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Glomerular filtration rate (GFR) measured by urinary clearance of inulin is considered the gold standard for assessment of kidney function in both adults and children. Because the procedure is cumbersome, GFR is estimated (eGFR) using algorithms based on the observed relationship between measured GFR (mGFR) and more accessible biomarkers such as creatinine and cystatin C. In children, most of the data on this relationship is retrieved from patients with reduced kidney function. Nonetheless, eGFR equations are widely in use in healthy children to evaluate kidney status and diagnose kidney disease. The aim of the present study was to compare the distribution of eGFR using two established pediatric eGFR equations incorporating age, height and serum creatinine (Schwartz-Lyon and Full Age Spectrum-height) and two recently published equations restricted to age and serum creatinine (Lund-Malmö Revised 18 and European Kidney Function Consortium equation) in 1200 healthy schoolchildren age 6-12 years. In addition, we present 2.5th, median and 97.5th percentiles for serum creatinine stratified by age and gender. Depending on the equation used, mean eGFR ranged from 101.6 to 115.4 mL/min/1.73 m2. The lower 2.5th percentile ranged from 83.3 to 89.0 mL/min/1.73 m2 and the fraction of children with eGFR < 90 mL/min/1.73 m2 ranged from 2.9% to 9.8%. In conclusion, expected values of eGFR in healthy children are significantly dependent on the equation used. When decision limits for diagnosis or classification are applied to eGFR results, the related equation should be clearly stated. [ABSTRACT FROM AUTHOR]

Plasma cystatin C and shrunken pore syndrome (SPS) are associated with increased mortality in older adults. The objective was to assess the association between these markers of kidney function at admission and mortality in hip fracture patients. Hip fracture patients presenting at Lund University Hospital were eligible for inclusion. Cox regression was used to assess association between plasma cystatin C, creatinine, cystatin C- or creatinine-based estimations of glomerular filtration rate (eGFRCYS and eGFRCREA), or SPS (defined as eGFRCYS/eGFRCREA < 0.7) and mortality during one year follow up. Improvement in discrimination relative to the Nottingham Hip fracture score was assessed by Receiver Operational Characteristics (ROC) analysis and calculation of Net Reclassification Index (NRI). 996 patients were included in the study. Cystatin C, creatinine, eGFRCYS and eGFRCREA were associated with one-year mortality in both unadjusted and adjusted analyses. The association with mortality was stronger for cystatin C and for eGFRCYS than for creatinine and eGFRCREA. Patients with SPS had doubled mortality compared with patients without SPS (43.7 and 20.2%, respectively, p <.001). Hazard ratio for SPS in the adjusted analysis was 1.66 (95%CI; 1.16–2.39, p =.006). None of the markers improved discrimination compared to the Nottingham Hip Fracture Score using ROC analysis whereas eGFRCYS and eGFRCREA improved NRI. Our conclusion is that plasma concentrations of creatinine or cystatin C, eGFRCYS or eGFRCREA or SPS at admission in hip fracture patients are associated with mortality when known risk factors are accounted for. Identification of high risk patients may be improved by eGFRCYS or eGFRCREA. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the influence of shrunken pore syndrome (SPS), defined as a cystatin C (CysC)-based estimated glomerular filtration rate (eGFRCysC) <60% of the creatinine (Cr)-based eGFR (eGFRCr), on bone mineral density (BMD) in patients with rheumatic diseases. A total of 831 patients with rheumatic diseases were enrolled in the study. Patients were classified into the SPS group (G-SPS) and non-SPS group (G-nSPS). The correlation between the presence of SPS and BMD of the lumbar spine (BMD_LS), BMD of the femoral neck (BMD_FN), serum parathyroid hormone (PTH) level, chronic kidney dysfunction (CKD), and parameters were evaluated statistically. The prevalence of SPS was 4.0%. Serum PTH level, tartrate-resistant acid phosphatase-5b (TRACP-5b), and eGFRCr in the G-SPS were significantly higher than in the G-nSPS, whereas BMD_LS and BMD_FN in the G-SPS were significantly lower than in the G-nSPS. Serum PTH level was significantly correlated with CysC. BMD_LS had no significant correlation with BMD_FN. The presence of SPS was the only factor that demonstrated significant negative correlation with both BMD_LS and BMD_FN. Relationship between BMD_LS and the presence of SPS was present regardless of CKD stage; however, the negative relationship between BMD_LS and serum PTH was observed only in CKD stage 1 and 2 patients. BMD_FN demonstrated significant negative correlation with serum PTH in the group with progression of CKD. These results suggest that there is a serious potential risk of osteoporosis in patients with SPS and increased PTH, and BMD_LS poses a higher risk in CKD stage 1 and 2. [ABSTRACT FROM AUTHOR]

The link between cystatin C and mortality independent of glomerular filtration rate (GFR) in adults has prompted the "Shrunken Pore Syndrome" (SPS) hypothesis, where high serum cystatin C with normal creatinine is explained by smaller glomerular pores, through which creatinine can pass freely, while the larger cystatin C, beta-trace protein (BTP) and pro-inflammatory molecules are retained. This study set out to apply the definition of SPS to children. In 294 children who underwent inulin clearance (Cin) test, serum creatinine, cystatin C and BTP were measured. For all three markers eGFRx was calculated using the full age spectrum equations. The ratio eGFRcys/eGFRcrea was plotted against the error of eGFRBTP(%) (i.e. eGFRBTP-Cin)/Cin*100%). Patients with and without SPS according to different cut-off points of eGFRcys/eGFRcrea and eGFRcys/Cin (i.e. ≤0.6,0.7,0.8) were compared in terms of eGFRx, Cin, error of eGFRx(%) and eGFRBTP/eGFRcrea-ratio. The ratio eGFRcys/eGFRcrea and error of eGFRBTP(%) were positively correlated. The prevalence of SPS by eGFRcys/eGFRcrea with a cut-off of 0.6 was 4.8%. Patients with SPS had a more negative error of eGFRcys(%) and eGFRBTP(%) and higher Cin regardless of the definition. Overestimation of eGFRcrea in patients with SPS was only present when using the eGFRcys/eGFRcrea rather than the eGFRcys/Cin definition. Cystatin C and BTP are related independent of creatinine, suggesting glomerular pore size as a common denominator. The prevalence of SPS in children is comparable to adults. For research in SPS, a definition based on eGFRcys/exogenous clearance study may be useful to study the effect of SPS on creatinine metabolism. [ABSTRACT FROM AUTHOR]

ABTRACTGlomerular filtration rate (GFR) has become the best indicator for assessing renal function. This study aims to validate the existing cystatin C (CysC)-derived estimated glomerular filtration rate (eGFR) equations in Chinese patients to explore whether the reported CysC-derived eGFR formulas could be applied to the Chinese population. This study validated the equations in a population totaling 1816 inpatients. We calculated eGFR by different CysC-derived equations, then compared with the mGFR. Equation performance was assessed by bias (mean difference between mGFR and eGFR), precision (inter-quartile range of difference) and accuracy (mainly, accuracy within 30% [P30]). All equations expressed poor performance in dialysis patients (n = 345), and the performance for non-dialysis patients (n = 1471) were significantly greater than that in dialysis patients. Feng and Pei equations had higher P30 (50.82% and 49.73%, respectively) than the widely used CKD-EPICysC (41.10%) and MacIsaac equations (48.23%), and the distribution of eGFR values is more similar to the distribution of mGFR in non-dialysis patients. Similar trends showed in mGFR, sex, age, and BMI subgroups. However, no equation met the guideline standard of P30 ≥ 75%. Our results suggest that the published CysC-based eGFR equations are not suitable for dialysis patients, and the accuracy of equations for non-dialysis patients significantly better than the dialysis ones. Moreover, Feng and Pei equation showed better performance in non-dialysis patients. [ABSTRACT FROM AUTHOR]

Shrunken pore syndrome (SPS) is a condition in which estimated glomerular filtration rate (eGFR) based upon cystatin C is lower than eGFR based upon creatinine. It has been associated with increased mortality even in the presence of normal GFR in both a cardiac surgical population and a general population. No systematic studies of the variation in eGFRcystatin C/eGFRcreatinine-ratio used for SPS diagnosis have been published. This study aims to evaluate whether early and midterm mortality following elective cardiac surgery varies with the ratio used to identify SPS. Preoperative levels of cystatin C and creatinine were analysed in 4007 patients undergoing elective coronary artery bypass grafting (CABG) and/or surgical aortic valve replacement (sAVR). The eGFRcystatin C/eGFRcreatinine-ratio was calculated based on the equation pairs CKD-EPIcystatin C/CKD-EPIcreatinine and CAPA/LMrev. The overall 1- and 3-year all-cause mortality was 2.9 and 6.8%, respectively. Mean follow-up time was 3.6 years. Mortality markedly and progressively increased with a decrease in the eGFRcystatin C/eGFRcreatinine-ratio for both equation pairs. An increase in mortality was noted already when the ratio decreased from 1.0 to 0.90. To facilitate the clinical decisions based upon the SPS-defining eGFRcystatin C/eGFRcreatinine-ratio, we calculated both the ratios defining the highest combined sensitivity and specificity and the ratios producing a high specificity of 95%, finding different cut-off for these scenarios. [ABSTRACT FROM AUTHOR]

Preterm neonates with respiratory distress syndrome (RDS) are at increased risk of acute kidney injury (AKI). Our study aimed at determining whether serum cystatin C (sCysC) on day 3 of life (D3) can early predict AKI in preterm neonates with RDS. This prospective study was conducted on 75 preterm neonates; 50 with RDS and 25 without RDS. On D3, sCysC, serum creatinine (sCr) and blood urea nitrogen (BUN) were measured and estimated glomerular filtration rate (eGFR) was calculated. sCr and BUN levels were measured again on days 5 and 7. Neonates were evaluated for development of AKI during first week of life according to the modified pediatric RIFLE (pRIFLE) criteria. Thirteen neonates with RDS developed AKI (26%).There was no significant difference between RDS and control groups with respect to sCysC. RDS neonates with AKI had significantly higher sCysC than those without AKI (1.62 ± 0.12 versus 1.16 ± 0.09 mg/l; p < .001). RDS grade III-IV neonates had significantly higher sCysC than RDS grade I-II. There was a significant positive correlation between D3 sCysC and (D5 and D7 sCr and BUN). Receiver operating characteristic (ROC) curve showed that D3 sCysC can predict AKI in preterm neonates with RDS at a cutoff point of >1.3 mg/l with sensitivity of 92.30% and specificity of 96%. We conclude that neonates with RDS are at increased risk of AKI. sCysC on day 3 of life can predict AKI earlier than Cr and eGFR. [ABSTRACT FROM AUTHOR]

Early biochemical identification of women at high risk for the development of pre-eclampsia (PE) is still unsatisfactory. Renal markers measured during the first trimester were analysed to predict later occurrence of PE. A nested case-control study was conducted within the prospective predictive markers for the diagnosis of preeclampsia study. Pregnant women were included at the end of the first trimester and followed up until birth. Controls were matched to PE cases. Renal markers [i.e. creatinine, cystatin C (CysC), β2microglobulin (B2M), β-trace protein (BTP), glomerular filtration rate estimations (eGFR) of the aforementioned markers, uric acid (UA), urea, and serum uromodulin (sUMOD)] were compared to placental growth factor (PlGF), a marker known to predict PE later in pregnancy. Reference intervals were determined for the different markers. In the 183 women (PE,n = 39; controls,n = 144), CysC, the CysC/PlGF ratio (p < .01) and UA were higher, whereas the eGFRCysC/eGFRCrearatio (a marker of glomerular endothelial integrity and shrunken pore syndrome) and PlGF were lower in women who developed PE (p < .05 for all). Compromised filtration of the larger molecule CysC together with a normal creatinine, in a subset of PE cases (15.3%) was a unique, strong and independent predictor of later PE if the baseline CysC concentration was >0.85 mg/l. In conclusion, CysC and its derivatives as well as UA, indicating volume expansion, measured at the end of the first trimester are predictive of PE. Thus, women can be easily identified and followed as an early reduction in glomerular filtration quality poses a high risk for a subsequent development of PE. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Estimating glomerular filtration rate (GFR) in adults by using the average of values obtained by a cystatin C- (eGFRcystatin C) and a creatinine-based (eGFRcreatinine) equation shows at least the same diagnostic performance as GFR estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparison of eGFRcystatin C and eGFRcreatinine plays a pivotal role in the diagnosis of Shrunken Pore Syndrome, where low eGFRcystatin C compared to eGFRcreatinine has been associated with higher mortality in adults. The present study was undertaken to elucidate if this concept can also be applied in children. Using iohexol and inulin clearance as gold standard in 702 children, we studied the diagnostic performance of 10 creatinine-based, 5 cystatin C-based and 3 combined cystatin C-creatinine eGFR equations and compared them to the result of the average of 9 pairs of a eGFRcystatin C and a eGFRcreatinine estimate. While creatinine-based GFR estimations are unsuitable in children unless calibrated in a pediatric or mixed pediatric-adult population, cystatin C-based estimations in general performed well in children. The average of a suitable creatinine-based and a cystatin C-based equation generally displayed a better diagnostic performance than estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparing eGFRcystatin and eGFRcreatinine may help identify pediatric patients with Shrunken Pore Syndrome. [ABSTRACT FROM AUTHOR]

Most studies that validate GFR equations present accuracy results stratified by measured GFR (mGFR; diagnostic correctness) or by estimated GFR (eGFR; diagnostic predictiveness) only, without a clear distinction in interpretation. The accuracy of a GFR equation is normally reported in percent (e.g. P30), but is often misinterpreted when stratified by eGFR. The aim of the study was to develop new accuracy measures and diagrams that allow straightforward interpretations and illustrations of the uncertainty in eGFR in clinical practice. We applied quantile regression to the distribution of estimation errors for two creatinine-based GFR equations, LM-REV and CKD-EPI, in a clinical cohort (n = 3495) referred for GFR measurement (plasma clearance of iohexol). Measures of bias and precision and accuracy intervals (AIs) were expressed in mL/min/1.73 m2. Diagrams with AIs were chosen as a novel way to present the error margin in eGFR at a pre-specified certainty level. It was shown that creatinine-based equations are still quite inaccurate in that large estimation errors could not be ruled out with satisfactory certainty. As an example, the 75% AI for the most accurate equation, LM-REV, was approximately ±10 mL/min/1.73 m2at eGFR = 45 mL/min/1.73 m2, whereas it ranged between −13 and +20 mL/min/1.73 m2at eGFR = 90 mL/min/1.73 m2. Accuracy intervals presented in diagrams can be used to illustrate the uncertainty of eGFR. Future validation studies should assess the variability in the predictiveness of eGFR across populations and clinical settings using tools and performance measures that are easy to interpret. [ABSTRACT FROM PUBLISHER]

The ratio of cystatin C to creatinine (cysC/crea) is regarded as a marker of glomerular filtration quality and predicts mortality. It has been hypothesized that increased mortality may be mediated by the retention of biologically active substances due to shrinking glomerular pores. The present study investigated whether cysC/crea is independently associated with the levels of two renally cleared hormones, which have been linked to increased mortality. We conducted a multicenter, cross-sectional study with a random selection of general practitioners (GPs) from all GP offices in seven Swiss cantons. Markers of glomerular filtration quality were investigated together with estimated glomerular filtration rate (eGFR), albuminuria and urinary neutrophil gelatinase associated lipocalin (uNGAL) as well as two renally cleared low-molecular-weight protein hormones (i.e. BNP and PTH), Morbidity was assessed with the Charlson Comorbidity Index (CCI). A total of 1000 patients (433 males; mean age 57 ± 17 years) were included. There was a significant univariate association of BNP (r = 0.36,p < 0.001) and PTH (r = 0.18,p < 0.001) with cysC/crea. An adjusted model that accounted for kidney function (eGFR), altered glomerular structure (albuminuria), renal stress (uNGAL), and CCI showed that BNP and PTH were independently associated with cysC/crea as well as with the ratio of cystatin C-based to creatinine-based eGFR. In conclusion, in primary care patients, BNP and PTH are independently associated both with markers of glomerular filtration quality and eGFR regardless of structural kidney damage or renal stress. These findings offer an explanation, how altered glomerular filtration quality could contribute to increased mortality. [ABSTRACT FROM PUBLISHER]

BackgroundIn critical care patients, the diagnosis of subclinical acute kidney injury (AKI) might be difficult with measurements of serum creatinine and estimated glomerular filtration rate (eGFR). Their ‘sensitive kidneys’ can easily be affected from sepsis, underlying diseases, medications and volume status and if they can be detected earlier, some preventive measures might be taken. In this study we aimed to determine whether admission serum cystatin C (sCys-C) and other clinical parameters can identify subclinical AKI in medical intensive care unit (ICU) patients with normal creatinine-based eGFR at admission.MethodsA prospective cohort study, performed in an adult ICU of a university hospital between January 2008 and March 2013. The blood samples were obtained within the first 24-48 hours of admission and sCys-C levels were analyzed with particle-enhanced immunonephelometric assay. AKI development was assessed according to RIFLE criteria. The cutoff value of sCys-C for the prediction of AKI was determined with receiver operating characteristic (ROC) curve analysis.ResultsA total of 72 patients were included in the study and 19 (26%) of them developed AKI. Among the patients with AKI admission sCys-C levels were significantly higher when compared with non-AKI patients (1.06 ± 0.29 vs. 0.89 ± 0.28 respectively,p = 0.026). With ROC curve analysis, the threshold level for sCys-C was 0.94 mg/L with 63% sensitivity and 66% specificity [AUC: 0.67,p = 0.026]. With logistic regression analysis ‘high sCys-C levels at admission’ (OR = 4.73; 95%CI 1.03–21.5,p = 0.044) was found as one of the independent variables for the prediction of AKI development, in addition to ‘being intubated before ICU admission’ (OR = 10.2; 95%CI 1.72–60.4,p = 0.01) and ‘hypotension during ICU follow-up’ (OR = 12.3; 95%CI 2.5–60.1,p = 0.002).ConclusionIn this cohort of patients, a high sCys-C level at admission was found to be a predictor of subclinical AKI arising during their ICU stay. If supported with further studies, it might be used to provide more accurate and earlier knowledge about renal dysfunction and to take appropriate preventive measures. [ABSTRACT FROM PUBLISHER]

Shrunken Pore Syndrome was recently suggested for the pathophysiologic state in patients characterized by an estimation of their glomerular filtration rate (GFR) based upon cystatin  C, which is lower or equal to 60% of their estimated GFR based upon creatinine, i.e. when eGFRcystatin  C ≤ 60% of eGFRcreatinine. Not only the cystatin  C level, but also the levels of other low molecular mass proteins are increased in this condition. The preoperative plasma levels of cystatin  C and creatinine were measured in 1638 patients undergoing elective coronary artery bypass grafting. eGFRcystatin  Cand eGFRcreatininewere calculated using two pairs of estimating equations, CAPA and LMrev, and CKD-EPIcystatin  Cand CKD-EPIcreatinine, respectively. The Shrunken Pore Syndrome was present in 2.1% of the patients as defined by the CAPA and LMrev equations and in 5.7% of the patients as defined by the CKD-EPIcystatin  Cand CKD-EPIcreatinineequations. The patients were studied over a median follow-up time of 3.5 years (2.0–5.0 years) and the mortality determined. Shrunken Pore Syndrome defined by both pairs of equations was a strong, independent, predictor of long-term mortality as evaluated by Cox analysis and as illustrated by Kaplan-Meier curves. Increased mortality was observed also for the subgroups of patients with GFR above or below 60 mL/min/1.73 m2. Changing the cut-off level from 60 to 70% for the CAPA and LMrev equations increased the number of patients with Shrunken Pore Syndrome to 6.5%, still displaying increased mortality. [ABSTRACT FROM PUBLISHER]

The plasma levels of cystatin C, β2-microglobulin, beta-trace protein, retinol binding protein (RBP) and creatinine were determined in plasma samples from 111 randomly selected patients with eGFRcystatin C ≤ 60% of eGFRcreatinine and from 55 control patients with 0.9eGFRcreatinine ≤ eGFRcystatin C ≤ 1.1eGFRcreatinine (eGFRcystatin C ≈ eGFRcreatinine). The concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, beta-trace protein/creatinine and RBP/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine. When the patients were divided into three groups with different estimated GFR intervals (≤ 40, 40-60 and ≥ 60 mL/min/1.73m2) the concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, and beta-trace protein/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine for all GFR intervals. Similar results were obtained when the population without pregnant women was studied as well as the subpopulations of men or of non-pregnant women. Populations of pre-eclamptic women and pregnant women in the third trimester display similar results. Since the production of these four proteins with sizes similar to that of cystatin C is not co-regulated, the most likely explanation for the simultaneous increase of their creatinine-ratios in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine is that their elimination by glomerular filtration is decreased. We suggest that this is due to a reduction in pore diameter of the glomerular membrane and propose the designation 'Shrunken pore syndrome' for this pathophysiological state. [ABSTRACT FROM AUTHOR]

Background and aim. Chronic kidney disease has recently been shown to be a major risk factor for cardiovascular disease and carotid intima-media thickness has been widely used as a biomarker for early detection of cardiovascular disease. The aim of this study was to confirm whether carotid thickening and carotid plaque are associated with preclinical chronic kidney disease in individuals without clinical cardiovascular disease and chronic kidney disease. Material and methods. We conducted a cross-sectional study on participants from Maanshan City, China. All participants underwent carotid ultrasonography. Kidney function was measured using cystatin C, serum creatinine, blood urea nitrogen and blood uric acid. Demographics and risk factors for cardiovascular diseases were obtained from each participant. Results. A total of 927 subjects were surveyed; 453 (48.87%) were men and 474 (51.13%) were women. A total of 525 (56.63%) of the participants were found to have carotid thickening of which 281 (53.52%) were men and 244 (46.48%) were women. Kidney function was strongly associated with carotid thickening and plaque in the unadjusted analysis. However, cystatin C was the only measure of kidney function that was significantly associated with carotid thickening and plaque in the adjusted analysis (in order to select risk factors from sex, age, BMI, hypertension, diabetes, smoking, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, apolipoprotein A, apolipoprotein B, cystatin C, creatinine, blood urea nitrogen, blood uric, estimated GFR). Conclusion. Cystatin C, an alternative measure of kidney function, was more strongly associated with carotid thickening and plaque than other measures of kidney function. [ABSTRACT FROM AUTHOR]

Objective. The purpose of this study in humans was to examine the influence of the gastrointestinal tract and liver on the serum concentrations of cystatin C. Methods. Eighteen healthy volunteers and 28 patients suspected of having chronic intestinal ischemia underwent catheterization of the abdominal aorta and the central hepatic vein. Blood samples were taken simultaneously from the abdominal aorta and the central hepatic vein 60, 90 and 120 minutes after the start of the investigation. After the first blood sample, a standard liquid meal was ingested. Measurement of splanchnic blood flow was performed using the Fick principle with constant infusion of 99mTc-Bridatec®. Angiography was performed at the end of the investigation. Results. The splanchnic blood flow increased significantly postprandially in the healthy volunteers and in the patients with normal angiography by 0.613-0.698 L/min and increased nonsignificantly in the patients with abnormal angiography (n = 5) by 0.135 L/min on average. ANOVA and the Bonferroni's multiple comparison test showed no significant difference between the means of cystatin C, creatinine or urea in the samples taken 60, 90 and 120 minutes after the start of the investigation in the abdominal aorta and the hepatic vein in the healthy volunteers or in the patients suspected of chronic intestinal ischemia with normal angiography. Conclusion. There was no indication of hepatic elimination of cystatin C, creatinine or urea. The serum concentrations of cystatin C, creatinine and urea in the central hepatic vein and the abdominal aorta were independent of the splanchnic blood flow. [ABSTRACT FROM AUTHOR]

In this study, creatinine-based equations to evaluate glomerular filtration rate (eGFR) were proposed to more accurately assess kidney function, and cystatin C, a parameter not dependent on muscular mass, was introduced to improve GFR calculation in professional cyclists during a long-lasting race. Nine cyclists participating in the 2011 Giro d'Italia were recruited. Blood and anthropometrical data were collected the day before (T − 1) the race, on the 12th day (T 12) and on the 22nd day (T 22) of the race. Haemoglobin and haematocrit were registered. Haemodilution was observed at T 12, whilst stabilization was evident at T 22. Creatinine, cystatin C concentrations and eGFR values were not modified during the observed period; only GFR evaluated with the Cockcroft-Gault (CG) formula and expressed as ml/min/1.73 m2 significantly decreased ( p < 0.05) at T 22 in comparison with T − 1, probably as a consequence of weight decrease. Cystatin C levels were in the reference range, while creatinine concentrations were lower. The lowest eGFR values were observed with CG normalized and the Modification of Diet in Renal Disease (MDRD) formulas. A good correlation was observed between the MDRD and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations and between CG normalized and both CKD-EPI and MDRD formulas. The worst correlation was registered between CKD-EPI creatinine and cystatin C and all the other equations. In conclusion, adaptive mechanisms of renal function allow athletes to maintain stable creatinine, cystatin C and eGFR values during a long-lasting race. The use of GFR equations to evaluate general health status of sportsmen should be recommended with caution, considering also weight modification during competition. [ABSTRACT FROM AUTHOR]

Objective. GFR-prediction equations based upon cystatin C and creatinine have better diagnostic performance in estimating GFR than equations based upon only one of the two markers. The present work concerns in what way a comparison between separate estimations of GFR based upon cystatin C (eGFRcystatin C) or creatinine (eGFRcreatinine) can be used to evaluate the diagnostic performance of a combined cystatin C- and creatinine-based estimation of GFR. Methods. The difference between eGFRcystatin C and eGFRcreatinine was compared with measured GFR (iohexol clearance) and a combined cystatin C- and creatinine-based estimation of GFR in a Swedish-Caucasian cohort of 857 adult patients. Results. A difference between eGFRcystatin C and eGFRcreatinine of ≥ 40% indicated a markedly reduced diagnostic performance of the combined cystatin C- and creatinine-based estimation of GFR. Conclusion. Comparison of the agreement between eGFRcystatin C and eGFRcreatinine can be used to evaluate the diagnostic performance of combined cystatin C- and creatinine-based estimations of GFR. If 'threshold values' for discordance are exceeded, it must be considered whether the clinical context requires the use of an invasive gold standard method to measure GFR. In some clinical contexts either creatinine or cystatin C are known to be invalidated as markers of GFR and in these situations the use of only the cystatin C- or the creatinine-based GFR estimate should be considered when the 'threshold values' are exceeded. [ABSTRACT FROM AUTHOR]

Objective. GFR-prediction equations based upon cystatin C and creatinine have better diagnostic performance in estimating GFR than equations based upon only one of the two markers. The present work concerns in what way a comparison between separate estimations of GFR based upon cystatin C (eGFRcystatin C) or creatinine (eGFRcreatinine) can be used to evaluate the diagnostic performance of a combined cystatin C- and creatinine-based estimation of GFR. Methods. The difference between eGFRcystatin C and eGFRcreatinine was compared with measured GFR (iohexol clearance) and a combined cystatin C- and creatinine-based estimation of GFR in a Swedish-Caucasian cohort of 857 adult patients. Results. A difference between eGFRcystatin C and eGFRcreatinine of ≥ 40% indicated a markedly reduced diagnostic performance of the combined cystatin C- and creatinine-based estimation of GFR. Conclusion. Comparison of the agreement between eGFRcystatin C and eGFRcreatinine can be used to evaluate the diagnostic performance of combined cystatin C- and creatinine-based estimations of GFR. If 'threshold values' for discordance are exceeded, it must be considered whether the clinical context requires the use of an invasive gold standard method to measure GFR. In some clinical contexts either creatinine or cystatin C are known to be invalidated as markers of GFR and in these situations the use of only the cystatin C- or the creatinine-based GFR estimate should be considered when the 'threshold values' are exceeded. [ABSTRACT FROM AUTHOR]

Objective: To establish a high-throughput system for testing the ability of drugs or monoclonal antibodies to reduce the in vitro formation of cystatin C dimers to identify substances potentially useful for treatment of patients with hereditary cystatin C amyloid angiopathy (HCCAA). Methods: Various combinations of incubation temperature, time period, guanidinium chloride concentration and concentration of cystatin C monomers were tested in low-volume formats to induce dimer formation of recombinant cystatin C. The extent of dimerization was analysed by gel filtration chromatography and agarose gel electrophoresis. Results: A high-throughput system based upon agarose gel electrophoresis was developed and used to test 1040 drugs in a clinical drug library for their capacity to reduce cystatin C dimer formation in vitro. Seventeen substances reducing dimer formation by more than 30% were identified. A similar system for testing the capacity of monoclonal antibodies against cystatin C to reduce the in vitro formation of cystatin C dimers was also developed and used to test a panel of 12 monoclonal antibodies. Seven antibodies reducing dimer formation by more than 30% were identified and the two most potent, Cyst28 and HCC3, reduced dimerization by 75 and 60%, respectively. Conclusion: We constructed a simple high-throughput system for testing the capacity of drugs and monoclonal antibodies to reduce the in vitro formation of cystatin C dimers and several candidates for treatment of HCCAA could be identified. [ABSTRACT FROM AUTHOR]

Background. The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery. Methods. Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days. Results. Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period. Conclusion. The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR. [ABSTRACT FROM AUTHOR]

Objective. The goal with this study was to evaluate the analytical performance of a new cystatin C immunoassay (Tina-quant® a Cystatin C, Roche Diagnostics GmbH). The evaluation was carried out at four centers according to a standardized protocol. Material and methods. The Tina-quant® a Cystatin C is a latex particle-enhanced immunoturbidimetric assay. Roche cobas® 6000, MODULAR ANALYTICS SWA and COBAS INTEGRA® instruments were included in the study. Method comparison studies were carried out against two turbidimetric methods (Dako Cystatin C, Gentian Cystatin C), and one nephelometric method (Siemens N-Latex Cystatin C). Results. Linearity was proven throughout the measuring range from 0.4 to 8 mg/L. Within-run CVs ranged from 0.7–2.8%, and total CVs from 1.4–4.7 % (concentration range 0.6–3.9 mg/L). Comparable results were obtained with paired serum and Li-heparinate plasma samples. Good agreement was achieved in the comparisons between the Tina-quant® a Cystatin C assay and the other commercially available cystatin C assays, two different turbidimetric methods (slope range 0.88–1.04, intercept < 0.17 mg/L, r ≥ 0.993) and one nephelometric assay (slope range 0.90–1.05, intercept < 0.21 mg/L, r ≥ 0.986). Conclusions. The Tina-quant® a Cystatin C assay was shown to be precise and accurate with proven linearity over the measuring range. Good comparability was obtained with other commercially available assays for the determination of cystatin C. The Tina-quant® a Cystatin C assay is very well suited for clinical use on routine clinical chemistry analysers to detect renal dysfunction with a 24 h availability. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the performance of the Roche Diagnostics Tina-quant Cystatin C particle enhanced immuno turbidimetric assay for the measurement of plasma and serum cystatin C, and to establish reference intervals for cystatin C in healthy blood donors. Methods and materials. The cystatin C measurements were performed on the Roche Modular Analytics P automated clinical chemistry analyzer. Results. The cystatin C assay was linear in the measuring range 0.40–7.00 mg/L. Within-run CVs ≤ 2.0%, between-run CVs ≤ 4.2%, and total CVs ≤ 5.5% in plasma pools and in commercial cystatin C control materials (range 1.0–4.7 mg/L). Recovery was 99.4–109.3%. No interference was detected from haemoglobin < 0.9 mmol/L, bilirubin < 330 μmol/L and Intralipid® < 20 g/L. Measurement of cystatin C in Li-heparin plasma did not differ significantly from cystatin C measured in serum. Forty patient samples run on the Modular Analytics P (y) were compared to the Siemens Cystatin C assay on the BN II (x): y = 0.817x + 0.270, Sy.x = 0.168 (Deming regression). The non-parametric reference interval for cystatin C was calculated to be 0.41–0.91 mg/L in females ( n = 86), and 0.43–0.94 mg/L in males ( n = 76). The Mann-Whitney U test showed a significant difference between the two genders ( p = 0.015), but the difference was without clinical relevance. A common reference interval for both genders ( n = 162) was calculated to be 0.41–0.92 mg/L. Conclusion. The performance of the Tina-quant Cystatin C assay was acceptable for clinical use. [ABSTRACT FROM AUTHOR]

Knowledge of glomerular filtration rate (GFR) is required to detect and follow impairment of renal function, to allow correct dosage of drugs cleared by the kidneys, and for the use of nephrotoxic contrast media. Correct determination of GFR requires invasive techniques, which are expensive, slow and not risk-free. Therefore, GFR-prediction equations based solely upon cystatin C or creatinine and anthropometric data or upon cystatin C, creatinine and anthropometric data have been developed. The combined prediction equations display the best diagnostic performance, but in several easily identifiable clinical situations (e.g. abnormal muscle mass, treatment with large doses of glucocorticoids) prediction equations based upon either cystatin C or creatinine are better than the combined equations. In Lund, where cystatin C has been used as a GFR-marker in the clinical routine since 1994, a strategy based upon this knowledge has therefore been developed. This comprises simultaneous use of a cystatin C-based and a creatinine-based GFR-prediction equation. If the GFRs predicted agree, the mean value is used as a reliable GFR-estimate. If the GFRs predicted do not agree, clinical data is evaluated to identify reasons for not using one of the two prediction equations and the GFR predicted by the other one is used. If no reasons for the difference in predicted GFRs are found, an invasive gold standard determination of GFR is performed. If the GFRs predicted agree for a patient, the creatinine value is reliably connected to a specific GFR and can be used to follow changes in GFR of that patient. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the day-to-day biological variation of cystatin C in comparison with creatinine in healthy subjects and in patients with impaired renal function. Material and methods: Eight weekly morning blood samples were taken from 20 healthy subjects (13 females and 7 males, median age 44 years, range 25–61) and 19 patients with impaired renal function (8 females and 11 males, median age 61 years, range 35–70). Serum cystatin C was measured using Dade Behring N Latex Cystatin C assay and serum creatinine by an enzymatic method (Roche). Results: In the healthy subjects mean serum cystatin C was 0.70 mg/L (range 0.44–1.09) and mean serum creatinine 77 μmol/L (range 54–100). The analytical variance was 2.0% for cystatin C and 1.6% for creatinine. The intra-individual variance was greater for cystatin C than for creatinine (8.6% vs. 4.7%). The inter-individual variance was similar for both analytes (cystatin C 15.1% vs. creatinine 14.4%). In the patients with impaired renal function mean serum cystatin C was 1.86 mg/L (range 0.45–3.31) and mean serum creatinine 224 μmol/L (range 103–430). The analytical variance was 1.8% for cystatin C and 1.4% for creatinine. The intra-individual variance was greater for cystatin C than for creatinine (16.0% vs. 8.9%). Conclusion: In the present study, the intra-individual variance was greater for cystatin C than for creatinine in both healthy subjects and in patients with impaired renal function. Accordingly, serum creatinine is the preferred marker for serial monitoring of renal function in individuals with stable muscle mass. [ABSTRACT FROM AUTHOR]

Background: Serum creatinine-based estimates of GFR may be inaccurate in the elderly and there is need for improvement. Serum Cystatin C, not being influenced by muscle volume, may be more accurate. Material and methods: GFR was measured with plasma clearance of iohexol in 50 elderly persons aged >70 years. Blood tests were drawn for analysis of creatinine, albumin and urea. Cystatin C was analysed on frozen specimens using the Dade Behring method. GFR estimates based on cystatin C were compared to estimates based on serum creatinine, using earlier published equations. Results: Significant increase with age was found with cystatin C (rs=0.62, p=0.0001) and urea (rs=0.43, p=0.0018) but no correlation with creatinine (rs=0.05, p=0.7502). All equations underestimated GFR with a bias ranging from −2.2 to −31%. The equation with the greatest accuracy was the Hoek equation (Cystatin C based) with 98% of estimates within 30% of mGFR and confidence interval 89-100%. Estimated GFR using the MDRD Study equations (creatinine based) showed accuracy of 94% with 4 or 6 factors used. There was a gender difference with an accuracy higher among males ( p<0.002). The Cockcroft Gault equation was not found useful with high bias and a low accuracy. Conclusion: S-cystatin C seems a useful marker for kidney function in the elderly. Two equations based on serum cystatin C as well as the two MDRD equations seem adequate for estimating kidney function. [ABSTRACT FROM AUTHOR]

Purpose: To test various ways of combining creatinine and cystatin C in equations to predict glomerular filtration rate (GFR). Material and methods: Performance of the following expressions to predict GFR was compared with measured GFR (iohexol clearance, mL/min/1.73m2) in 857 patients: (i) Lund-Malmo creatinine equation, (ii) Grubb cystatin C equation, (iii) arithmetic mean of (1) and (2), (iv) geometric mean of (1) and (2), (v) linear regression on (1) and (2), (vi) regression on (1) and cystatin C, and (vii) regression on creatinine, cystatin C, age and gender. Results: For the entire cohort median percent error (bias) was <5% for all expressions, though all expressions tended to underestimate (−8.3 to −15.8%) GFR at levels ≥90 mL/min/1.73m2. The five expressions combining creatinine and cystatin C significantly improved correlation and accuracy ( p<0.001) within 15 and 30% of measured GFR compared with the equations based on the separate analytes and with no significant difference between the five expressions. In a subgroup of patients with neurological disease and muscle atrophy the cystatin C equation performed better than the expressions combining creatinine and cystatin C. Conclusion: Simply calculating the arithmetic mean of predicted GFR based on separate creatinine and cystatin C equations performs equally well as more complex equations. Reporting GFR based on separate creatinine and cystatin C equations, and their arithmetic mean also has the definite advantage that the physician can choose the estimated GFR, most appropriate depending on the clinical setting and patient characteristics. [ABSTRACT FROM AUTHOR]

Background . The prevalence of stage 3 chronic kidney disease (CKD) is increasing, calculated using the modification of diet in renal disease (MDRD) study equation for estimating glomerular filtration rate (GFR). Cystatin C-based equations are also being used to estimate GFR. Using creatinine-based and cystatin C-based equations, the aim of our study was to measure the difference in prevalence of stage 3 CKD in a population. Methods . CKD screening is organized in the Province of Liege, Belgium. On a voluntary basis, people aged between 45 and 75 years are invited for screening. GFR is estimated using the MDRD study equation and by the three recent cystatin C-based equations proposed by Levey's group. The Levey 1 equation is based on cystatin C only and the Levey 2 equation on cystatin C corrected for age and sex. The Levey 3 equation combines cystatin C, creatinine, age and sex. Results . The population screened comprised 754 people. Cystatin C is highly correlated with creatinine (r = 0.6196, p<0.0001). Prevalence of stage 3 CKD when GFR is estimated by the MDRD equation study is 17.2 %, which is significantly and much higher than the prevalence obtained when cystatin C-based equations are used. Indeed, prevalence is 2 %, 3.3 % and 5.8 % with the Levey 1, 2 and 3 equations, respectively. Conclusions . The prevalence of stage 3 CKD varies strongly following the method used for estimating GFR, creatinine-based or cystatin C-based equations. Such discrepancies must be confirmed and explained in additional studies using GFR measured with a reference method. [ABSTRACT FROM AUTHOR]

Objective. The reliability of serum cystatin C (s-Cys) as a filtration marker depends on the intra- and inter-individual variation and influence of non-renal factors of its production rate (Cyspr), non-renal clearance (CLnr) and sieving coefficient (S). Haemodialysis patients with no residual renal function would be the best population in which to investigate these variables, which otherwise require reliable GFR measurements. Material and methods. Seventy-nine haemodialysis (HD) patients with negligible residual renal function (Group 1) were investigated and compared with 55 HD patients with varying degrees of residual renal function (Group 2) and 923 non-dialysis patients (Group 3). The equation eGFR = Cyspr/s-Cys-CLnr was used to analyse the turnover and variation of cystatin C. Results. A formula for estimating GFR, eGFR = 99/s-Cys-14.1, calculated from Group 3, was shown to fit the HD patients. The measured s-Cys in Group 1 was 6.9±0.9 and 6.4±1.1 mg/L in Group 2. The calculated 95 % confidence interval of eGFR of ±(30-40) % increased sharply below GFR 20 mL/min/1.73 m2, which means that s-Cys cannot be used for calculating low GFR, including the residual GFR of dialysis patients. Conclusions. Nicotine users in Group 1 had significantly higher s-Cys than non-users (7.5±0.9 mg/L compared to 6.7±0.8; p = 0.0008), which may be a factor to include in the eGFR formulae. However, s-Cys was independent of non-renal factors such as sex, age, LBM, body weight, malnutrition and CRP and also of changes in CRP. [ABSTRACT FROM AUTHOR]

Objective. Low molecular mass proteins (LMMP) are putative uraemic toxins, but their elimination is negligible in standard haemodialysis (HD). In this study, we used β2-microglobulin, cystatin C and β-trace protein, which differ in molecular mass and charge, to characterize the elimination patterns of three different dialysis modalities. Material and methods. Plasma samples were obtained at the start, 30 min after the start, at the end of the dialysis treatment and 30 min after termination of the dialysis session. Seventeen patients were treated with low-flux HD, 13 with post-dilution haemodiafiltration (HDF) and 8 with pre-dilution haemofiltration (HF). The changes in concentrations of the three LMMPs were monitored and expressed as percentages of the concentrations at the start of treatments. Results. Conventional HD with low-flux membranes showed a high elimination of small molecules (urea and creatinine), but did not reduce the levels of the three LMMPs studied. During HDF and HF, there was a significant decrease in the plasma levels of cystatin C (to 28 % and 44 %, respectively) (p<0.001) and of β2-microglobulin (to 23 % and 33 %, respectively) (p<0.001). However, the level of β-trace protein was significantly reduced (to 65 %) only after HDF. Conclusions . The three dialysis modalities showed significantly different elimination patterns for the LMMPs studied. Elimination of β-trace protein was lower than those of cystatin C and β2-microglobulin both in HDF and HF. β-trace protein was only moderately eliminated by HDF and not at all by HF, and may be a useful marker in the evaluation of different convective therapies. [ABSTRACT FROM AUTHOR]

The availability of a world-wide standard for creatinine is an important milestone improving glomerular filtration rate (GFR) estimations in adults. However, an unacceptable inter-laboratory variation is still observed which is mainly due to differences in calibration, especially in children and infants, where reference ranges for serum and plasma creatinine are low. Compensating calibration in Jaffe assays to IDMS standards results in an underestimation of serum or plasma creatinine due to the lower reference values for total protein in younger children. Alternatively, using enzymatic assays emphasizes the relative proportion of tubular secretion of creatinine, which renders serum or plasma creatinine less suited as a GFR marker in children. Updating the currently used estimation formulas for calculating creatinine clearance and GFR is far from easy. Low molecular mass marker proteins such as cystatin C and beta trace protein can be regarded as an attractive practical alternative for assessing GFR since they require determination only in serum or plasma and are better suited in the blind range of creatinine. [ABSTRACT FROM AUTHOR]

A Primary Reference Preparation has been produced using pure, recombinant, Cystatin C in a solvent of 0.1 mol/L KCl. Dry mass determination of the Primary Reference Preparation resulted in a Cystatin C concentration of 5.20 g/L. Agarose-electrophoresis and SDS-electrophoresis, as well as N-terminal sequencing, verified the purity, homogeneity and identity of Cystatin C in the Primary Reference Preparation. For the Secondary Reference Preparation, a serum pool was collected and stabilized. A pilot batch was made to verify the selected procedure and spiking with the pure, recombinant Cystatin C. The final Secondary Reference Preparation is now produced (4468 vials) and ready for value assignment and further characterization. [ABSTRACT FROM AUTHOR]