Serum cystatin C has been recognized as a reliable endogenous index of GFR, since its introduction in 1985 (5
). In addition, more sensitive indicators of GFR or renal function have been identified in a variety of diverse systemic diseases including nephropathy in type 2 diabetes mellitus (8
), hypertensive nephropathy (9
), solid organ transplantation (10
), and coronary angiopathy (11
). Few studies have investigated serum cystatin C as an endogenous marker of renal function in rheumatic diseases other than rheumatoid arthritis (15
). This is the first study to investigate the clinical application of serum cystatin C to assess renal function in gout patients with renal impairment. We found that serum cystatin C is closely associated with serum creatinine and a good potential marker of GFR in gout patients.
Gout is a common, manageable medical disease related to other systemic rheumatic diseases and has a wide spectrum of clinical features, ranging from acute gouty arthritis to chronic tophaceous gout. This disease is frequently associated with hyperuricemia (defined as a serum urate concentration over 7 mg/dL) due to overproduction or underexcretion of urate, or a combination of both. The physician should pay careful attention to the development of associated comorbidities, such as chronic renal diseases, cardiovascular diseases, or metabolic syndrome. Of special clinical interest is the association between gout and chronic renal diseases. However, some debate remains as to whether impairment of renal function is related to complicating factors such as hormonal changes, insulin resistance, therapeutic drugs, and untreated hypertension, or to excessive depositions within renal tissue leading to renal impairment, cell death and tissue hypoxia by hyperuricemia (17
). Talbott and Terplan (18
) presented diverse histopathological findings in the biopsies and autopsy from 279 gout patients, and identified both clinicolaboratory and pathologic findings. Murray and Goldberg (19
) showed that hyperuricemia was a primary cause of chronic interstitial nephritis in a retrospective study of 101 patients. Recent study determined that hyperuricemia may contribute to the development of chronic gouty nephropathy as well as play a crucial role in the progression of renal pathology (17
Until now, traditional measures for assessing renal function such as measuring serum creatinine have been widely used in gout patients, although they have some limitations for accurate estimation of GFR. Here, we evaluated the diagnostic efficacy and accuracy of using serum cystatin C levels to estimate GFR and compared these results to those obtained using traditional renal function indicators such as serum creatinine and Ccr. Analysis for linear associations showed that reciprocal cystatin C levels correlate well with Ccr of 24 hr urine (r=0.702). In addition, the level of cystatin C is better correlated with Ccr than the reciprocal creatinine level (r=0.665) (). Our results from 68 male gout patients indicate that serum cystatin C is a novel and reliable marker of GFR. Zahran et al. (20
) reviewed a number of studies to compare the diagnostic accuracy of serum cystatin C levels and serum creatinine levels in many clinical situations, including transplant patients, patients with native kidney disease, adults with native kidney disease, and pediatric patients with native kidney disease (20
). Their finding that serum cystatin C was superior to serum creatinine remains controversial; many investigators prefer to use serum cystatin C rather than serum creatinine as an index of GFR (1
). Our study found that the diagnostic accuracy of serum cystatin C levels were superior to that of serum creatinine using a ROC curve.
The weaknesses of traditional measures of GFR including serum creatinine have been recognized (1
). Although serum creatinine has became the most popularly used serum marker of renal function, serum creatinine may be unreliable because they are frequently affected by muscle mass, age, gender, and aberrant renal tubular regulation of serum creatinine resulting in an overestimation of GFR. Using serum cystatin C levels has some advantages over serum creatinine and creatinine-based calculated GFR formulas, in that serum cystatin C levels are independent of age, gender, muscle mass, and renal tubular secretion (1
). Tenstad et al. (21
) found that the renal plasma clearance of cystatin C correlated well with GFR using 51
Cr-EDTA with a linear correlation coefficient of 0.99. Given these characteristics, cystatin C can be considered to be an ideal indicator of GFR. The present study also found that serum cystatin C showed a good inverse correlation to Ccr in gout patients (r=0.702, P
It has long been known that cystatin C levels are not highly influenced by confounding factors, such as diet, nutrition, or inflammatory status, whereas measurements for GFR based on creatinine levels, including the MDRD or C&G formulas, have substantial limitations such as age, sex, muscle mass, ethnicity, and methodology of determining serum creatinine level (1
) However, cystatin C production was not thought to be affected by any factors until several authors demonstrated that serum cystatin C could be affected by both rheumatoid factor (22
) and high doses of glucocorticoid (23
). Additionally, indirect evidence, including decreasing cystatin C in asthmathic patients after cyclosporine therapy (24
) and the positive correlation between CRP and cystatin C levels in large populations indicates that inflammatory status may also contribute to changes in serum cystatin C levels (25
). In the present study, we assessed whether certain demographic and clinical factors were correlated with serum cystatin C levels among all enrolled patients. The data from our analyses indicates that the stage of renal disease, the age of patients at the time of study, serum uric acid, and HDL-cholesterol all influence the serum cystatin C level. In addition, allopurinol-treated patients have a tendency to have higher serum cystatin C levels. It may be considered that gout patients with renal impairment have allopurinol rather than benzbromarone as a uric acid lowering agent. Interestingly, our data illustrated a weakly positive association between ESR and serum cystatin C levels. This finding suggests that serum cystatin C can be influenced by inflammatory changes, which is in agreement with results of some previous studies (24
), but in contrast to the data of others (15
). These conflicting results necessitate further investigation into the effects of acute phase reactants such as ESR and CRP on changes in the levels of serum cystatin C. In addition, only age at study was significantly correlated with serum cystatin C at subgroup analysis according to renal function status. This discrepancy between whole enrolled patients and each group patients may be resulted from smallsized populations.
Our study evaluated the diagnostic performance of serum cystatin C using Ccr as a reference GFR, even though the limitations of this technique were highlighted in previous studies (26
). However, Herget-Rosenthal et al. (28
) discussed creatinine clearance for GFR as an equivalent marker of true GFR, likening it to different "gold standard" methods of GFR including inulin, 125
I-iothalamate, and 99m
Tc-DTPA. In their study, cystatin C was found to be an accurate index of GFR in 110 renal transplantation patients. Several studies regarding cystatin C as diagnostic index of renal function in renal transplant patients using Ccr as a reference GFR have been performed, although the accuracy of serum cystatin C and serum creatinine for evaluating GFR differed between the various studies (28
). Finally, some studies have demonstrated similar diagnostic performances of serum cystatin C and serum creatinine levels using different GFR references such as inulin (29
) and 51
Data derived from our cross-sectional study in 68 male gout patients with renal impairment illustrates that the serum cystatin C level is a novel and reliable marker for accurately predicting GFR that is superior to serum creatinine. This is the first study to demonstrate the clinical application of serum cystatin C levels in the field of gout, one of the inflammatory rheumatic diseases. In addition to renal parameters in gout patients, the results of this study revealed an association between non-renal components such as allopurinol use and HDL-cholesterol level and serum cystatin C. In the realm of inflammatory rheumatic diseases such as rheumatoid arthritis and gout, renal issues are continuous and prominent. There are some limitations for this study. The characteristics or patterns of changes of serum cystatin C level were not observed in this study because of limitation of cross-sectional study. And this study could not reveal relationship between serum cystatin C and inflammatory status of acute or interval stage of gout or serologic markers, such as CRP, ESR, or serum amyloid. To overcome these limitations, well-designed longitudinal study for serum cystatin C will be necessary in larger population.
In conclusion, serum cystatin C is a reliable endogenous marker for detection of renal impairment and estimation of true GFR. To conclusively determine the diagnostic value of serum cystatin C levels for monitoring renal function of gouty patients, further prospective studies in a larger study population are needed.