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1.  Association of serum chemerin levels with the severity of coronary artery disease in patients with metabolic syndrome 
Objectives: The newly identified adipokine chemerin has been shown to be associated with the components of MetS, inflammation and insulin resistance. In this study, the relationship between serum chemerin levels and the presence and severity of coronary artery disease (CAD) was evaluated in patients with MetS. Methods: The study population consisted of 84 MetS patients (43 patients with CAD and 41 without CAD), who had coronary angiography for suspected coronary artery disease, and 46 healthy individuals as a control group. Angiographic CAD was defined as ≥ 50% luminal diameter stenosis of at least one major epicardial coronary artery. The severity of CAD was determined by the Gensini score. Serum chemerin levels were measured with enzyme linked immunosorbent assay (ELISA). Results: Serum chemerin levels were significantly higher in patients with MetS (n=84) than those in the control group (120.47±25.32 vs. 90.4±11.4 ng/ml P < 0.001). In addition, MetS patients with CAD had higher chemerin levels than MetS patients without CAD (128.7±26.6 vs. 115.7±15.2 ng/ml, P < 0.001). Serum chemerin levels had a significant positive correlation with the Gensini score (r=0.58, P < 0.001). Multivariate logistic regression demonstrated that serum high-density lipoprotein cholesterol (HDL-C) and chemerin levels were significant and independent predictors for determining the presence of angiographic CAD (OR=1.009, 95% CI: 0.972-1.057; P=0.003 and OR=0.925, 95% CI: 0.896-0.922; P < 0.001, respectively). Conclusion: This study demonstrated that in patients with MetS, chemerin levels were higher in patients with CAD than patients without CAD and also showed a significant positive correlation with CAD severity.
PMCID: PMC4307503  PMID: 25664056
Chemerin; metabolic syndrome; coronary artery disease; gensini score
2.  Cystatin C is Associated with Inflammation but not Atherosclerosis in Systemic Lupus Erythematosus 
Lupus  2011;21(3):279-287.
Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independent of conventional measures of renal function. We examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis.
We measured serum cystatin C, creatinine, TNF-α, IL-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR) and other clinical parameters in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models.
Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than controls (1.09[Interquartile range, IQR: 0.85–1.28]mg/L vs. 0.89 [IQR: 0.76–0.99]mg/L; P<0.001 after adjusting for age, race and sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (P=0.04), ESR (P<0.001), CRP (P=0.04), TNF-α (P=0.008) and IL-6 (P=0.01) after adjustment for age, race and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, P= 0.31) and the association remained non-significant after adjustment for age, race, sex and Framingham risk score (P=0.99).
Cystatin C was higher in patients with SLE than control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.
PMCID: PMC3275887  PMID: 22072023
cystatin C; systemic lupus erythematosus; renal function; atherosclerosis; Inflammation
3.  Lack of Association between Serum Cystatin C Levels and Coronary Artery Disease in Diabetic Patients 
Korean Diabetes Journal  2010;34(2):95-100.
Serum cystatin C level is a more sensitive marker of renal dysfunction than serum creatinine level. Serum cystatin C level was recently reported to predict the development of cardiovascular disease. This study was performed to evaluate whether the cystatin C level is associated with coronary artery disease (CAD), independent of diabetic nephropathy.
We conducted a case-control study to assess the relationship between serum cystatin C level and coronary artery disease in diabetic patients. Among 460 diabetic patients, 38 diabetic patients had CAD. The control group consisted of 38 diabetic patients who were matched to cases by age, sex, and presence/absence of diabetic nephropathy. Serum cystatin C level was measured in stored samples.
Serum cystatin C level was significantly higher in patients with diabetic nephropathy, both in CAD and non-CAD patients. However, serum cystatin C level did not differ between CAD and non-CAD patients, regardless of diabetic nephropathy.
Serum cystatin C level is a marker of renal dysfunction, but not coronary artery disease, in diabetic patients.
PMCID: PMC2883357  PMID: 20548841
Cystatin C; Coronary artery disease; Diabetic nephropathies; Diabetes mellitus
4.  Association of cystatin C and estimated GFR with inflammatory biomarkers: the Heart and Soul Study 
Cystatin C is a marker of kidney function that may also be associated with inflammation. In this study, we compared the relative strengths of association of cystatin C and estimated glomerular filtration rate (eGFR) with inflammatory biomarkers.
We measured serum cystatin C and creatinine in 990 outpatients with coronary artery disease enrolled in the Heart and Soul Study. GFR was estimated (eGFR) by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. We compared the associations of serum cystatin C and eGFR with C-reactive protein (CRP) and fibrinogen, after adjustment for 24 h creatinine clearance.
Cystatin C concentrations had moderate correlations with CRP (r=0.15, P<0.001) and fibrinogen (r=0.26, P<0.0001); eGFR had similar correlations with CRP (r=−0.17, P=0.01) and fibrinogen (r=−0.25, P<0.001) among persons with eGFR≤60 ml/min, but had no association with either biomarker among those with eGFR>60 ml/min (r=0.04, P=0.32; r=−0.03, P=0.38). Quartiles of cystatin C were strongly and directly associated with CRP (P=0.02) and fibrinogen (P<0.007) after multivariate adjustment. However, these associations disappeared after adjustment for creatinine clearance (P=0.26 and 0.23, respectively).
Cystatin C concentrations have moderate associations with CRP and fibrinogen that are not independent of creatinine clearance. Although a gold standard of kidney function is lacking, this analysis suggests that cystatin C captures an association of mildly impaired kidney function with increased inflammation.
PMCID: PMC2770338  PMID: 17210589
chronic kidney disease; coronary artery disease; C-reactive protein; creatinine clearance; cystatin-C; inflammation
5.  Cystatin C: A Strong Marker for Lower Limb Ischemia in Chinese Type 2 Diabetic Patients? 
PLoS ONE  2013;8(7):e66907.
Cystatin C is growing to be an ideal indicator for renal function and cardiovascular events. The aim of this study was to investigate the relationship between serum cystatin C levels and peripheral arterial disease and to explore its diagnostic value for lower limb ischemia (LLI) in type 2 diabetic population.
A total of 1609 T2DM patients were included in this cross-sectional study. Their clinical and biochemical characteristics, ankle-brachial index (ABI), carotid and lower extremity arterial ultrasound were detected. LLI was defined by ABI <0.9 and lower extremity arterial stenosis >50% by ultrasound examination. Patients were divided to two groups: with LLI and without. The risk factors of LLI were explored by binary logistic regression analysis.
The serum concentrations of cystatin C were 1.53±0.60 and 1.08±0.30 mg/L in patients with and without LLI, respectively. Binary logistic regression analysis showed that the significant risk factors were cystatin C (P = 0.007, OR = 5.081), the presence of hypertension (P = 0.011, OR = 3.527), age (P<0.001, OR = 1.181), GA (P = 0.002, OR = 1.089) and diabetes duration (P = 0.008, OR = 1.074). The prevalence of coronary artery disease, cerebral infarction and LLI increased with cystatin C (P<0.01), and the prevalence of LLI in patients with cystatin C >1.2 mg/L was much higher than other three quartile groups. Receiver operating characteristic curve analysis revealed the cut point of cystatin C for LLI was 1.2 mg/L. The risk of LLI dramatically increased in patients with cystatin C >1.2 mg/L (OR = 21.793, 95% confidence interval 10.046−47.280, P<0.001). After adjusting for sex, age, duration, HbA1c, GA and hypertension, its OR still remained 3.395 (95% confidence interval 1.335–8.634).
There was a strong and independent association between cystatin C and limb arterial disease in diabetic population, and cystatin C >1.2 mg/L indicated a great increased risk of LLI.
PMCID: PMC3699611  PMID: 23843968
6.  Exercise electrocardiographic responses and serum cystatin C levels among metabolic syndrome patients without overt diabetes mellitus 
An impaired heart rate response during exercise (chronotropic incompetence) and an impaired heart rate recovery (HRR) after exercise are predictors of cardiovascular risk and mortality. Cystatin C is a novel marker for cardiovascular disease. We aimed to investigate exercise electrocardiographic responses in patients with metabolic syndrome who were without overt diabetes mellitus, in addition to the association of serum cystatin C levels with the exercise electrocardiographic test results.
Forty-three consecutive patients admitted to a cardiology outpatient clinic without angina pectoris were recruited if they met criteria for metabolic syndrome but did not have overt diabetes mellitus. Serum cystatin C levels were measured, and all participants underwent exercise electrocardiographic testing. Patients who were found to have ischemia had a coronary angiography procedure.
The mean cystatin C level of patients was higher in metabolic syndrome group than healthy controls (610.1 ± 334.02 vs 337.3 ± 111.01 μg/L; P < 0.001). The percentage of patients with ischemia confirmed by coronary angiography was 13.9% in the metabolic syndrome group. Cystatin C levels in the ischemic patients of the metabolic syndrome group were higher than that in nonischemic patients (957.00 ± 375.6 vs 553.8 ± 295.3 μg/L; P = 0.005). Chronotropic incompetence was observed in 30.2% of the patients with metabolic syndrome compared with 16.7% in the control group (P = 0.186). Chronotropic response indices were 0.8 ± 0.18 versus 0.9 ± 0.10 for the two groups, respectively (P = 0.259). HRR was significantly lower in the metabolic syndrome patients compared with the controls (20.1 ± 8.01 vs 25.2 ± 4.5 per min; P < 0.001), and the ST-segment adjustment relative to heart rate(ST/HR index ratio) was 1.4 ± 1.34 versus 0.4 ± 0.31 μV/beat (P < 0.001), respectively. Cystatin C was negatively correlated with the chronotropic response index (CRI) and HRR and was positively correlated with ST/HR index in the entire study population (R = −0.658, −0.346, 0.388, respectively; P < 0.05).
A substantial proportion of metabolic syndrome patients without overt diabetes mellitus had silent coronary ischemia in addition to impairment of objective exercise electrocardiographic parameters. In the metabolic syndrome patients without overt diabetes mellitus, cystatin C levels were found to be elevated and the elevation was more pronounced in the subgroup with silent ischemia. Cystatin C was also correlated with HRR and CRI.
PMCID: PMC3049540  PMID: 21415918
exercise electrocardiography; metabolic syndrome; silent ischemia; cystatin C
7.  Cystatin C as an Early Biomarker of Nephropathy in Patients with Type 2 Diabetes 
Journal of Korean Medical Science  2011;26(2):258-263.
This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m2 estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m2 estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.
PMCID: PMC3031011  PMID: 21286018
Cystatin C; Diabetic Nephropathies; Albuminuria
8.  Association of Cystatin C With Poor Exercise Capacity and Heart Rate Recovery: Data From the Heart and Soul Study 
Cystatin C, an alternative serum measure of kidney function, is a stronger predictor of cardiovascular events than creatinine or estimated glomerular filtration rate (eGFR). We hypothesized that serum cystatin C concentration would have a stronger more linear association with cardiovascular functional status than creatinine-based measures in outpatients with established coronary heart disease (CHD).
We measured serum cystatin C, serum creatinine, and eGFR in 906 outpatients with established CHD. We examined the association of these 3 measures of kidney function with treadmill exercise capacity (metabolic equivalent tasks achieved) and heart rate recovery (HRR) between peak and 1 minute after exercise by using linear and logistic regression.
Higher cystatin C concentrations were associated linearly with worse treadmill exercise capacity and HRR. The proportion of participants with poor exercise capacity (metabolic equivalent tasks achieved < 5) was 45% (99 of 222 participants) among those with cystatin C levels in the highest quartile (>1.30 mg/L) compared with 12% (29 of 241 participants) among those with cystatin C levels in the lowest quartile (<0.92 mg/L; adjusted odds ratio, 3.2; 95% confidence interval, 1.6 to 6.5; P = 0.001). The proportion of participants with poor HRR (<16 beats/min) was 42% (92 of 214 participants) among those with cystatin C levels in the highest quartile compared with 16% (37 of 238 participants) among those with cystatin C levels in the lowest quartile (adjusted odds ratio, 2.2; 95% confidence interval, 1.2 to 4.0; P = 0.01). The lowest quartile of eGFR (<61.8 mL/min [<1.03 mL/s]) was associated with decreased exercise capacity and prolonged HRR, but no difference was observed across the upper 3 quartiles of eGFR.
In patients with established CHD, cystatin C concentrations are associated linearly with worse exercise capacity and HRR. Cystatin C detects an association of impaired kidney function with decreased HRR and exercise capacity that is not fully captured using creatinine-based measurements.
PMCID: PMC2770341  PMID: 17336697
Coronary artery disease; cystatin C; creatinine; renal function; exercise capacity; heart rate recovery
9.  Serum Cystatin C is a Potential Endogenous Marker for the Estimation of Renal Function in Male Gout Patients with Renal Impairment 
Serum creatinine level is the most commonly used indices for assessment of glomerular filtration rate (GFR), even though these indices have been shown to have some limitations in clinical practice. We investigated the diagnostic efficacy of serum cystatin C compared to that of serum creatinine levels and identified the relating factors associated with changes in serum cystatin C levels in gout patients with renal impairment. A total of 68 gouty patients with renal impairment were enrolled in this study. Diagnostic efficacy of serum cystatin C levels was evaluated through non-parametric receiver operating characteristic (ROC) analysis. The risk factors for changes in serum cystatin C levels were confirmed using multivariate regression analysis. With 24-hr urine creatinine clearance (Ccr) as the reference for GFR, 1/cystatin C (r=0.702, P<0.001) showed a significantly higher correlation with Ccr than 1/creatinine (r=0.665, P<0.001). Multivariate correlation analysis demonstrated that the clinical parameters for increased serum cystatin C are a higher stage of chronic kidney disease, older age, use of allopurinol, and lower high density lipoprotein-cholesterol. The area under the curve (AUC) at ROC plots identified that of serum cystatin C was significantly greater than that of serum creatinine (AUC 0.804 of cystatin C and AUC 0.745 of creatinine). The study suggests that serum cystatin C is a reliable endogenous marker for the assessment of renal function or GFR in gout patients with renal impairment.
PMCID: PMC2800003  PMID: 20052346
Cystatin C; Gout; Creatinine; Kidney Failure; Glomerular Filtration Rate
10.  Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver 
Gut  2002;50(1):106-110.
Background and aims: Diagnosis of moderately impaired renal function is of particular importance in patients with cirrhosis of the liver. Whereas patients with a markedly impaired glomerular filtration rate can be diagnosed easily by elevated serum creatinine concentrations, moderately reduced renal function may be missed by this conventional parameter. Recently, cystatin C has been suggested as a sensitive marker of renal function, independent of sex or muscle mass. Therefore, the aim of this study was to investigate the value of serum cystatin C concentration for the detection of moderately impaired renal function.
Methods: Ninety seven inhospital patients with cirrhosis and a 24 hour creatinine clearance of at least 40 ml/min were investigated and divided into group 1 (creatinine clearance ≥70 ml/min; n=55) and group 2 (creatinine clearance 40–69 ml/min; n=42).
Results: Serum cystatin C concentrations (mean (SD): 1.31 (0.51) v 1.04 (0.34) mg/l (p=0.008)) and creatinine concentrations (1.03 (0.52) v 0.86 (0.22) mg/100 ml (p=0.03)) were higher in group 2 than in group 1; there was no significant difference in urea concentrations. Receiver-operator characteristics (ROC) revealed a differential diagnostic advantage of cystatin C over creatinine and urea. At cut off concentrations of 1.0 mg/l, 0.9 mg/100 ml, and 28 mg/100 ml, respectively, cystatin C, creatinine, and urea exhibited 69%, 45%, and 44% sensitivity (p<0.05). As patients with a small muscle mass or reduced physical activity could be particularly prone to overestimation of their renal function, separate analyses were performed for the subgroups of female and Child-Pugh class C patients, respectively. In both groups, discrimination between patients with moderately impaired and normal renal function was best with cystatin C. In female patients, sensitivity of cystatin C (77.8%) was superior (p<0.05) to that of creatinine (38.9%) and urea (41.2%). In Child-Pugh C patients, the ROC curve was significantly better for cystatin C than for creatinine.
Conclusions: Serum cystatin C determination could be a valuable tool in patients with cirrhosis, particularly with Child-Pugh class C or in female patients, for early diagnosis of moderately impaired renal function.
PMCID: PMC1773066  PMID: 11772976
creatinine clearance; urea; creatinine; glomerular filtration rate
11.  Association of renal function with cardiac calcifications in older adults: the cardiovascular health study 
Background. Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.
Methods. From the Cardiovascular Health Study, a community-based cohort of ambulatory adults ≥ age 65, a total of 3929 individuals (mean ± SD age 74 ± 5 years, 60% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.
Results. The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m2 (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m2 was significantly associated with MAC [odds ratio 1.54 (95% CI 1.16–2.06), P = 0.003] and not associated with AAC [1.30 (0.97–1.74), P = 0.085] and AVS [1.15 (0.86–1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05–1.21), P = 0.001] and not associated with AAC [1.07 (1.00–1.15), P = 0.054] and AVS [0.99 (0.93–1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m2 and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m2, increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).
Conclusions. In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m2 and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m2, increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.
PMCID: PMC2721419  PMID: 18840892
chronic kidney disease; cohort; creatinine; cystatin C; elderly
12.  Longitudinal study of Cystatin C in healthy term newborns 
Clinics  2011;66(2):217-220.
The purpose of this study was to determine the levels of Cystatin C in healthy term newborns in the first month of life.
Cystatin C may be a suitable marker for determining the glomerular filtration rate because it is not affected by maternal renal function.
Cohort study. Inclusion: term newborns with appropriate weight; mother without renal failure or drugs that could affect fetal glomerular filtration rate. Exclusion: malformations; hypertension or any condition that could affect glomerular filtration rate. Cystatin C (mg/L) and creatinine (mg/dl) were determined in the mother (Mo) and in the newborn at birth (Day‐0), 3rd (Day‐3), 7th(Day‐7) and 28th(Day‐28) days. Statistics: one way ANOVA and Pearson's correlation tests. Sample size of 20 subjects for α  =  5% and a power test  =  80% (p<0.05).
Data from 21 newborns were obtained (mean ± standard deviation): MoCystatin C = 1.00±0.20; Day‐0 Cystatin C 1.70±0.26; Day‐3 Cystatin C = 1.51±0.20; Day‐7 Cystatin C = 1.54±0.10; Day‐28 Cystatin C = 1.51±0.10.
MoCystatin C was smaller than Day‐0 Cystatin C (p<0.001), while MoCreatinine was not different from Day‐0 Creatinine. Cystatin C only decreased from Day‐0 to Day‐3 (p = 0.004) but newborns Creatinine decreased along the time. Correlations were obtained between MoCystatin C and MoCreatinine (p = 0.012), as well as Day‐3 (p = 0.047) and Day‐28 (p = 0.022) Cystatin C and Creatinine values.
Neonatal Cystatin C values were not affected by MoCystatin C and became stable from the 3rd day of life.
PMCID: PMC3061410  PMID: 21484036
Serum Cystatin C; Glomerular filtration rate; Serum creatinine; Reference values; Infant newborn
13.  Early Trends in Cystatin C and Outcomes in Patients with Cirrhosis and Acute Kidney Injury 
Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr−/CysC−); only cystatin increased 25 (24%) (Scr−/CysC+); only creatinine increased 15 (14%) (Scr+/CysC−); and both increased 28 (26%) (Scr+/CysC+). With Scr−/CysC− as the reference, in both instances where cystatin rose, Scr−/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, P = 0.02 and 0.03, respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes.
PMCID: PMC3976933  PMID: 24757564
14.  Cystatin C and Carotid Intima-Media Thickness in Asymptomatic Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Persons with early kidney disease have an increased risk of cardiovascular events and mortality, but the importance of accelerated atherosclerosis in promoting these outcomes is unclear. We therefore explored whether serum cystatin C level is associated with carotid intima-media thickness (IMT) in ambulatory adults without clinical heart disease.
Study Design
Cross-sectional study.
Setting & Participants
We evaluated 6,557 ethnically diverse persons free of clinical cardiovascular disease aged 45 to 84 years at the baseline visit of the Multi-Ethnic Study of Atherosclerosis.
Kidney function was estimated by using 2 methods: serum cystatin C level and estimated glomerular filtration rate, based on creatinine and cystatin C levels.
Outcomes & Measurements
Study outcomes were internal and common carotid IMT, measured by using high-resolution B-mode ultrasound. Multivariate linear and logistic regressions were used to evaluate the independent association of kidney function with carotid IMT.
In unadjusted linear analysis, each SD (0.23 mg/L) greater cystatin C level was associated with 0.091-mm greater internal carotid IMT (P < 0.001), but this association was diminished by 70% after adjustment for age, sex, and race/ethnicity (0.027 mm; P < 0.001) and was no longer significant after adjustment for cardiovascular risk factors (0.005 mm; P = 0.5). Similarly, the strong unadjusted associations of cystatin C level with common carotid IMT disappeared after adjustment. Chronic kidney disease, defined by using either creatinine level or cystatin C–based estimated glomerular filtration rate less than 60 mL/min/1.73 m2, had no independent association with internal and common carotid IMT.
There were few participants with severe kidney disease.
Cystatin C level had no independent association with carotid IMT in a population free of clinical heart disease. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.
PMCID: PMC3046734  PMID: 18823684
Cystatin C; intima-media thickness (IMT); atherosclerosis; cardiovascular diseases; kidney
15.  Cystatin C, a novel indicator of renal function, reflects severity of cerebral microbleeds 
BMC Neurology  2014;14:127.
Chronic renal insufficiency, diagnosed using creatinine based estimated glomerular filtration rate (GFR) or microalbumiuria, has been associated with the presence of cerebral microbleeds (CMBs). Cystatin C has been shown to be a more sensitive renal indicator than conventional renal markers. Under the assumption that similar pathologic mechanisms of the small vessel exist in the brain and kidney, we hypothesized that the levels of cystatin C may delineate the relationship between CMBs and renal insufficiency by detecting subclinical kidney dysfunction, which may be underestimated by other indicators, and thus reflect the severity of CMBs more accurately.
Data was prospectively collected for 683 patients with ischemic stroke. The severity of CMBs was categorized by the number of lesions. Patients were divided into quartiles of cystatin C, estimated GFR and microalbumin/creatinine ratios. Ordinal logistic regression analysis was used to examine the association of each renal indicator with CMBs.
In models including both quartiles of cystatin C and estimated GFR, only cystatin C quartiles were significant (the highest vs. the lowest, adjusted OR, 1.88; 95% CI 1.05-3.38; p = 0.03) in contrast to estimated GFR (the highest vs. the lowest, adjusted OR, 1.28; 95% CI 0.38-4.36; p = 0.70). A model including both quartiles of cystatin C and microalbumin/creatinine ratio also showed that only cystatin C quartiles was associated with CMBs (the highest vs. the lowest, adjusted OR, 2.06; 95% CI 1.07-3.94; p = 0.03). These associations were also observed in the logistic models using log transformed-cystatin C, albumin/creatinine ratio and estimated GFR as continuous variables. Cystatin C was a significant indicator of deep or infratenorial CMBs, but not strictly lobar CMBs. In addition, cystatin C showed the greatest significance in c-statistics for the presence of CMBs (AUC = 0.73 ± 0.03; 95% CI 0.66-0.76; p = 0.02).
Cystatin C may be the most sensitive indicator of CMB severity among the renal disease markers.
PMCID: PMC4077563  PMID: 24925313
Cystatin C; Estimated glomerular filtration rate; Microalbuminuria; Cerebral microbleeds
16.  Correlation analysis between eGFRcys and SXscore in patients with diabetes 
The aim of the present study was to explore the association between the cystatin C-based estimated glomerular filtration rate (eGFRcys) and the SYNTAX score (SXscore) in patients with diabetes. To the best of our knowledge, this correlation has not been reported previously. The eGFRcys and SXscore from 612 consecutive patients with diabetes were retrospectively included in this study. The patients were angiographically diagnosed with coronary artery disease (CAD) between July 2010 and March 2012 at the Department of Endocrinology. The SXscore was calculated using a previously described SXscore algorithm. Pearson correlations were used to analyze the correlation between eGFRcys and SXscore. Patients with renal dysfunction were older, more often female and more likely to have a history of hypertension when compared with those with normal renal function. The eGFRcys values were significantly lower and the cystatin C levels were significantly higher in the highest SXscore group than those in other groups (P<0.001). Correlation analysis indicated that eGFRcys was negatively correlated with the SXscore (r=−0.7918, P<0.001). In addition, a significantly positive correlation was identified between levels of cystatin C and the SXscore (r=0.8891, P<0.001). In conclusion, eGFRcys is an independent predictor of SXscore in patients with diabetes. The eGFRcys-estimating method may be considered important in the assessment of the SXscore in patients with diabetes.
PMCID: PMC3961135  PMID: 24669241
glomerular filtration rate; cystatin C; SYNTAX score; diabetes
17.  Differential Estimation of Chronic Kidney Disease Using Cystatin C Versus Creatinine-based Estimating Equations by Category of Body Mass Index 
Adiposity is associated with cystatin C. Cystatin C-based glomerular filtration rate (GFR) equations may result in the over-estimation of chronic kidney disease (CKD) prevalence at higher body mass index (BMI) levels.
Study Design
Setting and Participants
6,709 US adult NHANES III participants.
Body mass index
Absolute percent difference in the prevalence of stage 3 or 4 CKD between creatinine- and cystatin C-based estimating equations by level of BMI.
Normal weight, overweight, and obesity were defined as BMI levels of 18.5 to <25.0, 25 to <30.0, and ≥30 kg/m2, respectively. Stage 3 or 4 CKD (eGFR of 15 to 59 ml/min/1.73m2) was defined using the abbreviated creatinine-based Modification of Diet in Renal Disease equation (eGFRMDRD); a cystatin C, age, sex, and race equation (eGFRCysC,age,sex,race); a cystatin C only equation (eGFRCysC); cystatin C≥1.12 mg/L (elevated cystatin C); and an equation incorporating serum creatinine, cystatin C, age, sex, and race (eGFRCr,CysC,age,sex,race).
The differences in stage 3 or 4 CKD prevalence between eGFRCysC,age,sex,race, eGFRCysC, and elevated cystatin C, separately, and eGFRMDRD were larger at higher BMI levels. Specifically, compared to estimates derived using eGFRMDRD, for normal weight, overweight, and obese participants, the prevalence of stage 3 or 4 CKD was 2.1%, 3.0%, and 6.5% higher, respectively, when estimated by eGFRCysC,age,sex,race (p-trend=0.005); 0.1%, 0.6%, 2.2% higher, respectively, for eGFRCysC (p-trend=0.028); 2.9%, 5.2%, and 9.5% higher, respectively, for elevated cystatin C (p-trend<0.001); and −0.1%, −0.4%, and 0.0% higher, respectively, for eGFRCr,CysC,age,sex,race (p-trend=0.719).
No gold standard measure of GFR was available.
BMI may influence the prevalence of stage 3 or 4 CKD when cystatin C-based equations are used.
PMCID: PMC3028436  PMID: 19394726
18.  Serum cystatin C is a sensitive early marker for changes in the glomerular filtration rate in patients undergoing laparoscopic surgery 
Clinics  2014;69(6):378-383.
Pneumoperitoneum during laparoscopy results in transient oliguria and decreased glomerular filtration and renal blood flow. The presence of oliguria and elevated serum creatinine is suggestive of acute renal injury. Serum cystatin C has been described as a new marker for the detection of this type of injury. In this study, our aim was to compare the glomerular filtration rate estimated using cystatin C levels with the rate estimated using serum creatinine in patients with normal renal function who were undergoing laparoscopic surgery.
In total, 41 patients undergoing laparoscopic cholecystectomy or hiatoplasty were recruited for the study. Blood samples were collected at three time intervals: first, before intubation (T1); second, 30 minutes after the establishment of pneumoperitoneum (T2); and third, 30 minutes after deflation of the pneumoperitoneum (T3). These blood samples were then analyzed for serum cystatin C, creatinine, and vasopressin. The Larsson formula was used to calculate the glomerular filtration rate based on the serum cystatin C levels, and the Cockcroft-Gault formula was used to calculate the glomerular filtration rate according to the serum creatinine levels.
Serum cystatin C levels increased during the study (T1 = T2T3; p<0.05). The calculated eGlomerular filtration rate-Larsson decreased, whereas the eGlomerular filtration rate-Cockcroft-Gault increased. There was no correlation between cystatin C and serum creatinine. Additionally, Pearson's analysis showed a better correlation between serum cystatin C and the eGlomerular filtration rate than between serum creatinine and the eGlomerular filtration rate.
This study demonstrates that serum cystatin C is a more sensitive indicator of changes in the glomerular filtration rate than serum creatinine is in patients with normal renal function who are undergoing laparoscopic procedures.
PMCID: PMC4050320  PMID: 24964300
Cystatin C; Creatinine; Glomerular Filtration Rate; Laparoscopy
19.  Combined Association of Albuminuria and Cystatin C–Based Estimated GFR With Mortality, Coronary Heart Disease, and Heart Failure Outcomes: The Atherosclerosis Risk in Communities (ARIC) Study 
Serum cystatin C level has been shown to have a stronger association with clinical outcomes than serum creatinine level. However, little is known about the combined association of cystatin C–based estimated glomerular filtration rate (eGFRcys) and albuminuria with clinical outcomes, particularly at levels lower than current chronic kidney disease (CKD) cutoffs.
Study Design
Prospective cohort.
Setting & Participants
10,403 ARIC (Atherosclerosis Risk in Communities) Study participants followed up for a median of 10.2 years.
eGFRcys, albuminuria.
Mortality, coronary heart disease (CHD), and heart failure, as well as a composite of any of these separate outcomes.
Both decreased eGFRcys and albuminuria were associated independently with the composite outcome, as well as mortality, CHD, and heart failure. Although eGFRcys of 75-89 mL/min/1.73 m2 in the absence of albuminuria (albumin-creatinine ratio [ACR] <10 mg/g) or albuminuria with ACR of 10-29 mg/g with normal eGFRcys (90-104 mL/min/1.73 m2) was not associated significantly with any outcome compared with eGFRcys of 90-104 mL/min/1.73 m2 and ACR <10 mg/g, the risk of each outcome was significantly higher in those with both eGFRcys of 75-89 mL/min/1.73 m2 and ACR of 10-29 mg/g (for mortality, HR of 1.4 [95% CI, 1.1-2.0]; for CHD, HR of 1.9 [95% CI, 1.4-2.6]; for heart failure, HR of 1.8 [95% CI, 1.2-2.7]). Combining the 2 markers improved risk classification for all outcomes (P < 0.001), even in those without overt CKD.
Only one measurement of cystatin C.
Mildly decreased eGFRcys and mild albuminuria independently contributed to the risk of mortality, CHD, and heart failure. Even minimally decreased eGFRcys (75-89 mL/min/1.73 m2) is associated with increased risk in the presence of mild albuminuria. Combining the 2 markers is useful for improved risk stratification even in those without clinical CKD.
PMCID: PMC3582350  PMID: 22537422
Epidemiology; kidney; outcomes
20.  Metabolic abnormalities associated with elevated serum cystatin C in adults with an estimated GFR ≥ 60 ml/min/1.73m2 
Kidney international  2009;76(1):81-88.
Elevated serum cystatin C may represent an early stage of kidney disease. It is unclear whether metabolic abnormalities typically seen in advanced chronic kidney disease are present in adults with estimated glomerular filtration rate ≥60 ml/min/1.73m2 and elevated cystatin C. Participants of the Third National Health and Nutrition Examination Survey (n=6722) were categorized into three groups: estimated glomerular filtration rate ≥ 60 ml/min/1.73m2 and cystatin C <1.09 mg/L (normal cystatin C); estimated glomerular filtration rate ≥60 ml/min/1.73m2 and cystatin C ≥1.09 mg/L (elevated cystatin C); and estimated glomerular filtration rate of 15-59 ml/min/1.73m2 (stage 3 or 4 chronic kidney disease). Among those with normal cystatin C, elevated cystatin C, and stage 3 or 4 chronic kidney disease, the age, race-ethnicity, sex standardized prevalence of serum hemoglobin <12 g/dL (<13 g/dL for men) was 4.3%, 8.2%, and 13.8%; serum uric acid ≥ 5.9 mg/dL (≥7.4 mg/dL for men) was 12.6%, 30.0%, and 45.0%; serum homocysteine ≥13 μmol/L was 12.1%, 25.1%, and 41.0%; serum phosphorus ≥3.9 mg/dL was 17.2%, 23.2%, and 25.8%; serum albumin <3.8 mg/dL was 14.5%, 20.0%, and 20.4%; plasma fibrinogen ≥352 mg/dL was 10.5%, 21.7%, and 23.2%; and C-reactive protein ≥1.0 g/dL was 7.5%, 22.5%, and 21.6% (each p-trend<0.001). Among adults with estimated glomerular filtration rate ≥60 ml/min/1.73m2, elevated serum cystatin C is associated with an increased prevalence of several metabolic abnormalities.
PMCID: PMC3049931  PMID: 19295502
21.  Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients 
Critical Care  2005;9(2):R139-R143.
In critically ill patients sudden changes in glomerular filtration rate (GFR) are not instantly followed by parallel changes in serum creatinine. The aim of the present study was to analyze the utility of serum cystatin C as a marker of renal function in these patients.
Serum creatinine, serum cystatin C and 24-hour creatinine clearance (CCr) were determined in 50 critically ill patients (age 21–86 years; mean Acute Physiology and Chronic Health Evaluation II score 20 ± 9). They did not have chronic renal failure but were at risk for developing renal dysfunction. Serum cystatin C was measured using particle enhanced immunonephelometry. Twenty-four-hour body surface adjusted CCr was used as a control because it is the 'gold standard' for determining GFR.
Serum creatinine, serum cystatin C and CCr (mean ± standard deviation [range]) were 1.00 ± 0.85 mg/dl (0.40–5.61 mg/dl), 1.19 ± 0.79 mg/l (0.49–4.70 mg/l), and 92.74 ± 52.74 ml/min per 1.73 m2 (8.17–233.21 ml/min per 1.73 m2), respectively. Our data showed that serum cystatin C correlated better with GFR than did creatinine (1/cystatin C versus CCr: r = 0.832, P < 0.001; 1/creatinine versus CCr: r = 0.426, P = 0.002). Cystatin C was diagnostically superior to creatinine (area under the curve [AUC] for cystatin C 0.927, 95% confidence interval 86.1–99.4; AUC for creatinine 0.694, 95% confidence interval 54.1–84.6). Half of the patients had acute renal dysfunction. Only five (20%) of these 25 patients had elevated serum creatinine, whereas 76% had elevated serum cystatin C levels (P = 0.032).
Cystatin C is an accurate marker of subtle changes in GFR, and it may be superior to creatinine when assessing this parameter in clinical practice in critically ill patients.
PMCID: PMC1175926  PMID: 15774046
22.  Serum cystatin C is a poor biomarker for diagnosing acute kidney injury in critically-ill children 
Accurate diagnosis of acute kidney injury (AKI) is problematic especially in critically-ill patients in whom renal function is in an unsteady state.
Our aim was to evaluate the role of serum (S.) cystatin C as an early biomarker of AKI in critically-ill children.
Subjects and Methods:
S. creatinine and S. cystatin C were measured in 32 critically-ill children who were at risk for developing AKI. AKI was defined by both: Risk,-injury,-failure,-loss, and-endstage renal disease (RIFLE) classification and glomerular filtration rate (GFR) <80 ml/min/1.73 m2. GFR was estimated by both Schwartz formula and S. cystatin C-based equation.
S. cystatin C was not statistically higher in AKI patients compared with non-AKI by RIFLE classification (median 1.48 mg/l vs. 1.16 mg/l, P = 0.1) while S. creatinine was significantly higher (median 0.8 mg/dl vs. 0.4 mg/dl, P = 0.001). On estimating GFR by the two equations we found, a lag between rise of S. cystatin C and creatinine denoted by lower GFR by Schwartz formula in four patients, on other hand, six patients had elevated S. cystatin C with low GFR despite normal creatinine and GFR, denoting poor concordance between the two equations and the two markers. The ability of S. creatinine in predicting AKI was superior to S. cystatin with area under the curve (AUC) 0.95 with sensitivity and specificity (100% and 84.6%, respectively) using the RIFLE classification. The same findings were found when using Schwartz formula.
S. cystatin C is a poor biomarker for diagnosing AKI in critically-ill children.
PMCID: PMC3752874  PMID: 23983414
Cystatin C; risk-injury-failure-loss-end stage renal disease criteria; schwartz formula
23.  Serum Cystatin-C Is Not Superior to Serum Creatinine in Predicting Glomerular Filtration Rate in Cirrhotic Patients 
Assessment of glomerular filtration rate (GFR) by common creatininebased methods is potentially inaccurate in patients with cirrhosis. Cirrhotic patients have several underlying conditions that contribute to falsely low serum creatinine concentrations, even in the presence of moderate to severe renal impairment. Therefore creatinine-based methods usually overestimate true GFR in these patients. Cystatin-C is a low molecular weight protein and an endogenous marker of GFR. We compared the accuracy of plasma cystatin-C and creatinine in assessing renal function in cirrhotic patients.
We serially enrolled cirrhotic patients with stable renal function admitted in our ward if they met the inclusion criteria and consented to participate. Child-Pugh (CP) score was calculated for all patients. GFR was calculated using serum creatinine, serum cystatin-C, and 99m TC-DTPA clearance with the last one serving as the gold standard. The area under curve (AUC) on receiveroperating characteristic curves (ROC) were used to assess the diagnostic accuracy of each calculated GFR with that measured by DTPA.
Fourty-eight patients were enrolled (32 males, 66.7%). Nine were in class-A, 20 in class-B and 19 in class-C of CP. Cystatin-C did not perform well in predicting the true GFR, while serum creatinine performed relatively accurately at GFR<80ml/min (AUC=0.764, p=0.004). Serum creatinine at a cutoff of 1.4 mg/dl was 20% sensitive & 92% specific and with at a cutoff of 0.9 mg/dl was 77%sensitive & 72% specific for diagnosis of impaired renal function. Cystatin-C could not predict GFR effectively even after stratification for CP score, gender, and BMI. Serum creatinine could predict GFR<65ml/min in females (ROC curve AUC=0.844, p=0.045). In those with BMI>20 kg/m2 a GFR<80 ml/min could also be predicted by serum creatinine (ROC curve AUC=0.739, p=0.034). It also could predict GFR<80ml/min in patients with CP class A & B (ROC curve AUC=0.795, p=0.01), but not in patients with CP class C.
Neither serum creatinine nor Cystatin-C are good predictors of GFR in cirrhotic patients, although serum creatinine seems to perform better in selected subgroups.
PMCID: PMC3990151  PMID: 24829693
Creatinine; Cystatin-C; Glomerular filtration rate (GFR); Cirrhosis
24.  Association of Cystatin C with Ischemia in Patients with Coronary Heart Disease 
Clinical cardiology  2009;32(11):E18.
Elevated concentrations of cystatin C are associated with greater cardiovascular morbidity and mortality. We sought to determine whether elevated concentrations of cystatin C were associated with inducible ischemia in patients with coronary heart disease (CHD).
We measured serum cystatin C and performed exercise treadmill testing with stress echocardiography in a cross-sectional study of 899 outpatients with CHD.
Among the 241 participants in the highest quartile of cystatin C (>1.30 mg/L), 38% had inducible ischemia, compared with 13% of those in the lowest quartile of cystatin C <0.92 mg/L; adjusted odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.2 to 3.8; p = 0.01). However, this association differed in participants with and without a history of coronary artery bypass graft (CABG), as well as in users and nonusers of beta-blockers and statins (p values for interaction <0.1). Among participants without a history of CABG, 35% of those in the highest quartile and 9% of those in the lowest quartile of cystatin C had inducible ischemia (adjusted OR: 3.05; 95% CI: 1.3–6.9; p = 0.008). Among participants who were not using beta-blockers, 44% of those in the highest quartile and 7% in the lowest quartile of cystatin C had inducible ischemia (adjusted OR: 5.3; 95% CI: 1.8–15.5; p = 0.002). Among participants who were not using statins, 39% of participants in the highest quartile and 4% of those in the lowest quartile had inducible ischemia (adjusted OR: 10.3; 95% CI: 2.5–43.3; p = 0.001).
Elevated levels of cystatin C are independently associated with inducible ischemia among outpatients with stable coronary disease.
PMCID: PMC2818322  PMID: 19816865
cystatin C; inducible ischemia; coronary heart disease
25.  Presurgical Serum Cystatin C and Risk of Acute Kidney Injury After Cardiac Surgery 
Acute kidney injury (AKI) following cardiac surgery is associated with poor outcomes, but is challenging to predict from information available prior to surgery.
Study Design
Prospective cohort study
Setting & Participants
The TRIBE-AKI Consortium enrolled 1,147 adults undergoing cardiac surgery at six hospitals from 2007–2009; participants were selected for high AKI risk.
Pre-surgical cystatin C, creatinine, and creatinine-based estimated glomerular filtration rate (eGFR) were categorized into quintiles and grouped as ‘Best’ (quintiles 1–2), ‘Intermediate’ (quintiles 3–4), and ‘Worst’ (quintile 5) kidney function.
The primary outcome was AKI Network (Acute Kidney Injury Network) Stage 1 or higher; ≥0.3mg/dL or 50% rise in creatinine.
Analyses were adjusted for characteristics used clinically for pre-surgical risk stratification.
The average age and kidney function were: 71±10 years (mean ± standard deviation), serum creatinine 1.1±0.3 mg/dL, eGFR-Cr, 74±9 mL/min/1.73m2, and cystatin C, 0.9 ±0.3 mg/L. A total of 407 (36%) participants developed AKI during hospitalization. Adjusted odds ratios for intermediate and worst kidney function by cystatin C were 1.9 (95% CI, 1.4–2.7) and 4.8 (95% CI, 2.9–7.7) compared with 1.2 (95% CI, 0.9–1.7) and 1.8 (95% CI, 1.2–2.6) for creatinine and 1.0 (95% CI, 0.7–1.4) and 1.7 (95% CI, 1.1–2.3) for eGFR-Cr categories, respectively. After adjustment for clinical predictors, the C statistic to predict AKI was 0.70 without kidney markers, 0.69 with creatinine, and 0.72 with cystatin C. Cystatin C also substantially improved AKI risk classification compared to creatinine, based on a net reclassification index of 0.21 (p<0.001).
The ability of these kidney biomarkers to predict risk for dialysis-requiring AKI or death could not be reliably assessed in our study due to a small number of patients with either outcome.
Pre-surgical cystatin C is better than creatinine or creatinine-based eGFR at forecasting the risk of AKI after cardiac surgery.
PMCID: PMC3159705  PMID: 21601336
acute renal failure; creatinine; prognosis

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