Serum cystatin C as a marker of glomerular filtration rate

PURPOSE OF REVIEW: Glomerular filtration rate is widely accepted as the best overall measure of kidney function. Currently available methods to estimate glomerular filtration rate have strengths and limitations. Cystatin C is a novel endogenous filtration marker being considered as a potential replacement for serum creatinine. This review summarizes the currently available glomerular filtration rate estimating equations based on cystatin C and the literature comparing cystatin C and creatinine as filtration markers. RECENT FINDINGS: In most cystatin C estimating equations, inclusion of age and sex did not substantially improve their performance. Equations yield different glomerular filtration rate estimates for the same level of cystatin C. Variation among equations may be due to differences among the assays or populations in the individual studies. Studies comparing cystatin C with creatinine or creatinine-based estimating equations show heterogeneous results, with some showing improved performance and others showing equivalent performance even in similar populations. These heterogeneous results may be due to inappropriate comparisons between equations developed in one population with those developed in another, or to the differences between assays or population characteristics. SUMMARY: Cystatin C shows promise as an alternative to serum creatinine but several important questions remain before it can be recommended for use in clinical practice.     

Serum cystatin C is a more sensitive marker of glomerular function than serum creatinine

We determined the relationship between the levels of serum cystatin C or creatinine (s-Cr) and the grade of creatinine clearance (CCr) in patients with various glomerular diseases. Serum samples from 96 patients with glomerular diseases were obtained from our hospital. The levels of serum cystatin C were measured using the Dade Behring Cystatin C assay with the automated Dade Behring Nephelometer II (BNII). CCr levels were classified into six groups according to the Guidelines of the Japanese Society of Nephrology as follows: grade 1 (normal renal function); grade 2 (slight decrease of renal function); grade 3 (moderate decrease of renal function); grade 4 (severe decrease of renal function); grade 5 (renal failure), and grade 6 (uremia). The mean levels of serum cystatin C in grade 3 patients were significantly higher than those in grade 1. The mean levels of serum cystatin C in grades 4, 5 and 6 patients were also significantly higher than those in grade 1. However, the mean levels of serum Cr in grade 3 patients were not significantly higher than those in grade 1. The levels of s-Cr in grades 4, 5 or 6 patients were significantly higher than those in grade 1. In this study, an increase of serum cystatin C levels occurred earlier than that of s-Cr in various glomerular diseases. It appears that the levels of serum cystatin C may provide early prognostic marker of patients with various glomerular diseases rather than the levels of s-Cr.     

Evaluation of methods based on creatinine and cystatin C to estimate glomerular filtration rate in chronic kidney disease

Purpose

Estimated glomerular filtration rate (GFR) is a useful tool for the detection of chronic kidney disease (CKD). Several methods have been proposed, but findings can vary in specific groups such as patients with diabetes, elderly and high and low body mass index and, also, with the stage of CKD. The objective of this study was comparing the accuracy of the currently used equations for estimating GFR with that of the gold standard technetium-(99m)-diethylene triamine pentaacetic acid (99mTc-DTPA).

Methods

We performed a cross-sectional study of 129 patients with all five CKD stages. GFR was estimated using the following: 24-h urine creatinine clearance, Cockcroft–Gault equation, MDRD equation, CKD-EPI equation, Hoek’s cystatin C equation, and isotopic 99mTc-DTPA (as gold standard). We evaluated agreement in the whole study population and according to age, sex, weight, and diabetes.

Results

All methods had good agreement. The best agreement was observed with the cystatin C [intraclass coefficient correlation (ICC) 95 % confidence interval (95 % CI), 0.87 (0.82–0.91)], followed by CKD-EPI [ICC 0.83 (0.77–0.88)]. Twenty-four-hour urine creatinine clearance showed the worst agreement in patients older than 65 years [ICC 0.70 (0.56–0.79)]. The Cockcroft–Gault equation showed the worst agreement in younger than 65 years [ICC 0.64 (0.42–0.79)]. The best agreement for classification in the correct CKD stage was with the cystatin C equation [κ = 0.80 (0.74–0.87)]. GFR was overestimated with all methods in CKD stages 4 and 5.

Conclusions

The methods used in clinical practice are adequate for classification of CKD. Cystatin C is the most accurate method, followed by CKD-EPI. The Cockcroft–Gault equation is not accurate in young patients. Twenty-four-hour urine creatinine clearance loses accuracy in patients aged older than 65 years.     

Estimating glomerular filtration rate in kidney transplantation: a comparison between serum creatinine and cystatin C-based methods

Accurate measurement of GFR is critical for the evaluation of new therapies and the care of renal transplant recipients. Although not accurate in renal transplantation, GFR is often estimated using creatinine-based equations. Cystatin C is a marker of GFR that seems to be more accurate than creatinine. Equations to predict GFR based on the serum cystatin C concentration have been developed, but their accuracy in transplantation is unknown. GFR was estimated using four equations (Filler, Le Bricon, Larsson, and Hoek) that are based on serum cystatin C and seven equations that are based on serum creatinine in 117 adult renal transplant recipients. GFR was measured using radiolabeled diethylenetriaminepentaacetic acid (99mTc-DTPA), and the bias, precision, and accuracy of each equation were determined. The mean (99m)Tc-DTPA GFR was 58 +/- 23 ml/min per 1.73 m(2). The cystatin C-based equations of Filler and Le Bricon had the lowest bias (-1.7 and -3.8 ml/min per 1.73 m2), greatest precision (11.4 and 11.8 ml/min per 1.73 m2), and highest accuracy (87 and 89% within 30% of measured GFR, respectively). The cystatin C equations remained accurate even when the measured GFR was >60 ml/min per 1.73 m2. The creatinine-based equations were not as accurate, with only 53 to 80% of estimates within 30% of measured GFR. Cystatin C-based equations are more accurate at predicting GFR in renal transplant recipients than traditional creatinine-based equations. Further prospective studies with repetitive measurement of cystatin C are needed to determine whether cystatin C-based estimates of GFR will be sufficiently accurate to monitor long-term allograft function.     

Cystatin C is not superior to creatinine-based models in estimating glomerular filtration rate in former kidney donors

BACKGROUND: The long-term renal consequences of kidney donation need to be accurately quantitated. Cystatin C is a freely filtered glycoprotein that may not have the limitations of creatinine as a measure of glomerular filtration rate (GFR). Whether cystatin C is superior to creatinine-based estimates of GFR in those who have donated a kidney in the past has not been tested. METHODS: We assessed the performance of seven cystatin C and two creatinine-based GFR prediction equations in 187 former kidney donors against iohexol GFR for measuring GFR. We calculated bias, precision, and relative accuracy of these models. RESULTS: The majority of former donors had a GFR >60 mL/min/1.73 m(2). All cystatin C models, except the Rule model, overestimated GFR (range 5.3-31.4 mL/min/1.73 m(2)). Among the cystatin C models, the Hoek and Rule formulas were least biased at 5.3 and -3.8 mL/min/1.73 m(2), most precise at 0.41, and were within 30% of iohexol GFR, 89.3 and 96% of the time, respectively. The Modification of Diet in Renal Disease (MDRD) formula underestimated GFR by 7.2 mL/min/1.73 m(2), was most precise (R(2)=0.47) and fell within 30% of measured GFR at the highest frequency of 96%. When all models were given a rank based on their performance in the bias, precision and accuracy domains, the MDRD model was clearly superior. CONCLUSION: The MDRD equation is superior to cystatin C-based equations for estimating GFR in former kidney donors. Creatinine measurement is cheaper and the MDRD GFR is given out by most laboratories and therefore it should be the preferred model in this population.     

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.     

Parental donors in live-donor kidney transplantation associated with increased rejection rates and reduced glomerular filtration rates

BACKGROUND: Living unrelated and related kidney transplantation has been shown to have similar allograft survival. However, the effect of donor-recipient relatedness in living-related and unrelated kidney transplantation on graft and patient survival remains uncertain. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, primary living renal transplant recipients in Australia between 1995 and 2004 were studied (n=1989). Donors were categorized according to their relationship with recipients: parent (n=606), child (n=103), spouse (n=358), sibling (n=656), other living-related donors (n=81), and other living-unrelated donors (n=185). Outcomes analyzed included the presence of rejection at 6 months, estimated glomerular filtration rate (eGFR) at 1 and 3 years, graft survival, and patient survival. RESULTS: A greater proportion of renal transplant recipients from parental and spousal donors were transplanted preemptively. Donor groups had no relationship with graft or patient survival. Parental donors were associated with an increased relative odds of acute rejection (odds ratio 1.69, 95% confidence interval 1.13-2.53, P=0.009) and a lower eGFR at both 1 and 3 years (coefficient -2.99 and -5.68, respectively; P<0.0001) compared to other donor groups (reference sibling donor group). CONCLUSIONS: This study has established that donor-recipient relatedness in both related and unrelated living kidney transplantation had no significant effect on graft and patient survival. Parental donors were associated with a higher relative risk of rejection and lower eGFR in the transplant recipients, although these findings did not translate to a worse graft outcome.     

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.     

Performance of serum cystatin C versus serum creatinine as a marker of glomerular filtration rate as measured by inulin renal clearance

Introduction  

Serum cystatin C was recently proposed as an alternative marker of glomerular filtration rate (GFR), with a suggested better performance than creatinine. However, detailed studies are limited. We evaluated the performance of cystatin C as a GFR marker.     

Cimetidine improves the reliability of creatinine as a marker of glomerular filtration.

To investigate whether the administration of cimetidine can improve the reliability of creatinine as a marker of GFR, we compared the creatinine clearance (CCr) to the clearance of the true filtration markers 51Cr-EDTA (CEDTA) and inulin (CIn), after oral ingestion of cimetidine in 10 healthy men and 29 patients with varying degrees of renal dysfunction. After administration of cimetidine for three to six days, serum creatinine level rose in all participants, while CEDTA and CIn remained stable in a subgroup of 14 subjects in whom they were measured before as well as after the administration of cimetidine. The mean (+/- SD) ratios of CCr to CEDTA (N = 39) and of CCr to CIn (N = 19) after ingestion of cimetidine were 1.02 +/- 0.13 and 1.01 +/- 0.13, respectively, and did not differ significantly from unity. This high degree of accuracy of the cimetidine-aided CCr was present over the entire range of renal function in the study population. Our results also indicated an improved precision of the cimetidine-aided measurement of CCr, resulting in a variability that did not differ significantly from that of the measurement of CEDTA or CIn. We conclude that after oral administration of cimetidine, the creatinine clearance can be used as a reliable measure of GFR within a broad range of renal function.     

Estimation of glomerular filtration rate in South Asian healthy adult kidney donors

Aim:   We evaluated the performance of serum creatinine based equations to estimate glomerular filtration rate (GFR) in South Asian healthy renal donors.
Methods:   GFR by 99mTc-diethylenetriamine pentaacetic acid (DTPA) renogram (mGFR) in 599 renal donors was measured. GFR was estimated using a six variable modification of diet in renal disease formula (MDRD1), a four variable MDRD formula (MDRD2), Cockcroft-Gault creatinine clearance (CG CrCl), Cockcroft-Gault glomerular filtration rate (CG GFR) and the Mayo Clinic formula (Mayo GFR). The performance of various prediction equations was compared for global bias, precision (R²) and accuracy (percentage of estimated GFR (eGFR) falling within 15% and 30% of mGFR).
Results:   The mean age was 37.4 ± 11 years and 48.2% were male. The mGFR was 95.5 ± 11.6 mL/min per 1.73 m². The bias (mL/min per 1.73 m²) was 7.5 ± 0.9, −9.0 ± 0.75, 13.1 ± 0.9, 7.5 ± 0.9 and 23.4 ± 0.76 for CG CrCl, CG GFR, MDRD1, MDRD2 and Mayo GFR, respectively. R² was 0.082 for CG CrCl and MDRD1, 0.081 for CG GFR and MDRD2 and 0.045 for Mayo GFR. The percentages of eGFR falling within 15% and 30% of mGFR were 50.5 and 80.1 for CG CrCl, 65.8 and 84 for CG GFR, 50 and 74 for MDRD1, 54.3 and 80.1 for MDRD2 and 32 and 63.4 for Mayo GFR. Overall CG GFR performed better in estimating GFR in all subjects.
Conclusion:   The CG GFR equation was better than other equations to estimate GFR in South Asian healthy renal donors. We propose a new equation derived from the regression model in our study population to estimate GFR in a South Asian healthy adult population.     

Serum cystatin C and beta2-microglobulin as markers of glomerular filtration rate

Continuous efforts have been made to find out precise and simple method for determination of glomerular filtration rate (GFR). Cystatin C (cysteine proteinase inhibitor = CyC) is a low molecular weight (LMW) protein which is produced constantly by all nucleated cells independently of different pathological conditions and eliminated from the blood exclusively by glomeruli. So, CyC closely reflects the GFR. In the present study 75 patients aged between 18 and 74 (44.3 +/- 12.2) years were analyzed, with the aim to compare the reciprocal values of serum level of LMW proteins CyC and beta2-microglobulin (beta2-MG) with creatinine clearance (Ccr) as a measure of GFR. Patients were divided into groups according to sex, age (<60; >60 years) and renal diseases: patients with glomerulonephritis (GN) with and without nephrotic proteinuria, pyelonephritis (PyN), and renal transplant (Tx). High correlation between Ccr and 1/CyC (r = 0.81; p < 0.01) and Ccr and 1/beta2-MG (r = 0.80; p < 0.01) in all examined patients was found. There was significant correlation between Ccr and 1/CyC (0.82 vs. 0.79) and Ccr and 1/beta2-MG (0.85 vs. 0.76) in men as well in women, and also in two groups of patients formed according to the age (0.82 vs. 0.77; p < 0.01; 0.80 vs. 0.81; p < 0.01), without any statistical significant difference between the groups. In studied groups with different renal diseases, there were no differences in correlation coefficients between Ccr and 1/CyC and Ccr and 1/beta2-MG (p1 = 0.29; p2 = 0.21; p3 = 0.79; p4 = 0.43), without statistical differences between the groups, except significant difference in correlation coefficients for Ccr and 1/beta2-MG between patients with GN with and without nephrotic proteinuria (p < 0.032). LMW proteins, serum CyC and beta2-MG, are as good markers of GFR as Ccr, regardless sex and age. Both of these LMW proteins are good markers of GFR in patients with GN without nephrotic proteinuria, PyN and Tx patients. In patients with GN and nephrotic proteinuria serum CyC is a better marker of GFR than beta2-MG.     

Serum creatinine as marker of kidney function in South Asians: a study of reduced GFR in adults in Pakistan

Migrant populations of South Asian origin have a higher risk for chronic kidney disease than the native whites. Several formulas have been developed to estimate kidney function from serum creatinine concentration. However, none of these has been validated in the South Asian population, which generally has different muscle mass composition than whites. A population-based cross-sectional study was performed on 262 individuals who were aged > or = 40 yr in Karachi, Pakistan. Reduced GFR was defined as creatinine clearance (Ccr) measured in 24-h urine collection of <60 ml/min per 1.73 m2. Creatinine excretion was compared with age- and gender-matched white individuals by comparison of observed versus expected results on the basis of a formula using t test. The agreement among Cockcroft Gault (CG) Ccr and Modification of Diet in Renal Disease (MDRD) Study GFR equations was assessed by regression analyses, and the degree of accuracy of estimated versus measured GFR was determined. Mean (95% confidence interval) creatinine excretion was 1.7 (1.0 to 2.4) mg/kg per d lower than expected for age- and gender-matched white individuals (P < 0.001). The coefficient of determination for measured Ccr on the logarithmic scale was 66.7 and 55.6% for the CG and MDRD Study equations, respectively. The proportion of estimates within 20, 30, and 50% of measured Ccr values was 47.7 versus 32.8% (P < 0.001), 64.9 versus 49.6% (P < 0.001), and 79.4 versus 72.9 (P = 0.07) for CG versus MDRD Study equations, respectively. Lower mean creatinine excretion in these individuals may explain, in part, suboptimal agreement between estimated versus measured GFR. Inclusion of terms for ethnic and racial groups other than white and black might improve the performance of GFR estimating equations.     

多种肾小球滤过率的估算方程在活体供肾者肾功能评估中的适用性研究

目的 比较多种肾小球滤过率(GFR)估算方程在亲属活体供肾功能评估中的准确性,找出适合我国人群的GFR估算方程.方法 以44名亲属活体供肾者为对象,以99mTc-二乙三胺五乙酸(DTPA)肾动态显像测定的GFR为参考标准,并以体表面积(BSA)将其标准化(sGFR).将以Cockcroft-GauIt(C-G)方程估算的肌酐清除率(Ccr),C-G方程、改良C-G方程、肾脏疾病饮食调整研究组(MDRD)方程和改良MDRD方程估算的GFR(eGFR),分别与sGFR进行比较,分析其偏差、相关性、准确性和精确性.结果 sGFR为(123±24)ml/min,C-G方程估算的Ccr,以及C-G方程、改良C-G方程、MDRD方程和改良MDRD方程估算的GFR分别为(123±27)ml/min、(104±22)ml/min、(156±28)ml/min、(122±19)ml/min和(138±25)ml/min,其偏差值,MDRD方程最小,两种改良方程的偏差较大;配对t检验及相关性分析,C-G方程的Ccr估算值、MDRD方程的估算值与sGFR的差异无统计学意义,改良C-G方程和改良MDRD方程的GFR估算值与sGFR之间的相关性较好;MDRD方程的准确性最高,两种改良方程的准确性较差;改良MDRD方程、改良C-G方程的精确性稍高.结论 5个估算方程估算的GFR均有不用程度的误差,相对来说MDRD方程的偏差较小,准确性较高,相关性和精确性尚可,但若应用于临床,有必要对其进行适当修正.