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.     

Cystatin C as a marker for glomerular filtration rate in pediatric patients

Cystatin C is a non-glycated 13-kilodalton basic protein produced by all nucleated cells. The low molecular mass and the basic nature of cystatin C, in combination with its stable production rate, suggest that the glomerular filtration rate (GFR) is the major determinant of cystatin C concentration in the peripheral circulation. Recently published studies have shown that cystatin C correlates more strongly than creatinine with GFR measured using the ⁵¹Cr-EDTA clearance. The aim of this study was to evaluate serum cystatin C as a marker for GFR in children. GFR was determined on medical indications using the ⁵¹Cr-EDTA technique in pediatric patients (2–16 years) in our renal unit. Simultaneously their cystatin C and creatinine concentrations were also measured. Of our 52 patients, 19 had a reduced renal function (<GFR 89 ml/min per 1.73 m²) based on the ⁵¹Cr-EDTA clearance. The correlation of cystatin C with the isotopic measurement of GFR tended to be stronger (r=0.89, P=0.073) than that of creatinine (r=0.80). Receiver operating characteristic analysis showed that the diagnostic accuracy of cystatin C was better (P=0.037) than that of creatinine in discriminating between subjects with normal renal function and those with reduced GFR. This study demonstrates that serum cystatin C has an increased diagnostic accuracy for reduced GFR when compared with serum creatinine. Hence, cystatin C seems to be an attractive alternative for the estimation of GFR in children. Received: 13 May 1998 / Revised: 22 September 1998 / Accepted: 22 October 1998     

Clinical assessment of serum cystatin C as a marker of glomerular filtration rate in patients with various renal diseases

Background. Recent reports have raised questions about the validity of estimating glomerular function and changes in glomerular function from measurements of serum creatinine. To evaluate the clinical usefulness of serum creatinine levels in terms of estimation of glomerular filtration rate (GFR), we determined serum cystatin C levels in 152 patients with various renal diseases and compared them with serum creatinine levels. Methods. Serum cystatin C levels were measured by particle-enhanced immunonephelometry. Two-h creatinine clearance (Ccr) was used as an indicator of GFR. Results. There was a significant positive correlation between serum cystatin C and creatinine levels (r = 0.941) in patients with various renal diseases. Serum cystatin C and creatinine were inversely correlated to Ccr. The overall correlation between serum cystatin C and Ccr was slightly stronger than that between serum creatinine and Ccr. In the patient group with a critical Ccr level (Ccr, 60–80 ml/min per 1.48 m²), the correlation between the reciprocal serum cystatin C levels and Ccr (r = 0.441) was significantly stronger (P < 0.01) than that between the reciprocal serum creatinine levels and Ccr (r = 0.212). A mild reduction of Ccr was detected more easily by serum cystatin C than by serum creatinine, as the clinical sensitivity and specificity of serum cystatin C were superior to that of serum creatinine. Conclusions. The cystatin C assay by particle-enhanced immunonephelometry was found to be a sensitive, fully automated, and rapid method. Serum cystatin C appears to be a promising marker of GFR in patients with impaired renal function. Its diagnostic potential was slightly superior to that of serum creatinine in adults with various renal diseases. Received: October 7, 1998 / Accepted: November 4, 1999     

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.     

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.     

Estimation of residual glomerular filtration rate in dialysis patients from the plasma cystatin C level.

BACKGROUND: Residual renal function influences morbidity, mortality and quality of life of chronic dialysis patients. Residual glomerular filtration rate (rGFR) is therefore an important parameter in the follow-up of these patients. Because rGFR is measured as the mean of creatinine and urea clearance, a complete 24 h urine collection is essential, but often very difficult to manage for these patients. METHODS: We investigated if plasma cystatin C (cysC) could give a good estimate of rGFR in dialysis patients and compared it to the measured rGFR, as well as to the rGFR estimate obtained with the Modification of Diet in Renal Disease (MDRD) formula. A total of 465 patients were included in this study. CysC levels of 215 haemodialysis (HD) and 95 chronic ambulatory peritoneal dialysis (PD) patients were used to derive a formula for rGFR. This formula was tested in the validation group of 107 HD and 48 PD patients. RESULTS: The cysC formula derived in the modelling group was rGFR = -0.70 + 22 x (1/cysC). The mean estimated rGFR obtained with this formula in the validation group was not significantly different from the mean measured rGFR: difference 0.19 ml/min/1.73 m(2), 95% confidence interval (CI) -2.37 to 2.75 ml/min/1.73 m(2). The MDRD formula gave a larger difference from the mean measured rGFR (3.13 ml/min/1.73 m(2)) and a much wider 95% CI (-1.29 to 7.55 ml/min/1.73 m(2)). A separate model for HD and PD patients did not improve the estimation of rGFR. CONCLUSIONS: The cysC formula showed better accuracy and precision than the MDRD formula. Therefore the cysC formula and not the MDRD formula should be used to calculate rGFR in dialysis patients when no 24 h urine sample is available.     

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.     

Assessment of glomerular filtration rate in renal transplant patients using serum cystatin C

AIM: Serum cystatin C (SCysC) has been proposed as a better marker of glomerular filtration rate (GFR) than serum creatinine (Scr). However, few data are available in renal transplant patients, especially, during the early postoperative phase. METHODS: Thirty-nine renal transplant patients (22 men/17 women) were recruited for determination of SCysC and Scr before operation, at 1 week and at 4 weeks after operation. SCysC was determined by particle-enhanced turbidimetric immunoassay. Creatinine clearance (Ccr) was calculated using the Cockcroft-Gault formula. RESULTS: SCysC and Scr levels significantly decreased with the recovery of allograft function. SCysC showed a significant correlation with Scr and Ccr. The relationship between SCysC and Scr showed a positive correlation (r = .849 preoperation, and r = .940 postoperation). The relationship between SCysC and Ccr revealed a negative correlation (r = .857 preoperation, and r = .876 postoperation). At the Ccr level of 50 to 80 mL/min/1.73 m(2), the correlation between SCysC and Ccr (r = .778) was significantly better than that between Scr and Ccr (r = .553; P = .032). The concentration of SCysC was not affected by age, gender, height, body weight, hemoglobin, serum protein, glucose, or mycophenolate mofetil or azathioprine dosage. However, corticosteroids slightly increased the level of SCysC and cyclosporine (CsA) decreased it. The area under the curve of the receiver operating characteristic curve for SCysC and Scr are 0.964 and 0.915, respectively (P < .05). CONCLUSION: Although the concentration may be slightly influenced by prednisolone and CsA, SCysC is more sensitive than Scr to detect early and moderate deterioration of GFR in adult renal transplant recipients.     

Calculation of glomerular filtration rate based on cystatin C in cirrhotic patients.

BACKGROUND: Plasma creatinine and creatinine clearance are of limited value for the estimation of renal function in cirrhotics. In these patients, cystatin C (Cys C) has been proposed as an alternative marker of glomerular filtration rate (GFR) and Cys C-based equations for calculation of GFR have been developed in non-cirrhotic patient cohorts. METHODS: We retrospectively analyzed correlation, bias, precision and accuracy of two Cys C-based formulae (Larsson and Hoek) for GFR estimation in comparison with two creatinine-based equations (Cockroft & Gault and MDRD). The Cys C was determined by an immunonephelometric method. The GFR was measured by means of inulin clearance in 44 consecutive patients with liver cirrhosis. RESULTS: On average, inulin clearance was 28.3 (95% CI: 29.2-41.3 ml/min/1.73 m2). Creatinine as well as Cys C-based equations overestimated the true GFR by 105-154%. However, Cys C-based equations showed significantly lower bias and higher precision than the creatinine-based formulae. Correlation and accuracy tended to be better with the Hoek and Larsson equation than with the Cockroft & Gault or MDRD formulae. Hoek and Larsson equations showed a similar diagnostic performance in all statistical procedures. CONCLUSION: Our data suggest a significant improvement of GFR estimation in liver cirrhotics by means of the Cys C-based Hoek and Larsson formulae. However, all estimates remain a crude approximation of true GFR and thus cannot replace gold standard methods.     

Estimating the glomerular filtration rate using serum cystatin C levels in patients with spinal cord injuries

Study design:Prospective cohort study.Objectives:To investigate the relationship between (51)chromium-ethylene-diamine-tetra-acetate ((51)Cr-EDTA) clearance, serum cystatin C (CysC), serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR(MDRD), MDRD stands for modification of diet in renal disease) based on the serum creatinine in patients with complete or incomplete spinal cord injury (SCI) and to develop and evaluate a GFR-estimating equation using serum CysC.Settings:Spinal Cord Injury Unit, Viborg Regional Hospital, Viborg, Denmark.Methods:Ninety-eight men and 47 women with SCI were included in the study. Serum CysC levels were measured by an automated particle-enhanced nephelometric immunoassay, serum and urine creatinine levels were measured by an enzymatic method traceable to the IDMS creatinine reference method, and (51)Cr-EDTA clearance was measured by a multiple plasma sample method.Results:The area under the curves (AUCs) in the non-parametric receiver operating characteristics (ROC) plots for serum CysC were compared with serum creatinine and to eGFR(MDRD) and revealed a significant difference (P-value<0.05) for all SCI patients. There was no significant difference between the AUC for serum CysC compared with the AUC for creatinine clearance. GFR (ml?min(-1) per 1.73?m(2)) can be calculated from serum CysC values (mg?l(-1)) using the equation eGFR(CysC)=212·exp(0.914·CysC). The model accurately predicted the GFR of 88% of patients within ±30% of the measured GFR, and it was able to predict the GFR of 50% of patients within ±10% of the measured GFR.Conclusion:In patients with SCI, GFR can be estimated independent of age, sex and muscle mass by a newly developed equation based on a single serum CysC value.     

Left ventricular hypertrophy predicts the decline of glomerular filtration rate in patients with type 2 diabetes mellitus

Purpose

The heart and kidney are of utmost importance for the maintenance of cardiovascular (CV) homeostasis. The relationship between cardiac remodeling, especially the left ventricular hypertrophy (LVH) and renal damage reflected by the estimated glomerular filtration rate (eGFR), decline in type 2 diabetes mellitus (T2DM) patients is unclear. And it is also unknown whether cardiac remodeling can be used to assess the eGFR decline in T2DM patients.

Methods

We retrospectively analyzed the relationship between cardiac remodeling especially the LVH and the eGFR decline for 265 patients with T2DM, who were diagnosed between 2011 and 2015 and followed for ≥?3 months. The parameters of cardiac remodeling were determined using Doppler echocardiography.

Results

In the Cox regression model, the parameters of cardiac remodeling were associated with the composite endpoint in different models. These associations were independent of age, body mass index (BMI), history of hypertension, duration of diabetes, the baseline eGFR, 24-h urinary protein, or using angiotensin-converting enzyme inhibitors (ACEI) and (or) angiotensin receptor blockers (ARB). The risk of composite endpoint in patients with T2DM was higher (hazard ratio, 10.832; p?<?0.001 for trend) in the group with the highest number of abnormal echocardiographic parameters, than in the group with no abnormal echocardiographic parameters. In receiver operating characteristics (ROC) curve analyses, the parameter of left ventricular posterior wall (LVPW) thickness was superior to the other parameters of cardiac remodeling as represented by the higher area under the curve (AUC) values generated according to the sensitivity and specificity.

Conclusion

Echocardiographic parameters are strongly correlated with the eGFR decline in patients with T2DM. Moreover, the severity of cardiac remodeling, especially the LVH is closely associated with the eGFR decline in patients with T2DM. Therefore, the recognition of cardiac structural alterations in patients with T2DM may evaluate renal damage at an early stage.

     

Measuring glomerular filtration rate with cystatin C and beta-trace protein in children with spina bifida

PURPOSE: We compared the diagnostic performance of cystatin C and beta-trace protein with serum creatinine and the Schwartz formula for the estimation of glomerular filtration rate in children with spina bifida. MATERIALS AND METHODS: Cystatin C, beta-trace protein and serum creatinine in children who underwent routine measurement of glomerular filtration rate were obtained in a prospective study. A spina bifida group (27 measurements in 27 patients 1.4 to 20.0 years old, 15 female, 12 male) was compared with a group of controls (211 measurements in 201 patients with various other renal pathologies 1.0 to 20.2 years old, 89 female, 122 male). All patients underwent nuclear medicine clearance investigations with 99mtechnetium diethylenetetraminepentaacetic acid. Z scores were calculated for body mass index, height and weight. Receiver operating characteristic (ROC) analysis and ROC plots were done to assess their diagnostic accuracy. RESULTS: Serum creatinine and the Schwartz formula did not correlate with glomerular filtration rate in the patients with spina bifida. Correlation coefficients for cystatin C were 0.45 and 0.84 in the spina bifida and control groups, respectively, while correlation coefficients for beta-trace protein were 0.31 and 0.75, respectively. For both groups ROC area was highest for cystatin C (up to 0.97 ROC area in control group). CONCLUSIONS: Only cystatin C served as a suitable marker to estimate glomerular filtration rate in patients with spina bifida. Cystatin C proved to be a superior marker in patients with spina bifida. In the control group the Schwartz formula was comparable to cystatin C and beta-trace protein, although cystatin C remained superior.