia (ALL-9 protocol of the Dutch Childhood Oncology Group) and 6 with nephrotic syndrome. The study was approved by local and national ethics committees, and written informed consent was obtained from the patients and/or their guardians.

The markers were measured by particle-enhanced immunonephelometry on a Behring Nephelometer II (DADE Behring, Marburg, Germany).

As expected for endogenous GFR markers, multiple linear regression analysis between the reciprocals of the LMW protein serum concentrations, and inulin clearance showed a highly significant positive relationship (Table 1). There was a strong positive relationship between prednisone dose and the reciprocals of both [[beta].sub.2-microglobulin and [beta]-trace protein. Cystatin C showed a weak but statistically significant negative relationship with inulin clearance.

The paired analysis revealed that corticosteroid therapy significantly decreased mean (SD) [[beta].sub.2-microglobulin from 1.67 (0.46) mg/L to 1.19 (0.59) mg/L (mean difference -0.48 mg/L, 95% CI -0.76 to -0.21, P = 0.002 paired t-test) and 0-trace protein from 0.80 (0.23) mg/L to 0.54 (0.15) mg/L (mean difference -0.26 mg/L, 95% CI -0.37 to -0.15, P = 0.0001). Cystatin C concentrations, by contrast, did not change significantly: 0.862 (0.144) mg/L without vs 0.840 (0.210) mg/L with corticosteroids; P = 0.76. Mean (SD) inulin clearance tended to be higher with corticosteroids, 127 (25) ml, * [min.sup.-1] * (1.73 [m.sup.2).sup.-1] vs 118 (25) ml, * [min.sup.-1] * (1.73 [m.sup.2).sup.-1] P = 0.14. The ratio between a cystatin C-based GFR estimate and measured inulin clearance tended to be lower during corticosteroid treatment, but this difference was not statistically significant [mean difference -0.030 (CI -0.133 to 0.074); P = 0.54].

Our data confirm a dose-dependent decrease in serum [[beta].sub.2]-microglobulin and a weak but significant increase in cystatin C during corticosteroid treatment. Corticosteroid therapy was associated with a strong dose-dependent decrease in [beta]-trace protein in both the cross-sectional and the paired analyses. Indirect evidence to support these findings comes from Puge et al. (1), who studied steroid-treated transplant recipients and found a stronger increase in cystatin C than in [beta]-trace protein with decreasing GFR, although the opposite was shown in children who did not receive glucocorticoids (2). In another study, however, Risch et al. (3) followed 6 patients with subarachnoid hemorrhage treated with high-dose methylprednisolon, and did not find a significant change in serum [beta]-trace protein concentration. Their results may have been due to unrecognized changes in GFR or leakage of [beta]-trace protein through the blood-brain barrier.

We previously found in paired analysis of children with steroid-sensitive nephrotic syndrome that cystatin C concentrations were unchanged on and off corticosteroids (4), a finding that may be attributable to a parallel increase in GFR that obscured increased cystatin C production. This theory is supported by the slightly lower ratio between estimated and measured GFR during corticosteroid therapy. Chronic corticosteroid administration increases GFR by causing vasodilation of glomerular resistance vessels. Although this mechanism is maintained in chronic renal failure, it may be blunted in acute renal injury, possibly explaining why this phenomenon was not observed in patients treated for renal allograft rejection (5).

In conclusion, glucocorticoid therapy leads to a dose-dependent underestimation of GFR calculations based on cystatin C and overestimation of those based on [[beta].sub.2]-microglobulin and [beta]-trace protein. In patients receiving corticosteroids, [beta]-trace protein offers no advantage over cystatin C as a marker of GFR.

Grant/funding support: The study was supported by a grant from Madeleine Schickedanz Kinder-Krebsstiftung. The immunonephelometric assays were a kind gift from Dade Behring (Marburg, Germany).

Financial disclosures: A.B. received honoraria from Dade Behring (Marburg, Germany) and DAKO (Glostrup, Denmark).

Acknowledgments: We are indebted to the patients and their parents who agreed to participate in the study. This study would have been impossible without the diligent work of the pediatric nursing staff of VU Medical Center performing the inulin clearance studies. We also wish to thank Mareike Reichelt and Jennifer Roos, who did the immunonephelometric measurements at Bonn University Hospital and the technicians, who did the inulin determinations at VU Medical Center. Ingrid Metgod was involved in the logistics of the study. Lyonne van Rossum is kindly acknowledged for her advice during the introduction of the single injection inulin clearance technique, and Netteke Schouten is recognized for her support and comments on the study protocol.

DOI: 10.1373/clinchem.2007.094946


(1.) Poge U, Gerhardt TM, Stoffel-Wagner B, Palmedo H, Klehr HU, Sauerbruch T, et al. beta-Trace protein is an alternative marker for glomerular filtration rate in renal transplantation patients. Clin Chem 2005;51:1531-3.

(2.) Bokenkamp A, Franke I, Schlieber M, Duker G, Schmitt J, Buderus S, et al. Beta-trace protein: a marker of kidney function in children: "Original research communication-clinical investigation". Clin Biochem 2007;40:969-75.

(3.) Risch L, Saely C, Reist U, Reist K, Hefti M, Huber AR. Course of glomerular filtration rate markers in patients receiving high-dose glucocorticoids following subarachnoidal hemorrhage. Clin Chim Acta 2005;360:205-7.

(4.) Bokenkamp A, van Wiik JA, Lentze MJ, Stoffel-Wagner B. Effect of corticosteroid therapy on serum cystatin C and beta2-microglobulin concentrations. Clin Chem 2002;48:1123-6.

(5.) Risch L, Herklotz R, Blumberg A, Huber AR. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 2001;47:2055-9.

Arend Bbkenkamp [1] * Celeste A.R.C. Laarman [1] Katja I. Braam [1] Joanna A.E. van Wijk [1] Wijnanda A. Korsl Marijke Kool [1] Janneke de Valk [1] Anna A. Bouman [2] Marieke D. Spreeuwenberg [3] Birgit Stoffel-Wagner [4]

Departments of [1] Pediatrics, [2] Clinical Chemistry, and [3] Clinical Epidemiology and Biostatistics, VU Medical Center Amsterdam, The Netherlands [4] Department of Clinical Biochemistry, Bonn University Medical Center Bonn, Germany

* Address correspondence to this author at: Department of Pediatrics, Vrije Universiteit Medical Center, De Boelelaan 1117, NL-1081 HV Amsterdam. Fax 31-20-4440849; e-mail Bokenkamp@
Table 1. Factors influencing the serum concentrations of the
LMW proteins. (a)

 1/Cystatin C, L/mg

Whole model [r.sup.2] 0.72
b inulin clearance, mL x 0.0093, 0.0081 to 0.0104
 [min.sup.1] (1.73 [m.sup.2)-1]
P value <0.0001
b prednisone dose, mg/[m.sup.2]/d -0.0023, -0.0045 to -0.0001
P value 0.0445

 -microglobulin, L/mg

Whole model [r.sup.2] 0.67
b inulin clearance, mL x 0.0051, 0.0040 to 0.0061
 [min.sup.1] (1.73 [m.sup.2)-1]
P value <0.0001
b prednisone dose, mg/[m.sup.2]/d 0.0065, 0.0045 to 0.0085
P value <0.0001

 1/[beta]-Trace protein,

Whole model [r.sup.2] 0.63
b inulin clearance, mL x 0.0110, 0.0087 to 0.0133
 [min.sup.1] (1.73 [m.sup.2)-1]
P value <0.0001
b prednisone dose, mg/[m.sup.2]/d 0.0114, 0.0069 to 0.0159
P value <0.0001

(a) Multiple linear regression analysis between the reciprocal
of the respective serum concentrations, inulin clearance, and
corticosteroid dose.
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Title Annotation:Letters
Author:Bokenkamp, Arend; Laarman, Celeste A.R.C.; Braam, Katja I.; van Wijk, Joanna A.E.; Kors, Wijnanda A.
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Dec 1, 2007
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