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