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PubMed1994

Genetic polymorphisms of the CST2 locus coding for cystatin SA.

A new genetic polymorphism of cystatin SA has been identified in human submandibular-sublingual saliva by means of basic gel electrophoresis and immunoblotting with anti-cystatin S. Two proteins, SA1 and SA2, are given by two alleles of CST2, viz., CST2*1 and CST*2. Inheritance is controlled by two codominant alleles at an autosomal locus. This hypothesis is supported by studies of 16 families 32 children. Gene frequencies for CST2*1 and CST2*2 are 0.935 and 0.065, respectively (n = 341). Eighteen amino acids determined among 20 N-terminal residues of cystatin SA2 are identical with the sequence encoded by CST2. Three forms of cystatin S (mono-phosphorylated cystatin S, di-phosphorylated cystatin S, and non-phosphorylated cystatin S) are present in the 341 saliva samples tested.

Amino Acid Sequence↗
PubMed2003

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 ((99m)Tc-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:. 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.

Adolescent↗
PubMed2000

Reference intervals for cystatin C in pre- and full-term infants and children.

Cystatin C is a non-glycated, 13-kDa basic protein produced by all nucleated cells. Recent studies have indicated that the plasma concentration of cystatin C is a better marker for glomerular filtration rate (GFR) than plasma creatinine, which is most commonly used for this purpose. We established reference values for plasma cystatin C in pre- or full-term infants and children. For comparison we also measured the creatinine concentration in the same samples. Cystatin C was measured by a commercially available immunoturbidimetric method with a Hitachi 704 analyzer in sera obtained from 58 pre-term infants, 50 full-term infants and 299 older children (132 girls, 167 boys, median age 4.17 years, range 8 days to 16 years). No sex differences were found. The pre-term infants had higher cystatin C concentrations (mean 1.88 mg/l, SD 0.36 mg/l) than the full-term (mean 1.70 mg/l, SD 0.26 mg/l, P=0.0145). The reference interval for pre-term infants calculated non-parametrically was 1.34-2.57 mg/l and for full-term infants 1.36-2.23 mg/l. The cystatin C concentration decreased rapidly after birth, and above 3 years of age did not depend on age. The reference interval for children 3-16 years of age calculated non-parametrically was 0.51-1.31 mg/l. Younger children (<1 year: 0.75-1.87 mg/l; 1-3 years: 0.68-1.60 mg/l) had slightly, but significantly, higher plasma cystatin C levels.

Adolescent↗
PubMed1998

Reference values for cystatin C serum concentrations in children.

Cystatin C, a low molecular weight protein, is a new endogenous marker of renal function whose serum concentration correlates better with glomerular filtration rate than creatinine. The aim of the present study was to define a reference interval for cystatin C concentrations in children. Cystatin C was measured by an immunoturbidimetric assay in sera obtained from 258 children (93 girls, 165 boys, median age 6.29 years, range 1 day to 18 years) without evidence of kidney disease. The reference interval was calculated non-parametrically using the 2.5th and 97.5th percentiles. For comparison, creatinine was measured in the same samples. The cystatin C concentration was highest on the first days of life (range 1.64-2.59 mg/l) with a rapid decrease during the first 4 months. Beyond the 1st year, the cystatin C concentration was constant, with a reference interval of 0.7-1.38 mg/l. In contrast, serum creatinine concentrations steadily increased with age until adulthood. Compared with creatinine, cystatin C facilitates the recognition of abnormal renal function in children as its reference range is constant beyond the 1st year of life. The higher levels of cystatin C in the 1st year of life probably reflect the low glomerular filtration rate of neonates and infants.

Adolescent↗
PubMed2004

The effect of nitrogen source on yield and glycosylation of a human cystatin C mutant expressed in Pichia pastoris.

Human cystatin C is a cysteine proteinase inhibitor with potential applications as an anti-viral agent, cancer tumor growth inhibitor, and in prevention of proteolysis during food processing. A glycosylated cystatin C mutant with increased temperature stability was developed for the latter application [Nakamura et al. (1998) FEBS Lett 427:252-254]. A recombinant variant of cystatin C [Nakamura et al. (2000) International patent no. PLTCA99/00717] with two potential sites for N-linked glycosylation was expressed in Pichia pastoris Mut(s). Little of the cystatin C produced was in the glycosylated form under fermentation conditions of pH 6, temperature 28 degrees C, methanol only feed, and ammonium hydroxide as a nitrogen source. Thus, the effect of addition of complex nitrogen sources, peptone and amino acid supplements, on the yield and glycosylation of this mutant cystatin C were investigated. A full factorial design experiment using 2-l fermenters was performed with three factors: ammonium hydroxide, peptone, and an amino acid mix, at two levels, absent or present. Peptone addition was found to have a positive, and the most significant, effect on cell specific cystatin C yield. A maximum mutant cystatin C yield of 0.82 mumol (g-dry cell weight)(-1) min(-1) was obtained when all three nitrogen sources were used together. However, under these conditions only 16% of protein was in the glycosylated form since ammonia was found to have a significant negative effect on glycosylation extent. The maximum extent of glycosylation was 30% when peptone and amino acid mix were the only nitrogen sources added.

Culture Media↗
PubMed1992

Cystatin C secretion by rat glomerular mesangial cells: autocrine loop for in vitro growth-promoting activity.

Cystatin C, the major inhibitor of the cysteine proteinases found in human and rat body fluids, is particularly abundant in seminal plasma and cerebrospinal fluid. In a precedent report, we have evidenced noteworthy levels of cystatin C in rat kidney cortex. In the present study, we show that rat mesangial glomerular cells produce cystatin C. Immunoprecipitation of extracts of metabolically labeled cells and culture media showed that the synthesized cystatin C is a 15.5 +/- 0.5 kDa protein. The protein was released into the culture supernatant (1.6 +/- 0.26 micrograms/10(6) cells/24 h). Urinary rat cystatin C and PPPR synthetic peptide (5-8 N-terminal sequence of rat cystatin C) increased mesangial cell proliferation. Affinity chromatography on Ultrogel-avidin-biotin-PPPR of extracts of metabolically labeled cells indicate the existence of a PPPR binding protein of 46 kDa. The results described in this work suggest, for glomerular rat mesangial cells in vitro, an autocrine regulation of proliferation by cystatin C.

Amino Acid Sequence↗
PubMed1996

Cystatin C and apolipoprotein E immunoreactivities in CA1 neurons in ischemic gerbil hippocampus.

The distribution patterns of cystatin C and apolipoprotein E (apo E) were studied immunocytochemically in the gerbil hippocampus before and after 5 min ischemia. In the controls, cystatin C was distributed mainly in astrocytes. In addition, a large number of dots positive for cystatin C were observed around the outlines of neuronal perikarya in the CA1 subfields. One day after ischemia, cystatin C-positive stainings outlining neuronal cell bodies disappeared. On the fourth day, intense stainings for cystatin C appeared in atrophied pyramidal neurons and these stainings in neurons disappeared by the 14th day. A remarkable increase in the number of cystatin C-positive astrocytes occurred on the fourth day and thereafter these spread over the whole of the CA1 subfield. Apo E was also distributed in astrocytes in the control specimens. From the fourth day, extra- and/or intracellular distribution of apo E-immunoreactivities was noted in the stratum pyramidale. Apo E-positive astrocytes disappeared transiently on the fourth day and then reappeared and increased remarkably by the 14th day. These findings indicate that cystatin C and apo E are involved in the degeneration process of brain neuronal cells.

Animals↗
PubMed1987

Human cysteine-proteinase inhibitors: nucleotide sequence analysis of three members of the cystatin gene family.

Three genes from the human cystatin gene family of cysteine-proteinase inhibitors have been isolated from a bacteriophage lambda library containing HindIII digests of human genomic DNA. Two of the genes code for salivary cystatin SN and SA, the third is a pseudogene. The cloned genes were identified with a probe made from a salivary cystatin cDNA. The complete nucleotide sequence of the gene that codes for the precursor form of the neutral salivary protein, cystatin SN, was determined. The gene, which we name CST1, contains three exons and two intervening sequences. The expected CAT and ATA boxes are present in the 5'-flanking region of the gene. Partial nucleotide sequence determination of a second gene revealed that it codes for the precursor form of the acidic salivary protein, cystatin SA. This gene, which we name CST2, has the same gene organization as CST1. The complete nucleotide sequence of a third gene was determined. It does not contain a typical ATA box, and in addition, a premature stop codon and a frameshift deletion mutation occur within the gene. These inactivation mutations show that this gene, which we name CSTP1, is a cystatin pseudogene. These data combined with our genomic Southern-blot analyses show that the cystatin genes form a multigene family with at least seven members.

Base Sequence↗
PubMed2005

Plasma cystatin-C and development of coronary heart disease: The PRIME Study.

The pathogenesis of ischemic coronary events involves degradation of the extracellular matrix in atherosclerotic lesions. The cysteine protease inhibitor cystatin-C may be involved in this phenomenon. The association of plasma cystatin-C with the incidence of myocardial infarction-coronary death and angina, was examined in a nested case-control (two controls per case) design within the prospective cohort study (Prospective Epidemiological Study of Myocardial Infarction (PRIME Study)) which included 9,758 men aged 50-59 years who were free of coronary heart disease (CHD) on entry and followed for a 5-year period. Three hundred and thirteen participants suffered myocardial infarction or coronary death (n = 159) or angina pectoris (n = 154) during follow-up. Cystatin-C was positively correlated with body mass index (BMI), low-density lipoprotein (LDL)-cholesterol, triglycerides and several inflammatory markers such as fibrinogen (r = 0.18), C-reactive protein (CRP) (r = 0.24), interleukin-6 (= 0.20), tumor necrosis factor-alpha (TNFalpha) (r = 0.27) and two TNFalpha receptors: TNFR1A (r = 0.43) and TNFR1B (r = 0.41); and negatively with high-density lipoprotein (HDL)-cholesterol (r = -0.25). After adjustment for traditional risk factors (age, diabetes, smoking, hypertension, BMI, triglycerides, LDL- and HDL-cholesterol), cystatin-C was significantly associated with the occurrence of the first ischemic coronary event. However, this association was no longer significant when CRP was included in the analysis. A decrease in glomerular filtration rate did not explain higher cystatin-C in cases than in controls. Cystatin-C appears to participate in the inflammatory phenomenon observed in the atherosclerotic process. Cystatin-C is not a more predictive risk marker of CHD than CRP or interleukin-6, but could be useful in detecting moderate chronic renal disease.

Biomarkers↗
PubMed2004

Increased cystatin C serum concentrations in patients with hepatic diseases of various severities.

BACKGROUND: Indicators for long-term monitor of the progress of hepatic diseases are of great clinical importance. Since elevated cathepsin was observed in liver diseases, the aim of this study is to investigate the involvement of cystatin C, a very potent inhibitor of cathepsin and a recently introduced marker for renal function, and to see the applicability of serum cystatin C being a convenient marker for the progression of liver diseases. METHODS: One hundred eighty consecutive patients with chronic liver disease of various severities and 45 healthy controls were recruited to determine their serum cystatin C concentrations by N Latex Cystatin C kit, as well as certain relevant clinical values, including alanine transaminase (ALT), aspartate transaminase (AST) and AFP. RESULTS: Average serum cystatin C concentration of patients with hepatic diseases was significantly higher than that of control (0.0902+/-0.0025 mg/dl vs. 0.067+/-0.007 mg/dl; p<0.001), and a linear regression analysis has revealed a direct relation between cystatin C and the severity of liver diseases (Y=1.172+5.492X, R(2)=0.088, p<0.001). CONCLUSION: This study suggested that cystatin C may be an applicable monitoring marker for monitoring liver functions and progression of liver fibrosis.

Alanine Transaminase↗
PubMed2005

Relationship between matrix metalloproteinase-2 activity and cystatin C levels in patients with hepatic disease.

OBJECTIVES: A direct relationship between cystatin C levels and the severity of hepatic disease has been revealed in our previous study. This study was aimed to consider whether a correlation exists between matrix metalloproteinases (MMPs), which have been proven to be involved in liver cirrhosis, and cystatin C to reflect the severity of hepatic disease. DESIGN AND METHODS: A total of 154 consecutive patients with various liver diseases were recruited to determine their serum levels of cystatin C, MMP-2 and-9, together with other hepatic parameters. These were compared with 40 normal controls. RESULTS: Average levels of MMP-2 and cystatin C were significantly higher in patients while MMP-9 was significantly lower, as compared to controls. A linear regression analysis has revealed a direct relationship between cystatin C and MMP-2 (Y=83.39 + 270.56 X, R=0.38, P< 0.001), as well as between MMP-2 and the severity of liver diseases. CONCLUSION: This is the first study to demonstrate a correlation between cystatin C and MMP-2, suggesting that there may be certain interactions between cystatin C and MMP-2 in patients with hepatic diseases.

Alanine Transaminase↗
PubMed2005

Serum cystatin C level as a potentially good marker for impaired kidney function.

OBJECTIVES: To evaluate the diagnostic significance of serum cystatin C levels in clinical practice. DESIGN AND METHODS: Serum (99m)Tc-DTPA clearance was compared with serum cystatin C, creatinine, beta(2)-microglobulin levels and creatinine clearance in a group of patients aged 42.61 +/- 7.55 years with glomerular filtration rates of 10-60 mL/min/1.73 m(2) (n = 52) and healthy controls aged 43.90 +/- 12.06 years (n = 52). RESULTS: No effect of sex on serum cystatin C levels was observed, but average levels increased with age. No significant difference was evident between the mean cystatin C levels of three blood samples taken at 1 month intervals from healthy subjects. Reference clearance was correlated with creatinine clearance (r = 0.957), cystatin C (r = 0.828), beta(2)-microglobulin (r = 0.767) and creatinine (r = 0.682). 60 mL/min/1.73 m(2) was chosen as the borderline for receiver-operating characteristics analysis. The values for the cut-off point, sensitivity, specificity and the area under curve were determined for cystatin C as 1.36 mg/L, 98%, 99% and 0.99 +/- 00.1, respectively; for creatinine, the values were 103 micromol/L, 80%, 100% and 0.97 +/- 0.01, respectively, and for beta(2)-microglobulin, the values were 2.51 mg/L, 86%, 92% and 0.94 +/- 0.02, respectively. CONCLUSION: Serum cystatin C level can be used as a marker for renal damage.

Adult↗
PubMed2005

Cystatin C can be affected by nonrenal factors: a preliminary study on leukemia.

OBJECTIVE: The aim of this study was to evaluate the influence of malignancy and the impact of nephrotoxic drugs used in bone marrow transplantation (BMT) on the circulating levels of cystatin C in leukemia. METHODS: We studied nineteen patients (eleven men and eight women; mean age 30.1 +/- 11.2, 27.9 +/- 7.1 years) with acute lymphoblastic leukemia, acute myeloid leukemia and chronic myeloid leukemia. Cystatin C, urea, creatinine and creatinine clearance (CrCl) were measured 24 h before BMT, 1 week after BMT, 2 weeks after BMT and 3 weeks after BMT. The control group consisted of twenty healthy adults, and the mean age was 29.1 +/- 8.9. RESULTS: At the pretransplantation period, values of cystatin C were significantly higher than in the control group (P < 0.05). Urea, creatinine and CrCl values were not statistically different from the controls. One week after BMT, the level of cystatin C was significantly low as compared to the levels measured 24 h before BMT, but was still significantly higher than the controls (P < 0.05), whereas the levels of urea, creatinine and CrCl were in accordance with the levels of the controls. Two and three weeks after BMT, cystatin C values maintained the significant increase (P < 0.05), whereas the values of urea, creatinine and CrCl still corresponded with those of the controls in both group. CONCLUSIONS: Our preliminary data expose that cystatin C is not a reliable GFR marker in patients during leukemia or for monitoring nephrotoxic drugs used in BMT, but we can not reach definitive conclusion due to no gold standard for comparing the diagnostic accuracy of cystatin C. Further study is needed to elucidate the precise mechanism underlying this observation.

Acyclovir↗
PubMed2006

Presenilin 2 mutations alter cystatin C trafficking in mouse primary neurons.

Mutations in the presenilin genes account for the majority of familial Alzheimer disease (FAD) cases. In the present report we demonstrated that the FAD-linked presenilin 2 mutations (PS2 M239I and T122R) alter cystatin C trafficking in mouse primary neurons reducing secretion of its glycosylated form. These mutations showed a different impact on cystatin C: PS2 T122R had a much stronger effect determining a dramatic intracellular accumulation of cystatin C (native and glycosylated), followed by a reduction in the secretion of both forms. Several experimental evidences suggest that cystatin C exerts a protective role in the brain and favors stem cells proliferation. Confocal imaging showed that the effect of PS2 T122R mutation was a massive recruitment of cystatin C into the neuronal processes, in the presence of an intact cytoskeletal structure. The consequent reduction in the cystatin C extracellular levels might result in a failure of neuroregeneration. Understanding the interplay of PS2 and cystatin C in the pathogenesis of AD might highlight new therapeutic prospective.

Animals↗
PubMedDate not supplied

Effect of sympathectomy on isoproterenol-induced expression of the cysteine proteinase inhibitor gene, cystatin S, in rat submandibular glands.

The autonomic nervous system regulates the secretory function of salivary glands. The volume, rate of secretion and composition of saliva are regulated by both sympathetic (alpha 1-, alpha 2 and beta 1-adrenergic) and parasympathetic (muscarinic and cholinergic) receptor systems. The rat cystatin S gene, a member of family 2 of the cysteine proteinase inhibitor superfamily, has a very defined pattern of expression during the postnatal development of the rat submandibular gland. Its expression is not detected in the fetus or in rats up to three weeks of age. After this time, the amount of cystatin S mRNA increases, reaching a conspicuously high concentration at 28 days, and then it declines to a barely detectable level at 32 days of age; cystatin S mRNA is not detectable in the glands of adult animals. However, the beta-adrenoreceptor agonist isoproterenol (IPR) induces high concentrations of cystatin S mRNA in the submandibular gland in vivo. This paper reports experiments analysing the participation of the sympathetic nervous system in the IPR-induced expression of the cystatin S gene. Sympathetic denervation (unilateral and bilateral) by removing the superior cervical ganglion 14 days before a single injection of IPR reduced the expression of the cystatin S gene. Chemical denervation by reserpine (a drug that depletes neurotransmitters in sympathetic nerve terminals) also reduced IPR-induced expression of the gene. Morphological analyses of sympathectomized and reserpine-treated glands showed that the structure of the gland was similar to that of glands of intact animals and to those not treated with reserpine. The hypertrophic response to IPR was less obvious in the sympathectomized glands, but was similar in reserpine treated animals. Collectively, these data suggest that even in the presence of a functional beta 1-adrenergic receptor pathway, factor(s) from the sympathetic nervous system may be required for IPR-induced expression of the cystatin S gene.

Adrenergic beta-Agonists↗
PubMed2000

Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients.

The effect of asthma pathogenesis on serum cystatin C, a potent inhibitor of cysteine proteinases and a newly proposed marker of the renal function, has not been yet determined. The objectives were to determine the 24-h pattern of cystatin C and creatinine concentrations in sera of asthmatic patients in order to test whether their concentrations might reflect circadian rhythms, the disease severity and the effect of therapy. Serum concentrations of cystatin C and creatinine were determined in steroid-independent and steroid-dependent asthmatics before and after 1 week of treatment with methylprednisolone and cyclosporin A, respectively. Samples were collected every 4 h during a 24-h period. Little or no significant effects of time on cystatin C and creatinine concentrations over a 24-h period were observed in healthy and asthmatic sera. However, significantly higher cystatin C concentrations were found in asthmatic patients compared to controls which suggests its role in the pathogenesis of asthma. Methylprednisolone increased and cyclosporin A decreased serum cystatin C concentrations after 1 week of therapy. Additionally these results support the need for the evaluation of cystatin C as a marker of glomerular filtration rate determination in asthma.

Adrenal Cortex Hormones↗
PubMed2001

Serum cystatin C in renal transplant patients.

Assessment of renal function in clinical medicine is of great importance especially in patients with renal transplants. Cystatin C has the characteristics of an ideal marker to assess renal glomerular filtration rate. Forty patients with renal transplants under steady-state post-transplant conditions were included in the study. Steady-state was defined as lack of acute rejection periods during the last 6 months and stable cyclosporin A medication during the past 4 weeks. Gender was balanced with 20 male and 20 female patients, the mean age was 51+/-14 years, time since transplantation was 5+/-3.5 years. Fifteen percent of the patients suffered from diabetes mellitus. Immunosuppression consisted of cyclosporin A, imuran, and prednisolon. To assess renal function cystatin C, creatinine clearance, serum creatinine, and serum beta2-microglobulin were tested. Creatinine was analysed in serum and urine to calculate the creatinine clearance related to 1.73 m(2) body surface. Cystatin C and beta2-microglobulin were determined by using a particle-enhanced turbidimetric assay. Cystatin C correlated best with creatinine clearance (r=0.66), beta2-microglobulin (0.57), and serum creatinine (0.56). The diagnostic accuracy of cystatin C was significantly better than serum creatinine (p<0.05), but did not differ significantly from creatinine clearance (p=0.73), and beta2-microglobulin (p=0.46). Our data show that patients with renal transplants, cystatin C has a similar diagnostic value as creatinine clearance. However, it is superior to serum determination of creatinine and beta2-microglobulin. Cystatin C allows for rapid and accurate assessment of renal function in patients with renal transplants and is clearly superior to the commonly used serum creatinine.

Adult↗
PubMed2002

Cystatin C assay for the detection of renal dysfunction in Chinese renal transplant recipients.

BACKGROUND: Accurate and rapid assessment of kidney function in patients after renal transplantation is of major significance. We investigated whether cystatin C can accurately reflect creatinine clearance over the entire range of kidney graft function. The performance of serum cystatin C as a screening marker of reduced creatinine clearance in renal transplantation was evaluated and compared to serum creatinine. METHODS: Serum cystatin C, serum creatinine and creatinine clearance were measured in 103 adult renal transplant recipients. The cystatin C assay was performed using particle-enhanced immunonephelometry. RESULTS: We demonstrated a significant linear correlation between 1/cystatin C and creatinine clearance over the entire range of transplant function, comparable to that of creatinine. Cystatin C detected reduced creatinine clearance with higher sensitivity of 92.9% (95% CI 80.5-98.4%) than serum creatinine, 71.4% (95% CI 55.4-84.3%). From the receiver operating characteristic (ROC) plots, serum cystatin C is superior to serum creatinine at 90% and 95% sensitivity. CONCLUSIONS: Serum cystatin C accurately reflects creatinine clearance over the entire range of transplant kidney function and is more efficacious than serum creatinine to detect reduced creatinine clearance in renal transplant recipients.

Adult↗