Cystatin C and carotid intima-media thickness in asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA)

BACKGROUND: 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. PREDICTORS: 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. RESULTS: 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 m(2), had no independent association with internal and common carotid IMT. LIMITATIONS: There were few participants with severe kidney disease. CONCLUSIONS: 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.     

Serum cystatin C as an endogenous parameter of the renal function in patients with normal to moderately impaired kidney function

BACKGROUND: Cystatin C is a proteinase inhibitor with a low molecular weight. The serum levels of cystatin C are mainly dependent on glomerular filtration rate (GFR) making cystatin C an endogenous parameter of GFR. The aim of the study was to elucidate the applicability of serum cystatin C as a parameter of GFR in patients with normal to moderately impaired kidney function and to estimate a reference interval for serum cystatin C. PATIENTS AND METHODS: Forty-six patients (25 males and 21 females) aged 22 to 83 years with various kidney diseases and 250 blood donors (164 males and 86 females) aged 19 to 64 years were included. Cystatin C was measured by an automated particle-enhanced nephelometric immunoassay, serum creatinine by an enzymatic and by Jaffé method, urine creatinine by an enzymatic method, and GFR by 99mTc-DTPA clearance. RESULTS: Serum levels ofcystatin C and creatinine showed increments with decreasing values of 99mTc-DTPA clearance and a linear relationship was found between 99mTc-DTPA clearance and l/serum cystatin C, l/serum creatinine (enzymatic method), and creatinine clearance. Comparison of the non-parametric receiver-operating characteristic (ROC) plots for serum cystatin C (area under the curve (AUC) = 0.996; SE = 0.005), serum creatinine (enzymatic method) (AUC = 0.899; SE = 0.044), serum creatinine (Jaffé method) (AUC = 0.870; SE = 0.051), measured creatinine clearance (AUC = 0.959; SE = 0.025), and estimated creatinine clearance (0.950; SE = 0.029) revealed significant differences for serum cystatin C and serum creatinine (enzymatic and Jaffé method) (p values: 0.03 and 0.01). No significant differences were demonstrated between serum cystatin C and measured and estimated creatinine clearance (p value: 0.14 and 0.12). The non-parametric reference interval for serum cystatin C was calculated to be 0.51-1.02 mg/l (median: 0.79 mg/l; range: 0.33 - 1.07 mg/l). CONCLUSION: Serum cystatin C seems to be a better parameter of GFR than serum creatinine in adults with various types of kidney disease with normal to moderately impaired kidney function.     

Glomerular filtration rate estimated by cystatin C among different clinical presentations

Glomerular filtration rate (GFR) estimates from serum creatinine has not been generalizable across all populations. Cystatin C has been proposed as an alternative marker for estimating GFR. The objective of this study was to compare cystatin C with serum creatinine for estimating GFR among different clinical presentations. Cystatin C and serum creatinine levels were obtained from adult patients (n=460) during an evaluation that included a GFR measurement by iothalamate clearance. Medical records were abstracted for clinical presentation (healthy, native chronic kidney disease or transplant recipient) at the time of GFR measurement. GFR was modeled using the following variables: cystatin C (or serum creatinine), age, gender and clinical presentation. The relationship between cystatin C and GFR differed across clinical presentations. At the same cystatin C level, GFR was 19% higher in transplant recipients than in patients with native kidney disease (P<0.001). The association between cystatin C and GFR was stronger among native kidney disease patients than in healthy persons (P<0.001 for statistical interaction). Thus, a cystatin C equation was derived using only patients with native kidney disease (n=204). The correlation with GFR (r(2)=0.853) was slightly higher than a serum creatinine equation using the same sample (r(2)=0.827), the Modification of Diet in Renal Disease equation (r(2)=0.825) or the Cockcroft-Gault equation (r(2)=0.796). Averaged estimates between cystatin C and serum creatinine equations further improved correlation (r(2)=0.891). Cystatin C should not be interpreted as purely a marker of GFR. Other factors, possibly inflammation or immunosuppression therapy, affect cystatin C levels. While recognizing this limitation, cystatin C may improve GFR estimates in chronic kidney disease patients.     

Method of Glomerular Filtration Rate Estimation Affects Prediction of Mortality Risk

Decreased kidney function, determined using a serum creatinine–based estimation of GFR, is associated with a higher risk for mortality from cardiovascular disease. Equations incorporating cystatin C improve the estimation of GFR, but whether this improves the prediction of risk for mortality is unknown. We measured cystatin C on 6942 adult participants in the Third National Health and Nutrition Examination Survey Linked Mortality File, including all participants who had high serum creatinine (>1.2 mg/dl for men; >1.0 mg/dl for women) or were older than 60 yr and 25% random sample of participants who were younger than 60 yr. We estimated GFR using equations that included standardized serum creatinine, cystatin C, or both. Participant data were linked to the National Death Index. A total of 1573 (22.7%) deaths (713 deaths from cardiovascular disease) occurred during a median of 8 yr. Lower estimated GFR based on cystatin C was strongly associated with higher risk for overall and cardiovascular mortality across the range of normal to moderately decreased estimated GFR. Creatinine-based estimates of GFR resulted in weaker associations, with the association between estimated GFR and all-cause mortality reversed at higher levels of estimated GFR. An equation using both creatinine and cystatin C (in addition to age, race, and gender) resulted in weaker associations than equations using only cystatin C (with or without age, race, and gender). In conclusion, despite better performance in terms of estimating GFR, equations based on both cystatin C and creatinine do not predict mortality as well as equations based on cystatin C alone.Moderately decreased kidney function, as estimated from equations based on serum creatinine, is associated with an elevated risk for mortality, both in individuals with existing cardiovascular disease (CVD) and in the general population.^1–3 Serum levels of creatinine, however, are affected by other factors in addition to GFR, most importantly, variations in creatinine generation as a result of differences in muscle mass and turnover.⁴ Muscle wasting as a result of chronic illness is associated with lower creatinine generation, leading to an overestimation of GFR in such individuals. Because these same individuals are at an elevated risk for mortality, this systematic bias would result in an underestimation of the association between decreased GFR and mortality risk. This may be a particular problem in the elderly because of their higher prevalence of chronic illness and higher risk for mortality. In addition, currently available GFR estimates based on serum creatinine are less accurate at higher levels of kidney function, probably reflecting a greater proportional contribution of creatinine generation to variation in the serum creatinine level than at lower levels of kidney function.⁵Cystatin C is a marker of kidney function that is less sensitive to differences in muscle mass than is serum creatinine.⁴ Cystatin C predicted total and cardiovascular mortality risk more strongly than creatinine-based estimates of GFR in prospective studies of older adults.^6,7 Data on younger individuals are lacking. Recent data allow GFR estimation from serum cystatin C and showed that equations using both serum creatinine and cystatin C, in addition to age, race, and gender, are more closely correlated with directly measured GFR among individuals with chronic kidney disease (CKD) than equations based on either marker alone.⁸ The associations with mortality risk of eGFR based on serum creatinine, cystatin C, or the combination of the two, however, has not been studied. As the use of cystatin C as a marker of cardiovascular risk increases, it is critical to understand how one should combine information on serum creatinine with cystatin C for risk prediction. We analyzed up to 13 yr of mortality follow-up on 6942 participants in the Third National Health and Nutrition Examination Survey (NHANES III) to assess the association of eGFR based on equations using creatinine, cystatin C, or both markers with the risk for all-cause and cardiovascular mortality in a representative sample of US adults.     

Serum cystatin C--a superior marker of rapidly reduced glomerular filtration after uninephrectomy in kidney donors compared to creatinine

AIMS: Acute renal failure (ARF), defined by a rapid decrease of glomerular filtration rate (GFR), is associated with high mortality. Early and accurate detection of decreasing GFR is critical to prevent the progression of ARF and to potentially improve its outcome. Serum creatinine, the conventional GFR marker, has major limitations. We prospectively evaluated whether serum cystatin C detected a rapid GFR decrease earlier and more accurately than serum creatinine. METHODS: In ten patients undergoing nephrectomy for living related kidney transplantation, serum creatinine and cystatin C were determined daily. The decrease of GFR was quantitated preoperatively by creatinine clearance and MAG3 scintigraphy. The GFR decrease was defined by a 50-100% increase of cystatin C or creatinine from preoperative values. Ten patients without renal impairment served as controls. RESULTS: Initially, patients had a creatinine clearance of 105 +/- 14 ml/min/1.73 m2. Due to nephrectomy, patients lost 45 +/- 3% of their renal function. Serum cystatin C significantly increased already one, serum creatinine two days after nephrectomy. Cystatin C demonstrated an increase by 50-100% 1.4 +/- 0.9 days earlier than creatinine (p = 0.009). Serum cystatin C performed well detecting the GFR decrease with higher diagnostic values compared to creatinine. This was indicated by a sensitivity of 50, 70 and 80% of cystatin C to detect the GFR decrease on the three days following nephrectomy. CONCLUSIONS: Serum cystatin C detects rapid GFR decreases one to two days earlier than creatinine. Cystatin C is an early and accurate marker to detect rapid GFR decreases as in ARF.     

Cystatin C,creatinine, estimated glomerular filtration,and long-term mortality in stroke patients

Renal dysfunction is associated with mortality in patients after ischemic stroke. Cystatin C is a potentially superior marker of renal function compared to creatinine and estimated glomerular filtration rate (GFR). In our observational cohort study, 390 Caucasian patients suffered from acute ischemic stroke (mean age 70.9 years; 183 women and 207 men) were included and prospectively followed up to maximal 56 months. Serum creatinine and cystatin C were measured at admission to the hospital; GFR was estimated according to CKD-EPI creatinine and CKD-EPI creatinine/cystatin equations. According to values of serum creatinine, estimated GFR and serum cystatin C patients were divided into quintiles. In the follow-up period, 191 (49%) patients died. For serum cystatin C and estimated GFR based on creatinine and cystatin C, the mortality and the hazard ratios for long-term mortality increased from the first to the fifth quintile nearly linearly. The associations of serum creatinine and estimated GFR categories based on creatinine with long-term mortality were J-shaped. As compared with lowest quintile of serum cystatin C, the fifth quintile was associated with long-term mortality significantly also after multivariate adjustment (age, gender, initial stroke severity, known risk factors for stroke mortality). In contrast, in adjusted analysis serum creatinine and estimated GFR (CKD-EPI creatinine and CKD-EPI creatinine/cystatin) were not associated with long-term mortality. In summary, serum cystatin C was independently and better associated with the risk of long-term mortality in patients suffering from ischemic stroke than were creatinine and estimated GFR using both CKD-EPI equations.     

Spatial inhomogeneity of common carotid artery intima-media is increased in dialysis patients.

BACKGROUND: Structural abnormalities of the common carotid artery (CCA), as assessed by ultrasound techniques, are related to cardiovascular outcome in dialysis patients. An increased intima media thickness (IMT) of the CCA may both represent a reaction to a haemodynamic burden as well as atherosclerosis. With a new ultrasound technique CCA-IMT and IMT-inhomogeneity, a novel parameter of spatial variance of the IMT, were measured and related to traditional and non-traditional risk factors. METHODS: In a cross-sectional study, we included 134 dialysis patients, aged 61+/-13 years (103 on haemodialysis, 31 on peritoneal dialysis) and 41 controls, aged 60+/-8 years. Age, sex, pulse pressure, diabetes, prevalent cardiovascular disease (CVD) and height were included in the basic multiregression analysis. Ultrasound examination of the CCA was performed. We also measured serum fetuin-A, high-sensitivity C-reactive protein (hsCRP), antibodies to oxidized low density lipoproteins (anti-oxLDL antibodies), calcium, phosphate, albumin and parathyroid hormone. RESULTS: Compared with controls, dialysis patients had a greater CCA-IMT (670 microm vs 590+/-10 microm; P=0.002) and a greater CCA-IMT inhomogeneity (11.0 vs 8.1%; P=0.013). Dialysis patients with CVD had a greater CCA-IMT (734 microm vs 631 microm; P=0.001) and IMT-inhomogeneity (13.2 vs 9.7; P=0.008) compared with patients without CVD. IMT-inhomogeneity strongly correlated with IMT (R=0.65, P<0.0001). In multiregression analysis, serum fetuin-A and anti-oxLDL antibodies correlated with IMT-inhomogeneity but not with IMT. HsCRP neither correlated with IMT-inhomogeneity nor with IMT. CONCLUSION: The present study shows that CCA-IMT and IMT-inhomogeneity were increased in dialysis patients compared with controls. Although CCA-IMT and IMT-inhomogeneity are related, the different associations between both measurements and non-traditional risk factors show that they are distinct entities.     

Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula?

It is common practice to estimate glomerular filtration rate (GFR) from the Schwartz formula (a height creatinine/ratio), although it has its limitations. Cystatin C was found to be a superior marker of GFR. No formula has been validated to estimate GFR from cystatin C in children. Children (aged 1.0–18 years, n=536) with various renal pathologies undergoing nuclear medicine GFR clearance studies (^99mTc-DTPA single-injection technique) were tested. Cystatin C was measured with a nephelometric assay. The Schwartz GFR was calculated using enzymatically determined serum creatinine in micromoles per liter using the constant 48 for adolescent males and 38 otherwise. Using multiple stepwise regression analysis on log/log-transformed data, we derived the following relationship between the cystatin C concentration and GFR: log(GFR)=1.962+[1.123*log(1/Cystatin C)]. Using the Bland and Altman analysis to test agreement between the Schwartz formula and gold standard GFR showed considerable bias, with a mean difference of +10.8% and a trend towards overestimation of the GFR by the Schwartz formula with lower GFRs. In contrast, the Bland and Altman analysis applied on the GFR estimate derived from cystatin C showed the mean difference to be negligible at +0.3% and no trend towards overestimation of the GFR with lower GFRs. In the regression analysis of the estimate and the GFR, the Schwartz estimate showed significant deviation from linearity, whereas the cystatin C estimate did not. In conclusion, the data suggest that this novel cystatin C-based GFR estimate shows significantly less bias and serves as a better estimate for GFR in children.This study was supported by a research grant from Dade Behring GmbH, Germany. There is no conflict of interest.     

Cystatin C identifies chronic kidney disease patients at higher risk for complications

Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9% had CKD by the creatinine-based equation only, 2% had CKD by the cystatin C-based equation only, and 4% had CKD by both equations; in CHS, these percentages were 12, 4, and 13%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95% CI 0.98 to 1.21), 1.78 (95% CI 1.53 to 2.08), and 1.74 (95% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.     

Pulse pressure and subclinical cardiovascular damage in primary hypertension.

BACKGROUND: High pulse pressure (PP) values have recently been implicated in the development and progression of large vessel atherosclerosis, small vessel disease, and in the occurrence of cardiovascular events. The aim of the present study is to investigate the relationship between PP and subclinical cardiovascular damage in a cohort of unselected middle-aged patients (204 male, 129 female) with untreated primary hypertension. METHODS: PP was calculated as the difference between systolic (SBP) and diastolic blood pressure (DBP). Left ventricular mass index (LVMI) was assessed by M-B mode echocardiography (LVH=LVMI>51 g/m(2.7)), and carotid intima-media thickness (IMT) by high-resolution US scan. Albuminuria was measured as the albumin to creatinine ratio (ACR) in three non-consecutive first morning urine samples. RESULTS: PP was positively correlated to gender (P<0.05), duration of disease (P<0.001), age (P<0.0001), LDL cholesterol (P=0.007), and to early signs of target organ damage (TOD), namely LVMI (P<0.0001), IMT (P<0.0001), and ACR (P=0.036). Patients in the upper quartile of PP showed higher LVMI (P<0.001), thicker carotid walls (P<0.001), as well as higher ACR (P<0.04). Multiple linear regression analysis showed that PP and ACR independently influence LVMI (F=26.476, r(2)=0.29, P<0.0001) and IMT (F=17.813, r(2)=0.26, P<0.0001). Patients with LVH, increased carotid IMT and microalbuminuria showed higher PP values as compared with those with lesser degrees of target organ involvement (F=4.97, P<0.003 inter-group comparison). Moreover, the risk of having the simultaneous occurrence of various signs of TOD increases significantly with each SD increase in PP or SBP, but is not influenced by DBP. CONCLUSIONS: PP is an independent marker of preclinical cardiovascular damage in relatively young patients with primary hypertension and, therefore, can be useful for identifying those at higher risk of cardiovascular events.     

Serum cystatin C as a reliable marker of changes in glomerular filtration rate in children with urinary tract malformations

PURPOSE: Cystatin C has been suggested as a simple method of estimating GFR more accurately than creatinine in children. We compared the diagnostic accuracy of cystatin C with serum creatinine and the Schwartz formula for estimating GFR in patients with UTMs. MATERIALS AND METHODS: We prospectively compared 72 patients with UTMs (20 days to 36 months old, 58 males and 14 females) with a group of 72 healthy controls (10 days to 48 months old, 53 males and 19 females). All patients underwent nuclear medicine clearance investigations with (99m)Tc DTPA. RESULTS: Serum concentration of cystatin C revealed a higher correlation with (99m)Tc DTPA (r = 0.62, p <0.001) than serum concentration of creatinine (r = 0.30, p <0.01) or Schwartz formula (r = 0.51, p <0.001). These results were more evident in patients with uropathy (19) with mild renal impairment. Agreement between methods was assessed using Bland Altman analysis. Mean differences between GFR calculated with (99m)Tc DTPA and cystatin C based GFR estimation or Schwartz formula were -2.6% +/- 46.7% and -73.4% +/- 53.6%, respectively. Diagnostic accuracy in identifying decreased GFR measured as AUC was always highest for cystatin C but hardly sufficient for the 3 variables. Cystatin C performed better in the 0 to 6-month-olds (0.70 +/- 0.08 for cystatin C, 0.58 +/- 0.07 for Schwartz estimate) and patients older than 12 months (0.82 +/- 0.09 for cystatin C, 0.65 +/- 0.11 for Schwartz estimate). CONCLUSIONS: Cystatin C proved to be a superior marker rate over serum creatinine in estimating glomerular filtration in children younger than 3 years with UTMs and mild renal impairment, thus, offering a more specific and practical measure for monitoring GFR.     

Association of cystatin C and estimated GFR with inflammatory biomarkers: the Heart and Soul Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 eGFR60 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). CONCLUSIONS: 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.     

Subclinical atherosclerosis is increased in type 2 diabetic patients with microalbuminuria evaluated by intima-media thickness and pulse wave velocity

BACKGROUND: Microalbuminuria appears to be a risk marker for atherosclerosis. However, little is known about the direct association between microalbuminuria and vascular wall properties. METHODS: Subjects were 306 type 2 diabetic patients with normoalbuminuria (N= 200) and microalbuminuria (N= 106). Those who had macroalbuminuria, atherosclerotic vascular disease, and/or ankle brachial index being less than 0.9 were not included. Brachial-ankle pulse wave velocity (PWV) was measured by automatic oscillometric method. Intima-media thickness (IMT) of the common carotid artery was measured using high-resolution B-mode ultrasonography and a computerized image-analyzing system. RESULTS: Average IMT, maximum IMT, and PWV were significantly higher in patients with microalbuminuria than in patients with normoalbuminuria. Both average and maximum IMT increased significantly as albuminuria increased in the microalbuminuric range. Average IMT and maximum IMT correlated significantly with PWV (P < 0.0001), although some patients exhibited increased levels of only PWV or IMT. By a multiple linear regression, age and albuminuria were independent predictors of IMT and PWV. Waist circumference was an independent predictor of IMT. Hypertension and hemoglobin A(1c) (HbA(1c)) were independent predictors of PWV. After adjustment for conventional cardiovascular risk factors including age, sex, waist circumference, HbA(1c), hypertension, hyperlipidemia, and smoking, albuminuria revealed a significant association with average IMT, maximum IMT, and PWV (P < 0.05, P < 0.0001, and P < 0.05, respectively). CONCLUSION: A slight elevation of albuminuria is a significant determinant of IMT and PWV independent of conventional cardiovascular risk factors in type 2 diabetic patients with no clinical nephropathy or any vascular diseases. This significant association might point to a link in the pathogenesis of atherosclerosis and diabetic nephropathy.     

Cystatin C does not detect acute changes in glomerular filtration rate in early diabetic nephropathy

BACKGROUND: The measurement of renal functional reserve (acute change in glomerular filtration rate [GFR] after protein load) allows the detection of sub-clinical renal dysfunction and has prognostic implications in diabetes. Our aim was to test cystatin C as an index of GFR and renal functional reserve. METHODS: GFR was measured by C(Sinistrin) at baseline and after protein load in 28 diabetic patients with serum creatinine <1.2 mg/dL. The C(Sinistrin) was compared with cystatin C, serum creatinine, creatinine clearance, and Cockcroft-Gault formula. RESULTS: Baseline C(Sinistrin) ranged from 67-172 mL/min. Regression analysis showed an overall low relationship between C(Sinistrin) and the indirect markers of GFR. The highest correlation with C(Sinistrin) was obtained for cystatin C clearance (R(2) = 0.58, r = 0.76, p < 0.001), the 1/serum cystatin C (R(2) = 0.58, r = 0.76, p < 0.001), and serum cystatin C (R(2) = 0.52, r = 0.72, p < 0.001). Renal functional reserve was preserved in 6 of 28 patients. There was no significant change in cystatin C in response to protein load. CONCLUSION: Wide variation in baseline GFR emphasizes the need for the early detection of renal dysfunction. Cystatin C correlated best with C(Sinistrin) at baseline, but did not detect renal functional reserve.     

血清半胱氨酸蛋白酶抑制剂C在急性肾衰早期诊断中的价值

目的 探讨半胱氨酸蛋白酶抑制剂C（cystatin C）在早期预测和诊断急性肾衰竭（ARF）中是否优于血清肌酐（Scr）。方法 前瞻性收集我院103例重症监护室危重患者资料，每例患者每天采集血标本。同时应用酶法测Scr水平；用颗粒增强透射免疫比浊法（PETIA）检测血清cystatin C水平；用Cockroft-Gauh公式估算肾小球滤过率（eGFR）。ARF运用ADQI的RIFLE标准进行诊断（R：Scr升高≥50％基础值，I：Scr升高≥100％基础值，F：Scr升高≥200％基础值，L：肾功能丧失；E：终末期肾脏病ESRD）；同时ARF也按cystatin C升高≥50％、≥100％和≥200％的标准进行诊断。结果 27（26．2％）例患者发生不同程度ARF，其中15例经历R标准，18例经历I标准，9例经历F标准，3例经历LE标准。其余76例没有发生ARF的患者作为对照组。ARF患者的cystatinC较非ARF患者显著升高（P〈0．01），ARF患者的cystatin C与Scr（r=0．747，P〈0．01）、（cystatinC）^-1与eGFR（R=0．815，P〈0．01）呈明显线性相关。分别按照cystatin C和Scr两种方法诊断ARF，不同程度ARF诊断的中位时间是：R标准的15例患者分别为2d（1～4d）和3d（2～6d）（P=0．011）；Ⅰ标准18例患者分别为4d（1～8d）和5．5d（2～10d）（P=0．006）；F标准的9例患者分别为5d（3～lld）和6d（3～13d）（P=0．02）。ROC分析证实cystatinC在ARF诊断中的准确性高，曲线下面积为0．995，95％可信区间为0．984～1．006（P〈0．001）。当以cystatin C升高≥50％时作为ARF的诊断截点时，cystatin C在ARF诊断中的敏感性和特异性分别为93％和96％。结论 cystatin C可以作为急性肾衰竭的诊断指标：cystatin C在ARF的诊断时间上较Scr更早，可作为ARF的早期预测指标之一。     

Cystatin C is a more sensitive marker than creatinine for the estimation of GFR in type 2 diabetic patients

BACKGROUND: Glomerular filtration rate (GFR) is the best overall index of renal function in health and disease. Inulin and 51Cr-EDTA plasma clearances are considered the gold standard methods for estimating GFR. Unfortunately, these methods require specialized technical personnel over a period of several hours and high costs. In clinical practice, serum creatinine is the most widely used index for the noninvasive assessment of GFR. Despite its specificity, serum creatinine demonstrates an inadequate sensitivity, particularly in the early stages of renal impairment. Recently, cystatin C, a low molecular mass plasma protein freely filtered through the glomerulus and almost completely reabsorbed and catabolized by tubular cells, has been proposed as a new and very sensitive serum marker of changes in GFR. This study was designed to test whether serum cystatin C can replace serum creatinine for the early assessment of nephropathy in patients with type 2 diabetes. METHODS: The study was performed on 52 Caucasian type 2 diabetic patients. Patients with an abnormal albumin excretion rate (AER) were carefully examined to rule out non-diabetic renal diseases by ultrasonography, urine bacteriology, microscopic urine analysis, and kidney biopsy. Serum creatinine, serum cystatin C, AER, serum lipids, and glycosylated hemoglobin (HbA1c) were measured. GFR was estimated by the plasma clearance of 51Cr-EDTA. In addition the Cockcroft and Gault formula (Cockcroft and Gault estimated GFR) was calculated. RESULTS: Cystatin C serum concentration progressively increased as GFR decreased. The overall relationship between the reciprocal cystatin C and GFR was significantly stronger (r = 0.84) than those between serum creatinine and GFR (r = 0.65) and between Cockcroft and Gault estimated GFR and GFR (r = 0.70). As GFR decreased from 120 to 20 mL/min/1.73 m2, cystatin C increased more significantly that serum creatinine, giving a stronger signal in comparison to that of creatinine over the range of the measured GFR. The maximum diagnostic accuracy of serum cystatin C (90%) was significantly better than those of serum creatinine (77%) and Cockcroft and Gault estimated GFR (85%) in discriminating between type 2 diabetic patients with normal GFR (>80 mL/min per 1.73 m2) and those with reduced GFR (<80 mL/min/1.73 m2). In particular, the cystatin C cut-off limit of 0.93 mg/L corresponded to a false-positive rate of 7.7% and to a false-negative rate of 1.9%; the serum creatinine cut-off limit of 87.5 micromol/L corresponded to a false-positive rate of 5.8% and to a false-negative rate of 17.0%. CONCLUSIONS: Cystatin C may be considered as an alternative and more accurate serum marker than serum creatinine or the Cockcroft and Gault estimated GFR in discriminating type 2 diabetic patients with reduced GFR from those with normal GFR.     

Evaluation of cystatin C with iohexol clearance in cardiac surgery

Background: Post‐operative renal dysfunction after cardiac surgery is not uncommon and can lead to adverse outcome. The ability to accurately monitor renal function is therefore important. Cystatin C is known to be a sensitive marker of the glomerular filtration rate (GFR), but it has not been fully evaluated in cardiac surgery. Iohexol clearance is considered a reliable reference method for the determination of GFR. The aim of this study is to, for the first time, evaluate the diagnostic accuracy of plasma cystatin C compared with iohexol clearance in cardiac surgery. Methods: Twenty‐one patients scheduled for elective coronary artery bypass grafting were prospectively enrolled in the study. Before surgery and on the second post‐operative day, an iohexol clearance was performed. Plasma cystatin C, plasma creatinine and plasma C‐reactive protein were determined before surgery and on the first, second, third and fifth post‐operative day. Estimated creatinine and cystatin C clearances were determined. Results: Post‐operative cystatin C and 1/cystatin C correlated strongly to iohexol clearance (r=?0.90 and 0.86) and so did creatinine and 1/creatinine (r=?0.83 and 0.78). Estimated creatinine clearance differed from iohexol clearance (P<0.01), whereas estimated cystatin C clearance did not differ from iohexol clearance (P=0.81). No correlation was found between C‐reactive protein and cystatin C. Conclusion: This study indicates that clearance estimations based on cystatin C are more accurate compared with estimations based on creatinine in determining GFR in cardiac surgery. Cystatin C has, in this study population, a stronger correlation to iohexol clearance than creatinine.     

Renal artery calcified plaque associations with subclinical renal and cardiovascular disease

BACKGROUND: The prognostic significance of renal artery calcified plaque (RAC) and its relationship with renal function, albuminuria, and systemic atherosclerosis are unknown. METHODS: Calcified atherosclerotic plaque was measured in the renal arteries of 96 unrelated Caucasian subjects with type 2 diabetes mellitus (DM) using four-channel multidetector-row computed tomography (MDCT4). Renal artery calcium was measured as the sum of ostial and main renal artery calcium scores. Participants also underwent MDCT scanning to measure coronary artery calcium (CAC), carotid artery calcium, common iliac artery calcium, infra-renal aorta calcium, and B-mode ultrasound to measure carotid artery intima-medial thickness (IMT). Spearman's rank correlation coefficients were used to assess associations between RAC and measures of subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, gender, body mass index (BMI), DM duration, smoking, and serum cholesterol and triglyceride levels. RESULTS: Characteristics of the study group were 54% (52/96) female with a mean +/- SD (median) age 62.8 +/- 8.4 (62.5) years, DM duration 10.6 +/- 6.3 (8.0) years, hemoglobin A1C 7.5 +/- 1.5 (7.2)%, BMI 32.1 +/- 6.3 (31.1) kg/m(2), serum creatinine concentration 1.11 +/- 0.18 (1.10) mg/dL, urine albumin:creatinine ratio (ACR) 105.3 +/- 423.1 (17.6) mg/g, modified MDRD equation glomerular filtration rate (GFR) 64.3 +/- 12.6 (63.6) mL/min, RAC 372 +/- 799 (101), CAC 1819 +/- 2594 (622), carotid artery calcium 264 +/- 451 (72), and B-mode ultrasound carotid IMT 0.70 +/- 0.12 (0.69) mm. Sixty-five percent of subjects (62/96) had detectable RAC. Renal artery calcium was significantly associated with CAC (r= 0.50, P < 0.0001), carotid artery calcium (r= 0.58, P < 0.0001), common iliac artery calcium (r= 0.45, P < 0.0001), infra-renal aorta calcium (r= 0.70, P < 0.0001), IMT (r= 0.40, P= 0.0004), diastolic blood pressure (r=-0.33, P= 0.0009), BMI (r=-0.19, P= 0.0573), and age (r= 0.54, P < 0.0001). There was no association between RAC and GFR (r=-0.15, P= 0.1637) or between RAC and urine ACR (r= 0.07, P= 0.5083). CONCLUSION: Renal artery calcium is strongly associated with older age, diastolic blood pressure, BMI, carotid artery IMT, and coronary, carotid, common iliac artery, and infra-renal aorta calcium in Caucasians with type 2 diabetes mellitus. Renal artery calcium, similar to CAC and IMT, appears to be a useful noninvasive marker of subclinical atherosclerosis. However, RAC is not significantly associated with either GFR or albuminuria.     

Cystatin C--a marker for assessment of the glomerular filtration rate in patients with cisplatin chemotherapy

BACKGROUND: Cystatin C has recently been proposed as an ideal marker for glomerular filtration rate (GFR). In this study, cystatin C serum levels were evaluated in comparison to serum creatinine concentrations and inulin clearances in patients with normal kidney function receiving cisplatin-based chemotherapy to assess the validity of cystatin C as an alternative endogenous marker of GFR. METHODS: Blood samples for the assessment of cystatin C, creatinine and inulin clearances were collected in patients before and after application of cisplatin in a clinical trial. Overall, 41 patients were included in the study, 35 of them were eligible receiving cisplatin in two different cisplatin-based chemotherapy schedules. RESULTS: A 21% increase of cystatin C serum levels was demonstrated in the placebo group after application of cisplatin. Analysis of inulin clearances revealed a 23% loss of inulin clearance in patients of the placebo arm. In contrast, significant changes could not be detected by analysis of serum creatinine levels. CONCLUSIONS: Cystatin C represents a more sensitive clinical marker than serum creatinine for the early assessment of GFR damage caused by cisplatin. Changes in cystatin C serum concentrations correlate well to GFR decrease as measured by inulin clearance.     

血半胱氨酸蛋白酶抑制剂C在筛查早期肾功能异常中的临床意义

目的探讨血半胱氨酸蛋白酶抑制剂C在健康体检中筛查早期肾功能异常的临床意义。方法选择在我院健康体检中心的体检者75名,根据半胱氨酸蛋白酶抑制剂C水平将研究对象分为实验组和对照组,比较2组血半胱氨酸蛋白酶抑制剂C、血肌酐、尿素氮和99mTc—DTPA清除率。结果实验组血清半胱氨酸蛋白酶抑制剂C浓度高于对照组（P〈0．01）,实验组肾小球滤过率低于对照组（P〈0．01）。2组血肌酐和尿素氮均在正常范围,组间无统计学差异（P〉0．05）。血清半胱氨酸蛋白酶抑制剂C浓度与肾小球滤过率呈负相关（r=-0．75,P〈0．01）。结论血半胱氨酸蛋白酶抑制剂C是反映肾小球滤过率灵敏指标,为在健康体检中筛查早期肾功能异常提供了一个优于其他的指标。