Elsevier

Clinical Biochemistry

Volume 40, Issues 13–14, September 2007, Pages 946-951
Clinical Biochemistry

Increased urinary cystatin C reflects structural and functional renal tubular impairment independent of glomerular filtration rate

https://doi.org/10.1016/j.clinbiochem.2007.04.013Get rights and content

Abstract

Objectives:

The ratio of the urinary mass concentrations of cystatin C and creatinine (UcysC/Ucrea)  11.3 mg/mmol has recently been proposed as an accurate marker for the detection of GFR  60 mL/min/1.73 m2.

Design and methods:

We prospectively evaluated the diagnostic performance of UcysC/Ucrea  11.3 mg/mmol and factors associated with increased UcysC/Ucrea in 72 children and adults with a wide variety of renal disorders. UcysC/Ucrea was calculated, and GFR wad estimated from serum creatinine and cystatin C by equations.

Results:

UcysC/Ucrea  11.3 mg/mmol had a low diagnostic value to detect GFR values  60 mL/min/1.73 m2 estimated by creatinine or cystatin-C-based equations with sensitivities of 72% and 63%, and specificities of 42% and 34%. ROC curves for UcysC/Ucrea to detect GFR  60 mL/min/1.73 m2 confirmed this with AUCs of 0.59 for creatinine and 0.57 for cystatin-C-based equations. Multivariate analysis identified tubular proteinuria, tubulointerstitial disease and heavy proteinuria, but not GFR  60 mL/min/1.73 m2, as factors independently associated with increased UcysC/Ucrea.

Conclusions:

UcysC/Ucrea  11.3 mg/mmol is not an accurate marker to detect GFR  60 mL/min/1.73 m2, but reflects tubular dysfunction and proteinuria due to heavy proteinuria and tubulointerstitial disease.

Introduction

Chronic kidney disease (CKD), defined as a glomerular filtration rate (GFR)  60 mL/min/1.73 m2, is a major health problem worldwide with dramatically rising incidence and prevalence [1], [2]. Especially cardiovascular diseases (CVD), which are closely associated with CKD, have been identified as major causes of morbidity and mortality [3], [4]. CKD and CVD start to have a negative impact already at early stages of CKD [3], [4]. There are interventions available to reduce the enormous morbidity and mortality associated with CKD and CVD, but these interventions need to be initiated early in the course of CKD to be most effective [5]. However, most patients with CKD are only identified or adequately treated with substantial delay [1], [2]. Thus, simple, sensitive and accurate GFR markers are critical for the early detection of GFR reduction  60 mL/min/1.73 m2.

Serum creatinine has been most commonly used to detect reductions in GFR. However, there are major limitations to the use of serum creatinine to estimate GFR and it is insensitive as an early marker of CKD [6], [7]. This has prompted research for better early markers of GFR reduction [7]. Recently, the ratio of the urinary mass concentrations of the low molecular weight (LMW) protein cystatin C and creatinine (UcysC/Ucrea)  0.10 g/g, or  11.3 mg/mmol when converted to SI units has been proposed as a simple, sensitive and accurate marker to detect a GFR reduction  60 mL/min/1.73 m2 [8]. Cystatin C is a 13-kDa cysteine proteinase inhibitor and is produced by all nucleated cells at a constant rate [9]. Cystatin C is almost freely filtered by the glomerulus [10]. In the healthy kidney, urinary cystatin C is almost entirely reabsorbed in the proximal tubule, there is no tubular secretion and it is virtually absent in the final urine like other LMW proteins [10], [11], [12], [13]. Measurement of cystatin C in the urine is highly accurate, precise and rapid with the commercially available, automated nephelometric assay [11]. However, tubular proteinuria may be unreliable as a marker of GFR when heavy proteinuria or tubular injury interferes with tubular absorption of LMW proteins [14], [15], [16]. The purpose of the present study was (i) to prospectively validate the diagnostic performance of UcysC/Ucrea  11.3 mg/mmol to detect a GFR reduction  60 mL/min/1.73 m2, and (ii) to identify factors associated with UcysC/Ucrea  11.3 mg/mmol in a broadly mixed cohort of nephrological patients.

Section snippets

Patients and methods

We prospectively studied serum and urine samples from 72 consecutive patients (16 children and adolescents, 56 adults) with biopsy-proven glomerular (n = 50) or tubulointerstitial diseases (n = 22) who were referred to the two participating nephrological departments for diagnostic purposes from October 2004 to February 2005. Additionally, in 12 patients with minimal change nephropathy serial samples during active disease and in remission were available for a paired analysis. Demographic, clinical

Results

UcysC/Ucrea  11.3 mg/mmol had a low diagnostic value to detect eGFR values  60 mL/min/1.73 m2, regardless whether GFR was estimated by serum creatinine or serum cystatin-C-based equations. Although an increased UcysC/Ucrea ratio had moderate sensitivity to detect a GFR reduction  60 mL/min/1.73 m2, specificity, diagnostic accuracy, positive and negative predictive values were low (Table 3). In keeping with these results, ROC curves of UcysC/Ucrea demonstrated a low diagnostic performance to detect

Discussion

Our results indicate that UcysC/Ucrea  11.3 mg/mmol is not a reliable marker to detect an eGFR  60 mL/min/1.73 m2 calculated by either serum creatinine or cystatin-C-based equations. By contrast, UcysC/Ucrea  11.3 mg/mmol was independently associated with tubular proteinuria, biopsy-proven tubulointerstitial disease and heavy proteinuria. In line with the latter, we observed significantly increased UcysC/Ucrea in patients with minimal change nephropathy and heavy proteinuria in the absence of

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