Early detection of acute renal failure by serum cystatin C

BACKGROUND: Acute renal failure (ARF) is associated with high mortality. Presently, no specific therapy for ARF exists. Therefore, early detection of ARF is critical to prevent its progression. However, serum creatinine, the standard marker to detect ARF, demonstrates major limitations. We prospectively evaluated whether serum cystatin C detected ARF earlier than serum creatinine. METHODS: In 85 patients at high risk to develop ARF, serum creatinine and cystatin C were determined daily. ARF was defined according to the Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and ESRD (RIFLE) classification when creatinine increased by >/=50% (R-criteria), by >/=100% (I-criteria), or by >/=200% (F-criteria). In analogy, ARF was detected when cystatin C increased by >/=50%, by >/=100%, or by >/=200%. RESULTS: Forty-four patients developed ARF and 41 served as controls. In ARF by R-, I-, and F-criteria, the increase of cystatin C significantly preceded that of creatinine. Specifically, serum cystatin C increased already by >/=50% 1.5 +/- 0.6 days earlier compared to creatinine. Serum cystatin C demonstrated a high diagnostic value to detect ARF as indicated by area under the curve of the ROC analysis of 0.82 and 0.97 on the two days before the R-criteria was fulfilled by creatinine. Cystatin C detected ARF according to the R-criteria with a sensitivity of 55% and 82% on these days, respectively. Cystatin C also performed excellently, detecting ARF defined by the I- and F-criteria two days prior to creatinine, and moderately well predicting renal replacement therapy in the further course of ARF. Additionally, low T(3)- or T(3)/T(4) syndrome, glucocorticoid deficiency and excess did not affect cystatin C levels, adding to its usefulness in critically ill patients with ARF. CONCLUSION: Serum cystatin C is a useful detection marker of ARF, and may detect ARF one to two days earlier than creatinine.     

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.     

血清半胱氨酸蛋白酶抑制剂C在急性肾衰早期诊断中的价值

目的 探讨半胱氨酸蛋白酶抑制剂C（cystatin C）在早期预测和诊断急性肾衰竭（ARF）中是否优于血清肌酐（Scr）。方法 前瞻性收集我院103例重症监护室危重患者资料，每例患者每天采集血标本。同时应用酶法测Scr水平；用颗粒增强透射免疫比浊法（PETIA）检测血清cystatin C水平；用Cockroft-Gauh公式估算肾小球滤过率（eGFR）。ARF运用ADQI的RIFLE标准进行诊断（R：Scr升高≥50％基础值，I：Scr升高≥100％基础值，F：Scr升高≥200％基础值，L：肾功能丧失；E：终末期肾脏病ESRD）；同时ARF也按cystatin C升高≥50％、≥100％和≥200％的标准进行诊断。结果 27（26．2％）例患者发生不同程度ARF，其中15例经历R标准，18例经历I标准，9例经历F标准，3例经历LE标准。其余76例没有发生ARF的患者作为对照组。ARF患者的cystatinC较非ARF患者显著升高（P〈0．01），ARF患者的cystatin C与Scr（r=0．747，P〈0．01）、（cystatinC）^-1与eGFR（R=0．815，P〈0．01）呈明显线性相关。分别按照cystatin C和Scr两种方法诊断ARF，不同程度ARF诊断的中位时间是：R标准的15例患者分别为2d（1～4d）和3d（2～6d）（P=0．011）；Ⅰ标准18例患者分别为4d（1～8d）和5．5d（2～10d）（P=0．006）；F标准的9例患者分别为5d（3～lld）和6d（3～13d）（P=0．02）。ROC分析证实cystatinC在ARF诊断中的准确性高，曲线下面积为0．995，95％可信区间为0．984～1．006（P〈0．001）。当以cystatin C升高≥50％时作为ARF的诊断截点时，cystatin C在ARF诊断中的敏感性和特异性分别为93％和96％。结论 cystatin C可以作为急性肾衰竭的诊断指标：cystatin C在ARF的诊断时间上较Scr更早，可作为ARF的早期预测指标之一。     

Cystatin C in a rat model of end-stage renal failure

BACKGROUND: Cystatin C (MW 13kDa) serum concentration reflects glomerular filtration rate better than creatinine. Like other low-molecular weight proteins it is not eliminated by dialysis. Still, cystatin C serum concentrations do not rise progressively in end-stage renal failure and rarely exceed 10 mg/L (i.e. 8 times the upper limit of normal). OBJECTIVE: To study cystatin C kinetics in a rat model of end-stage renal failure. METHODS: Sequential bilateral nephrectomy was performed seven days apart in 13 male Sprague-Dawley rats as described by Levine and Saltzman. Serum cystatin C (Cystatin C PET-kit, DAKO), creatinine and total protein were measured in daily intervals after the second nephrectomy. Linearity of the anti-human cystatin C assay for rat cystatin C was tested using dilutions of uremic rat serum. Rats were sacrificed for signs of severe uremia on days 10 (n=5), 11 (n=4) and 12 (n = 5). RESULTS: At baseline, mean (+/- SE) cystatin C was 1.59+/-0.041 mg/L, creatinine 19.6+/-1.2 micromol/L. Following bilateral nephrectomy, cystatin C immediately rose to 3.82+/-0.15 mg/L, creatinine to 312+/-20 micromol/L. During the following days, cystatin C concentration stabilized to 4 mg/L approximately whereas creatinine continued to rise to 822+/-185 kmol/L on day 12. Correction for the decrease in serum total protein concentration from 48.9+/-2.3 g/L to 37.4+/-3.6 g/L did not alter these results. CONCLUSION: The kinetics of cystatin C and creatinine in this rat model of end-stage renal failure are in accordance with human data suggesting a change in cystatin C production or extra-renal elimination in severe chronic uremia.     

Time course of serial cystatin C levels in comparison with serum creatinine after application of radiocontrast media

BACKGROUND: The delayed increase of creatinine after radiocontrast application is a potential reason for overlooking radiocontrast nephrotoxicity. Cystatin C may be more useful to rapidly assess a decrease in glomerular filtration rate (GFR). We compared cystatin C and creatinine to examine their kinetics after application of radiocontrast media. PATIENTS AND METHODS: Forty-one patients (60.8 +/- 8.8 years, 68% males) with normal to subnormal GFR scheduled for coronary angiography (27% with angioplasty), were studied for serum cystatin C and creatinine levels before, 5 h, 24 h and 48 h after angiography. Furthermore, alpha1-microglobulin was checked for evidence of tubular damage. RESULTS: At 5 hours after angiography, there was no significant change compared to baseline in either serum creatinine nor cystatin C. In comparison with the value immediately before coronary angiography, the increase of cystatin C achieved a maximum at 24 h after the application of the contrast agent (+7.2%). Within 48 h, cystatin C decreased to the level before angiography. Serum creatinine increased at 24 h (+7.7%) and continued to increase at 48 h (+11.3%). CONCLUSION: Cystatin C increases earlier after radiocontrast application compared with creatinine. Therefore, cystatin C needs to be investigated as a potential early marker for nephrotoxicity, especially in the upcoming setting of short-time hospitalizations for coronary angiographies and interventions. Thus, further studies in patients with renal failure undergoing radiocontrast application are warranted to assess the usefulness of cystatin C in respect of an earlier detection of radiocontrast nephrotoxicity.     

Evolution and predictive power of serum cystatin C in acute renal failure

AIMS: The serum concentration of cystatin C has recently been proposed as a better indicator of glomerular filtration rate (GFR) than plasma creatinine. Little is known about cystatin C in critical illness. We assessed serum cystatin C as a marker of renal function in acute renal failure (ARF) and its power in predicting survival of ARF patients. MATERIAL: 202 consecutive adult patients admitted into the intensive care unit (ICU) during a period of 9 months. METHOD: Serum cystatin C, plasma creatinine and plasma urea were measured on admission, daily during the first 3 days, and 5-7 times a week during the rest of the ICU stay. The patients with and without ARF were compared by the Mann-Whitney U-test. The correlation between different variables was calculated by Spearman's correlation. Forward stepwise multiple regression analysis was performed to test independent predictors of mortality. The positive predictive value of serum cystatin C and plasma creatinine for ARF and mortality was calculated by ROC analysis. RESULTS: ARF occurred in 54 patients (27%). Serum cystatin C showed excellent positive predictive value for ARF in critical illness by ROC analysis. In acute renal dysfunction, abnormal values of serum cystatin C and plasma creatinine appeared equally quickly (median 3 days). The diagnosis of ARF, the day 1 Apache II score and admission plasma creatinine appeared as independent predictors of hospital mortality. ROC analysis showed only weak predictive power for serum cystatin C and plasma creatinine regarding hospital mortality. CONCLUSIONS: Serum cystatin C was as good as plasma creatinine in detecting ARF in intensive care patients. Neither marker was clinically useful in predicting mortality.     

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.     

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.     

Cystatin C ‐ an accurate marker of glomerular filtration rate after renal transplantation?

The performance of serum cystatin C as a screening marker of reduced creatinine clearance in renal transplantation was evaluated and compared to serum creatinine. In addition we studied whether cystatin C accurately reflects creatinine clearance over the entire range of transplant function. Serum cystatin C, serum creatinine, and creatinine clearance were measured in 110 adult renal transplant recipients. Cystatin C detected reduced creatinine clearance with the high sensitivity of 95 %. Serum cystatin C and serum creatinine did not differ regarding 90 and 95 % sensitivity, derived from the receiver-operating characteristics plot. We demonstrated a strong correlation and linear association between 1/cystatin C and creatinine clearance over the entire range of transplant function, equivalent to that of 1/creatinine. In summary, serum cystatin C accurately reflects creatinine clearance over the entire range of transplant function and is as efficacious as serum creatinine to detect reduced creatinine clearance in renal transplant recipients. Received: 5 June 1999 Revised: 8 March 2000 Accepted: 20 April 2000     

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.     

血清半胱氨酸蛋白酶抑制剂C在各期慢性肾脏病诊断中的应用价值

目的：探讨血清半胱氨酸蛋白酶抑制剂c（CystatinC）与血清肌酐（Scr）在不同时期慢性肾脏病（chronic kidney disease，CKD）患者肾功能检测中的敏感性，评价血清Cystatin C在各期CKD患者中的临床应用价值。方法：对129例不同时期CKD患者检测CystatinC，以^99mTc—DTPA清除率测得的肾小球滤过率（GFR）作为诊断评价的金指标，乳胶颗粒增强免疫透射比浊法检测血清CystatinC浓度，用全自动生化分析仪检测血清Scr。结果：与正常对照组比较，各期CKD组CystatinC值均有统计学差异，而各期CKD组Scr值与正常组比较，CKD1、CKD2期无统计学差异，CKD3～5期才有统计学差异；各期CKD组间比较显示CystatinC值均有统计学差异，而Scr值差异仅局限于CKD3～5期。并且血清CystatinC，Scr与^99mTc-DTPA清除率呈显著相关，尤其CystatinC相关性更好。结论：血清CystatinC在各期CKD中均能准确反映肾小球滤过功能，尤其能敏感提示早期肾功能损害，可成为判断肾功能损害程度的敏感指标，而且方法简便、敏感。     

Rapid and accurate assessment of glomerular filtration rate in patients with renal transplants using serum cystatin C.

BACKGROUND: Assessment of renal function in patients with renal transplants is of great importance. Various studies have reported cystatin C as an easily and rapidly assessable marker that can be used for accurate information on renal function impairment. To date, no study is available to define the role of cystatin C in patients with renal transplants. METHODS: Thirty steady-state patients (50% male/50% female) with status post-kidney transplantation were studied. To assess renal function, cystatin C, creatinine clearance, serum creatinine, beta2-microglobulin (beta2M), and [125I]iothalamate clearance were determined. Correlations and non-parametric ROC curves for accuracy, using a cut-off glomerular filtration rate (GFR) of 60 ml/min, were obtained for the different markers allowing for calculations of positive predictive values (PPV), positive likelihood ratios (PLR), specificity and sensitivity, respectively. Further, to evaluate the usefulness of these markers for monitoring, intraindividual coefficients of variation (CVs) for cystatin C and creatinine measurements were compared in 85 renal transplant patients. Measurements consisted of at least six pairs of results, which were obtained at different time points during routine follow-up. RESULTS: Cystatin C correlated best with GFR (r=0.83), whereas serum creatinine (r=0.67), creatinine clearance (r=0.57) and beta2M (r=0.58) all had lower correlation coefficients. The diagnostic accuracy of cystatin C was significantly better than serum creatinine (P=0.025), but did not differ significantly from creatinine clearance (P=0.76) and beta2M (P=0.43). At a cut-off of 1.64 mg/l, cystatin C has a PPV of 93%, PLR of 6.4, specificity 89% and sensitivity 70%, respectively. For beta2M, PPV 83%, PLR 1.7, specificity 67% and sensitivity 75% was seen at a cut-off of 3.57 mg/l. Accordingly, at a cut-off of 125 micromol/l for serum creatinine, a PPV 76%, PLR 1.4, specificity 44% and sensitivity 80% was revealed. Finally, at a cut-off of 66 ml/min/1.73 m2 for creatinine clearance, the following characteristics were found: PPV 94%, PLR 7.7, specificity 89% and sensitivity 85%. The intraindividual variation of creatinine was significantly lower than that of cystatin C (P<0.001). With increasing concentrations, their ratios of CV tended towards a value of 1, demonstrating identical variability at low GFR. CONCLUSION: Together, our data show that in patients with renal transplants, cystatin C, in terms of PPV and PLR, has a similar diagnostic value as creatinine clearance. However, it is superior to serum determinations of creatinine and beta2M. The intraindividual variation of cystatin C is greater than that of creatinine. This might be due to the better ability of cystatin C to reflect temporary changes especially in mildly impaired GFR, most critical for early detection of rejection and other function impairment. Thus, cystatin C allows for rapid and accurate assessment of renal function (GFR) in renal transplants and is clearly superior to the commonly used serum creatinine.     

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.     

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.     

CYSTATIN C IN A RAT MODEL OF END-STAGE RENAL FAILURE

Background: Cystatin C (MW 13 kDa) serum concentration reflects glomerular filtration rate better than creatinine. Like other low-molecular weight proteins it is not eliminated by dialysis. Still, cystatin C serum concentrations do not rise progressively in end-stage renal failure and rarely exceed 10 mg/L (i.e. 8 times the upper limit of normal). Objective: To study cystatin C kinetics in a rat model of end-stage renal failure. Methods: Sequential bilateral nephrectomy was performed seven days apart in 13 male Sprague-Dawley rats as described by Levine and Saltzman. Serum cystatin C (Cystatin C PET-kit, DAKO), creatinine and total protein were measured in daily intervals after the second nephrectomy. Linearity of the anti-human cystatin C assay for rat cystatin C was tested using dilutions of uremic rat serum. Rats were sacrificed for signs of severe uremia on days 10 (n = 5), 11 (n = 4) and 12 (n = 5). Results: At baseline, mean (± SE) cystatin C was 1.59 ± 0.041 mg/L, creatinine 19.6 ± 1.2 μmol/L. Following bilateral nephrectomy, cystatin C immediately rose to 3.82 ± 0.15 mg/L, creatinine to 312 ± 20 μmol/L. During the following days, cystatin C concentration stabilized to 4 mg/L approximately whereas creatinine continued to rise to 822 ± 185 μmol/L on day 12. Correction for the decrease in serum total protein concentration from 48.9 ± 2.3 g/L to 37.4 ± 3.6 g/L did not alter these results. Conclusion: The kinetics of cystatin C and creatinine in this rat model of end-stage renal failure are in accordance withh uman data suggesting a change in cystatin C production or extra-renal elimination in severe chronic uremia.     

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.     

血半胱氨酸蛋白酶抑制剂C在筛查早期肾功能异常中的临床意义

目的探讨血半胱氨酸蛋白酶抑制剂C在健康体检中筛查早期肾功能异常的临床意义。方法选择在我院健康体检中心的体检者75名,根据半胱氨酸蛋白酶抑制剂C水平将研究对象分为实验组和对照组,比较2组血半胱氨酸蛋白酶抑制剂C、血肌酐、尿素氮和99mTc—DTPA清除率。结果实验组血清半胱氨酸蛋白酶抑制剂C浓度高于对照组（P〈0．01）,实验组肾小球滤过率低于对照组（P〈0．01）。2组血肌酐和尿素氮均在正常范围,组间无统计学差异（P〉0．05）。血清半胱氨酸蛋白酶抑制剂C浓度与肾小球滤过率呈负相关（r=-0．75,P〈0．01）。结论血半胱氨酸蛋白酶抑制剂C是反映肾小球滤过率灵敏指标,为在健康体检中筛查早期肾功能异常提供了一个优于其他的指标。     

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,creatinine, estimated glomerular filtration,and long-term mortality in stroke patients

Renal dysfunction is associated with mortality in patients after ischemic stroke. Cystatin C is a potentially superior marker of renal function compared to creatinine and estimated glomerular filtration rate (GFR). In our observational cohort study, 390 Caucasian patients suffered from acute ischemic stroke (mean age 70.9 years; 183 women and 207 men) were included and prospectively followed up to maximal 56 months. Serum creatinine and cystatin C were measured at admission to the hospital; GFR was estimated according to CKD-EPI creatinine and CKD-EPI creatinine/cystatin equations. According to values of serum creatinine, estimated GFR and serum cystatin C patients were divided into quintiles. In the follow-up period, 191 (49%) patients died. For serum cystatin C and estimated GFR based on creatinine and cystatin C, the mortality and the hazard ratios for long-term mortality increased from the first to the fifth quintile nearly linearly. The associations of serum creatinine and estimated GFR categories based on creatinine with long-term mortality were J-shaped. As compared with lowest quintile of serum cystatin C, the fifth quintile was associated with long-term mortality significantly also after multivariate adjustment (age, gender, initial stroke severity, known risk factors for stroke mortality). In contrast, in adjusted analysis serum creatinine and estimated GFR (CKD-EPI creatinine and CKD-EPI creatinine/cystatin) were not associated with long-term mortality. In summary, serum cystatin C was independently and better associated with the risk of long-term mortality in patients suffering from ischemic stroke than were creatinine and estimated GFR using both CKD-EPI equations.     

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.