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1.  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
2.  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
3.  Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients 
Medicine  2016;95(10):e3011.
Uromodulin, released from tubular cells of the ascending limb into the blood, may be associated with kidney function. This work studies the relevance of plasma uromodulin as a biomarker for kidney function in an observational cohort of chronic kidney disease (CKD) patients and subjects without CKD (CKD stage 0). It should be further evaluated if uromodulin allows the identification of early CKD stages.
Plasma uromodulin, serum creatinine, cystatin C, blood-urea-nitrogen (BUN) concentrations, and estimated glomerular filtration rate (eGFR CKD-EPIcrea-cystatin) were assessed in 426 individuals of whom 71 were CKD stage 0 and 355 had CKD. Besides descriptive statistics, univariate correlations between uromodulin and biomarkers/eGFR were calculated using Pearson-correlation coefficient. Multiple linear regression modeling was applied to establish the association between uromodulin and eGFR adjusted for demographic parameters and pharmacologic treatment. Receiver-operating-characteristic (ROC) analysis adjusted for demographic parameters was performed to test if uromodulin allows differentiation of subjects with CKD stage 0 and CKD stage I.
Mean uromodulin plasma levels were 85.7 ± 60.5 ng/mL for all CKD stages combined. Uromodulin was correlated with all biomarkers/eGFR in univariate analysis (eGFR: r = 0.80, creatinine: r = −0.76, BUN: r = −0.72, and cystatin C: r = −0.79). Multiple linear regression modeling showed significant association between uromodulin and eGFR (coefficient estimate β = 0.696, 95% confidence interval [CI] 0.603–0.719, P < 0.001). In ROC analysis uromodulin was the only parameter that significantly improved a model containing demographic parameters to differentiate between CKD 0° and I° (area under the curve [AUC] 0.831, 95% CI 0.746–0.915, P = 0.008) compared to creatinine, cystatin C, BUN, and eGFR (AUC for creatinine: 0.722, P = 0.056, cystatin C: 0.668, P = 0.418, BUN: 0.653, P = 0.811, and eGFR: 0.634, P = 0.823).
Plasma uromodulin serves as a robust biomarker for kidney function and uniquely allows the identification of early stages of CKD. As a marker of tubular secretion it might represent remaining nephron mass and therefore intrinsic “kidney function” rather than just glomerular filtration, the latter only being of limited value to represent kidney function as a whole. It therefore gives substantial information on the renal situation in addition to glomerular filtration and potentially solves the problem of creatinine-blind range of CKD, in which kidney impairment often remains undetected.
PMCID: PMC4998896  PMID: 26962815
4.  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
5.  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
6.  Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate 
All of the components of Metabolic syndrome (MetS) have been regarded as risk factors for coronary artery disease (CAD). Early detection of CAD in asymptomatic patients with MetS remains a challenge. Cystatin C,which has been proposed as a novel marker of renal dysfunction,is correlated with mortality in CAD, The purpose of the study was to evaluate whether cystatin C is a potential marker of asymptomatic CAD in MetS patients with normal kidney function.
A total of 211asymptomatic MetS patients without prior history of CAD patients were included in a cross-sectional study. Patients were divided into MetS with asymptomatic CAD (n = 136) and MetS without CAD (n = 75) groups according to coronary angiograph results. Serum cystatin C levels were measured using particle enhanced immunonephelometric assays. We first assessed whether there is an independent association of cystatin C with the presence and severity of asymptomatic CAD. Then, we investigated the association between cystatin C and other biochemical risk factors for atherosclerosis.
Serum cystatin C levels in patients with asymptomatic CAD were significantly higher than those without CAD (P = 0.004). A multiple logistic regression analysis demonstrated cystatin C was independently associated with the presence of asymptomatic CAD (OR = 1.326, 95%CI: 1.086-1.619). On receiver operating characteristics (ROC) analysis, the area under the curve (AUC) was 0.622 (95 % CI: 0543–0.701, P = 0.003), and cystatin C showed a moderate predictive value. Furthermore, cystatin C was independently correlated with Gensini score (standardized β = 0.183, P = 0.007), and serum cystatin C levels increased with the increasing of number of disease vessels (P = 0.005). In a multiple stepwise regression analysis, uric acid (UA)(P < 0.001), body mass index (BMI)(P = 0.002), triglyceride(TG)(P = 0.03), estimated glomerular filtration rate (eGFR)(P < 0.001), and fibrinogen(P = 0.001) were independently associated with cystatin C.
Serum cystatin C in our study was significantly associated with the presence and severity of asymptomatic CAD in MetS patients with normal kidney function, suggesting that cystatin C is probably more than a marker of glomerular filtration rate.
PMCID: PMC3473246  PMID: 22978689
Cystatin C; Gensini score; Metabolic syndrome; Asymptomatic coronary artery disease
7.  Performance of Chronic Kidney Disease Epidemiology Collaboration Creatinine-Cystatin C Equation for Estimating Kidney Function in Cirrhosis 
Hepatology (Baltimore, Md.)  2013;59(4):1532-1542.
Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by non-radiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the “bias”, “precision” and “accuracy” of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG) and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores [differences between mGFR and estimated GFR (eGFR) or between mGFR and CrCl, or between mGFR and CG equation for each subject] (RMSE=23.56) was significantly better than that of CrCl (37.69, P=0.001), CG (RMSE=36.12, P=0.002) and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P=0.024), CG (P=0.0001), 4-variable MDRD (P=0.027) and CKD-EPI creatinine 2009 (P=0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%.
The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.
PMCID: PMC3883887  PMID: 23744636
End-stage liver disease; liver transplantation; cystatin C; glomerular filtration rate; gender disparity
8.  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
9.  Diagnostic value of cystatin C for predicting acute kidney injury in patients with liver cirrhosis 
The Korean Journal of Hepatology  2010;16(3):301-307.
The present study aimed to determine the role of cystatin C as a prognostic factor for acute kidney injury and survival in cirrhotic patients.
The study investigated 53 liver cirrhosis patients. The renal function was evaluated by serum creatinine, serum and urine cystatin C, and 24-hour creatinine clearance on admission. Acute kidney injury was defined as a serum creatinine level exceeding the normal range (>1.2 mg/dl) and an increase of at least 50% from the baseline value. Multivariate analysis, receiver operating characteristic curve, and survival analysis were used to investigate prognostic factors for acute kidney injury and survival.
Nine of the 53 cirrhotic patients (17.0%) developed acute kidney injury within 3 months. Both serum creatinine and cystatin C were predictive factors for acute kidney injury in univariate analysis, with a diagnostic accuracy of 0.735 (95% confidence interval (CI), 0.525-0.945; p=0.028) for serum cystatin C and 0.698 (95% CI, 0.495-0.901, p=0.063) for creatinine. In multivariate analysis, only serum cystatin C was an independent risk factor for acute kidney injury. The sensitivity and specificity of a serum cystatin C level of >1.23 mg/L to acute kidney injury were 66% and 86%, respectively. Serum cystatin C was positively correlated with the Model for End-Stage Liver Disease (MELD) and MELD-Na scores (r=0.346 and p=0.011, and r=0.427 and p=0.001, respectively). Comparison of the survival rates over the observation period revealed that a serum cystatin C level of >1.23 mg/L was a useful marker for short-term mortality (p<0.001).
The accuracy in predicting acute kidney injury and short-term mortality was higher for a serum cystatin C level of >1.23 mg/L than for the serum creatinine concentration in patients with cirrhosis.
PMCID: PMC3304597  PMID: 20924213
Cystatin C; Liver cirrhosis; Acute kidney injury
10.  Early Acute Kidney Injury based on Serum Creatinine or Cystatin C in Intensive Care Unit after Major Trauma 
Acute kidney injury (AKI) is a common problem in critically ill patients and is independently associated with increased morbidity and mortality. Recently, serum cystatin C has been shown to be superior to creatinine in early detection of renal function impairment. We compared estimated GFR based on serum cystatin C with estimated GFR based on serum creatinine for early detection of renal dysfunction according to the RIFLE criteria.
During 9 months, three hundred post trauma patients that were referred to the intensive care unit of a referral trauma hospital were recruited. Serum creatinine and serum cystatin C were measured and the estimated GFR within 24 hours of ICU admission was calculated. The primary outcome was the incidence of AKI according to the RIFLE criteria within 2nd to 7th day of admission.
During the first week of ICU admission, 21% of patients experienced AKI. After adjusting for major confounders, only the patients with first day’s serum cystatin level higher than 0.78 mg/l were at higher risk of first week AKI (OR=6.14, 95% CI: 2.5-14.7, P<0.001). First day’s serum cystatin C and injury severity score were the major risk factors for ICU mortality (OR=3.54, 95% CI: 1.7-7.4, P=0.001) and (OR=4.6, 95% CI: 1.5-14, P=0.007), respectively.
Within 24 hours after admission in ICU due to multiple trauma, high serum cystatin C level may have prognostic value in predicting early AKI and mortality during ICU admission. However, such correlation was not seen neither with creatinine nor cystatin C based GFR.
PMCID: PMC4628138  PMID: 26538776
Acute kidney injury; Trauma; Cystatin C; Creatinine; Glomerular filtration rate
11.  Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate 
Kidney international  2010;79(4):471-477.
Cystatin C is being considered as a replacement for serum creatinine for estimating glomerular filtration rate (GFR). Data are limited on the non-GFR determinants of cystatin C and their relationship with protein intake. We compared creatinine and cystatin C levels at baseline (N=741) and at 24 months post-randomization (N=426) for participants in the Modification of Diet in Renal Disease Study. Participants in Study A (GFR 25-55 ml/min/1.73 m2) were assigned a low (0.58 g/kg/day) vs. usual (1.3 g/kg/day) protein intake, and in Study B (GFR 13-24 ml/min/1.73 m2), a very low (0.28 g/kg/day) vs. low protein intake. We associated creatinine, cystatin C and estimated protein intake at baseline and compared randomized groups to examine the effect of protein intake on creatinine and cystatin C independent of GFR. The mean (SD) measured GFR, creatinine and cystatin C at baseline was 38.6 (8.9) ml/min/1.73 m2, 1.9 (0.5) mg/dl, 1.9 (0.4) mg/l in Study A and 18.5 (3.4) ml/min/1.73 m2, 3.4 (0.9) mg/dl, 3.0 (0.5) mg/l in Study B. Lower dietary protein intake reduced change in creatinine, but did not affect change in cystatin C [Δ(CI) creatinine vs. cystatin C, −0.22 (−0.36, −0.08) mg/dl vs. 0.02 (−0.08, 0.13) mg/l in Study A, −0.28 mg/dl (−0.82, 0.21) vs. 0.10 (−0.15, 0.26) mg/l in Study B]. Creatinine, but not cystatin C, is affected by dietary protein intake independent of GFR. Cystatin C may allow more accurate GFR estimates than creatinine for patients with reduced protein intake.
PMCID: PMC4557795  PMID: 20980977
12.  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
13.  Comparison of glomerular filtration rates calculated by different serum cystatin C-based equations in patients with chronic kidney disease 
We aimed to evaluate the performance of serum cystatin C-based equations in calculating the glomerular filtration rate (GFR) in patients with varying stages of chronic kidney disease (CKD).
Serum cystatin C and creatinine levels were measured in 615 CKD patients. The CKD stage was determined by the creatinine-based estimated GFR (eGFR) equation using the four-variable abbreviated Modification of Diet in Renal Disease equation suggested by the Kidney Disease Outcome Quality Initiative with the addition of a coefficient applicable to Korean populations (K-aMDRD). In each CKD stage, the ratio of serum cystatin C to creatinine was calculated and six different cystatin C-based equations were used to estimate GFR. Cystatin C-based eGFR and aMDRD eGFR values were compared using the paired t test, Pearson correlation test, and the Bland–Altman plot.
The mean age of patients was 53.21±14.45 years; of the 615 patients, 346 were male. The serum cystatin C-to-creatinine ratio was inversely correlated with the CKD stage. Compared with the K-aMDRD values, the results of the Hoek, Filler, and Le Bricon’s cystatin C-based eGFR equations were lower in CKD Stages 1–3 and higher in Stages 4 and 5. However, the results of the Orebro-cystatin (Gentian) equation [GFR=100/ScytC (mL/minute/1.73 m2) – 14] were similar to those of the K-aMDRD equation in CKD Stages 4 and 5 (15.44±9.45 vs. 15.17±9.05 mL/minute/1.73 m2, respectively; P=0.722; bias=0.27±8.87).
The eGFRs obtained from the six cystatin C-based equations differed widely. Therefore, further studies are required to determine the most accurate equation to estimate GFR in Koreans with CKD.
PMCID: PMC4714174  PMID: 26877949
Chronic kidney disease; Cystatin C; Estimated glomerular filtration rate; Serum creatinine
14.  Simple Cystatin C Formula for Estimation of Glomerular Filtration Rate in Overweight Patients with Diabetes Mellitus Type 2 and Chronic Kidney Disease 
Experimental Diabetes Research  2012;2012:179849.
In clinical practice the glomerular filtration rate (GFR) is estimated from serum creatinine-based equations like the Cockcroft-Gault formula (C&G) and Modification of Diet in Renal Disease formula (MDRD). Recently, serum cystatin C-based equations, the newer creatinine formula (The Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI)), and equation that use both serum creatinine and cystatin C (CKD-EPI creatinine & cystatin formula) were proposed as new GFR markers. Present study compares serum creatinine-based equations, combined (including both serum creatinine and cystatin C) equation, and serum simple cystatin C formula (100/serum cystatin C) against 51CrEDTA clearance in 113 adult overweight Caucasians with diabetes mellitus type 2 (DM2) and chronic kidney disease (CKD). The results of present study demonstrated that the simple cystatin C formula could be a useful tool for the evaluation of renal function in overweight patients with DM2 and impaired kidney function in daily clinical practice in hospital and especially in outpatients. Despite the advantages of the simple cystatin C formula, cystatin C-based equations cannot completely replace the “gold standard” for estimation of the GFR in a population of DM2 patients with CKD, but may contribute to a more accurate selection of patients requiring such invasive and costly procedures.
PMCID: PMC3447360  PMID: 23008697
15.  Higher Levels of Cystatin C are Associated with Worse Cognitive Function Among Older Adults with Chronic Kidney Disease: The CRIC COG Study 
Cystatin C, a measure of kidney function, has been linked to cognitive impairment, but the association between cognition and levels of cystatin C in persons with chronic kidney disease (CKD) is unknown.
We studied 821 participants from the Chronic Renal Insufficiency Cohort Cognitive Study with a baseline cognitive assessment completed at the same visit as serum cystatin C measurement.
Levels of serum cystatin C were categorized into tertiles; cognitive function was assessed with six neuropsychological tests. We compared scores on these tests across tertiles of cystatin C using linear regression and logistic regression to examine the association between cystatin C level and poor cognitive performance (1 SD difference from the mean).
The mean participant age was 64.9 years, 50.6% were male, and 48.6% were white. After multivariable adjustment for age, race, education, and medical comorbidities in linear models, higher levels of cystatin C were associated with worse cognition on the 3MS, Buschke Delayed Recall, Trails A, Trails B, and Boston Naming (p<0.05 for all). This association remained statistically significant for Buschke Delayed Recall (p=0.01) and Trails A (p=0.03) after additional adjustment for eGFR. Compared to the lowest tertile of cystatin C, the highest tertile was associated with increased likelihood of poor cognitive performance on Trails A (OR=2.17; 95% CI: 1.16-4.06), Trails B (OR=1.89; 95% CI: 1.09-3.27), and Boston Naming (OR=1.85; 95% CI: 1.07-3.19) after multivariate adjustment in logistic models.
Among patients with CKD, higher levels of serum cystatin C were associated with worse cognition and increased likelihood of poor cognitive performance on attention, executive function, and naming. Cystatin C is a marker of cognitive impairment and may be associated with cognition independent of eGFR levels.
PMCID: PMC4201363  PMID: 25125225
cystatin C; cognition; chronic kidney disease
16.  Comparative Assessment of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C as Early Biomarkers for Early Detection of Renal Failure in Patients with Hypertension 
Iranian Biomedical Journal  2015;19(2):76-81.
Hypertension is one the most common causes of chronic kidney disease (CKD). One of the major concerns in hypertensive patients is early detection of renal disorders. In the past, serum creatinine (Scr) concentration was used as a marker of kidney function, but it proffers a late reflection of reduced glomerular filtration rate. Cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) have been recently proven to be useful for quantification of CKD. Therefore, we compared the diagnostic value of NGAL with cystatin C and creatinine to evaluate kidney function in hypertensive patients.
In this study, 42 hypertensive patients and 30 healthy volunteers were recruited. Serum cystatin C (Scys C) and plasma NGAL were measured using ELISA method. Creatinine, urea, hemoglobin, fibrinogen, and C-reactive protein were measured according to the routine methods. Estimated glomerular filtration rate (eGFR) was considered as the gold standard method (cut-off value of < 78 ml/min/1.73 m2.
In the patient group, plasma NGAL, cystatin C, and creatinine were all significantly correlated with eGFR, and plasma NGAL correlated best with eGFR. Receiver-operating characteristics analysis indicated that plasma NGAL was a better indicator than creatinine and cystatin C for predicting a GFR < 78 ml/min/1.73 m2. The sensitivity and specificity for NGAL were 96% and 100%, for cystatin C were 92% and 60% and for creatinine were 76% and 47%, respectively.
Plasma NGAL demonstrated a higher diagnostic value to detect kidney impairment in the early stages of CKD as compared to Scys C and Scr in hypertensive patients.
PMCID: PMC4412917  PMID: 25864811
Neutrophil gelatinase-associated lipocalin (NGAL); Cystatin C; Creatinine; Hypertension
17.  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
18.  Relationship Between Serum Cystatin C and Creatinine or Dialysis Adequacy in Patients on Chronic Maintenance Hemodialysis 
Nephro-urology Monthly  2013;5(2):733-735.
Glomerular filtration rate (GFR) is widely estimated by serum creatinine based equations such as Cockcroft-Gault (CG) standardized for body surface, and an abbreviated formula derived from MDRD (modification of diet in renal disease) study. However, some studies suggested that creatinine based estimation of GFR formula can be replaced by cystatin C based formula.
The aim of this study was to determine whether cystatin C based equation could be used as an indicator for renal function in hemodialysis patients compared to MDRD equation; and whether cystatin C, a dialyzable molecule, was related to Kt/V, the marker for dialysis adequacy.
Patients and Methods
In this cross-sectional study, 98 patients on chronic hemodialysis were included. Plasma levels of urea and creatinine were measured before and after dialysis, and cystatin C was measured before dialysis. GFR was calculated and compared.
The mean age of patients was 55.50 ± 16.10 (24-86) years and 66 cases were male (67.3%). The GFR was estimated at 6.05 ± 2.36 and 5.83 ± 2.19 cc/min by MDRD and cystatin C based formulas, respectively, with a significant correlation (r = 0.51; P < 0.001). Serum cystatin C level was 9.74 ± 2.47 mg/L which showed significant reverse correlation with both MDRD (r = -0.46; P < 0.001) and cystatin C based formulas (r = -0.87; P < 0.001). Neither creatinine nor serum cystatin C showed correlation with Kt/V, as the marker of dialysis adequacy.
Serum cystatin C may be considered as an indicator of renal function in patients under maintenance hemodialysis.
PMCID: PMC3703130  PMID: 23841035
Cystatin C; Glomerular Filtration Rate; Creatinine; Renal Dialysis
19.  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
20.  Neutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement 
We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C in comparison to established markers of renal function in patients with heart failure (HF).
Patients with advanced HF develop progressive renal dysfunction. The renal biomarkers NGAL and cystatin C might improve prognostic assessment of patients with HF.
Serum samples were collected from 40 patients with stable HF (58±8 yrs, BMI 29.4±4.2 kg/m2), 40 HF patients undergoing ventricular assist device (VAD) implantation (53±11 yrs, BMI 26.8±5.5 kg/m2) and VAD removal at cardiac transplantation, and 24 controls (48±7 yrs, BMI 29.4±4.2 kg/m2). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by ELISA and eGFR calculated using MDRD formula.
Patients with stable HF showed elevated NGAL and cystatin C levels compared to controls (114.2±52.3 ng/mL vs. 72.0±36.1 ng/mL, p<0.0001; cystatin C: 1490.4±576.1 ng/mL vs. 986.3±347.5 ng/mL, p=0.0026). Unlike cystatin C, NGAL increased in advanced HF requiring VAD implantation (158.7±74.8 ng/mL, p<0.001). On VAD, NGAL levels decreased (127.1±80.4 ng/mL, p=0.034). NGAL was higher in patients who developed right ventricular failure (187.8±66.0 vs. 130.9±67.0 ng/mL, p=0.03) and irreversible renal dysfunction (190.0±73.8 ng/mL vs. 133.8±54.2 ng/mL, p<0.05) while cystatin C, creatinine and eGFR were not different. NGAL correlated with eGFR (r=−0.2188, p=0.01).
NGAL levels correlate with HF severity and hemodynamic improvement after VAD placement. Our findings suggest a role of this novel biomarker as a marker of severity and prognosis in patients with HF.
PMCID: PMC4252882  PMID: 25049066
Heart Failure; Renal Function; NGAL
21.  Correlation of cystatin C and creatinine based estimates of renal function in children with hydronephrosis 
Introduction: The use of a simple and accurate glomerular filtration rate (GFR) estimating method aiming minute assessment of renal function can be of great clinical importance.
Objectives: This study aimed to determine the association of a GFR estimating by equation that includes only cystatin C (Gentian equation) to equation that include only creatinine (Schwartz equation) among children.
Patients and Methods: A total of 31 children aged from 1 day to 5 years with the final diagnosis of unilateral or bilateral hydronephrosis referred to Besat hospital in Hamadan, between March 2010 and February 2011 were consecutively enrolled. Schwartz and Gentian equations were employed to determine GFR based on plasma creatinine and cystatin C levels, respectively.
Results: The proportion of GFR based on Schwartz equation was 70.19± 24.86 ml/min/1.73 m2, while the level of this parameter based on Gentian method and using cystatin C was 86.97 ± 21.57 ml/min/1.73 m2. The Pearson correlation coefficient analysis showed a strong direct association between the two levels of GFR measured by Schwartz equation based on serum creatinine level and Gentian method and using cystatin C (r = 0.594, P < 0.001). The linear association between GFR values measured with the two methods included cystatin C based GFR = 50.8+ 0.515 × Schwartz GFR. The correlation between GFR values measured by using serum creatinine and serum cystatin C measurements remained meaningful even after adjustment for patients’ gender and age (r = 0.724, P < 0.001).
Conclusion: The equation developed based on cystatin C level is comparable with another equation, based on serum creatinine (Schwartz formula) to estimate GFR in children.
PMCID: PMC4827382  PMID: 27069964
Cystatin C; Creatinine; Hydronephrosis; Renal function
22.  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
23.  Renal markers in normal and hypertensive disorders of pregnancy in Indian women: a pilot study 
Altered renal function is an essential component of the pathophysiological process in pre-eclampsia. Kidneys play an important role in the turnover of low molecular weight substances such as creatinine, uric acid and cystatin C. The present study was undertaken if these serum markers were characteristically altered in Indian pregnant women.
Serum levels were therefore determined in samples from 69 healthy women at term as well as in 27 samples of patients with Pregnancy induced hypertension (PIH) and in 20 patients with pre-eclampsia (PE).
The levels of all three components were significantly higher in pre-eclamptic patients when compared to healthy controls with the mean ± SD being 1.47 ± 0.9 vs. 1.06 ± 0.2 for cystatin C, 0.95 ± 0.2 vs. 0.67 ± 0.1 for creatinine and 6.13 ± 1.8 vs. 4.28 ±1.1 for uric acid respectively. In PIH cystatin C was significantly higher, 1.25 ± 0.9 unlike creatinine, 0.67 ± 0.14 and uric acid, 4.30 ± 1.0. Receiver operating characteristic (ROC) plots demonstrated that the diagnostic accuracy of serum creatinine was superior to serum uric acid and serum cystatin C and serum uric acid was better than serum cystatin C.
The maternal serum cystatin C, creatinine and uric acid were all significantly elevated at the end of pregnancy in pre-eclampsia compared to those of healthy pregnant women. If this rise in the above markers during early pregnancy could predict the onset of PIH/PE, needs to be investigated.
PMCID: PMC4032820  PMID: 24872960
Pregnancy; Pregnancy induced hypertension; Pre-eclampsia; Cystatin C; Creatinine; Uric acid
24.  Serum Cystatin C as a Marker of Renal Function in Critically Ill Patients With Normal Serum Creatinine 
Nephro-urology Monthly  2014;6(2):e15224.
Serum creatinine as a classic marker of renal function has several limitations in the detection of renal dysfunction.
This study assessed the validity of serum cystatin C as a marker of renal function in critically ill patients with normal serum creatinine.
Patients and Methods:
Eighty adult patients referred to intensive care units with serum creatinine levels < 1.5 mg/dL and without hemodynamic instability were chosen and their serum creatinine and cystatin C levels were measured. A 24-hour urine sample was collected to calculate creatinine clearance (Ccr). Renal dysfunction was defined as Ccr < 80 mL/min/1.73 m2.
There were significant correlations between measured Ccr and 1/serum creatinine (R = 0.51, P < 0.001) and 1/serum cystatin C (R = 0.25, P = 0.028). The difference between false negative rates of serum creatinine (93.33%) and cystatin C (80%) in the detection of renal dysfunction was significant (P = 0.032). Receiver operating characteristic curve analysis illustrated that area under the curve of serum creatinine and cystatin C for detecting renal dysfunction were 0.711 and 0.607, respectively; however, this difference was not significant (P = 0.222).
Our data demonstrated that serum cystatin C is not superior to serum creatinine in the early detection of renal dysfunction in critically ill patients.
PMCID: PMC3997954  PMID: 24783172
Critically Ill; Patients; Creatinine; Cystatin C; Acute Kidney Injury
25.  Kidney function and clinical recommendations of drug dose adjustment in geriatric patients 
BMC Geriatrics  2013;13:92.
In elderly patients chronic kidney disease often limits drug prescription. As several equations for quick assessment of kidney function by estimating glomerular filtration rate (eGFR) and several different clinical recommendations for drug dose adjustment in renal failure are published, choosing the correct approach for drug dosage is difficult for the practitioner. The aims of our study were to quantify the agreement between eGFR-equations grouped by creatinine-based or cystatin C-based and within the groups of creatinine and cystatin C-based equations and to investigate whether use of various literature and online references results in different recommendations for drug dose adjustment in renal disease in very elderly primary care patients.
We included 108 primary care patients aged 80 years and older from 11 family practices into a cross-sectional study. GFR was estimated using two serum creatinine-based equations (Cockroft-Gault, MDRD) and three serum cystatin C-based equations (Grubb, Hoek, Perkins). Concordance between different equations was quantified using intraclass correlation coefficients (ICCs). Essential changes in drug doses or discontinuation of medication were documented and compared in terms of estimated renal function as a consequence of the different eGFR-equations using five references commonly used in the US, Great Britain and Germany.
In general, creatinine-based equations resulted in lower eGFR-estimation and in higher necessity of drug dose adjustment than cystatin C-based equations. Concordance was high between creatinine-based equations alone (ICCs 0.87) and between cystatin C-based equations alone (ICCs 0.90 to 0.96), and moderate between creatinine-based equations and cystatin C-based equations (ICCs 0.54 to 0.76). When comparing the five different references consulted to identify necessary drug dose adjustments we found that the numbers of drugs that necessitate dose adjustment in the case of renal impairment differed considerably. The mean number of recommended changes in drug dosage ranged between 1.9 and 2.5 per patient depending on the chosen literature reference.
Our data suggest that the choice of the literature source might have even greater impact on drug management than the choice of the equation used to estimate GFR alone. Efforts should be deployed to standardize methods for estimating kidney function in geriatric patients and literature recommendations on drug dose adjustment in renal failure.
PMCID: PMC3850264  PMID: 24020893
Estimated kidney function; Aged 80 years and older; Drug dose adjustment; Primary care; Literature references

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