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Technical Briefs |
Departments of1 Medicine,2 Clinical Biochemistry, and 3 Nuclear Medicine, University of Bonn, Bonn, Germany;
aaddress correspondence to this author at: Medizinische Klinik und Poliklinik I der Universität Bonn, Allgemeine Innere Medizin, Sigmund-Freud-Strasse 25, D 53105 Bonn, Germany; fax 49-228-287-4952, e-mail u.poege{at}uni-bonn.de
Careful monitoring of graft function after renal transplantation (RTx) is necessary for short- and long-term success. Because of the many difficulties in performing serial measurements of glomerular filtration rate (GFR) by use of exogenous substances such as inulin, 51Cr-EDTA, or technetium-diethylenetriaminepentaacetic acid (99mTc-DTPA), graft function is often estimated from serum creatinine concentrations. Tubular secretion as well as various nonrenal factors may alter creatinine concentrations, thus rendering it an imprecise marker for GFR (1). Cystatin C (Cys C) is at least as good as creatinine as a marker of renal function (2)(3)(4), but corticosteroid treatment can alter serum Cys C concentrations (5)(6)(7), making it potentially less useful in RTx patients.
ß-Trace protein (BTP), also known as prostaglandin D synthase, is a 23- to 29-kDa enzyme that has been proposed as an alternative marker for GFR in children and in persons with diabetes or various renal diseases (8)(9)(10)(11), but it has not been examined as an endogenous renal function marker in RTx patients. The aim of this study was to compare the diagnostic performances of BTP, Cys C, and creatinine as estimates of GFR in RTx patients.
We prospectively performed GFR measurements in 85 consecutive RTx patients (34 females and 51 males) who attended our outpatient department. GFR was determined by 99mTc-DTPA clearance with a single-injection technique based on the method described by Russell et al. (12).
Patients included into the study were in "steady-state" conditions, defined as the lack of increases or decreases >15% in creatinine within 2 weeks before and after the investigation.
The mean (SD) patient age was 49.6 (13.3) years (range, 19–72 years), and the time frame of investigation was 75.7 (71.2) months after transplantation (range, 3–240 months; 21 patients within 12 months after RTx, 39 patients at 1 to 10 years after RTx, and 25 patients more than 10 years after RTx).
Immunosuppression was based on a calcineurin inhibitor regimen in 83 patients (51 on cyclosporin A, 32 on tacrolimus). Of these, 81 patients were treated with corticosteroids, and 42 patients also received mycophenolate-mofetil (n = 40) or azathioprine (n = 2). One patient was on sirolimus, mycophenolate-mofetil, and corticosteroids, and another was on sirolimus, tacrolimus, and corticosteroids.
The study was approved by the local ethics boards and was performed in accordance with the ethics guidelines of the revised Helsinki Declaration of 1996. Informed consent was obtained from all patients.
Creatinine, BTP, and Cys C concentrations were measured simultaneously. Serum creatinine was measured by a modification of the Jaffe method according to Knapp and Mayne (13). Cys C and BTP were measured by fully automated latex-enhanced immunonephelometric methods (N Latex Cystatin C and N Latex beta-trace protein; Dade Behring) on a Behring Nephelometer II according to the manufacturer’s instructions (9)(10). Bias was 2.55% (mean, 1.06 mg/L; n = 20) for the Cys C assay and 2.35% for the BTP assay (mean, 1.49 mg/L; n = 20). The within-run imprecision (CV) for the Cys C assay was 3.4% at 1.09 mg/L (n = 20), and the between-run CV was 4.7% at 1.06 mg/L (n = 20). Corresponding values for the BTP assay were 3.6% (at 1.47 mg/L; n = 20) and 4.6% (at 1.49 mg/L; n = 20).
Reference intervals established from a representative cohort of 200 healthy blood donors [100 female; median age, 31 years; 95% confidence interval (CI), 19.0–60.5 years] were 0.48–0.82 mg/L for Cys C, 0.40–0.74 mg/L for BTP, and 53–106 µmol/L for creatinine.
Results are presented as the mean and 95% CI unless indicated otherwise. Statistical analysis was performed with Medcalc® (Ver. 4.2) and StatView® (Ver. 5.0 for Windows; SAS Institute Inc.). P <0.05 (2-tailed) was considered significant.
The mean (95% CI) GFR was 38.6 (35.3–41.9) mL · min–1 · (1.73 m2)–1 in our cohort, and the mean (95% CI) concentrations of plasma BTP, creatinine, and Cys C were 1.59 (1.41–1.76) mg/L, 156 (140–173) µmol/L, and 2.22 (2.00–2.47) mg/L, respectively.
The correlation coefficients for BTP and Cys C with creatinine were 0.86 and 0.82, and that of BTP with Cys C was 0.80. The reciprocals of all analytes correlated significantly with the GFR: r1/BTP = 0.83 (95% CI, 0.75–0.89; P <0.0001); r1/cystatin C = 0.85 (0.78–0.90; P <0.0001); r1/creatinine = 0.88 (0.80–0.91; P <0.0001). These correlation coefficients did not differ significantly.
ROC curve analyses were used to describe the diagnostic performance of creatinine, Cys C, and BTP for detection of renal impairment. The data for GFR cutoffs of 30, 40, 50, and 60 mL · min–1 · (1.73 m2)–1 are given in Table 1
. The areas under the curves (AUCs) were not significantly different. The sensitivities were 73%–94%, and specificities were 85%–100%.
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The highest sensitivity for BTP (85%; 95% CI, 74%–92%) was for detecting a GFR of 50 mL · min–1 · (1.73 m2)–1 with a serum BTP of 1.17 mg/L. The highest specificity for BTP (94%; 95% CI, 80%–99%) was for detecting a GFR <40 mL · min–1 · (1.73 m2)–1 and using a cutpoint of 1.29 mg/L (see Table 1
).
Patients were stratified into 6 renal impairment groups according to the DTPA clearance results: <20, 20–30, 30–40, 40–50, 50–60, and >60 mL · min–1 · (1.73 m2)–1. The relative increases in analytes above the upper reference values determined for each subgroup are shown in Fig. 1
. BTP and Cys C showed a significantly greater proportional increase than creatinine at all selected stages of renal impairment (Fig. 1
; P <0.003 for all groups).
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To evaluate the influence of steroids, we performed a matched-pair analysis of 20 patients in groups A and B with respect to gender, age, weight, and GFR. Group A received 
10 mg of prednisone per day [mean (SD), 14.8 (5.1) mg; n = 10], whereas group B received 5 mg of prednisone per day. Despite the small sample size, the matched-pair analysis showed significantly higher Cys C concentrations in group A [mean (95% CI), 2.86 (1.75–3.98) mg/L] than in group B [2.3 (1.48–3.14) mg/L; P = 0.049]. BTP concentrations were not affected by steroids [1.58 (0.93–2.22) mg/L vs 1.79 (1.21–2.38) mg/L; P = 0.1].
Our data show similar diagnostic performance for BTP, Cys C, and creatinine in RTx patients. In fact, when renal function decreased, BTP and Cys C detected a diminished GFR earlier and increased more prominently than creatinine.
We found only 5 published studies using ROC analyses for evaluation of the diagnostic performance of BTP. BTP was superior to creatinine in 2 investigations in children (8)(14). In adults, at cutoff points of 70 and 80 mL · min–1 · (1.73 m2)–1, the diagnostic performance of BTP was similar to or slightly better than that of creatinine (9)(10)(11). However, none of these investigations showed an advantage of BTP over Cys C, which is in line with our results. In the cited studies, the range of GFR defined as normal was wide, giving decision points of 70–90 mL · min–1 · (1.73 m2)–1. In fact, the mean GFR in our cohort was <40 mL · min–1 · (1.73 m2)–1. Nonetheless, ROC analysis revealed similar AUCs for all tested analytes, irrespective of the cutoff value used.
In accordance with a recent study showing that BTP increased when GFR was <75 mL · min–1 · (1.73 m2)–1 (11), we saw an earlier increase in BTP than creatinine. Because virtually all measured BTP (96.5%) and all Cys C (100%) concentrations were above the upper reference values, in contrast to 75% of creatinine results, we evaluated the impact of concomitant prednisone treatment. We found that steroid maintenance treatment (10 mg/day) was associated with higher Cys C concentrations, whereas we observed no association between steroid dose and BTP concentration.
On the basis of the above results, we believe that BTP may be a useful and reliable analyte to estimate GFR, particularly when RTx patients receive steroids that may falsely increase Cys C concentrations. Thus, despite similar diagnostic sensitivities and specificities, BTP may have a place alongside Cys C and creatinine as an alternative endogenous GFR marker in RTx patients.
References
The following articles in journals at HighWire Press have cited this article:
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  U. Poge, T. Gerhardt, and R. P. Woitas Estimation of Glomerular Filtration Rate by Use of Beta-Trace Protein Clin. Chem., August 1, 2008; 54(8): 1403 - 1405. [Full Text] [PDF]
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 T. Gerhardt, U. Poge, B. Stoffel-Wagner, B. Klein, H.-U. Klehr, T. Sauerbruch, and R. P. Woitas Serum levels of beta-trace protein and its association to diuresis in haemodialysis patients Nephrol. Dial. Transplant., January 1, 2008; 23(1): 309 - 314. [Abstract] [Full Text] [PDF]
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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]
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C. A. White, A. Akbari, S. Doucette, D. Fergusson, N. Hussain, L. Dinh, G. Filler, N. Lepage, and G. A. Knoll A Novel Equation to Estimate Glomerular Filtration Rate Using Beta-Trace Protein Clin. Chem., November 1, 2007; 53(11): 1965 - 1968. [Abstract] [Full Text] [PDF]
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C. White, A. Akbari, N. Hussain, L. Dinh, G. Filler, N. Lepage, and G. A. Knoll Chronic kidney disease stage in renal transplantation classification using cystatin C and creatinine-based equations Nephrol. Dial. Transplant., October 1, 2007; 22(10): 3013 - 3020. [Abstract] [Full Text] [PDF]
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A. R. Huber and L. Risch Recent Developments in the Evaluation of Glomerular Filtration Rate: Is There a Place for {beta}-Trace? Clin. Chem., August 1, 2005; 51(8): 1329 - 1330. [Full Text] [PDF]
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