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PubMed2003

Impact of thyroid dysfunction on serum cystatin C.

BACKGROUND: Serum cystatin C (CysC) is a novel marker for kidney function that has been claimed to be superior to serum creatinine. Thyroid dysfunction may alter creatinine, which has been found to be increased in hypothyroidism and decreased in hyperthyroidism. This study was performed to evaluate whether changes in CysC and creatinine are parallel during the treatment of hypo- and hyperthyroidism, respectively. METHODS: Prospective case series of 22 consecutively referred patients with thyroid dysfunction. Creatinine and CysC were determined at the time of diagnosis of hypo- and hyperthyroidism, and when free thyroxine (fT4) returned into the normal range. Hypothyroid patients were treated with levothyroxine. Hyperthyroid patients were treated with antithyroid drugs, surgery, or radioiodine. RESULTS: Nine patients with hypothyroidism and 13 patients with hyperthyroidism were included. In patients with hypothyroidism mean fT4 (+/-SD) was 4.9 +/- 2.5 pmol/L (reference, 12 to 22) at diagnosis and increased to 16.6 +/- 3.6 pmol/L when patients were treated with levothyroxine. Creatinine decreased from 86 +/- 13 micromol/L (reference, 70 to 105) in the hypothyroid state to 76 +/- 16 micromol/L when fT4 normalized (P = 0.062), whereas CysC increased from 0.84 +/- 0.17 mg/L (reference, 0.63 to 1.33) to 1.1 +/- 0.28 mg/L (P < 0.001). In patients with hyperthyroidism, mean fT4 was 54.6 +/- 22.7 pmol/L (reference, 12 to 22) at diagnosis and decreased to 15.8 +/- 3.6 pmol/L following treatment with antithyroid drugs, thyroid surgery, or radioiodine. Creatinine increased from 67 +/- 15 micromol/L at diagnosis of hyperthyroidism to 75 +/- 9 micromol/L when fT4 normalized (P = 0.004), whereas CysC declined from 1.32 +/- 0.17 mg/L to 0.95 +/- 0.19 mg/L (P < 0.001). CONCLUSION: Thyroid dysfunction has a major impact on CysC levels. Therefore, thyroid function has to be considered when CysC is used as a marker of kidney function. In contrast to creatinine concentrations, CysC levels are lower in the hypothyroid and higher in the hyperthyroid state as compared with the euthyroid state.

Adolescent↗

PubMed2002

Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis.

BACKGROUND: Serum cystatin C (Cys C) has been proposed as a simple, accurate, and rapid endogenous marker of glomerular filtration rate (GFR) in research and clinical practice. However, there are conflicting reports regarding the superiority of Cys C over serum creatinine (Cr), with a few studies suggesting no significant difference. METHODS: We performed a meta-analysis of available data from various studies to compare the accuracy of Cys C and Cr in relation to a reference standard of GFR. A bibliographic search showed 46 articles until December 31, 2001. We also retrieved data from eight other studies presented and published in abstract form. RESULTS: The overall correlation coefficient for the reciprocal of serum Cys C (r = 0.816; 95% confidence interval [CI], 0.804 to 0.826) was superior to that of the reciprocal of serum Cr (r = 0.742; 95% CI, 0.726 to 0.758; P < 0.001). Similarly, receiver operating characteristic (ROC)-plot area under the curve (AUC) values for 1/Cys C had greater identity with the reference test for GFR (mean ROC-plot AUC for Cys C, 0.926; 95% CI, 0.892 to 0.960) than ROC-plot AUC values for 1/Cr (mean ROC-plot AUC for serum Cr, 0.837; 95% CI, 0.796 to 0.878; P < 0.001). Immunonephelometric methods of Cys C assay produced significantly greater correlations than other assay methods (r = 0.846 versus r = 0.784; P < 0.001). CONCLUSION: In this meta-analysis using currently available data, serum Cys C is clearly superior to serum Cr as a marker of GFR measured by correlation or mean ROC-plot AUC.

Biomarkers↗

PubMed2006

Derivation and validation of cystatin C-based prediction equations for GFR in children.

BACKGROUND: Cystatin C (CysC) may be a better marker of glomerular filtration rate (GFR) than serum creatinine (SCr) level. Few studies derived CysC-based GFR prediction equations for children. Objectives of this study are to: (1) derive CysC-based GFR prediction equations for children, and (2) compare these equations with published formulae. METHODS: Patients younger than 18 years undergoing iothalamate GFR (IoGFR) testing were studied prospectively. Data collected were age, sex, CysC level, SCr level, IoGFR, height, weight, and diagnosis. By using linear regression, 2 equations were derived and compared with 3 previously published formulae by using Bland-Altman analysis and diagnostic characteristics. Local coefficients were derived for comparison formulae. RESULTS: There were 111 GFR tests from 103 patients (age, 12.7 +/- 4.7 years; IoGFR, 73.6 +/- 35.7 mL/min/1.73 m(2) [1.23 +/- 0.60 mL/s/1.73 m(2)]; 60% male; and 25% post-renal transplantation). The 2 equations derived were the CysEq (including CysC level) and the CysCrEq (including CysC and SCr levels). Overall, the 2 new equations had bias and precision similar to previously published formulae when local coefficients were used. However, in patients with a renal transplant or spina bifida, the 2 new equations were less biased and more precise. All CysC-based equations performed better than the Schwartz formula. CONCLUSION: This study provides 2 CysC-based GFR prediction equations that are accurate, precise, and sensitive for detecting abnormal GFRs. Three previously published CysC GFR prediction equations have been validated for the first time. Prediction equations based on CysC level are likely to provide more accurate estimates of GFR than SCr-based equations.

Adolescent↗

PubMed2006

GFR estimation using cystatin C is not independent of body composition.

BACKGROUND: Cystatin C (CysC) is an endogenous marker of glomerular filtration rate (GFR) that is claimed to be unaffected by body composition. In this study, we tested this speculation. METHODS: In 77 patients with chronic kidney disease (mean age, 65.1 +/- 11.9 [SD] years; mean indexed GFR, 45.7 +/- 28.6 mL/min/1.73 m(2) [0.76 +/- 0.48 mL/s]), we evaluated kidney function (GFR) by means of inulin clearance. CysC level was determined by using a particle-enhanced turbidimetric immunoassay. Total lean (LM) and fat masses were measured by means of dual-energy x-ray absorptiometry. Multiple regression was used to analyze relationships between absolute GFR, LM, fat mass, demographic and anthropometric variables (age, sex, height, and weight), and CysC levels. Then prediction equations were built that included only CysC level or CysC level and LM. Their performance to predict absolute GFR was evaluated in a subset of patients with extreme body composition (LM or fat mass > +/-1 SD of the entire sample). RESULTS: Only absolute GFR and LM significantly explained variance in CysC levels, and an equation including LM explained more variance in absolute GFR than an equation including CysC level alone. Consequently, the equation including LM performed better than the equation with only CysC level, especially in patients with extreme body composition, showing reduced bias and improved limits of agreement and accuracy (71.4% versus 51.4% of patients' predicted GFR did not deviate by >30% of GFR). CONCLUSION: LM is a previously unrecognized, but important, factor affecting CysC level, and GFR estimation improves when including LM. CysC level is not independent of body composition, as previously assumed, and hence accounting for body composition improves CysC-based GFR estimation.

Aged↗

PubMed2002

Glomerular filtration rate assessment in individuals after orthotopic liver transplantation based on serum cystatin C levels.

Individuals after orthotopic liver transplantation (OLT) often show renal dysfunction, which may substantially affect the post-OLT course. Renal function after OLT is commonly assessed by means of serum creatinine (S(cr)) concentration or renal creatinine clearance (C(cr)). A glomerular filtration rate (GFR) estimate based on S(cr) level is not accurate enough because even a more marked decrease in GFR need not be associated with an increase in S(cr) level, especially in jaundiced patients. The study intends to try to estimate GFR in individuals after OLT by means of determining serum cystatin C (S(cyst)) concentrations. In 58 individuals (mean age, 49 +/- 7 years; 31 men, 27 women) at various intervals from OLT (mean, 14 +/- 10 months), GFR was estimated by using simultaneous determinations of S(cyst), S(cr), C(cr), and renal inulin clearance (C(in)). In most subjects (91.3%), C(in) was decreased to less than the lower limit of normal (80 mL/min/1.73 m(2)). A significant correlation (r = 0.70; P <.001) was found between 1/S(cyst) and C(in). Receiver operating characteristic analysis was performed on S(cyst) and S(cr) using a C(in) cutoff value of 80 mL/min/1.73 m(2). The area under the curve for S(cyst) was 0.912 +/- 0.044, and that for S(cr), 0.899 +/- 0.049. There was no statistically significant difference between these values. The sensitivity for a S(cyst) level of 1.20 mg/L (upper limit of normal value) to detect a decrease in GFR (measured as C(in)) below the lower limit of normal (80 mL/min/1.73 m(2)) was 96.1%. The sensitivity of S(cyst) level was significantly greater (P <.01) than the sensitivity of S(cr) level for men and at borderline significance for women (P =.05). Findings support the assumption that a S(cyst) level less than 1.2 mg/L indicates with a high degree of probability (P <.001) that GFR is not decreased to less than the normal limit. S(cyst) assessment in individuals after OLT could be proposed as a confirmatory test of a decrease in GFR in individuals with normal S(cr) levels.

Adolescent↗

PubMed2004

Beta2-microglobulin and cystatin C in type 2 diabetes: assessment of diabetic nephropathy.

BACKGROUND: Changes in glomerular filtration rate (GFR) provide a valuable indicator of the progression of diabetic nephropathy (DN). This study was designed to demonstrate the clinical values of serum cystatin C (Cys C) and beta2-microglobulin in the assessment of renal function in type 2 diabetics by comparing them with the GFR, estimated from the uptake phase of 99 m technetium dimetiltriamino pentaacetic acid renogram (GFR-DTPA) and creatinine clearances. MATERIALS AND METHODS: 68 type 2 diabetic patients with (urinary albumin excretions (UAE) 30 - 300 mg/24 h) (n = 39) and without (UAE < 30 mg/24 h) (n = 29) microalbuminuria and 32 controls were enrolled in the study. Serum Cys C, beta2-microglobulin, creatinine, urinary microalbumin levels, creatinine clearances and GFR-DTPA values were determined in all groups. Non-parametric ROC curves, using a cut-off GFR-DTPA of 60 mL/min/1.73 m (2), were obtained for these markers. RESULTS: Serum Cys C, beta2-microglobulin, glucose and HbA1c concentrations were significantly higher in the group with diabetes compared to controls. In the patients with microalbuminuria, serum Cys C and glucose concentrations increased significantly in comparison to patients with normoalbuminuria, while no differences were observed for beta2-microglobulin levels. Serum creatinine concentrations, GFR-DTPA values and creatinine clearances were not different between both diabetic groups and controls. Cys C was positively correlated with beta2-microglobulin and creatinine and negatively with GFR values; beta2-microglobulin was also positively correlated with serum creatinine in microalbuminurics. A significant inverse correlation was found between beta2-microglobulin and GFR values in both microalbuminurics and normoalbuminurics. CONCLUSIONS: Increased Cys C and beta2-microglobulin in diabetics may be early indicators of incipient DN. The diagnostic accuracies of Cys C and beta2-microglobulin are superior to that of serum creatinine in distinguishing between mild and moderately reduced GFR.

Adult↗

PubMed1986

Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

A gamma-trace variant protein is the major constituent of the amyloid fibrils in patients from Iceland with hereditary cerebral hemorrhage with amyloidosis. The protein consists of 110 residues and is similar to human urinary gamma-trace basic protein (or cystatin C) beginning at its 11th amino-terminal residue. It has an amino acid substitution (glutamine for leucine) at position 58 (position 68 in gamma-trace numbering), which is near the proposed active site of related proteins--namely, cysteine protease inhibitors and kininogens. It is postulated that a point mutation has occurred, leading to the production of an unusual protein that is abnormally degraded, bound, and/or precipitated. Alternatively, gamma-trace basic protein may be genetically polymorphic, and the variant described here may represent an as-yet-undiscovered isotype or an allelic form that is linked to, but not responsible for, the deposition disease. Our data on the structure of a gamma-trace variant protein suggests that its gene expresses a polyprotein precursor in which active peptides are flanked by basic amino acid residues that permit cleavage to liberate small internal peptides. It is likely that the nucleotide sequence coding for Arg-Xaa and Lys-Xaa repeated several times in the molecule may function as alternative splicing sites for mRNA processing.

Amino Acid Sequence↗

PubMed2003

Glomerular filtration rate: measure creatinine and height rather than cystatin C!

AIM: Inulin clearance (Cin) is the gold standard for assessing glomerular filtration rate (GFR). Other methods are based on the plasma creatinine concentration (Pcreat), creatinine clearance (Ccreat), the Haycock-Schwartz formula and the plasma concentration of cystatin C (PcysC), a 13 kDa basic protein produced at a constant rate by all nucleated cells. The present prospective study was thus designed to evaluate the reliability of PcysC as a marker of GFR in comparison with that of Pcreat, Ccreat and the Haycock-Schwartz formula, using Cin as the gold standard. METHODS: Ninety-nine children (51 m/48 f), with a median age of 8.3 y (1.0-17.9) were studied. Using a cut-off for Cin of 100 ml/min per 1.73 m2, 54 children (54.5%) had impaired GFR. Those with normal GFR were comparable for age, height, weight and body mass index. RESULTS: Logistic regression, ROC analysis and linear regression all showed that Ccreat was the best parameter to discriminate between impaired and normal GFR, followed by the Haycock-Schwartz formula, PcysC, and finally Pcreat, each one being significantly more predictive than the next. CONCLUSION: GFR is better assessed by the Haycock-Schwartz formula than by PcysC or Pcreat alone. It is therefore concluded that when urine collection is not possible, simply measuring the child's Pcreat and height is the best, easiest and cheapest way to assess GFR.

Adolescent↗

PubMed2026

The association between normalized creatinine-to-cystatin C ratio and incident circadian syndrome in middle-aged and older adults: a national cohort study.

BACKGROUND: Evidence on the association between the normalized creatinine-to-cystatin C ratio (NCCR) and Circadian Syndrome (CircS) in the general population remains scarce. This study aimed to investigate this relationship using data from middle-aged and elderly participants in the China Health and Retirement Longitudinal Study (CHARLS). METHODS: We conducted a cross-sectional analysis of 5,981 participants (2011 wave) and a prospective cohort analysis of 2,053 participants (2015 wave, median follow-up 4.0 years). CircS was defined as a cluster including elevated blood pressure, dyslipidemia, hyperglycemia, abdominal obesity, depression, and abnormal sleep duration. RESULTS: During follow-up, 552 participants developed incident CircS. A significant inverse association was observed: the risk of new-onset CircS progressively decreased with higher baseline NCCR levels. After adjusting for multiple confounders, each standard deviation increase in NCCR was associated with a 40% reduced odds of CircS (adjusted odds ratio = 0.60, 95% confidence interval: 0.48 to 0.75). Subgroup and dose-response analyses confirmed the robustness of this inverse relationship. CONCLUSIONS: In conclusion, a lower NCCR is independently associated with an elevated risk of developing CircS. These findings support NCCR's role as a practical serum indicator of sarcopenia and implicate muscle loss as a potentially key underlying pathway in the pathogenesis of Circadian Syndrome.

Humans↗

PubMed2003

Serum cystatin C and beta2-microglobulin as markers of glomerular filtration rate.

Continuous efforts have been made to find out precise and simple method for determination of glomerular filtration rate (GFR). Cystatin C (cysteine proteinase inhibitor = CyC) is a low molecular weight (LMW) protein which is produced constantly by all nucleated cells independently of different pathological conditions and eliminated from the blood exclusively by glomeruli. So, CyC closely reflects the GFR. In the present study 75 patients aged between 18 and 74 (44.3 +/- 12.2) years were analyzed, with the aim to compare the reciprocal values of serum level of LMW proteins CyC and beta2-microglobulin (beta2-MG) with creatinine clearance (Ccr) as a measure of GFR. Patients were divided into groups according to sex, age (<60; >60 years) and renal diseases: patients with glomerulonephritis (GN) with and without nephrotic proteinuria, pyelonephritis (PyN), and renal transplant (Tx). High correlation between Ccr and 1/CyC (r = 0.81; p < 0.01) and Ccr and 1/beta2-MG (r = 0.80; p < 0.01) in all examined patients was found. There was significant correlation between Ccr and 1/CyC (0.82 vs. 0.79) and Ccr and 1/beta2-MG (0.85 vs. 0.76) in men as well in women, and also in two groups of patients formed according to the age (0.82 vs. 0.77; p < 0.01; 0.80 vs. 0.81; p < 0.01), without any statistical significant difference between the groups. In studied groups with different renal diseases, there were no differences in correlation coefficients between Ccr and 1/CyC and Ccr and 1/beta2-MG (p1 = 0.29; p2 = 0.21; p3 = 0.79; p4 = 0.43), without statistical differences between the groups, except significant difference in correlation coefficients for Ccr and 1/beta2-MG between patients with GN with and without nephrotic proteinuria (p < 0.032). LMW proteins, serum CyC and beta2-MG, are as good markers of GFR as Ccr, regardless sex and age. Both of these LMW proteins are good markers of GFR in patients with GN without nephrotic proteinuria, PyN and Tx patients. In patients with GN and nephrotic proteinuria serum CyC is a better marker of GFR than beta2-MG.

Adolescent↗

PubMed2004

Comparison of cystatin C, creatinine and creatinine clearance vs. GFR for detection of renal failure in renal transplant patients.

BACKGROUND: Serum cystatin C (Scyst) has been suggested as an alternative index of glomerular filtration rate (GFR) and could be useful in renal transplant patients. METHODS: In a 60-subject cohort (40 +/- 12 years old), we compared the simultaneous measurements of Scyst, serum creatinine (Screat), creatinine clearance (Ccreat), Cockcroft and Gault's estimated clearance (Ccg) and GFR measured using inulin clearance (Cin). Receiver operating characteristic (ROC) analysis was performed using two Cin cut-off (60 and 90 mL/min/1.73 m2). RESULTS: A significant correlation was found among Cin on one hand and 1/Scyst, Ccreat, 1/Screat and Ccg on the other hand. Best fits (sensitivity/specificity) at 90 mL/min/1.73 m2 were 1.18 mg/L (0.72/0.80) for Scyst, 1.32 mg/dL (0.67/0.90) for Screat, 77 mL/min (0.80/0.70) for Ccg and 104 mL/min (0.88/0.80) for Ccreat. The areas under the ROC curves were not significantly different. CONCLUSIONS: This study provides cut-off values for Screat and Ccg for detection of renal failure in renal transplant patients. However, the results also suggest that Scyst is not a more sensitive marker than Screat or Ccg for detecting renal failure in renal transplant patients.

Adult↗

PubMed2001

Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes.

Loss-of-function mutations in the cystatin B (Cstb) gene cause a neurological disorder known as Unverricht-Lundborg disease (EPM1) in human patients. Mice that lack Cstb provide a mammalian model for EPM1 by displaying progressive ataxia and myoclonic seizures. We analyzed RNAs from brains of Cstb-deficient mice by using modified differential display, oligonucleotide microarray hybridization and quantitative reverse transcriptase polymerase chain reaction to examine the molecular consequences of the lack of Cstb. We identified seven genes that have consistently increased transcript levels in neurological tissues from the knockout mice. These genes are cathepsin S, C1q B-chain of complement (C1qB), beta2-microglobulin, glial fibrillary acidic protein (Gfap), apolipoprotein D, fibronectin 1 and metallothionein II, which are expected to be involved in increased proteolysis, apoptosis and glial activation. The molecular changes in Cstb-deficient mice are consistent with the pathology found in the mouse model and may provide clues towards the identification of therapeutic points of intervention for EPM1 patients.

Animals↗

PubMed1999

Altered spacing of promoter elements due to the dodecamer repeat expansion contributes to reduced expression of the cystatin B gene in EPM1.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder characterized by seizures, myoclonus and progression to cerebellar ataxia. EPM1 arises due to mutations in the cystatin B (CSTB) gene which encodes a cysteine proteinase inhibitor. Only a minority of EPM1 alleles carry point mutations, while the majority contain large expansions of the dodecamer CCCCGCCCCGCG repeat which is present at two to three copies in normal individuals. The dodecamer repeat is located in the 5' flanking region of the CSTB gene, presumably in its promoter. The pathological repeat expansion results in a reduction in CSTB mRNA, which may be cell specific. To elucidate the mechanism of this reduction of gene expression, we have studied the putative CSTB promoter in vitro. A 3.8 kb fragment, containing the putative promoter with a 600 bp repeat expansion, showed a 2- to 4-fold reduction in luciferase activity compared with an identical fragment with a normal repeat; this reduction was observed only in certain cell types. Introduction of heterologous DNA fragments of 730 and 1000 bp into the normal promoter, instead of the repeat expansion, showed similarly reduced activity. Terminal deletions of the promoter implicate a putative AP-1 binding site, upstream of the repeat, in CSTB transcription activation. We propose that a novel mechanism of pathogenesis, the altering of the spacing of transcription factor binding sites from each other and/or the transcription initiation site due to repeat expansion, is among the causes of reduction in CSTB expression and thus EPM1.

Base Sequence↗

PubMed2005

Calculation of glomerular filtration rate based on cystatin C in cirrhotic patients.

BACKGROUND: Plasma creatinine and creatinine clearance are of limited value for the estimation of renal function in cirrhotics. In these patients, cystatin C (Cys C) has been proposed as an alternative marker of glomerular filtration rate (GFR) and Cys C-based equations for calculation of GFR have been developed in non-cirrhotic patient cohorts. METHODS: We retrospectively analyzed correlation, bias, precision and accuracy of two Cys C-based formulae (Larsson and Hoek) for GFR estimation in comparison with two creatinine-based equations (Cockroft & Gault and MDRD). The Cys C was determined by an immunonephelometric method. The GFR was measured by means of inulin clearance in 44 consecutive patients with liver cirrhosis. RESULTS: On average, inulin clearance was 28.3 (95% CI: 29.2-41.3 ml/min/1.73 m2). Creatinine as well as Cys C-based equations overestimated the true GFR by 105-154%. However, Cys C-based equations showed significantly lower bias and higher precision than the creatinine-based formulae. Correlation and accuracy tended to be better with the Hoek and Larsson equation than with the Cockroft & Gault or MDRD formulae. Hoek and Larsson equations showed a similar diagnostic performance in all statistical procedures. CONCLUSION: Our data suggest a significant improvement of GFR estimation in liver cirrhotics by means of the Cys C-based Hoek and Larsson formulae. However, all estimates remain a crude approximation of true GFR and thus cannot replace gold standard methods.

Creatinine↗

PubMed1999

Expression of a selenomethionyl derivative and preliminary crystallographic studies of human cystatin C.

Human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of papain-like mammalian proteases, has been produced in its full-length form by recombinant techniques and crystallized in two polymorphic forms: cubic and tetragonal. A selenomethionyl derivative of the protein, obtained by Escherichia coli expression and with complete Met-->Se-Met substitution confirmed by mass spectrometry, amino-acid analysis and X-ray absorption spectra, was crystallized in the cubic form. A truncated variant of the protein, lacking ten N-terminal residues, has also been crystallized. The crystals of this variant are tetragonal and, like the two polymorphs of the full-length protein, contain multiple copies of the molecule in the asymmetric unit, suggesting oligomerization of the protein.

Amino Acid Sequence↗

PubMed2005

In vitro study of stability and amyloid-fibril formation of two mutants of human stefin B (cystatin B) occurring in patients with EPM1.

Myoclonus epilepsy of type 1 (EPM1) is a rare monogenic progressive and degenerative epilepsy, also known under the name Unverricht-Lundborg disease. With the aim of comparing their behavior in vitro, wild-type (wt) human stefin B (cystatin B) and the G4R and the R68X mutants observed in EPM1 were expressed and isolated from the Escherichia coli lysate. The R68X mutant (Arg68Stop) is a peptide of 67 amino acids from the N terminus of stefin B. CD spectra have shown that the R68X peptide is not folded, in contrast to the G4R mutant, which folds like wild type. The wild type and the G4R mutant were unfolded by urea and by trifluoroethanol (TFE). It has been shown that both proteins have closely similar stability and that at pH 4.8, where a native-like intermediate was demonstrated, TFE induces unfolding intermediates prior to the major transition to the all-alpha-helical state. Kinetics of fibril formation were followed by Thioflavin T fluorescence while the accompanying changes of morphology were followed by the transmission electron microscopy (TEM). For the two folded proteins the optimal concentration of TFE producing extensive lag phases and high fibril yields was predenaturational, 9% (v/v). The unfolded R68X peptide, which is highly prone to aggregate, formed amyloid fibrils in aqueous solution and in predenaturing 3% TFE. The G4R mutant exhibited a much longer lag phase than the wild type, with the accumulation of prefibrillar aggregates. Implications for pathology in view of the higher toxicity of prefibrillar aggregates to cells are discussed.

Amino Acid Substitution↗

PubMed2006

A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function.

AIMS: Since cefuroxime mainly is excreted by renal filtration, dosing is currently based on serum creatinine (Scr) or creatinine clearance (CLcr). However, it has been suggested that cystatin C (CysC) is superior to Scr as a marker of renal function. The aim of this prospective study was to develop a population model that describes the pharmacokinetics of cefuroxime and to investigate the usefulness of CysC as a covariate of the model parameters. METHODS: Ninety-seven patients were studied (CLcr range 6.5-115 ml min(-1)). Blood samples (n = 407) for the determination of cefuroxime were withdrawn according to a sparse data sampling schedule and analysed by liquid chromatography mass spectrometry. The population analysis was performed in NONMEM. RESULTS: A two-compartment model described the data well. The biomarkers Scr, CLcr and CysC were evaluated as covariates on clearance (CL). The model that included CysC generated the best fit. In the final population model CL was a function of CysC and body weight, whereas V(1) was only a function of body weight. Final parameter estimates (relative standard errors) were 6.00 (3.2%) l h(-1), 11.4 (5.3%) l and 5.11 (11%) l for CL, V(1) and V(2), respectively. CONCLUSIONS: Based on the results of the present study, and because CysC is practical to use in the clinic, it is suggested that individual dosing of cefuroxime may be based on CysC rather than on Scr or CLcr. Furthermore, our final population model may be useful as a tool when designing new dosing schedules for cefuroxime.

Anti-Bacterial Agents↗

PubMed2004

Estimation of glomerular filtration rate in the elderly: a comparison of creatinine-based formulae with serum cystatin C.

OBJECTIVES: To estimate the prevalence of decreased kidney function in an elderly population and to evaluate the impact of using alternative markers of glomerular filtration rate (GFR), focusing on serum cystatin C (Cys C) and the Modification of Diet in Renal Disease (MDRD) Study prediction equation. DESIGN AND METHODS: In a cross-sectional community-based survey renal function was assessed by serum creatinine (SCreat), Cys C and GFR predicted by the Cockcroft-Gault (CG) and the MDRD Study formulae. Associations with age, gender and proteinuria were analysed by linear models. SUBJECTS: A total of 1246 elderly residents in Lieto, Finland, 64-100 years of age. RESULTS: The prevalence of moderately or severely decreased renal function, estimated by the MDRD Study equation, was 35.7%; the CG formula yielded 58.6%. The profile of Cys C performance, including variation across age groups and level of health status, showed greater similarity to GFR estimated using the MDRD Study equation than to SCreat alone, or GFR estimated using the CG formula. Discordance between high Cys C levels and only mildly decreased GFR estimates was observed in subjects with functional limitations. Microalbuminuria was associated with Cys C levels only (P =0.047). CONCLUSION: Prevalence estimates of decreased renal function amongst the elderly vary considerably depending on prediction formula used. Variation in creatinine metabolism amongst elderly comorbid patients and the critical dependence on the SCreat assay and exact calibration, make the use of creatinine-based formulae to predict GFR questionable in geriatric clinical practice. In this setting, Cys C is a promising alternative.

Aged↗