Higher CysC Research Articles

CYSTATIN C IS ASSOCIATED WITH THE PRESENCE OF CAROTID ATHEROSCLEROSIS IN PATIENTS WITH DIABETES TYPE 2 AND CHRONIC KIDNEY DISEASE

Objective: Cystatin C has been proposed as a novel marker of renal function and as a predictor of the severity of coronary atherosclerosis and future cardiovascular events. The aim was to evaluate the possible role of chronic kidney disease and particularly CysC on the characteristics of carotid atherosclerosis in patients with type 2 diabetes (DT2). Design and method: We investigated 195 patients both sexes with DT2 aged 56.54 ± 4.17 years. Control group included 84 healthy subjects the same age. The intima-media thickness (IMT) was measured as the distance between the lumen-intima interface and the media-adventitia interface. Atherosclerotic plaque was defined as a focal structure encroaching into the arterial lumen of 0.5 mm or 50% of the surrounding IMT value. Total plaque area (TPA) was calculated as the sum of all plaque areas. GFR was estimated using the modification of diet in renal disease (MDRD) equation. Results: Patients were divided into 2 groups by CysC levels tertiles. Patients in the high CysC tertile (n = 76) had significantly higher mean carotid IMT (0.88 ± 0.12 mm vs. 0.76 ± 0.07 mm, P = 0.03), and TPA (4.69 ± 2.03 mm2 vs. 2.71 ± 0.57 mm2, P = 0.02) compared to patients in the lower tertiles (n = 119). CysC levels demonstrated significant positive correlation with the mean carotid IMT (r = 0.35, P = 0.011). In multivariate analyses adjusted for cardiovascular risk factors, the association between CysC and IMT remained significant (P = 0.037). In contrast, neither serum creatinine nor estimated GFR were associated with IMT (P = 0.17). Conclusions: Our study demonstrated a significant association of increased CysC levels with characteristics of carotid atherosclerosis in patients with type 2 diabetes and chronic kidney disease.

Serum cystatin C is associated with kidney function but not with cardiovascular risk factors or subclinical atherosclerosis in patients with Systemic Lupus Erythematosus.

Cystatin C (CysC) is a protein considered as an excellent marker of renal function, and it has been suggested as an independent predictor of cardiovascular (CV) risk. We evaluated the association of serum CysC with renal function, CV risk factors, inflammation, and subclinical atherosclerosis in Systemic Lupus Erythematosus (SLE) patients. Sixty-one SLE female patients were selected according to estimated glomerular filtration rate (GFR) > 60ml/min/1.73m2. Renal function parameters, SLE specific factors, CV risk factors, and inflammatory markers were assessed. Subclinical atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry. Serum CysC concentration was measured using a particle-enhanced immunonephelometric assay that established 0.59-1.01mg/l as reference values. Patients with high CysC showed significantly altered creatinine, microalbuminuria, and GFR in addition to a significant higher presence of traditional CV risk factors such as arterial hypertension (p<0.001), metabolic syndrome (p<0.001), hypertrigliceridemia (p<0.001), tobacco habit (p<0.05), and a strong association with arterial stiffness (p=0.017). Positive correlation between CysC, homocysteine (r=0.511; p<0.001) and fibrinogen levels (r=0.304; p<0.02) were also observed. A significantly higher SLICC/ACR score was related to high CysC level (p=0.011), together with higher endothelin-1 and lower TNF serum concentration (p<0.005). Considering only patients without any renal impairment (microalbumin/creatinine <30mg/g), no association between CysC level and CV risk factors, arterial stiffness, or SLE-related factors was found. Serum CysC is a good marker of renal function in SLE patients, but it is not independently associated with cardiovascular risk factor or subclinical atherosclerosis.

Correlation of serum cystatin C and N-terminal pro-brain natriuretic peptide with severity of coronary heart disease

Objective To investigate the correlation of serum cystatin C(CysC) and N-terminal brain natriuretic peptide (NT-proBNP) levels with severity of coronary heart disease. Methods 240 patients with coronary artery disease were selected.According to coronary angiography, they were divided into four groups: 52 cases of non-CAD group, coronary single vessel disease group (73 cases), 62 cases of double vessel disease, 53 cases of triple vessel disease group.The serum CysC, NT-proBNP levels were determined and compared among the four groups.The relationship between CysC, NT-proBNP levels and severity of coronary artery disease was analyzed. Results The CysC, NT-proBNP levels in the single coronary vessel disease group, double vessel disease group and multivessel disease group were higher than non-CHD group, the differences were statistically significant(t=2.019, 3.870, 7.449, P=0.046, 0.000, 0.000; t=6.068, 15.365, 24.851, P=0.000, 0.000, 0.000); and with the crown pulse lesion count increased, the serum CysC, NT-proBNP levels increased gradually, the differences were statistically significant(t=2.080, 3.070, P=0.039, 0.000; t=10.953, 12.078, P=0.000, 0.000). Coronary artery disease severity was positively correlated with CysC, NT-proBNP levels (r1=0.562, r2=0.503). Conclusion The severity of coronary artery disease is closely related to the levels of CysC, NT-proBNP, which has some predictive value for coronary artery disease, patients with high CysC, NT-proBNP levels should be given high priority. Key words: serum cystatin C (CysC); Natriuretic peptide, brain; Coronary artery disease

Lack of association between cystatin C and different coronary atherosclerotic manifestations

Cystatin C (CysC) is known to be related to cardiovascular disease (CVD), including the presence and severity of coronary artery disease (CAD) and future clinical events. In this study, the association between CysC levels and (1) coronary artery calcification (CAC) in asymptomatic individuals from the general population as well as (2) different subgroups of patients with suspected or definite acute myocardial infarction (MI) was investigated. CysC levels were measured in serum from asymptomatic individuals as part of a screening study for CAC using non-contrast cardiac CT scan (N = 1039) as well as in subgroups of hospitalized patients with a suspected MI (N = 769). CysC was not associated with CAC in asymptomatic individuals after adjusting for relevant risk factors. No difference in CysC levels was observed between patients with type 1 MI (1.07 mg/L) and patients with normal troponin (with or without prior CAD: 1.14 and 1.01 mg/L, respectively). However, patients with type 2 MI and patient subgroups with elevated troponin but without MI had significantly higher CysC levels (1.24, 1.23 and 1.31 mg/L), even after adjusting for other risk factors. CysC was not associated with CAC in middle-aged asymptomatic individuals from the general population. Furthermore, CysC levels were found to be significantly lower in patients with type 1 MI compared to patients with type 2 MI and patients with elevated troponins but without MI. Thus, in two independent and clinically different populations, no association between CysC and coronary atherosclerotic manifestations could be demonstrated.

Correlations of serum cystatin C and glomerular filtration rate with vascular lesions and severity in acute coronary syndrome

BackgroundThe aim of this study was to evaluate the predictive value of cystatin C (CysC) and estimated glomerular filtration rate (eGFR) regarding vascular lesions and their severity in patients with acute coronary syndrome (ACS).MethodsAccording to the results of coronary angiography, 195 ACS patients were divided into a single-vascular-lesion group (91 cases), a dual-vascular-lesion group (67 cases), and a multiple-vascular-lesion group (37 cases) to assess the severity of coronary artery disease according to Gensini scores and to analyze the correlations of CysC and eGFR level with vascular lesions and severity in ACS patients.ResultsIntergroup comparisons of univariate and multivariate regression analyses showed that CysC was positively correlated with vascular lesions (P < 0.05), but eGFR showed no correlation. Regarding the severity of vascular lesions, CysC was positively correlated with Gensini score (Pearson’s correlation coefficient r = 0.1811, P < 0.05), but eGFR was not correlated (P > 0.05).ConclusionsSerum CysC levels could reflect the severity of vascular lesions in ACS patients, and a high CysC level had predictive value regarding the severity of vascular lesions in ACS.

Association between high cystatin C levels and carotid atherosclerosis.

AIMTo investigate the association between carotid atherosclerosis and cystatin C (CysC) and to determine the optimal CysC cut-off value.METHODSOne hundred twenty-eight subjects were included in this study. Atherosclerosis was defined as a maximum carotid plaque thickness (MCPT) of greater than 2 mm. A receiver operating characteristic curve analysis was used to determine the diagnostic value of serum CysC for atherosclerosis. The subjects were divided into two groups according to the CysC cut-off value. We screened for diabetes, hypertension, dyslipidemia, smoking status, alcohol consumption, and exercise behavior. The association between atherosclerosis and CysC levels was assessed using multivariate analysis.RESULTSThe subjects were then divided into two groups according to the CysC cut-off value (0.73 mg/L). The median age of the high CysC group was 72 years (85% males), whereas that of the low CysC group was 61 years (63% males). The CysC levels were significantly correlated with Cr and estimated glomerular filtration rate (eGFR) values. Body-mass index, visceral fat area, hypertension, diabetes mellitus, and MCPT were significantly higher in the high CysC group than in the low CysC group. Furthermore, the eGFR was significantly lower in the high CysC group. Regarding lifestyle habits, only the exercise level was lower in the high CysC group than in the low CysC group. Multivariate analysis, adjusted for age and sex, revealed that high CysC levels were significantly associated with an MCPT of ≥ 2 mm (odds ratio: 2.92; 95%CI: 1.13-7.99).CONCLUSIONHigher CysC levels were associated with an MCPT of ≥ 2 mm. The CysC cut-off value of 0.73 mg/L appears to aid in the diagnosis of atherosclerosis.

Cystatin C and the Risk of Frailty and Mortality in Older Men.

This study examines the association between cystatin C (cysC) levels and risks of progression of frailty status or death in older men. Prospective study of 2,613 men without overt frailty aged 67 years and older enrolled in the MrOS ancillary sleep study. Baseline measurements included serum cysC, serum creatinine, and frailty status. Repeat frailty status, performed an average of 3.4 years later, was assessed as an ordinal outcome of robust, intermediate stage (prefrail), frail or dead. Mean age was 75.7 years. Men with higher cysC were older and had a higher comorbidity burden. After adjusting for age, clinical site, and race, higher cysC was associated with nearly twofold greater odds of being classified as intermediate stage versus robust (OR quartile 4 vs 1; 1.82, 95% confidence interval [CI] 1.35-2.45), a threefold greater odds of frailty versus robust (OR quartile 4 vs 1; 3.13, 95% CI 2.03-4.82), and a more than fivefold greater odds of death versus robust (OR quartile 4 vs 1; 5.48, 95% CI 2.98-10.08). Results were similar for cysC-based estimated glomerular filtration rate (eGFR). This relationship was attenuated but persisted after adjusting for additional potential confounders including baseline frailty status, body mass index, smoking status, comorbidity burden, self-reported disability, and serum albumin. In contrast, neither serum creatinine nor creatinine-based eGFR was associated in a graded manner with higher risks of development of frailty or death. In this cohort of older men without overt frailty, higher cysC and cysC-based eGFR, but not creatinine or creatinine-based estimates of GFR, were associated with increased risks of frailty or death. These findings suggest that higher cysC level may be a promising biomarker for unsuccessful aging as manifested by increased risks of frailty and death.

Establishment of reference ranges for serum cystatin C in healthy middle-aged and elderly Chinese individuals

Objective To establish normal reference ranges for serum cystatin C(Cys C)in relatively healthy middle-aged and elderly(>50 years)Chinese individuals. Methods A total of 1087 candidates were consecutively selected and serum Cys-C levels were measured by transmission turbidimetry.Frequency analysis and histogram were used to establish the 95% confidence reference range according to methods provided by CLSI(C28-A2). Results Based on the definition and verification procedures for clinical laboratory reference ranges(CLSI C28-A2, second edition), Cys-C levels of 1087 participants fell within the range of 0.30-1.55 mg/L; Male participants had higher serum Cys-C levels than female participants(Z=-10.19, P<0.01). The serum Cys-C level increased with age, regardless of gender(R=0.600, P<0.01). Differences in Cys-C levels between age groups were statistically significant(χ2=411.17, P<0.01). The reference ranges of normal serum Cys-C levels for different age groups(50-, 55-, 60-, 65-, 70-, 75-, )were 0.42-0.98mg/L, 0.45-1.04mg/L, 0.47-1.34mg/L, 0.46-1.38mg/L, 0.61-1.33mg/L, 0.61-1.28 mg/L, respectively, for males, and 0.39-0.94mg/L, 0.42-1.01mg/L, 0.40-0.91mg/L, 0.46-1.03mg/L, 0.57-1.04mg/L, 0.55-1.27mg/L, respectively, for females. Conclusions This study established preliminary normal serum Cys-C reference ranges for healthy middle-aged and elderly(>50 years)individuals in this region, which can serve as parameters for disease diagnosis and treatment evaluation. Key words: Cystatin-C; Reference values

Relationship between serum cystatin-C levels and vibrating perception threshold in patients with Type 2 diabetes mellitus

To explore the relationship between serum cystatin-C (Cys-c) levels and vibrating perception threshold (VPT) in patients with Type 2 diabetes mellitus (T2DM). According to the symptoms, signs and results of lab examination, a total of 352 patients with T2DM were divided into a diabetic peripheral neuropathy group (DPN group, n=107) and a non-diabetic peripheral neuropathy group (NDPN group, n=245). Serum Cys-c levels were measured by radioimmunoassay method. The relationship between serum Cys-c levels and VPT, estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), glucose and blood pressure and other parameters were also analyzed by correlation and multiple regression analysis. All T2DM patients were divided into a high Cys-c levels group (n=89) and a low Cys-c levels group (n=263) according to the upper quartile of Cys-c, and the incidence of DPN and VPT levels in each group were compared. Risk factors of DPN in T2DM patients were analyzed by binary logistic regression analysis and receiver operating characteristic (ROC) curve was used to identify the optimal cutoff of serum Cys-c levels for predicting DPN in patients with T2DM. Serum Cys-c levels were significantly higher in the DPN group than that in the NDPN group [(1.04±0.43) vs (0.80±0.25) mg/L, P<0.01]. Correlation analysis showed that serum Cys-c levels were positively correlated with age, body mass index (BMI), serum creatinine (SCr), blood urea nitrogen (BUN), ACR, VPT, pulse pressure (PP), white blood cell( WBC) , red cell distribution width (RDW), hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) (r=0.410, 0.115, 0.613, 0.433, 0.291, 0.300, 0.156, 0.129, 0.282, 0.314, 0.236, respectively, P<0.05 or P<0.01); and negatively correlated with diastolic blood pressure (DBP), eGFR and indirect bilirubin (IBIL) (r=-0.135, -0.647, -0.114, respectively, P<0.05 or P<0.01). Serum Cys-c levels in T2DM patients were positively correlated with VPT after adjusting for gender, age, BMI, ACR and eGFR (r=0.235, P<0.01). Multiple regression analysis revealed that VPT, age, SCr, eGFR, PP, ACR and HbA1C were independent related factors affecting serum Cys-c levels in T2DM patients. Compared with those in the low Cys-c levels group, the prevalence rate and VPT value was increased in the high Cys-c levels group (all P<0.01). Binary logistic regression analysis found that age, Cys-c and HbA1C were independent risk factors for predicting DPN in T2DM patients (all P<0.01). ROC curve analysis revealed that the optimal cutoff of Cys-c to predict DPN in T2DM patients was 0.996 mg/L, the sensitivity was 43.9%, the specificity was 83.7%, and the area under curve was 0.663. Serum Cys-c levels are well correlated with VPT in patients with T2DM. When the serum Cys-c levels>0.996 mg/L, the predicts have high risk of DPN in T2DM patients, which might be related to diabetic nephropathy, oxidative stress and inflammatory reaction induced by advanced age, hyperglycemia and hypertension.

Abstract 17471: Cardiorenal Syndrome Patients With High NT-proBNP and Cystatin C Levels and Patients With Irreversible Cardiorenal Syndrome Identified by Persistently High Levels of Cystatin C Have Worse Outcomes in Cardiac Resynchronization Therapy: The BIOCRT Study

Introduction: Cardiorenal syndrome comprises of a heterogeneous group of acute and chronic cardiac and renal dysfunction. We examine the association of a dual marker strategy using amino-terminal pro brain natriuretic peptide (NT-proBNP, heart failure) and cystatin C (CysC, renal function) with major adverse cardiac events (MACE) in cardiac resynchronization therapy (CRT) patients. Methods: In 92 patients (age 66±13; 80% male; ejection fraction 26±7%), NT-proBNP and CysC levels were measured at CRT implantation, and 1 month. NT-proBNP&gt;1000 pg/mL and CysC&gt;1mg/L were considered high. At baseline, cardiorenal patients were defined as having high NT-proBNP and CysC. One month after implant, we categorized CRT patients as (1) irreversible cardiorenal if CysC was persistently high, (2) progressive cardiorenal with low transition to high CysC, (3) reversible cardiorenal with high transition to low CysC, and (4) "normal" with stable low CysC. MACE was defined as death, cardiac transplant, left ventricular assist device, and heart failure hospitalization by 2 years. Results: There were 25 (27%) MACE. Prior to CRT, 34 (37%) patients had cardiorenal syndrome. Compared to patients with low NT-proBNP and CysC levels, cardiorenal patients had &gt;6-fold risk of MACE (adjusted HR 6.3, p=0.02) with an estimated 52% probability of having MACE (Figure A). One month after CRT, 33 (36%) patients were irreversible, 15 (16%) progressive, 7 (8%) reversible, and 37 (40%) "normal". Compared to "normal" and reversible patients (referent), irreversible patients had &gt;4-fold risk of MACE (adjusted HR 4.7, p=0.002) with an estimated 52% probability of having MACE (Figure B) while progressors had similar MACE risk (adjusted HR 1.0, p=1.0). Conclusions: CRT patients with cardiorenal syndrome, especially irreversible, have worse prognosis compared to those with acute renal injury or "normal" renal function. Cardiorenal status by NT-proBNP and CysC can identify high-risk CRT patients.

Increased cystatin C levels as a risk factor of cardiovascular events in patients with preserved estimated glomerular filtration rate after elective percutaneous coronary intervention with drug-eluting stents.

Chronic kidney disease (CKD) is an important risk factor for coronary artery disease (CAD) and cardiovascular events. Cystatin C (CysC) has been proposed as a sensitive marker for CKD. However, the predictive value of CysC for cardiovascular events in CAD patients with preserved estimated glomerular filtration rate (eGFR) is unclear. We enrolled 277 consecutive patients undergoing elective percutaneous coronary intervention with sirolimus-eluting stents (SES). Patients with an eGFR ≤60ml/min/1.73m(2) were excluded. Serum CysC levels were measured immediately before SES implantation. Major adverse cardiac and cerebrovascular events (MACCE) were defined as cardiovascular death, acute coronary syndrome, stroke, and hospitalization because of congestive heart failure. After a median follow-up of 63months, 29 patients had MACCE. The subjects were divided into 2 groups based on median serum CysC levels and eGFR (0.637mg/L and 72.43ml/min/1.73m(2), respectively). Kaplan-Meier curves showed that the high CysC group had a significantly higher occurrence of MACCE than the low CysC group (p=0.006), although a low level of eGFR was not significantly associated with an increased risk for occurrence of MACCE. Multivariate analysis revealed that serum CysC levels were an independent predictor of MACCE [hazards ratio: 1.30 per 0.1mg/L (1.01-1.63), p=0.038]. These data suggested that serum CysC level is an independent predictor of MACCE, even in patients with preserved eGFR after elective SES implantation.

AB0551 Cystatin C Associates with Disease Activity in Patients with Systemic Lupus Erythematosus Independent of Renal Function

BackgroundCystatin C (CysC) is produced at a constant rate by all nucleated cells. It is freely filtered by the renal glomeruli and reabsorbed and catabolized in the proximal renal tubules....

Predictive value of elevated cystatin C in patients undergoing primary angioplasty for ST-elevation myocardial infarction

ObjectivesThe prognostic value of cystatin C (CysC) has been documented in patients with acute coronary syndrome without ST-segment elevation. However, its value in acute ST-segment elevation myocardial infarction (STEMI) remains unclear. The aim of this study was to evaluate the prognostic value of CysC in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). MethodsWe prospectively enrolled 475 consecutive STEMI patients (mean age 55.6 ± 12.4 years, 380 male, 95 female) undergoing primary PCI. The study population was divided into tertiles based on admission CysC values. The high CysC group (n = 159) was defined as a value in the third tertile (>1.12 mg/L), and the low CysC group (n = 316) included those patients with a value in the lower two tertiles (≤1.12 mg/L). Clinical characteristics and in-hospital and one-month outcomes of primary PCI were analyzed. ResultsThe patients of the high CysC group were older (mean age 62.8 ±13.1 vs. 52.3±10.5, P < .001). Higher in-hospital and 1-month cardiovascular mortality rates were observed in the high CysC group (9.4% vs. 1.6%, P < .001 and 14.5% vs. 2.2%, P < .001, respectively). In Cox multivariate analysis; a high admission CysC value (>1.12 mg/L) was found to be a powerful independent predictor of one-month cardiovascular mortality (odds ratio, 5.3; 95% confidence interval, 1.25-22.38; P = .02). ConclusionsThese results suggest that a high admission CysC level was associated with increased in-hospital and one-month cardiovascular mortality in patients with STEMI undergoing primary PCI.

Reference intervals of serum cystatin C for determining cystatin C-based glomerular filtration rates in preterm neonates

Objective: The aim of this study is to determine the reference values of serum Cystatin C (CysC) and CysC-based estimated glomerular filtration rate (GFR) on the 3rd and 30th day of life in comparison with serum creatinine (Cr) and Cr-based estimated GFR.Methods: This prospective study was performed on 52 preterm neonates whose gestational ages were between 28 and 34 weeks. Preterm neonates were divided into three groups according to the gestational age as follows: gestational week of 28–29 (group 1), gestational week of 30–32 (group 2) and gestational week of 33–34 (group 3). Blood samples were obtained on the 3rd and the 30th days of life. CysC was determined by particle-enhanced nephelometric immunoassay.Results: The group 1 preterm neonates have higher CysC values (1.34 ± 0.1 mg/L) on the 3rd day of life than the group 2 (1.28 ± 0.2 mg/L) and the group 3 (1.24 ± 0.2 mg/L) but the differences were not significant (p > 0.05, for each). CysC values were independent of gestational age, birth weight and gender (p > 0.05, for each). No correlation was found between CysC and Cr on the 3rd day of life (p > 0.05).Conclusions: CysC is regarded as an alternative for assessing the renal function in preterm neonates.

Cystatin C: An Emerging Biomarker in Cardiovascular Disease

Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It's near constant production rate, the fact that it is freely filtered from the glomerular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing understanding of the role of cysteinyl cathepsins in the pathophysiology of CVD inspired researchers to explore the potential association of cys-C with CVD. Throughout the spectrum of CVD (peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure, coronary artery disease) adverse outcomes and risk stratification have been associated with high plasma levels of cys-C. The exact mechanisms behind the observed correlations have not been comprehensively clarified. Plausible links between high cys-C levels and poor cardiovascular outcome could be impaired renal function, atherogenesis and inflammatory mediators, remodeling of myocardial tissue and others (genetic factors, aging and social habits). The scope of the present article is to systematically review the current knowledge about cys-C biochemistry, metabolism, methods of detection and quantification and pathophysiological associations with different aspects of CVD.

Clinical Correlates and Heritability of Cystatin C (from the Framingham Offspring Study)

Cystatin C (CysC) is associated with cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined the clinical correlates and heritability of CysC and determined if associations between CVD risk factors and CysC differed by CKD status. Among Framingham Heart Study offspring (examined from 1998-2001, n = 3,241, mean age 61 years, 54% women), the 95(th) percentile cut-point was developed for CysC in a healthy subset (n = 779) after excluding participants with diabetes, hypertension, low high-density lipoproteins, obesity, smoking, high triglycerides, prevalent CVD, and CKD (as defined by glomerular filtration rate <60 mL/min per 1.73 m(2)). Multivariable logistic regression was used to evaluate the association between CVD risk factors and high CysC (CysC > or =95(th) percentile cut-point). In a family-based subset (n = 1,188), we estimated CysC heritability using the variance-components method. The cut-point for high CysC was 1.07 mg/L. Age, hypertension treatment, low diastolic blood pressure, body mass index, low high-density lipoprotein cholesterol, and smoking were associated with high CysC in multivariable models. These factors and estimated glomerular filtration rate (egFR) explained 39.2% of CysC variability (R(2)). Excluding CKD did not materially change associations. Multivariable-adjusted heritability for CysC was 0.35 (p <0.001). In conclusion, high CysC is associated with CVD risk factors even in the absence of CKD. The strong associations between CysC and CVD risk factors may partially explain why CysC is a strong predictor of incident CVD.

Cystatin-C Is a Sensitive Marker of Renal Impairment with an Independent Predictive Value for Survival in Multiple Myeloma; Reduction Post Bortezomib Monotherapy.

Renal impairment is a common complication of multiple myeloma (MM). Standard assessment of kidney function in MM includes serum creatinine and creatinine clearance (Ccr) that possibly underestimate the prevalence of renal impairment in this disease. Cystatin-C (Cys-C) is a cysteine-proteinase inhibitor, which participates in the intracellular protein catabolism. It is freely filtered in the glomeruli and totally reabsorbed in the proximal tubular cells; therefore, it is a perfect endogenous marker of glomerular filtration rate. The aim of this study was to evaluate the serum levels of Cys-C in MM and explore possible correlations with clinical data, including survival. We studied 157 newly-diagnosed MM patients (87M/70F, median age 68 years), 28 patients with relapsed disease (17M/11F, median age 68 years) pre- and post-bortezomib therapy, and 15 healthy controls (9M/6F, median age 67 years). Serum Cys-C was determined by particle enhanced immunonephelometry (Dade Behring, Liederbach, Germany). In newly-diagnosed MM patients, serum Cys-C was increased compared with controls [median (range) 1.01 mg/L (0.24–5.61 mg/L) vs. 0.7 mg/L (0.59–0.95 mg/L); p<0.0001]. Ninety patients (57.3%) had higher Cys-C levels than the upper normal limit of 0.95 mg/L, while only 35 (22.2%) had elevated serum creatinine. Patients with ISS stage 3 had increased median Cys-C (1.91 mg/L) compared with stage 1 (0.84 mg/L; p<0.0001) and stage 2 patients (0.95 mg/L; p<0.0001). Cys-C showed strong correlations with beta2-microglobulin (r=0.648, p<0.0001), creatinine (r=0.705, p<0.0001), Ccr (r=−0.549, p<0.0001) and urea (r=0.471, p<0.0001), and weaker correlations with albumin (r=−0.241, p=0.002), hemoglobin (r=−0.333, p<0.0001), LDH (r=0.177, p=0.027) and ferritin (r=0.277, p=0.001). The median survival of all patients was 48 months and the median follow-up period was 26 months. The univariate analysis showed that Cys-C, beta2-microglobulin, LDH, hemoglobin, Ccr, and ISS stage predicted for survival. The median survival for patients with normal Cys-C levels (≤0.95 mg/L) has not been reached yet, while in patients with high Cys-C (>0.95 mg/L) the median survival was 27 months (95% CI 16.9–37.0; p<0.0001). The multivariate analysis revealed that only Cys-C and LDH had independent prognostic value. Patients with both high levels of Cys-C and LDH (>upper normal limit) (n=46) had a median survival of 24 months (95% CI 18.2–29.7), while the median survival of all other patients has not been reached yet (p<0.0001). Cys-C could also separate patients with ISS 2 in terms of survival: patients with elevated Cys-C (n=25) had a median survival of 37 months, while the median survival of patients with normal Cys-C levels (n=26) has not been reached yet (p=0.021). Patients with relapsed myeloma had increased median Cys-C (1.36 mg/L) compared with controls (p<0.0001) and newly-diagnosed patients (p<0.01). Bortezomib therapy produced a strong reduction of Cys-C levels (median: 1.07 mg/L, p<0.01). Responders had a greater reduction than non-responders (p<0.01). The results of this study suggest that Cys-C is a sensitive marker of renal impairment and predicts independently for survival in MM. Furthermore, Cys-C seems to be able to separate ISS 2 patients in terms of survival. Bortezomib monotherapy reduces Cys-C levels, mainly in responders.

Clinical value of cystatin C determination

It has been reported that cystatin C (cys-C) is elevated in patients with malignant disease. In order to investigate whether this phenomenon is linked to or independent of renal function, and at the same time examine the role of this marker in other pathological situations, cys-C concentrations were compared with 24-h creatinine clearance values in three groups of patients; the first group were undergoing treatment for malignant disease, the second group were renal transplant patients and the third randomly taken from patients for whom a routine creatinine clearance had been requested. Several patients with malignant disease had high cys-C levels without any correspondence to creatinine clearance values. Additionally, although cys-C shows a high sensitivity for detecting impaired glomerular function in renal transplant patients, the specificity was very low, with little discrimination being observed between patients with normal and pathological creatinine clearance levels. In other patients both the sensitivity and specificity of cys-C could be shown to be very good. Thus although cys-C can generally be recommended as a marker of the glomerular filtration rate, there are some patients for whom the clinical relevance is unclear.