| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Technical Briefs |
1 Children’s Hospital, Medical Center of Bonn University, D-53113 Bonn, Germany;
2
Children’s Hospital, Vrije Universiteit Medical Center, NL-1007 MB Amsterdam, The Netherlands;
3
Department of Clinical Biochemistry, Medical Center of Bonn University, D-53105 Bonn, Germany
aaddress correspondence to this author at: Kindernefrologie, Vrije Universiteit Medisch Centrum, De Boelelaan 1117, NL-1007 MB Amsterdam, The Netherlands; fax 31-20-444-0849, e-mail bokenkamp{at}VUMC.nl
Cystatin C, a cationic low-molecular-weight protein (Mr 13 300) (1), has been described as a promising endogenous marker of glomerular filtration rate (GFR) in both adults (2)(3) and children (4). The correlation of serum cystatin C concentrations with the results of inulin and 51Cr-EDTA clearance examinations was superior to the correlation obtained with serum creatinine (2)(3)(4). The gene for cystatin C is expressed in all nucleated cells (5) and bears the characteristics of a housekeeping gene (6). Therefore, the cystatin C production rate is assumed to remain constant (3). This is supported by clinical evidence from several studies (7)(8). In renal transplant recipients, however, increases in serum cystatin C concentrations out of proportion to renal function impairment have been reported (9)(10)(11)(12)(13). Although serum cystatin C decreases before serum creatinine falls after successful transplantation, serum cystatin C concentrations increase by almost 30% between days 2 and 6 despite stable allograft function (14)(15). The pathogenesis of this observation is as yet unexplained. Because patients receive high doses of corticosteroids after transplantation, a potential role of concomitant steroid therapy has been discussed (9)(12). In patients with severe asthma, Cimerman et al. (16) observed an increase in serum cystatin C with high-dose corticosteroid therapy. In vitro, dexamethasone produces a significant and dose-dependent increase in cystatin C production in HeLa cells (17).
To investigate the effect of systemic steroid therapy on serum cystatin C concentrations in patients with normal excretory renal function, the present study analyzed cystatin C, ß2-microglobulin (Mr 11 800), and serum creatinine during steroid therapy of idiopathic nephrotic syndrome of childhood.
Two cases of first attack and 10 relapses of steroid-sensitive nephrotic syndrome were followed in 5 children (2 girls and 3 boys), 3.5–11.2 years of age (median, 8.3 years). Patients were treated according to the current protocol of the German Working Group for Pediatric Nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie) (18), i.e., 60 mg · m-2 · day-1 prednisone in three doses for 6 weeks followed by 40 mg · m-2 · 48 h-1 for another 6 weeks in first attacks, and prednisone 60 mg · m-2 · day-1 in three doses until 3 days after urinary remission followed by 40 mg · m-2 · 48 h-1 for 4 weeks in relapses. Because steroid doses were identical, data from first attacks and relapses were pooled for statistical analysis. Two children were steroid-dependent, i.e., suffered relapses during alternate-day steroid therapy. For this reason, only six samples in remission were available.
Serum samples were obtained as part of routine clinical visits before initiation of steroid therapy (Initial), at the end of the first week of daily prednisone administration (Daily steroid), 1 week after the switch to alternate-day prednisone (Alternate-day steroid), and at least 2 weeks after discontinuation of steroids in remission (Remission).
Serum was stored at -20 °C for up to 1 week until measurement of creatinine (multilayer film-slide enzymatic method; Ortho Clinical Diagnostics), albumin (nephelometry; Beckman Coulter), cystatin C, and ß2-microglobulin (particle-enhanced immunonephelometry; Dade Behring). GFR was estimated according to Schwartz et al. (19). Data are presented as median (range) and as box-plots. Statistical analysis was performed with the Kruskal–Wallis test, using StatView 4.01 software (Abacus Concepts) for Macintosh computers (Apple Computers).
During treatment of the nephrotic syndrome, the Schwartz GFR did not change significantly: Initial, 165 (128–218) mL · min-1 · 1.73 m-2; Daily steroid, 142 (81–195) mL · min-1 · 1.73 m-2; Alternate-day steroid, 133 (122–226) mL · min-1 · 1.73 m-2; and Remission, 135 (126–188) mL · min-1 · 1.73 m-2 (H = 5.489; P = 0.14). Serum albumin steadily increased [Initial, 34.2 (13.0–39.8) g/L; Daily steroid, 37.1 (30.0–41.6) g/L; Alternate-day steroid, 43.0 (33.0–52.5) g/L; and Remission, 45.2 (42.0–46.5) g/L], reflecting remission of nephrotic syndrome during steroid treatment.
Serum cystatin C concentrations were within the reference interval and remained unchanged (H = 4.66; P = 0.20) both under daily and alternate-day prednisone administration (Fig. 1A
). ß2-Microglobulin concentrations, however, showed a sharp decrease during daily prednisone therapy with a steady increase after reduction of steroid dose (H = 20.6; P <0.0001; Fig. 1B
).
|
Corticosteroids are among the most commonly prescribed drugs in nephrology. Therefore, a potential interaction of corticosteroid therapy with serum cystatin C concentrations or cystatin C measurement is highly relevant for its potential as a marker of GFR. The present study failed to reproduce the 1.8-fold increase in serum cystatin C concentrations during high-dose systemic methylprednisone treatment of asthma reported by Cimerman et al. (16). However, cystatin C concentrations were also increased by 50% in asthma patients not receiving corticosteroids. Takeyabu et al. (20) demonstrated increases in cystatin C and cathepsin L in bronchoalveolar fluid from emphysema patients, possibly pointing to a disease- and not a drug-related phenomenon.
Why might the effect of steroids on cystatin C production by HeLa cells (17) not be demonstrable in our clinical model? One possible explanation is that the nephrotic syndrome might have been associated with an increase in GFR, leading to increased elimination of the excess cystatin C. Although not statistically significant, the Schwartz GFR was indeed highest at manifestation of the nephrotic syndrome (i.e., before initiation of steroid therapy) and slowly decreased during the course of the nephrotic syndrome. However, cystatin C concentrations at presentation were not decreased. In addition, parallel increases in GFR and cystatin C production followed by parallel decreases during the course of the nephrotic syndrome driven by independent processes appear highly unlikely. A second explanation could be the difference in the biological potency of dexamethasone, used in vitro at 10-7 to 10-4 mol/L, and the prednisone doses prescribed for the treatment of nephrotic syndrome. Thus, the in vitro effect might not translate into biochemical changes in vivo. This is supported by a recent study by Risch et al. (12) who demonstrated a reversible increase in serum cystatin C concentrations after injection of 500 mg of methylprednisolone. In the same study, these authors also noted an increase in serum cystatin C in renal transplant recipients who received prednisone at 5–10 mg/day compared with controls on steroid-free medication. This effect was more pronounced at low GFR (increase of 0.20 mg/L at normal GFR vs 1.85 mg/L at a GFR of 20 mL · min-1 · 1.73 m-2). Thus, differences in GFR in the patients studied might explain the apparent disagreement between our two studies.
Unlike cystatin C, ß2-microglobulin concentrations decreased sharply within 1 week of daily corticosteroid therapy and progressively normalized after the prednisone dose was reduced. This probably reflects the antilymphoproliferative effect of corticosteroids on mononuclear cells, which are the principal source of ß2-microglobulin (21). Similarly, gamma irradiation leads to a rapid decrease in serum ß2-microglobulin concentrations (22). In patients with chronic persistent hepatitis, steroid therapy was also associated with a decrease in ß2-microglobulin concentrations (23).
In conclusion, cystatin C serum concentrations remained unaffected by a standardized high-dose corticosteroid therapy in children with corticosteroid-sensitive nephrotic syndrome. This supports its potential as an endogenous marker of GFR. In patients with impaired renal function receiving corticosteroids, especially methylprednisolone pulses, serum cystatin C concentrations may be increased out of proportion to GFR impairment. By contrast, ß2-microglobulin concentrations decreased in a dose-dependent manner, reflecting the production of ß2-microglobulin by mononuclear cells, which limits its use as a GFR marker.
Acknowledgments
We thank Ulla Aberfeld for assistance in sample and data collection. Anke Carstensen, Claudia Blasius, and Ulla Schmitz are kindly acknowledged for performing the laboratory analyses.
References
The following articles in journals at HighWire Press have cited this article:
|
|
 |
|
  A. Bokenkamp, C. A.R.C. Laarman, K. I. Braam, J. A.E. van Wijk, W. A. Kors, M. Kool, J. de Valk, A. A. Bouman, M. D. Spreeuwenberg, and B. Stoffel-Wagner Effect of Corticosteroid Therapy on Low-Molecular Weight Protein Markers of Kidney Function Clin. Chem., December 1, 2007; 53(12): 2219 - 2221. [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Maahs, L. G. Ogden, A. Kretowski, J. K. Snell-Bergeon, G. L. Kinney, T. Berl, and M. Rewers Serum Cystatin C Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals With Type 1 Diabetes Diabetes, November 1, 2007; 56(11): 2774 - 2779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaffanello, M. Franchini, and V. Fanos Is Serum Cystatin-C a Suitable Marker of Renal Function in Children? Ann. Clin. Lab. Sci., January 1, 2007; 37(3): 233 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Poge, T. Gerhardt, A. Bokenkamp, B. Stoffel-Wagner, H.-U. Klehr, T. Sauerbruch, and R. P. Woitas Time course of low molecular weight proteins in the early kidney transplantation period--influence of corticosteroids Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2858 - 2863. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
