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PubMed2002

Serum cystatin C reliably detects renal dysfunction in patients with various renal diseases.

A clinical investigation was conducted to clarify the reliability and efficacy of serum cystatin C measurement for estimation of the glomerular filtration rate (GFR). Two hundred twelve patients with various renal diseases enrolled in the study. All patients were evaluated for 24-hour creatinine clearance (24 h C(Cr)) and the standard sodium thiosulfate clearance test (C(Thio)) within a week of blood sample collection. Serum cystatin C concentration was determined by a particle-enhanced immunonephelometry method. C(Thio) and 1/cystatin C, 24 h C(Cr), 1/beta2-microglobulin and 1/creatinine were well correlated. The correlation coefficients for C(Thio) obtained by 24 h C(Cr) and 1/cystatin C were comparable to each other (0.701 vs. 0.679). Receiver-operated characteristic (ROC) analysis revealed that 24 h C(Cr) showed the highest area under the curve when C(Thio) = 60 ml/min or C(Thio) = 100 ml/min were applied as the discrimination point. However, the ROC value obtained by cystatin C was slightly greater than 24 h C(Cr) when C(Thio) = 80 ml/min was used as the discrimination point. Patient age, gender, glucose tolerance, presence of proteinuria, systemic inflammation, lupus, or systemic use of steroids did not interfere in the relationship between C(Thio) and 1/cystatin C. In conclusion, serum cystatin C measurement is an excellent diagnostic test for detecting patients with subclinical renal dysfunction.

Adolescent↗
PubMed2004

Proatrial natriuretic peptide (1-98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients.

INTRODUCTION: N-terminal prohormone of atrial natriuretic peptide ((proANP(1-98)) has been extensively analyzed in patients with chronic renal failure. It has been found to be closely related to the renal function and to interdialytic hydration status. The clinical relevance of proANP(1-98) and cystatin C, a novel marker of glomerular filtration, has not been investigated in the subgroup of critically ill septic patients with no history of chronic renal impairment. METHODS: We measured plasma level ofproANP(1-98) and cystatin C in 29 critically ill septic patients on admittance to the surgical intensive care unit and correlated it with the occurrence of acute renal failure. RESULTS: The proANP(1-98) plasma level was significantly higher in the group of patients who developed renal failure (12,722 +/- 12,421 vs. 2,801+/- 2,023 fmol/ml, p < 0.05). Multiple regression analysis shows that proANP(1-98) on the first day in the intensive care unit has a superior predictive value for the occurrence of renal failure to diuresis, calculated creatinine clearance or cystatin C (r = 0.42, p < 0.039). proANP(1-98) is also higher in non-survivors (9,303.8 +/- 11,053 vs. 2,448.5 +/- 1,803 fmol/ml, p < 0.018). CONCLUSION: proANP(1-98) is possibly a better predictor of acute renal failure to calculated creatinine clearance or diuresis among critically ill septic patients. Cystatin C was not correlated with occurrence of acute renal failure in this subgroup of patients.

Acute Kidney Injury↗
PubMedDate not supplied

Reference values of umbilical cord and third-day cystatin C levels for determining glomerular filtration rates in newborns.

The aim of this study was to determine reference values for serum cystatin C at, and 3 days after, birth, and to determine if the concentration was influenced by gender, gestational age or bilirubin level. Umbilical cord and peripheral venous blood was taken, and serum cystatin C, creatinine, and total and direct bilirubin levels were measured. The mean concentration of cystatin C was not significantly different between cord blood and blood taken on day 3 (1.36 +/- 0.35 mg/l and 1.35 +/- 0.33 mg/l, respectively). Comparison of subgroups, divided by gender, duration of gestation and bilirubin levels, using the Mann-Whitney U-test and Wilcoxon analysis, showed no effect of these parameters on cystatin C levels.

Bilirubin↗
PubMed2000

Absence of cystatin C mutation in sporadic cerebral amyloid angiopathy-related hemorrhage.

In Icelandic pedigrees a cystatin C mutation, glutamine 68 (L68Q), causes autosomal dominant cerebral amyloid angiopathy-related hemorrhage (CAAH). We examined 33 patients with sporadic CAAH for this mutation. None carried L68Q and, including this report, only one of 52 published cases of sporadic CAAH has had the cystatin C mutation. Despite vascular colocalization of cystatin C with amyloid beta-protein, cystatin C L68Q is rare in sporadic CAAH.

Aged↗
PubMed1997

The expression and function of cystatin C and cathepsin B and cathepsin L during mouse embryo implantation and placentation.

The implantation of the mouse embryo requires the controlled invasion of the uterine stroma by the embryonic trophoblast. This event is dependent, in part, on the secretion of matrix metalloproteinases and serine proteinases for the extracellular degradation of the uterine matrix. Proteinase activity is controlled by stromal decidualization and specific proteinase inhibitors. This work adds to our understanding of implantation and placentation by reporting the expression and function of another class of proteinases/inhibitors closely related to invasive cell behavior. We focused on the cysteine proteinases, cathepsins B and L, and their inhibitor cystatin C. Northern blots showed that trophoblast expressed cathepsin B throughout the invasive period (days 5.5-10.5). Both cathepsin B message and cathepsin L protein were localized to the mature, invasive trophoblast giant cells. Substrate gel electrophoresis showed an increase in giant cell cathepsin activity with enzyme profiles changing at the end of the invasive period. Northern and western blotting showed that cystatin C, the main inhibitor of cathepsins, was a major product of the decidualizing stroma. Message levels first increased in peripheral decidualizing cells, with the protein localizing close to the embryo during implantation (days 5.5-8.5). With the regression of the decidua beginning on day 9.5, a coordinated upregulation of both cathepsin B and cystatin C was observed implying a role for controlled cathepsin expression during apoptosis. E-64, a synthetic inhibitor of cathepsins B and L, was injected into pregnant females at the stage of blastocyst attachment (days 4.5-5.5). High doses resulted in the complete failure of implantation while lower doses resulted in stunted embryos and a reduced decidual reaction. These results suggested that cathepsins B and L are necessary for normal embryo development and uterine decidualization, and that decidua contributes to their control by a coordinated expression of cystatin C within the implantation site.

Animals↗
PubMed2002

Cystatin C in milk basic protein (MBP) and its inhibitory effect on bone resorption in vitro.

A cystein protease inhibitor was identified in the basic fraction of bovine milk. We have reported in our previous study that the milk basic protein (MBP) fraction suppressed osteoclast-mediated bone resorption in vitro. Since osteoclasts secreted cystein protease to digest collagen in the bone matrix, we identified the cystein protease inhibitor in MBP. A 12-kDa inhibitor was purified from MBP by papain affinity gel chromatography and subsequent Hi-Load Superdex 75 gel filtration chromatography. The N-terminal sequence of the 18 amino acid residues of the inhibitor corresponded to bovine cystatin C. The 12-kDa cystein protease inhibitor in MBP therefore seemed to be cystatin C. Purified cystatin suppressed bone resorption with the use of isolated osteoclasts in vitro. Cystatin in MBP is suggested as one of the factors inhibiting bone resorption.

Amino Acid Sequence↗
PubMed2005

Purification of human wild-type or variant cystatin C from conditioned media of transfected cells.

The characterization of proteins in their native state is essential for the understanding of patho-genic isoforms. A variant of the cysteine protease inhibitor cystatin C is the major constituent of the amyloid deposited in the cerebral vasculature of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). In order to study the nature of the bio-physical changes owing to the Leu68Gln substitution in cystatin C, we have developed a purification procedure of human cystatin C in its native state. The protein is isolated from media of stably transfected tissue culture cells using physiological conditions that preclude protein denaturation. The importance of mild purification conditions is underscored by the finding that denaturation of the wild-type and variant proteins facilitates a similar folding of both molecules, diminishing their differences in structure and biophysical properties. Following native purification conditions, variant cystatin C has a distinct structure compared to the wild-type protein.

Blotting, Western↗
PubMed1996

Characterization of cystatin C from bovine parotid glands: cysteine proteinase inhibition and antiviral properties.

Cystatin C, a low Mr cysteine proteinase inhibitor was isolated from bovine parotid glands by a procedure which includes alkaline treatment of the homogenate, affinity chromatography, gel filtration and ion exchange chromatography. The purified inhibitor has a pl of 8.0 and Mr of 14500. The identity with bovine cystatin C from colostrum was confirmed by N-terminal sequence of the inhibitor and amino acid composition. Cystatin C rapidly (kass = 5.5 x 10(7) M-1s-1) and tightly inhibits papain (Ki = 0.02 nM), whereas its interaction with bovine cathepsin B is substantially weaker (Ki = 4.4 nM). Bovine cystatin C also shows a weak antiviral effect on poliovirus infected human Hela cells.

Amino Acid Sequence↗
PubMed1987

Cystatin C, alias post-gamma-globulin: a marker for multiple sclerosis?

Cystatin C, alias post-gamma-globulin or gamma-trace protein, has been shown to be a potent inhibitor of cysteine proteinases; this protein is normally present in different biological fluids, but particularly so in cerebrospinal fluid. The concentration of cystatin C was determined by radial immunodiffusion in cerebrospinal fluid from patients affected with multiple sclerosis, patients affected with various neurological diseases and in controls; it was also determined in brain tissue from 2 patients affected with multiple sclerosis and 3 control brains. Cystatin C cerebrospinal fluid levels were undetectable or depressed in many multiple sclerosis cases and the median value differed significantly from the control one. Its low concentration in multiple sclerosis suggests that the regulation of cysteine proteinases is impaired in this disease; hence enhanced activity of cysteine proteinases could initiate, or increase the breakdown of myelin. Although it is perhaps a little premature to consider cystatin C as a marker for multiple sclerosis, this protein is nevertheless associated to demyelination; consequently its biochemical assay in cerebrospinal fluid is recommended as a complementary diagnostic tool.

Adolescent↗
PubMed1998

The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C.

One of the main determinants of plasma homocysteine in healthy subjects is serum creatinine. In the present study, we therefore investigated the relation between plasma homocysteine concentration, serum creatinine and a new marker for glomerular filtration rate, plasma cystatin C concentration. Cystatin C reflects the glomerular filtration better than serum creatinine and is not related to the muscle mass and formation of creatinine. The study group consisted of 255 healthy subjects from a well-defined area in the southern part of Sweden. The concentration of plasma homocysteine was increased in men compared to women. This difference disappeared when men and women were stratified by serum creatinine values. Statistically significant correlations were noted between plasma homocysteine and age, plasma cystatin C and serum creatinine. It is shown that plasma homocysteine is not only correlated to serum creatinine as a result of renal function but also as a result of the relationship between homocysteine production and creatine-creatinine synthesis. Using linear regression we were able to show that plasma cystatin C had a higher explanatory value than age. Serum creatinine showed a lower explanatory power than age. The findings in the present study might suggest that the increase of plasma homocysteine concentration with age could be partly due to the deterioration of renal function.

Adult↗
PubMed2005

Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study.

Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individual's trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individual's trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r = 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.

Adult↗
PubMed2006

Assessment of serum beta-trace protein (BTP) measurement in the prediction of glomerular filtration rate. Comparison with serum cystatin C.

Serum BTP measurement is sometimes believed to be an alternative marker of glomerular filtration rate (GFR) assessment. The aim of the present work was to investigate the correlation between creatinine, cystatin C, and BTP values in sera and to compare the diagnostic efficacy for serum BTP and cystatin C with the glomerular filtration rate estimate. 25 individuals were tested. GFR was estimated from creatinine clearance, serum cystatin C and BTP and urine alpha-1 microglobulin, albumin, GMT and creatinine were measured. BTP values correlated with cystatin C (r = 0.75; p < 0.01), creatinine (r = 0.73, p < 0.01), GFR (r = -0.46; p = 0.02), urine alpha-1-microglobulin (r = 0.66; p < 0.01). The diagnostic efficacy of BTP for reduced GFR was insufficient and the calculation of GFR with BTP was not included in the regression model.

Adolescent↗
PubMed2000

Diagnostic applications of cystatin C.

Cysteine proteases are proteolytic enzymes involved in many pathological processes and found in the lysosomes of cells; examples include the cathepsins B, H and L. The role of cysteine proteases is crucial in normal cellular metabolism, being fundamental to intracellular protein turnover, degradation of collagen, and cleaving of precursor proteins. Cysteine protease inhibitors, of which the cystatin superfamily are one example, constitute the final regulatory step in the control of cysteine proteases. Currently, cystatin C is the most frequently investigated family member and is involved in processes such as tumour invasion and metastasis, inflammatory processes and some neurological diseases. In such diseases the emphasis is placed on the fine balance and regulation of both the cysteine proteases and their inhibitors, with an imbalance resulting in a pathological state. In addition, the constant serum concentration of cystatin C means it has possible application as a replacement for creatinine in the measurement of glomerular filtration rate. To date, several assays have been developed and studies show a promising future for its use in the medical laboratory, and not just as a research tool. This review of cystatin C includes a brief history of its discovery and characterisation, provides a guide to some of the processes in which its role is fundamental, and highlights developments in its use as a clinical biomarker in the disease processes discussed.

Adult↗
PubMed2000

Cystatin C in LS lymphosarcoma and HA-1 hepatoma treated with Ukrain and cyclophosphamide and involvement of apoptosis.

The concentration of cystatin C, a cysteine proteinase inhibitor, was measured during the treatment of murine LS lymphosarcoma with cyclophosphamide and HA-1 murine hepatoma with the antitumor drug Ukrain. It was shown that concentrations of cystatin C were very low in both the tumor tissues studied (HA-1 hepatoma cells and LS lymphosarcoma); increased cystatin C concentrations were found only in Ukrain-treated murine hepatoma, suggesting the mechanism of antitumor effect of this drug. Cyclophosphamide treatment in LS lymphosarcoma did not influence the concentration of cystatin C in tumor cells. At the same time, a marked increase in cathepsin B and cathepsin L activity in LS lymphosarcoma was found, indicating the involvement of apoptosis in the mechanism of antitumor action of cyclophosphamide. While the DNA from untreated LS lymphosarcoma was very homogenous and its molecular weight was high, the DNA from tumors of treated mice broke down, giving rise to the ladder figure characteristically produced by cells dying from apoptosis. Evidence was obtained that cyclophosphamide-induced tumor regression was effected by apoptosis.

Alkaloids↗
PubMed2002

Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis.

BACKGROUND: Plasma creatinine concentration and calculated creatinine clearance are of limited value as glomerular filtration rate (GFR) markers in patients with decompensated liver cirrhosis. We assessed plasma cystatin C as an indicator of GFR in such patients. METHODS: We studied 36 patients with decompensated liver cirrhosis and 56 noncirrhotic controls, both groups including individuals with normal and impaired renal function. GFR was measured in all individuals by inulin clearance, with values <72 mL x min(-1) x 1.73 m(-2) considered decreased. We measured cystatin C and creatinine in plasma and calculated (from plasma concentrations) and measured creatinine clearances, using for them decision points of 1.25 mg/L, 115 micromol/L, and 72 and 72 mL x min(-1) x 1.73 m(-2), respectively. RESULTS: Plasma cystatin C concentrations were similar in controls and cirrhotics and, at the usual cutpoint, could detect decreased GFR with similar sensitivities in the two groups (73% and 88%, respectively). Serum creatinine was markedly lower in cirrhotics and remained mostly within the reference interval at all GFR values; the diagnostic sensitivity of creatinine was much lower in cirrhotics than in controls (23% vs 64%). Lower diagnostic sensitivity was also observed for calculated creatinine clearance (53% vs 100% in controls), whereas similar sensitivities were found for measured creatinine clearance (86% and 81%) in controls and cirrhotics, respectively. ROC analysis showed that all four variables had similar diagnostic accuracies in cirrhotic patients. However, it also revealed that good diagnostic accuracies for plasma creatinine and calculated creatinine clearance can be obtained only if reference intervals different from those used for the general population are adopted. CONCLUSIONS: Plasma cystatin C concentration is an accurate GFR marker in cirrhotic patients. Plasma creatinine concentration and calculated creatinine clearance are of no practical value, as their reference values vary with the severity of the liver disease.

Adult↗
PubMed2001

[Cystatin C in estimates of glomerular filtration in patients with renal disease--initial experience].

Cystatin is reported in the literature with increasing frequency as a new reliable parameter for estimates of glomerular filtration. The authors examined cystatin C by the PET method of DAKO Co. in 151 patients from the nephrological out-patient clinic. 91 patients had normal renal functions, 60 suffered from renal insufficiency of different severity. Between cystatin C and glomerular filtration assessed by creatinine clearance was a close correlation, R = -0.787 according to Pearson. The authors evaluated separately a group of 36 patients with glomerulonephritis, 34 diabetic patients with diabetic nephropathy, 38 patients with tubulointerstitial nephritis and 43 subjects with other kidney diseases. The groups did not differ significantly when compared with the whole group nor mutually (p = n.s.). The authors of the study confirmed that a good correlation of cystatin with creatinine filtration is not influenced by the type of basic nephrological disease. The effect of administration of insulin, antihypertensive drugs, cyclosporin A and glucocorticoids was not proved in the investigated group. The published method is accurate, not demanding from the technical aspect. The examined subject is not restricted by conditions ensuring the accuracy of assessment and seems thus useful and perspective for nephrological patients.

Adult↗
PubMed2006

[Serum cystatin C concentration in children with urinary stones].

UNLABELLED: Stone formation precedes long period, when the crystals are accumulated in basement membranes of renal tubules and intestinal tissue. Accumulated, inside of renal tubules crystals and stones in urinary tract cause urinary tract obstruction, what may lead to impairment of renal function. The aim of work was the assessment of serum cystatin C (cys C) concentration in children with urolithiasis, confirmed by the presence of renal stones in renal pelvis in comparison to serum creatinine concentration and creatinine clearance (Cr cl). MATERIAL AND METHODS: Examined group (B) consisted of 30 children aged (13.08 +/- 4.14 years) with urolithiasis, which was divided into 3 subgroups (I, II, Ill) in dependence on stones' diameter (0.35-1.6cm). Control group (C) consisted of 26 healthy children at the same age. Nephelometric method was used to determine serum cystatin C level, Jaffe method to assess serum creatinine and the Schwartz formula to estimate glomerular filtration rate. RESULTS: In control group (C) serum cys C did not exceed 0.95 mg/l. In group B serum cystatin C and serum creatinine concentration and Cr cl was similar to the results of control group (p > 0.05). However in 16% of children with urolithiasis, in whom the stones of 0.8-1.6cm diameter were found in both renal pelvis, the concentration of serum cys C exceed 1.2 mg/l, and the value differed significantly from the results of control group (p < 0.05). A weak positive correlation between cys C and creatinine concentration and also between cys C and Cr cl was found. The serum cys C concentration in children with single stones of 0.35-0.8 diameter was normal. CONCLUSION: Serum cystatin C increases with increased degrees of urolithiasis assessed by stone size and their number in kidney.

Adolescent↗
PubMed2006

Cystatin C: a promising marker and predictor of impaired renal function.

Cystatin C is a relatively stable protein in serum and heparinized plasma that shows promise as a convenient measure of glomerular filtration rate (GFR). However, it is becoming clear that the relationship between cystatin C and GFR can depend on the clinical presentation. Factors influencing cystatin C levels are those that affect the rate of synthesis of the protein, such as thyroid status and the use of steroids. As with all laboratory tests, results should be interpreted in the light of the method's known limitations and in conjunction with other clinical and laboratory information. Nevertheless, accumulating evidence suggests that cystatin C is a useful biomarker for renal function, and may even be the method of choice in a range of clinical situations, from GFR surveillance in diabetics to the assessment of acute kidney injury in critically ill patients.

Acute Kidney Injury↗