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     

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).     

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.     

Cystatin C: influence of perfusion and myocardial injury on early (<24 h) renal function after pediatric cardiac surgery

Background: Cardiopulmonary bypass (CPB)‐associated renal dysfunction following cardiac surgery is well recognized. In patients with renal disease, cystatin C has emerged as a new biomarker which in contrast to creatinine (Cr) is sensitive to minor changes in glomerular filtration rate (GFR). Aim: We utilized cystatin C to investigate the association of CPB perfusion parameters with acute renal injury after pediatric cardiac surgery. Methods: Twenty children, aged 4–58 months (AVSD, n = 7; VSD, n = 9; and ASD, n = 4), were prospectively studied. Glomerular filtration rate was quantified postoperatively by creatinine clearance (first and second 12‐h periods; CrCl_0–12 and CrCl_12–24). Serum cystatin C and Cr were measured preoperatively and on days 0–3. Recorded CPB parameters included bypass duration (BP), perfusion pressure (PP), lowest pump flow (Q_min), lowest hematocrit, and corresponding lowest oxygen delivery (DO_{2 min}). Myocardial injury was determined by troponin‐I. Results: Postoperatively, GFR remained unchanged (CrCl_0–12 63.6 ± 37.0 vs CrCl_12–24 65.1 ± 27.5; P = 0.51) and only correlated with cystatin C (CrCl_0–12 vs cystatin C_Day0 [r = 0.58, P = 0.018] and Cr_Day0 [r = 0.09, P = 0.735]). Cr and cystatin C increased postoperatively to peak on days 2 and 3, respectively (Cr_PreOp 31 ± 6.9 vs Cr_Day2 36.9 ± 12.2, P = 0.03; cystatin C_Day0 0.83 ± 0.27 vs cystatin C_Day3 1.45 ± 0.53, P = 0.02). Increased cystatin C was significantly associated with BP (P = 0.001), mean PP (P = 0.029), Q_min (P = 0.005), troponin‐I (P < 0.001), and DO_2min <300 ml·min^?1·m^?2 (P = 0.007). Receiver–operator cutoff >1.044 mg·l^?1 for cystatin C exhibited 100% sensitivity and 67% specificity for detecting renal dysfunction, defined as GFR <55 ml·min^?1·1.73 m^?2. Conclusions: Cystatin C is a sensitive marker of early renal dysfunction following pediatric heart surgery. Variations in bypass parameters, myocardial injury, and ultimately critical oxygen delivery are significantly associated with the degree of renal impairment.     

Clinical usefulness of serum cystatin C and the pertinent estimation of glomerular filtration rate based on cystatin C

Aim: Although cystatin C has been developed as an alternative marker for estimating glomerular filtration rate (GFR), its clinical use is as yet limited. The significance of cystatin C for differentiating chronic kidney disease (CKD) stages and established cystatin C‐based equations estimating GFR were evaluated. Methods: The fresh frozen serum samples from CKD (n = 119) and healthy volunteers (n = 22) were evaluated. Serum creatinine (sCr) was measured by the kinetic Jaffé method, and recalibrated to the isotope dilution mass spectrometry (IDMS). Cystatin C was measured using a particle‐enhanced nephelometric assay. Results: CKD stages were more sensitively differentiated by cystatin C compared to sCr, especially in moderate and severe kidney dysfunction. Sex and body mass index did not affect cystatin C level. Pearson's correlation coefficients of reciprocal of cystatin C, measured and recalibrated sCr compared to systemic inulin clearance (Cl_in) were 0.757, 0.734 and 0.709, respectively. We derived novel pertinent equations based on cystatin C (model 1: 1.404 × cystatin C^?0.895 × age^0.006 × weight^1.074 × height^?1.562 × (0.865; if female); model 2: 43.287 × cystatin C^?0.906 × age^0.101 × (0.762; if female)]. Models 1 and 2 showed superior performance in representing systemic Cl_in than the IDMS Modification of Diet in Renal Disease (MDRD) study equations did (adjusted r² = 0.76 and 0.72 for models 1 and 2, and 0.64 and 0.65 for 4 and 6 variable IDMS MDRD equations, respectively). Conclusion: Cystatin C reflects kidney dysfunction sensitively, and thus cystatin C‐based estimation of GFR could provide a reliable support for clinical practice.     

Evaluation of the renal function in cardiac surgery with CPB: role of the cystatin C and the calculated creatinine clearance

Objectives

The evaluation of the renal function in cardiac surgery is difficult. The gold standard remains the creatinine clearance in clinical practice. Cystatin C was recently proposed in order to evaluate the renal function. The aim of our study was to evaluate the cystatin C in cardiac surgery with CPB.

Patients and methods

After informed consent and ethical committee agreement, 60 patients operated in cardiac surgery with CPB were prospectively included. Cystatin C,measured and calculated (Cockcroft and MDRD methods) creatinine were compared with the Student t-test and with the Bland and Altman method. p < 0,05 was considered as a significant threshold.

Results

The reproducibility of the calculated creatinine clearance was better when the urinary collecting time was below 400 minutes. The estimation of the creatinine clearance by the Cockcroft and MDRD methods is better when the clearance is low. A significant correlation between the creatinine clearance and the cystatin C does exist, but the correlation coefficient was low. In case of acute renal dysfunction, the increase of the creatinine occurred earlier than the increase of the cystatin C.

Conclusion

In cardiac surgery with CPB, the evaluation of the renal function was not improved by the cystatin C.     

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.     

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

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

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

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

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     

Glomerular filtration rate estimated by cystatin C among different clinical presentations

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

Strong relationship between NT‐proXNP levels and cardiac output following cardiac surgery in neonates and infants

Background: NT‐proXNP, a new natriuretic peptide analyte, incorporates information about the concentrations of both N‐terminal pro‐atrial and pro‐brain natriuretic peptides (NT‐proANP, NT‐proBNP). We aimed to investigate whether NT‐proXNP is a reliable indicator of the cardiac index (CI) and the hemodynamic state in neonates and infants undergoing an open heart surgery. Methods: We enrolled 26 children under the age of 1 year into this prospective study. All patients underwent an elective cardiac operation with cardiopulmonary bypass (CPB) to achieve complete biventricular repair. Peri‐operative hemodynamic parameters were assessed by transpulmonary thermodilution and natriuretic peptide levels were recorded. Results: The NT‐proXNP level correlated significantly with the simultaneously measured NT‐proANP level (r=0.60, P<0.001), but more strongly with the NT‐proBNP level (r=0.89, P<0.001) and the arithmetic sum of both (r=0.88, P<0.001). NT‐proXNP had a strong correlation with CI (r=?0.85, P<0.001), the stroke volume index (r=?0.80, P<0.001) and the global ejection fraction (r=?0.67, P<0.009) throughout the post‐operative period. Conventionally measured parameters such as heart rate, mean arterial pressure and pulse‐pressure product exhibited weaker correlations with CI than NT‐proXNP. Among laboratory values, creatinine levels correlated significantly with CI (r=?0.77, P<0.001) and NT‐proXNP (r=0.76, P<0.001) during the post‐operative period. A post‐operative NT‐proXNP level of 3079 pmol/l was diagnostic for CI <3 l/min/m² with 89% sensitivity and 90% specificity (area under the curve: 0.91 ± 0.05). Conclusion: NT‐proXNP is a good marker of cardiac output following pediatric cardiac surgery and might be a useful tool in the recognition of a low output state.     

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.     

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.     

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.     

Metabolic status in diabetes mellitus affects markers for glomerular filtration rate

The present study was performed in newly diagnosed diabetic children to evaluate the effect of metabolic derangement on routine tests for glomerular filtration rate (GFR). Children with ( n=16) and without ( n=10) ketonuria at diagnosis of diabetes followed a routine clinical treatment program. Serum creatinine, creatinine clearance, serum cystatin C, and iohexol clearance were analyzed at diagnosis and after 20 days of treatment. Iohexol clearance was used as the "true GFR". Serum creatinine and iohexol clearances were not affected by the acute metabolic status or ketonuria. In contrast, serum cystatin C was significantly influenced by ketonuria. Creatinine clearance was an unreliable marker for GFR both in the more deranged and in the balanced metabolic situation.     

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.     

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.     

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

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

Determining 'true' glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations

OBJECTIVE: To determine 'true' glomerular filtration rate (GFR) in healthy adults as renal clearance following infusion of inulin, and compare that result with those obtained using other markers and clearance techniques and with estimations of GFR using creatinine-based prediction equations. MATERIAL AND METHODS: Twenty healthy volunteers (11 females) with a median age of 27 years (range 19-36 years) received bolus doses of inulin and iohexol i.v. and 16 blood samples were taken after injection. Then, inulin and iohexol were infused to give stable plasma concentrations and blood and urine samples were collected. Residual bladder volume was estimated using ultrasound scanning. Plasma and urine concentrations of inulin and iohexol were determined using chromatography and resorcinol methods, respectively. Different methods of GFR determination were compared as well as four formulae for GFR estimation based on serum creatinine. RESULTS: 'True' GFR, i.e. renal clearance of inulin during its infusion, was a median of 117 ml/min/1.73 m2 (inter-quartile range 106-129 ml/min/1.73 m2). Similar values of GFR were obtained with renal clearance of iohexol during its infusion and also with plasma (body) clearance of inulin or iohexol following bolus injections and using 16 or five plasma samples. Endogenous creatinine clearance was higher (p<0.001) than true GFR (median 23 ml/min/1.73 m2). Plasma clearance of iohexol and inulin based on their concentrations in four blood samples underestimated their renal clearance considerably. All four creatinine-based formulae markedly underestimated renal inulin clearance. CONCLUSIONS: Plasma and renal clearance of iohexol and inulin were similar in healthy adults. Underestimation of GFR was noted when plasma clearance of iohexol and inulin was based on four but not five or more blood samples. Some prediction equations underestimate true GFR to such an extent that caution must be taken when using them to evaluate normal or high GFR values.