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PubMed2005

Cystatin C as a marker for detection of early renal failure in diabetes type 2 patients.

UNLABELLED: The epidemiological studies have show dramatic increase and prevalence of end stage renal disease in patients with type 2 diabetes therefore early markers of diabetic nephropathy need to be identified (1). During the treatment of patients at the Clinic of endocrinology, diabetes mellitus and metabolic diseases in Sarajevo, we observed a necessity of application of new markers in assessment of early renal failure. Serum cystatin C level is another marker of renal function. Cystatin C is freely filtered at the level of the glomerulus and virtually all is re-absorbed and metabolized by the proximal tubular cells. Serum cystatin C is a screening test and an early indicator and predictor of the development of renal failure. AIM OF THE STUDY: To estimate correlation among cystatin C, serum creatinine and albuminuria in diabetes type 2 patients for assessment of early renal failure. Serum cystatin C as a screening test has to be considered in the treatment of diabetes type 2 patients for assessment of early renal failure.

Albuminuria↗
PubMed1985

The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate.

The blood serum concentrations of creatinine and the low molecular weight proteins cystatin C, beta 2-microglobulin and retinol-binding protein were measured in 106 patients whose glomerular filtration rates were assessed by Cr-ethylenediaminetetraacetate (EDTA)-clearance determinations. The reciprocals of the serum concentrations of creatinine, cystatin C and beta 2-microglobulin were closely correlated to the Cr-EDTA-clearance (r = 0.73, 0.75 and 0.70, respectively) in contrast to the corresponding values for retinol-binding protein (r = 0.39). The calculated values of the glomerular elimination rate for creatinine and cystatin C were normally distributed in contrast to those for beta 2-microglobulin. The calculated glomerular elimination rate of cystatin C was not correlated to age, sex, type of disorder or disease activity. The results demonstrate that the serum level of cystatin C is a better measure of the glomerular filtration rate than the serum level of beta 2-microglobulin.

Adolescent↗
PubMed1996

Renal handling of radiolabelled human cystatin C in the rat.

Serum cystatin C concentration correlates negatively with glomerular filtration rate as well as or better than that of serum creatinine, suggesting a constant formation, and elimination from extracellular fluid mainly by glomerular filtration. It is not known, however, how well the renal plasma clearance of this 13-kDa basic polypeptide matches the glomerular filtration rate. This was investigated in rats during control conditions and after reduced renal perfusion pressure. 125I-cystatin C and an indicator for glomerular filtration (51Cr-EDTA or 131I-aprotinin) were injected intravenously. The renal accumulation and urinary excretion of the tracers were recorded in periods of 2.5 to 20.0 min. The renal plasma clearance of 125I-cystatin C (Ccy) based on the renal content of 125I correlated well with the glomerular filtration rate (CCr-EDTA) in periods up to 6 min; i.e. Ccy = 0.94 x CCr-EDTA, r = 0.99. Less than 0.5% of the filtered amount appeared in the urine. During more prolonged periods, Ccy increasingly underestimated glomerular filtration rate, reaching about 0.4 x CCr-EDTA in a 20-min period. Free 125I relative to total plasma 125I activity increased from about 2% at 5 min to about 70% at 20 min. In nephrectomized rats, free 125I accumulated in plasma at a slower rate, accounting for about 15% of the total activity 20 min after injection of 125I-cystatin C. We conclude that cystatin C is (a) mainly removed from the extracellular fluid by the kidneys, (b) practically freely filtered in the glomeruli, and (c) completely absorbed and rapidly broken down by the proximal tubular cells.

Animals↗
PubMed1999

[Practical considerations respecting the clinical use of serum cystatin C as a marker of glomerular filtration].

A curvilinear relationship of potential type was observed between serum concentrations of cystatine C and creatinine in 187 patients attended at our Nephrology Department. This relationship became linear when considering the reverse values, but the estimation error was much higher than what is clinically acceptable, which prevents the interconversion of values. In 78 critical patients, in whom an antibiotic therapeutic monitoring was being carried out, serum creatinine concentrations in the reference range were observed to be associated with pathologic concentrations of cystatine C. In 22 regularly hemodialysed patients, using Hemophan or Cuprophan membranes, increments of approximately 5% for cystatine C and beta 2-microglobuline in post-dialysis samples were observed. The chronic administration of inducer antiepileptic drugs, capable of modifying the concentration of different plasmatic proteins and reducing the serum concentration of creatinine, does not seem to limit the applicability of cystatine C as marker for glomerular filtration. The routine measurement of cystatine C seems to be warranted for estimating the glomerular filtration rate in patients in whom creatinine synthesis might be impaired.

Adult↗
PubMed1999

Plasma cystatin C concentration in non-insulin-dependent diabetes mellitus: relation with nephropathy.

We determined plasma concentrations of cystatin C, beta2-microglobulin - beta2-MG (low molecular mass protein markers of glomerular filtration rate - GFR), creatinine (marker of GFR) and urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion (marker of glomerular and tubular dysfunction) in 41 non-insulin-dependent diabetic patients. A significant increase of all the measured parameters (p<0.001, p<0.05, p<0.05 and p<0.001, respectively) in comparison to the control group, was observed. In the patients with microalbuminuria, only plasma cystatin C concentration and urinary NAG excretion increased significantly in comparison to patients with normoalbuminuria. At a cut-off level of 1.74 mg/l for cystatin C and 1.81 U/g creatinine for NAG (95% percentile of the normoalbuminuric group), the sensitivity of the tests for detecting microalbuminuria was 82% for cystatin C and 86% for NAG. The specificities were 88 and 92%, respectively. The present study demonstrated that determination of plasma cystatin C might be useful in the detection of incipient diabetic nephropathy and is a potentially better marker than creatinine or beta2-MG. No correlation between parameters measured in plasma or urine and glycated hemoglobin was found.

Acetylglucosaminidase↗
PubMed2003

Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies.

OBJECTIVE: To study the correlation between serum cystatin C levels and renal structural changes in normal, hypertensive and pre-eclamptic pregnancy to evaluate it as a marker of the degree of renal involvement in pre-eclampsia. DESIGN: An observational prospective study. SETTING: University Hospital of Lund, Sweden. SAMPLE: Thirty-six women with hypertensive disease in pregnancy and 12 healthy pregnant women in the third trimester recruited from maternal health care centres in the catchment area of the hospital. METHODS: Renal biopsy samples were obtained from all participants and the degree of endotheliosis as well as the mean glomerular volume was evaluated by light microscopy in silver methenamin-stained sections. Serum cystatin C levels were measured and correlated to the structural changes. MAIN OUTCOME MEASURES: Correlation among degree of glomerular endotheliosis, glomerular volume and serum cystatin C. RESULTS: Serum cystatin C levels differed between the different degrees of endotheliosis, showing a highly significant increasing linear trend. They also correlated significantly with glomerular volume (r = 0.60, P < 0.001). Mean serum urate and creatinine levels also increased with the degree of endotheliosis, but not above the reference interval for normal term pregnancy, even in pre-eclamptic women. CONCLUSION: Serum cystatin C may be used as a marker, not only for impaired renal function, but also for the degree of glomerular endotheliosis and increase in glomerular volume in pregnancy. It may be of value in the monitoring of pregnancies complicated by pre-eclampsia.

Adult↗
PubMedDate not supplied

Does cystatin C improve the precision of Cockcroft and Gault's creatinine clearance estimation?

BACKGROUND: Cystatin C is increasingly used to estimate renal function, but its large intraindividual variability limits its practical value. This study aimed at verifying whether the clinical practice of associating cystatin C determination with serum creatinine (Cr) improved the ability of the Cockcroft and Gault formula to estimate creatinine clearance (CrCl). METHODS: It was an observational cross-sectional study of 134 in-patients with mildly impaired renal function. Using the Hoek et al formula (glomerular filtration rate (GFR)/1.73m2 = - 4.32 + 80.35/cystatin C mg/L), multivariate linear regressions (LREG) and artificial neural networks (ANN), we integrated cystatin C in the Cockcroft and Gault formula and analyzed the potential superiority of this procedure by comparing its performance with that of the two algorithms taken separately. RESULTS: The inclusion of cystatin C in the Cockcroft and Gault formula using the data of an LREG (CrCl = 0.371 x (Hoek et al) + 0.589 x Cockcroft and Gault), a simple mean between the two algorithms or ANN ameliorated the CrCl estimation precision allowing an absolute error reduction of approximately 4, 4 and 6%, respectively (relative values 12, 12 and 17%). CONCLUSIONS: Although the combination of the Hoek et al and Cockcroft and Gault formulae using both linear and non-linear mathematical methods allowed a statistically significant reduction in the estimation error generated by Cockcroft and Gault, considering the small impact on the estimation precision and the large intraindividual variation of both cystatin C and Cr, this procedure probably has no clinical relevance.

Adult↗
PubMed2005

Expression of cystatin C in clinical human colorectal cancer tissues.

We studied the relation between the antipapain activity of cysteine proteinase inhibitors (CPI) and immunohistochemical staining for cystatin C, using anti-chicken cystatin antibodies, in the colorectal cancer tissues. In primary tumour tissues immuno-peroxidase reactivity was present in the cytoplasm and on the cell surface membranes. Sections of non malignant tissues showed no staining. The percentages of positive staining were greater for adenocarcinoma than carcinoma,100% and 77% respectively. Antipapain activity which was increased in malignant tissues in comparison to control, rose successively from well differentiated carcinomas through moderately to poor differentiated. Invasive adenocarcinomas had higher antipapain activity than noninvasive ones. The results indicated that immunohistochemical detection of cystatin using anti-chicken cystatin antibodies could be useful in studying the prognostic significance of cystatin C expression in colorectal cancer.

Adenocarcinoma↗
PubMed2006

Cystatin C as a marker of immune complex-associated renal impairment in a Sudanese population with visceral leishmaniasis.

Renal function was studied in visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) by means of the specific marker cystatin C and related to circulating immune complexes and cytokine production. Forty patients with VL (23 with sub-acute disease and 17 with acute disease), 17 patients with PKDL, and 22 healthy controls were included. Cystatin C, but not creatinine, was significantly raised in VL (P = 0.004). The highest levels of cystatin C were found in those with acute disease (P < 0.0001). In VL, cystatin C levels were positively correlated to circulating immune complexes and production of granulocyte-macrophage colony stimulating factor (GM-CSF), but negatively correlated to aspartate aminotransferase and lactate dehydrogenase. We conclude that cystatin C is a superior marker of glomerular function in leishmaniasis and that immune complex deposition and GM-CSF are two functions that most likely are causally involved in the mechanisms leading to glomerular dysfunction in leishmaniasis.

Antibodies, Protozoan↗
PubMed1991

Regulation of cystatin C activity by serine proteinases.

The effect of four human serine proteinases on the human cysteine proteinase inhibitor, cystatin C, has been studied in vitro. Neutrophil elastase in catalytic amounts was observed to rapidly cleave cystatin C at neutral pH, thereby giving rise to a modified form of the inhibitor lacking the N-terminal Ser1-Val10 decapeptide. The two other leukocyte serine proteinases, cathepsin G and neutrophil proteinase 4, did not catalytically hydrolyse cystatin C bonds. Neither had the seminal plasma serine proteinase, prostate-specific antigen, any effect on cystatin C. The physiological implications of neutrophil elastase catalysed modification of cystatin C are discussed, and recent findings indicating that this reaction also occurs in vivo are reviewed.

Amino Acid Sequence↗
PubMed1989

Mutation in the cystatin C gene causes hereditary brain hemorrhage.

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder leading to massive brain hemorrhage and death in young adults (Jensson et al., 1987). A variant of a potent inhibitor of cysteine proteinases, cystatin C (Barrett et al., 1984), is deposited as amyloid fibrils in the cerebral arteries of the patients (Ghiso et al., 1986). We have used the full length cystatin C cDNA probe (Abrahamson et al., 1987) to demonstrate a mutation in the codon for leucine at position 68, which abolishes an Alu I restriction site in cystatin C gene of the HCCAA patients. The Alu I marker has been used to show that this mutation is transmitted only in the affected members in all eight families investigated, proving that the mutated cystatin C gene causes HCCAA. This DNA marker will be useful for the diagnosis of HCCAA in patients, asymptomatic affected individuals and also for pre-natal diagnosis. HCCAA is the first human disorder known to be caused by an abnormal gene for a cysteine proteinase inhibitor.

Amyloidosis↗
PubMed1993

Sandwich enzyme immunoassay of cystatin C in serum with commercially available antibodies.

We developed a sandwich enzyme immunoassay for determining cystatin C in serum by using commercially available antibodies. We optimized each assay step (e.g., concentrations of coating rabbit anti-human cystatin C antibodies and horseradish peroxidase-conjugated antibodies) and studied the binding kinetics of antigen and antibodies. The within-assay CV was < 5%, the between-assay CV was 8.8%, the detection limit was 0.9 microgram/L, and the assay can be performed within 2 h. Cystatin C concentrations in sera from men were significantly higher than in women (mean and SD: 2.14 +/- 0.31 vs 1.78 +/- 0.26 mg/L). We studied the cystatin C concentrations in sera of 31 outpatients with suspected kidney damages to characterize the behavior of this low-M(r) protein as a possible indicator for estimating the glomerular filtration rate. The correlation with the values obtained by a standard isotopic method involving 99mTc-diethylenetriaminopentaacetic acid was rs = -0.89. The diagnostic sensitivity of cystatin C was 88.2% of that of the standard isotope clearance method and better than those of the conventional serum indicators of reduced kidney function, beta 2-microglobulin (64.7%) and creatinine (52.9%).

Adolescent↗
PubMed1998

Serum cystatin C as a determinant of glomerular filtration rate in children.

The serum levels of cystatin C and creatinine were determined in a population comprising 69 children, 1-16 years old, and including children with both normal and reduced glomerular filtration rate (GFR) as determined by Cr-EDTA clearance measurement. The overall correlation between the reciprocal cystatin C concentration and GFR was significantly stronger (p < 0.05) than that between the reciprocal creatinine concentration and GFR and this was true also for the subpopulation of children with reduced GFR. Receiver-operating characteristic analysis also indicated superior diagnostic accuracy of serum cystatin C compared to that of serum creatinine for reduced GFR. The serum cystatin C reference values (mean +/- 1.96 SD) determined for children over one year of age was 0.63-1.33 mg/l, which is similar to that previously determined for adults. Serum cystatin C appears to be an attractive alternative to creatinine for estimation of GFR not only in adults, but also in children.

Adolescent↗
PubMed1998

Biological variation of cystatin C: implications for the assessment of glomerular filtration rate.

To assess the inherent potential for detecting mild to moderate reductions in glomerular filtration rate, this study determined the biological variability of serum cystatin C and creatinine in 12 healthy subjects. After accounting for analytical variation, interindividual variance accounted for 93% and intraindividual variance accounted for 7% of serum creatinine biological variation. As such, to lie outside the assay reference interval, some subjects must exceed 13 SD from their usual mean value, whereas in others, a change of only 2 SD would be sufficient. For cystatin C, interindividual variation explained 25% and intraindividual variance explained 75% of biological variability. Therefore, the upper limit of the population reference interval for cystatin C is seldom more than 3-4 SD from the mean value of any healthy individual. The critical difference for sequential values significant at P < or = 0.05 was calculated as 37% for serum cystatin C and 14% for serum creatinine. We conclude that cystatin C is potentially a better marker for detecting impaired renal function than serum creatinine, but serum creatinine is probably still the better marker for detecting temporal changes of renal function in individuals with established renal disease.

Adult↗
PubMed1988

The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases.

The crystal structure of chicken egg white cystatin has been solved by X-ray diffraction methods using the multiple isomorphous replacement technique. Its structure has been refined to a crystallographic R value of 0.19 using X-ray data between 6 and 2.0A. The molecule consists mainly of a straight five-turn alpha-helix, a five-stranded antiparallel beta-pleated sheet which is twisted and wrapped around the alpha-helix and an appending segment of partially alpha-helical geometry. The 'highly conserved' region from Gln53I to Gly57I implicated with binding to cysteine proteinases folds into a tight beta-hairpin loop which on opposite sides is flanked by the amino-terminal segment and by a second hairpin loop made up of the similarly conserved segment Pro103I - Trp104I. These loops and the amino-terminal Gly9I - Ala10I form a wedge-shaped 'edge' which is quite complementary to the 'active site cleft' of papain. Docking experiments suggest a unique model for the interaction of cystatin and papain: according to it both hairpin loops of cystatin make major binding interactions with the highly conserved residues Gly23, Gln19, Trp177 and Ala136 of papain in the neighbourhood of the reactive site Cys25; the amino-terminal segment Gly9I - Ala10I of bound cystatin is directed towards the substrate subsite S2, but in an inappropriate conformation and too far away to be attacked by the reactive site Cys25. As a consequence, the mechanism of the interaction between cysteine proteinases and their cystatin-like inhibitors seems to be fundamentally different from the 'standard mechanism' defined for serine proteinases and most of their protein inhibitors.

Animals↗
PubMed2004

Fetal serum ss2-microglobulin and cystatin C in the prediction of post-natal renal function in bilateral hypoplasia and hyperechogenic enlarged kidneys.

OBJECTIVES: To evaluate fetal serum ss2-microglobulin and cystatin C in the prediction of post-natal renal function in bilateral hypoplasia and hyperechogenic enlarged kidneys. Predicting post-natal renal function is crucial to the prenatal evaluation of fetal nephropathies. Prenatal ultrasound can identify terminal renal failure, but is not sensitive enough to identify infants whose post-natal renal function will be impaired. Fetal serum ss2-microglobulin and cystatin C are potential predictors of post-natal renal function. METHODS: Fifty-four prenatally diagnosed cases of bilateral nephropathy were retrospectively reviewed. Final diagnosis was established using histological or post-natal findings: renal hypoplasia (n = 7), cystic dysplasia (n = 9), autosomal dominant polycystic kidney disease (ADPKD; n = 8) or autosomal recessive polycystic kidney disease (ARPKD; n = 22) and transient sonographic abnormalities (n = 8). Fetal serum ss2-microglobulin and cystatin C were assayed respectively in 54 and 38 cases. The prognostic value of these markers was assessed in terms of the post-natal outcome. RESULTS: In bilateral kidney hypoplasia and cystic dysplasia, ss2-microglobulin and cystatin C were significantly (p < 0.0001 and p < 0.02 respectively) higher than in the normal control group. In hyperechogenic fetal kidneys (ARPKD, ADPKD and transient sonographic abnormalities), these markers were not different from controls. However, whereas normal values cannot exclude renal failure, abnormal values predict post-natal renal failure. CONCLUSIONS: In bilateral renal hypoplasia and dysplasia, fetal serum ss2-microglobulin and cystatin C are good markers for post-natal renal function. However, in bilateral renal hyperechogenic enlargement, abnormal values are associated with poor post-natal renal function, but normal values cannot preclude renal failure.

Cystatins↗
PubMed2006

Molecular modeling and inhibitory activity of cowpea cystatin against bean bruchid pests.

Plant cystatins show great potential as tools to genetically engineer resistance of crop plants against pests. Two important potential targets are the bean weevils Acanthoscelides obtectus and Zabrotes subfasciatus, which display major activities of digestive cysteine proteinases in midguts. In this study a cowpea cystatin, a cysteine proteinase inhibitor found in cowpea (Vigna unguiculata) seeds, was expressed in Escherichia coli and purified with a Ni-NTA agarose column. It strongly inhibited papain and proteinases from midguts of both A. obtectus and Z. subfasciatus bruchids, as seen by in vitro assays. When the protein was incorporated into artificial seeds at concentrations as low as 0.025%, and seeds were consumed by the bruchids larva, dramatic reductions in larval weight, and increases in insect mortality were observed. Molecular modeling studies of cowpea cystatin in complex with papain revealed that five N-terminal residues responsible for a large proportion of the hydrophobic interactions involved in the stabilization of the enzyme-inhibitor complex are absent in the partial N-terminal amino acid sequencing of soybean cystatin. We suggest that this structural difference could be the reason for the much higher effectiveness of cowpea cystatin when compared to that previously tested phytocystatin. The application of this knowledge in plant protein mutation programs aiming at enhancement of plant defenses to pests is discussed.

Agriculture↗
PubMed1998

Structural and phylogenetic relationships among plant and animal cystatins.

The plant cystatins or phytocystatins (PhyCys) are cysteine proteinase inhibitors containing the QxVxG motif and have been placed in the cystatin superfamily of proteins. The primary sequences of PhyCys have a high degree of homology with the members of the cystatin family, but they resemble stefins by the absence of disulfide bonds and cysteine residues. A multialignment and a phylogenetic analysis of 63 cystatins, 32 of which are PhyCys, demonstrate that all PhyCys cluster in a major evolutionary tree branch and support the classification of PhyCys as a new cystatin family. The PhyCys also possess a specific consensus sequence [LVI]-[AGT]-[RKE]-[FY]-[AS]-[VI]-x-[EDQV]-[HYFQ] -N placed on the region corresponding to a predictable amino-terminal alpha-helix. This sequence can be used to specifically identify PhyCys on protein data banks and to differentiate them from the other members of the superfamily.

Amino Acid Sequence↗