Diagnostic sensitivity of serum cystatin for impaired glomerular filtration rate

Recently, the reciprocal of cystatin C (Cys-C), a non-glycosylated 13-kilodalton protein that is produced by all investigated nucleated cells, was found to correlate closely with glomerular filtration rate (GFR). In order to determine the diagnostic validity in children for the detection of impaired GFR, venous blood samples from 381 children (aged 1.7–18 years) with various renal pathology referred for ⁵¹Cr-EDTA clearance investigations were obtained for measurement of Cys-C as well as β₂-microglobulin (β2-MG) and serum creatinine. Two hundred and sixteen children with clearance values >90 ml/min per 1.73 m² constituted a control group, with a normal GFR. In the control group, Cys-C values were normally distributed with a mean of 0.94±0.27 mg/l and an upper reference limit (97.5th percentile) of 1.47 mg/l. In all children, there was a positive correlation between ⁵¹Cr-EDTA clearance and the reciprocal of Cys-C (r=0.64, P<0.0001), β₂-MG (r=0.59, P<0.0001), creatinine (r=0.55, P<0.0001), and the height/creatinine ratio (r=0.73, P<0.0001). Receiver-operating characteristics analysis showed that there were no significant differences between these three parameters for discriminating between patients with normal and reduced GFR, although there was a tendency towards the best diagnostic sensitivity of the GFR estimate according to the Schwartz formula. We conclude that for the detection of mildly impaired GFR, a full clearance study cannot be replaced by measurement of serum Cys-C or β2-MG concentrations. Received: 15 June 1998 / Revised: 22 September 1998 / Accepted: 23 September 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     

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

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

Estimation of renal function in diabetic nephropathy. Comparison of five methods

Plasma as well as renal clearance of 51Cr-EDTA, serum creatinine, plasma beta-2-microglobulin and endogenous creatinine clearance were compared and evaluated in patients with diabetic nephropathy and in control patients with renal disease of other origin. The difference between the plasma clearance and the renal clearance of 51Cr-EDTA, that is the extrarenal clearance, was found to be higher in diabetics than in control patients (7.0 vs. 3.5 ml/min; p less than 0.001). The serum creatinine correlated well with the glomerular filtration rate (GFR), but in the individual case the GFR was not at all predictable from serum creatinine. The plasma beta-2-microglobulin did not correlate better than serum creatinine to 51Cr-EDTA clearance, and did not permit an earlier diagnosis of renal insufficiency. Endogenous creatinine clearance overestimated GFR by 0-180%. Due to residual urine, the coefficient of variation was higher in diabetic patients than in controls, but the effect of this imperfection was reduced by using multiple collection periods. In conclusion, the renal clearance of 51Cr-EDTA was found to be preferable to the other methods.     

Evaluation of plasma cystatin C as a marker for glomerular filtration rate in patients with type 2 diabetes

AIM: To evaluate plasma cystatin C as a marker of the glomerular filtration rate in patients with type 2 diabetes and their age and sex-matched controls. MATERIALS AND METHODS: Forty-seven patients with one decade of type 2 diabetes and 51 non-diabetic control subjects were studied. Plasma cystatin C was measured by particle-enhanced turbidimetric immunoassay in a new application for the Hitachi 704 analyzer. For comparison, plasma creatinine and creatinine clearance were measured. The plasma clearance of 51Cr-EDTA by the single injection method was utilized as reference. RESULTS: In patients with type 2 diabetes the correlation coefficient between plasma cystatin C and the plasma clearance of 51Cr-EDTA was 0.774 (Spearman's coefficient) and that between plasma creatinine and the plasma clearance of 51Cr-EDTA was 0.556 (p = 0.001 for the difference). The correlation between creatinine clearance and the plasma clearance of 51Cr-EDTA was 0.411. In receiver operating characteristic (ROC) curve analysis the diagnostic accuracy of plasma cystatin C was significantly better than that of plasma creatinine (p = 0.047) or creatinine clearance (p = 0.001). The best diagnostic efficiency (98%) for cystatin C was obtained when the cut-off limit was set at 1.32 mg/l. In the control group the correlation coefficients were: between cystatin C and the plasma clearance of 51Cr-EDTA 0.627, between creatinine and the plasma clearance of 51Cr-EDTA 0.466 and between creatinine clearance and the plasma clearance of 51Cr-EDTA 0.416. The area under the ROC plot curve of cystatin C was also greatest in the control group, but the diagnostic accuracy of cystatin C was marginally better than that of either plasma creatinine (p = 0.05) or creatinine clearance (p = 0.08). Among the control subjects various non-renal causes may have interfered with cystatin C concentrations reducing the correlations. CONCLUSIONS: Cystatin C measurement is a more sensitive and specific test for GFR in patients with type 2 diabetes than plasma creatinine or its clearance, when GFR is normal or only slightly reduced. If an elevated cystatin C concentration is found, non-renal factors have to be excluded. The turbidimetric application described here can easily be applied for most clinical chemistry analyzers and is therefore useful in daily clinical practice.     

Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease

Very few biomarkers exist for monitoring chronic kidney disease (CKD). We have recently shown that serum neutrophil gelatinase-associated lipocalin (NGAL) represents a novel biomarker for early identification of acute kidney injury. In this study, we hypothesized that serum NGAL may also represent a biomarker for the quantitation of CKD. Forty-five children with CKD stages 2–4 were prospectively recruited for measurement of serum NGAL, serum cystatin C, glomerular filtration rate (GFR) by Ioversol clearance, and estimated GFR (eGFR) by Schwartz formula. Serum NGAL significantly correlated with cystatin C (r=0.74, P<0.000). Both NGAL and cystatin C significantly correlated with measured GFR (r=0.62, P<0.000; and r=0.71, P<0.000, respectively) as well as with eGFR (r=0.66, P<0.000 and r=0.59, P<0.000, respectively). At GFR levels of ≥30 ml/min per 1.73 m², serum NGAL, cystatin C, and eGFR were all significantly correlated with measured GFR. However, in subjects with lower GFRs (<30 ml/min per 1.73 m²), serum NGAL levels correlated best with measured GFR (r=0.62), followed by cystatin C (r=0.41). We conclude that (a) both serum NGAL and cystatin C may prove useful in the quantitation of CKD, and (b) by correlation analysis, NGAL outperforms cystatin C and eGFR at lower levels of measured GFR.     

Evaluation of cystatin C with iohexol clearance in cardiac surgery

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

Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impairment of kidney function.

BACKGROUND: Estimation of the glomerular filtration rate (GFR) is essential for the evaluation of patients with chronic kidney disease (CKD). Recently, serum cystatin C was proposed as a new endogenous marker of GFR and in our study its diagnostic accuracy was compared with that of other markers of GFR. METHODS: In this study, 164 patients with CKD stages 2-3 (GFR 30-89 ml/min/1.73 m2), who had performed 51Cr-labelled ethylenediaminetetra-acetic acid clearance, were enrolled. In each patient, serum creatinine and serum cystatin C were determined. Creatinine clearance was calculated using the Cockcroft-Gault (C&G) and the modification of diet in renal disease (MDRD) formulas. RESULTS: The mean 51CrEDTA clearance was 57 ml/min/1.73 m2, the mean serum creatinine 149 micromol/l and the mean serum cystatin C 1.74 mg/l. We found significant correlation between 51CrEDTA clearance and serum creatinine (R = -0.666), serum cystatin C (R = -0.792), reciprocal of serum creatinine (R = 0.628), reciprocal of serum cystatin C (R = 0.753) and calculated creatinine clearance from the formulas C&G (R = 0.515) and MDRD formulas (R = 0.716). The receiver operating characteristic (ROC) curve analysis (cut-off for GFR 60 ml/min/1.73 m2) showed that serum cystatin C had a significantly higher diagnostic accuracy than serum creatinine (P = 0.04) and calculated creatinine clearance from the C&G formula (P < 0.0001), though only in female patients. No difference in diagnostic accuracy was found between serum cystatin C and creatinine clearance calculated from the MDRD formula. CONCLUSIONS: Our results indicate that serum cystatin C is a reliable marker of GFR in patients with mildly to moderately impaired kidney function and has a higher diagnostic accuracy than serum creatinine and calculated creatinine clearance from the C&G formula in female patients.     

Cystatin C, an easy and reliable marker for assessment of renal dysfunction in children with liver disease and after liver transplantation.

Renal dysfunction of variable severity is being increasingly recognized as a major complication of calcineurin inhibitors (CI), in some patients even necessitating renal transplantation. Close and effective monitoring of the renal function is indicated. Current methods for this monitoring are calculation of the glomerular filtration rate (GFR) based on creatinine or exogenous substances like 51Cr-EDTA. The first method is unreliable in children and the second is expensive and cumbersome. Cystatin C has been shown to be an accurate marker of glomerular filtration but has not been evaluated in a large cohort of pediatric patients before and after liver transplantation (LT). We evaluated the accuracy of cystatin C in 62 children (30 male) with LT, who had their 51Cr-EDTA measured on 40 occasions prior to LT and on 47 occasions after LT. The reciprocal of cystatin C correlated better with 51Cr-EDTA GFR (r = .78) than the reciprocal of creatinine (r = .40). Diagnostic accuracy in the identification of reduced GFR was assessed by ROC analysis. Cystatin C yielded the highest area under the ROC curve (AUC) in all groups assessed. From these data a cutoff level of cystatin C predicting 51Cr-EDTA GFR < 80 ml/min/1.73 m2 was calculated. A level of 1.06 mg/L was found to have a sensitivity of 91% and a specificity of 81%. Applying this cutoff level in our patient group would have avoided 51Cr-EDTA GFR estimation in 43 of the 87 estimations. In conclusion, the use of this simple test could be recommended as screening of renal dysfunction in children with liver disease and after LT.     

Comparison of serum cystatin C and creatinine levels in determining glomerular filtration rate in children with stage I to III chronic renal disease

Abstract

Background: Pediatric studies are relatively scarce on the superiority of cystatin C over creatinine in estimation of glomerular filtration rate (GFR). This study measured cystatin C and serum creatinine levels, and compared GFR estimated from these two parameters in patients with chronic renal disease. Methods: This prospective, observational, controlled study included 166 patients aged 1–18 years diagnosed with stage I to III chronic renal disease, and 29 age- and sex-matched control subjects. In all patients, GFR was estimated via creatinine clearance, Schwartz formula, Zappitelli 1 and Zappitelli 2 formula and the results were compared using Bland–Altman analysis. Results: Patients and controls did not differ with regard to height, body weight, BMI, serum creatinine and serum cystatin levels, and Schwartz formula-based GFR (p?>?0.05). There was a significant relationship between creatinine and cystatin C levels. However, although creatinine levels showed a significant association with age, height, and BMI, cystatin C levels showed no such association. ROC analysis showed that cystatin C performed better than creatinine in detecting low GFR. Conclusion: Cystatin C is a more sensitive and feasible indicator than creatinine for the diagnosis of stage I to III chronic renal disease.     

The Utility of Combined Urine Urea and Creatinine Clearance for Pretransplant Renal Function Assessment

BackgroundEvaluation of donor renal function as glomerular filtration rate (GFR) is a crucial part of pretransplant workup. Most guidelines recommend measured GFR (mGFR) using exogenous markers with creatinine clearance (CrCl) as an alternative. However, exogenous markers are difficult to obtain and perform, and CrCl may overestimate GFR.ObjectiveWe explore the use of CrCl and combined urea and creatinine clearance as an alternative for GFR assessment.MethodsA retrospective study involving 81 kidney donors from 2007 to 2020, with mGFR collected by chromium 51-labeled ethylenediaminetetraacetic acid (⁵¹Cr-EDTA) and CrCl and combined urea and creatinine clearance. We analyzed the performance of CrCl and combined urea and creatinine clearance against ⁵¹Cr-EDTA. Adequacy of urine volume was taken into consideration.ResultsA total of 81 candidates with a mean age of 44.80 ± 10.77 years were enrolled. Mean mGFR from ⁵¹Cr-EDTA was 123.66 ± 26.91 mL/min/1.73 m², and combined urea and creatinine clearance and CrCl were 122.13 ± 47.07 and 133.40 ± 36.32 mL/min/1.73 m², respectively. CrCl overestimated ⁵¹Cr-EDTA. Though combined urea and creatinine clearance had minimal bias, it had a lower correlation coefficient (0.25 vs 0.43), lower precision (49.51 vs 38.10), and slightly lower accuracy within 30% of ⁵¹Cr-EDTA (74.07% vs 76.54%).ConclusionsCombined urea and creatinine clearance did not improve the performance of CrCl. Nevertheless, it can potentially be used as first-line GFR assessment, followed by mGFR in selected donors, to ascertain threshold of safe kidney donation. A stringent urine collection method is essential to ensure accurate measurement.     

Serum cystatin C levels in children with sickle cell disease

Patients with sickle cell disease (SCD) may develop kidney dysfunction from childhood. The purpose of this study was to examine the value of serum cystatin C as a marker for glomerular filtration rate (GFR) in children with SCD, as compared to serum creatinine and creatinine clearance (CrCl). Twenty children (ages 9–21, ten males) with SCD with and without albuminuria were studied. The mean serum cystatin for the whole group was 0.89 mg/l (0.5–1.7 mg/l). Mean serum cystatin C was significantly different among the children with proteinuria (n=4), microalbuminuria (n=5), and without albuminuria (n=11) (1.25 mg/l, 0.84 mg/l, and 0.78 mg/l, respectively). The mean GFR derived from serum cystatin was significantly different among these subgroups, becoming abnormal in the proteinuric cohort (63 ml/min per 1.73 m²), in contrast to 94 for the microalbuminuric, and 103 for the normal subgroups. Serum creatinine (mean: 0.58 mg/dl, range: 0.3–1.1) did not change significantly with the level of albuminuria. Mean CrCl remained normal to increased within the subgroups, (133 ml/min per 1.73 m² for those with proteinuria, 144 for those with microalbuminuria, and 163 for the normal subgroup). We conclude that serum cystatin C correlates with the level of albuminuria and may be a reliable method to measure renal function in SCD. An erratum to this article can be found at     

Glomerular filtration rate estimated from the uptake phase of 99mTc-DTPA renography in chronic renal failure.

BACKGROUND: The purpose of the study was to compare the estimation of glomerular filtration rate (GFR) from 99mTc-DTPA renography with that estimated from the renal clearance of 51Cr-EDTA, creatinine and urea. METHODS: Fifty patients with reduced renal function (serum creatinine between 150 and 600 micromol/l) were enrolled in the study. GFR was estimated from the uptake phase of 99mTc-DTPA renography (GFR(DTPA)). The renal clearance of 51Cr-EDTA (GFR(EDTA)) was used as the reference method. Creatinine clearance (C(Cr)), urea clearance (C(Ur)) and the mean of urea and creatinine clearance (C(Cr+Ur)/2) were also calculated from urine collected during a period of 24 h. Limits of agreement were used for method comparison. RESULTS: The limit of agreement between GFR(DTPA) and GFR(EDTA) was 2 +/- 17 ml/min. The mean difference did not deviate significantly from zero. The other clearance techniques had larger limits of agreement and a mean difference significantly different from zero. Furthermore, C(Ur) and C(Cr+Ur)/2 had systematic deviations of the differences, indicating that C(Ur) and C(Cr+Ur)/2 are poor estimates of GFR. CONCLUSION: The limit of agreement between GFR(DTPA) and GFR(EDTA) are acceptable and, therefore, GFR estimated from 99mTc-DTPA renography is acceptable for clinical use in patients with reduced renal function. Furthermore, the method is simple and less time consuming compared with renal clearance techniques.     

Correlation between cystatin C- and renal scan-determined glomerular filtration rate in children with spina bifida

We report on the relationships between serum cystatin C level, glomerular filtration rate (GFR) estimated from a cystatin C-based prediction equation (that of Filler and Lepage), GFR calculated by the Schwartz formula and technetium 99m-diethylene triamine penta-acetic acid (⁹⁹Tc-DTPA)-determined GFR in 28 children with spina bifida. All children underwent measurement of height, weight, serum cystatin C level, and serum creatinine level at the time of their renal scan. The relationship between variables was assessed by Pearson correlation. Pearson correlation for the relationship between ⁹⁹Tc-DTPA GFR and GFR calculated by the cystatin C-based equation was significant and higher than that of the relationship between ⁹⁹Tc-DTPA GFR and GFR calculated by the Schwartz equation, which was not statistically significant. The correlation for Filler GFR was 0.42 (P = 0.03) and for Schwartz GFR was 0.21 (P = 0.28). Although we use renal scan determination of GFR as the best measure, and a creatinine-based formula as the most practical measure, perhaps a formula such as that published by Filler and Lepage, which is not dependent on anthropometric data, might be a more useful (and accurate) tool for establishing GFR in children with spina bifida.     

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.     

Determination of glomerular filtration rate in advanced renal insufficiency.

The glomerular filtration rate (GFR) has been determined in 17 patients with advanced renal insufficiency (GFR less than 15 ml/min) by different clearance techniques using creatinine, inulin and 51Cr-EDTA as filtration markers. With renal inulin clearance as reference method for GFR, endogenous renal creatinine clearance overestimated GFR by an average of 30%. Renal clearance of 51Cr-EDTA and inulin were closely correlated and thus 51Cr-EDTA is a suitable GFR marker even at low filtration rates. However, it was found that the plasma clearance of 51Cr-EDTA overestimated the GFR often by more than 100% in the range 2.6--11.2 ml/min. Renal clearance measured during 24 h was lower than 4 h renal clearance with the patient well hydrated and resting in bed. It is concluded that the precise measurement of low glomerular filtration rates requires the use of renal clearance techniques. Four-hour 51Cr-EDTA renal clearance is a suitable method for measuring and following the development of renal function in advanced renal insufficiency.     

Serum cystatin C as an endogenous marker of renal function in patients with chronic kidney disease

The estimation of the glomerular filtration rate (GFR) is an essential part of the evaluation of patients with chronic kidney disease (CKD). Recently, serum cystatin C has been proposed as a new endogenous marker of GFR. Authors compared serum creatinine, creatinine clearance calculated from Cockcroft and Gault formula and serum cystatin C against (51)CrEDTA clearance in 252 patients with CKD and GFR <90 mL/min/1.73 m(2). Analysis of correlations and diagnostic accuracy (receiver operating characteristic curves) of different GFR markers indicate that serum cystatin C is a more reliable marker of GFR in patients with CKD than serum creatinine.     

Cystatin C: efficacy as screening test for reduced glomerular filtration rate

Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and creatinine clearance were measured in 226 patients with various nephropathies, covering the entire range of renal function, to evaluate the efficacy of cystatin C as a screening test to detect reduced creatinine clearance in comparison to creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular impairment were compared to assess whether cystatin C performed differently in either glomerular or tubular impairment. Cystatin C detected reduced creatinine clearance with higher sensitivity (97 vs. 83%), and higher negative predictive value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of cystatin C as derived from receiver-operating characteristic plot was significantly higher (p < 0.05). In the subgroups with glomerular or tubular impairment, cystatin C and creatinine did not significantly differ with regard to efficacy. Serum cystatin C is as efficacious as serum creatinine to detect reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a screening test may even be superior compared to creatinine. In addition, the efficacy of cystatin C is independent of either glomerular or tubular impairment.     

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

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

Glomerular filtration rate measurement and estimation in chronic kidney disease

Glomerular filtration rate (GFR) assesses kidney function. GFR is measured by renal clearance techniques; inulin clearance is the gold standard but is not easily measured. Thus, other methods to determine GFR have been utilized. Endogenous creatinine clearance (CrCl) is the most widely used, but creatinine secretion falsely elevates GFR. Cimetidine inhibits creatinine secretion, such that CrCl equals GFR, provided there are no difficulties with bladder emptying. Estimation of GFR from serum creatinine (e.g. Schwartz formula) is useful clinically; however, such formulae have not been updated for enzymatic creatinine autoanalyzers. Cystatin C, a small protein, is produced at a relatively constant rate and is reabsorbed in the proximal tubule. Cystatin C may be more sensitive than creatinine in detecting a reduction in GFR, but further studies are needed to prove this. Single injection (plasma) clearance techniques are the most precise measures of GFR. Iohexol is an exogenous marker that is comparable to inulin and ⁵¹Cr-EDTA and can be measured by high-performance liquid chromatography (HPLC). Our pilot and the Chronic Kidney Disease in Children (CKiD) North American studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve national studies show that iohexol can accurately measure GFR using a four-point plasma disappearance curve (10, 30, 120, and 300 min) or, in most cases, a two-point disappearance time (120 and 300 min).