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1.
  • Grubb, Anders, et al. (författare)
  • Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator
  • 2014
  • Ingår i: Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 60:7, s. 974-986
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>BACKGROUND:</strong></p><p>Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays.</p><p><strong>METHODS:</strong></p><p>Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR.</p><p><strong>RESULTS:</strong></p><p>We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C.</p><p><strong>CONCLUSIONS:</strong></p><p>A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.</p>
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3.
  • Backlund, Alexandra, et al. (författare)
  • Cystatin C influences the autoimmune but not inflammatory response to cartilage type II collagen leading to chronic arthritis development
  • 2011
  • Ingår i: Arthritis Research and Therapy. - BioMed Central (BMC). - 1478-6362. ; 13:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis (RA) and is induced after immunization with type II collagen (CII). CIA, like RA, is an autoimmune disease leading to destruction of cartilage and joints, and both the priming and inflammatory phases have been suggested to be dependent on proteases. In particular, the cysteine proteases have been proposed to be detrimental to the arthritic process and even immunomodulatory. A natural inhibitor of cysteine proteases is cystatin C. Methods: Cystatin C-deficient, sufficient and heterozygous mice were tested for onset, incidence and severity of CIA. The effect of cystatin C-deficiency was further dissected by testing the inflammatory effector phase of CIA; that is, collagen antibody-induced arthritis model and priming phase, that is, T cell response both in vivo and in vitro. In addition, in order to determine the importance of T cells and antigen-presenting cells (APCs), these cell populations were separated and in vitro T cell responses determined in a mixed co-culture system. Finally, flow cytometry was used in order to further characterize cell populations in cystatin C-deficient mice. Results: Here, we show that mice lacking cystatin C, develop arthritis at a higher incidence and an earlier onset than wild-type controls. Interestingly, when the inflammatory phase of CIA was examined independently from immune priming then cystatin C-deficiency did not enhance the arthritis profile. However, in line with the enhanced CIA, there was an increased T cell and B cell response as delayed-type hypersensitivity reaction and anti-CII antibody titers were elevated in the cystatin C-deficient mice after immunization. In addition, the ex vivo naive APCs from cystatin C-deficient mice had a greater capacity to stimulate T cells. Interestingly, dendritic cells had a more activated phenotype in naive cystatin C-deficient mice. Conclusions: The lack of cystatin C enhances CIA and primarily affects in vivo priming of the immune system. Although the mechanism of this is still unknown, we show evidence for a more activated APC compartment, which would elevate the autoimmune response towards CII, thus resulting in an enhanced development of chronic arthritis.
4.
  • Balbin, M, et al. (författare)
  • Determination of allotypes G1m(f) and G1m(z) at the genomic level by subclass specific amplification of DNA and use of allele specific probes
  • 1991
  • Ingår i: Experimental and Clinical Immunogenetics. - Karger. - 0254-9670. ; 8:2, s. 88-95
  • Tidskriftsartikel (refereegranskat)abstract
    • Two oligonucleotide primers were used for selective enzymatic amplification of a DNA segment encoding a major portion of the first constant region domain (CH1) of the human IgG1 heavy chain. The selective amplification was confirmed by use of subclass-specific oligonucleotide probes. Two 15-mer oligonucleotides, hybridizing with the alleles for the allotypes G1m(f) and (z), respectively, could then be used for determination at the genomic level of these two truly allelic allotypes. Serum and DNA samples from 12 individuals, one of them with a considerable amount of anti-Gm(f) antibodies, were used for allotype assignment by classical serological methods and by the new method operating at the genomic level. The resulting classifications agreed completely, demonstrating the reliability of the new method.
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5.
  • Balbin, Milagros, et al. (författare)
  • Structural and functional characterization of two allelic variants of human cystatin D sharing a characteristic inhibition spectrum against mammalian cysteine proteinases
  • 1994
  • Ingår i: Journal of Biological Chemistry. - ASBMB. - 1083-351X. ; 269:37, s. 23156-23162
  • Tidskriftsartikel (refereegranskat)abstract
    • Human cystatin D is a novel member of the cystatin superfamily of cysteine proteinase inhibitors present in saliva and tears. Two alleles of the cystatin D gene (CST5), encoding protein variants with either Cys or Arg as residue 26 in their 122-residue polypeptide chains, are present in the population. Expression of the two alleles was investigated by immunochemical analyses of the secreted cystatin D in saliva from individuals homozygous for each of the two alleles, with results demonstrating that both are expressed at similar levels. The inhibitory characteristics of the two cystatin D variants were studied, by determination of dissociation equilibrium constants (Ki) for their complexes with papain and with the mammalian cysteine proteinases, cathepsins B, H, L, and S. The results demonstrate that 1) cystatin D has a characteristic inhibition profile since it does not inhibit cathepsin B (Ki > 1 microM), and when compared to cystatin C and all other known cystatins it is a much poorer inhibitor of cathepsin L (mean Ki 25 nM) but binds cathepsin H and S relatively tightly (mean Ki values of 8.5 and 0.24 nM, respectively); and 2) the inhibitory activities of the two cystatin D variants are not significantly different, demonstrating that the presence of an extra cysteine residue in the cystatin D molecule affects neither the stability nor the functional activity of the inhibitor, thus explaining the widespread distribution of the Cys26-cystatin D encoding allele in the population. The inhibitory properties displayed by cystatin D suggest that it has a function in saliva as inhibitor of either endogenous or exogenous enzymes with cathepsin S- or H-like properties.
6.
  • Björk, Jonas, et al. (författare)
  • A novel method for creatinine adjustment makes the revised Lund-Malmö GFR estimating equation applicable in children.
  • 2020
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - 0036-5513 .- 1502-7686. ; s. 1-8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The aim of this study was to establish creatinine growth curves separately for males and females that can be used to adjust childhood levels of serum creatinine to corresponding adult levels. Linear regression with fractional polynomials of age as independent variable was used to construct creatinine growth curves for a reference cohort (n = 83,157 samples from Belgium and Sweden, age 2-40 years). Adjusted creatinine obtained from the growth curves was used to improve accuracy of estimated glomerular filtration rate (eGFR) based on the Lund-Malmö revised (LMR) equation in children. The LMR equation based on creatinine values adjusted to age 18 years was validated against measured GFR (mGFR) in a separate cohort of 4005 children from four different European countries. Validation metrics included median bias, precision, and accuracy expressed as percentage of estimates within ±30% (P<sub>30</sub>) of mGFR. Remarkable improvements in bias and accuracy were observed; P<sub>30</sub> increased from 56% to 74% after creatinine adjustments in children with mGFR &lt;75 mL/min/1.73 m<sup>2</sup> (<em>n</em> = 932), while P<sub>30</sub> was relatively unchanged (89-90%) at mGFR ≥75 mL/min/1.73 m<sup>2</sup> (n = 3073). The suggested approach with adjusted creatinine makes LMR applicable in children irrespective of their renal function.</p>
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7.
  • Björk, Jonas, et al. (författare)
  • A novel method for creatinine adjustment makes the revised Lund–Malmö GFR estimating equation applicable in children
  • ????
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - Informa Healthcare. - 0036-5513.
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to establish creatinine growth curves separately for males and females that can be used to adjust childhood levels of serum creatinine to corresponding adult levels. Linear regression with fractional polynomials of age as independent variable was used to construct creatinine growth curves for a reference cohort (n = 83,157 samples from Belgium and Sweden, age 2–40 years). Adjusted creatinine obtained from the growth curves was used to improve accuracy of estimated glomerular filtration rate (eGFR) based on the Lund–Malmö revised (LMR) equation in children. The LMR equation based on creatinine values adjusted to age 18 years was validated against measured GFR (mGFR) in a separate cohort of 4005 children from four different European countries. Validation metrics included median bias, precision, and accuracy expressed as percentage of estimates within ±30% (P30) of mGFR. Remarkable improvements in bias and accuracy were observed; P30 increased from 56% to 74% after creatinine adjustments in children with mGFR <75 mL/min/1.73 m2 (n = 932), while P30 was relatively unchanged (89–90%) at mGFR ≥75 mL/min/1.73 m2(n = 3073). The suggested approach with adjusted creatinine makes LMR applicable in children irrespective of their renal function.
8.
  • Björk, Jonas, et al. (författare)
  • Accuracy of GFR estimating equations combining standardized cystatin C and creatinine assays : a cross-sectional study in Sweden
  • 2015
  • Ingår i: Clinical Chemistry and Laboratory Medicine. - 1434-6621 .- 1437-4331. ; 53:3, s. 403-414
  • Tidskriftsartikel (refereegranskat)abstract
    • <p> <strong>Background</strong>: The recently established international cystatin C calibrator makes it possible to develop non-laboratory specific glomerular filtration rate (GFR) estimating (eGFR) equations. This study compares the performance of the arithmetic mean of the revised Lund-Malmö creatinine and CAPA cystatin C equations (MEANLM-REV+CAPA), the arithmetic mean of the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) creatinine and cystatin C equations (MEANCKD-EPI), and the composite CKD-EPI equation (CKD-EPICREA+CYSC) with the corresponding single marker equations using internationally standardized calibrators for both cystatin C and creatinine.</p><p><strong> Methods</strong>: The study included 1200 examinations in 1112 adult Swedish patients referred for measurement of GFR (mGFR) 2008-2010 by plasma clearance of iohexol (median 51 mL/min/1.73 m2). Bias, precision (interquartile range, IQR) and accuracy (percentage of estimates ±30% of mGFR; P30) were compared.</p><p><strong>Results</strong>: Combined marker equations were unbiased and had higher precision and accuracy than single marker equations. Overall results of MEANLM-REV+CAPA/MEANCKD-EPI/CKD-EPICREA+CYSC were: median bias -2.2%/-0.5%/-1.6%, IQR 9.2/9.2/8.8 mL/min/1.73 m2, and P30 91.3%/91.0%/91.1%. The P30 figures were about 7-14 percentage points higher than the single marker equations. The combined equations also had a more stable performance across mGFR, age and BMI intervals, generally with P30 ≥90% and never &lt;80%. Combined equations reached P30 of 95% when the difference between eGFRCREA and eGFRCYSC was &lt;10% but decreased to 82% at a difference of ≥40%.</p><p><strong>Conclusions</strong>: Combining cystatin C and creatinine assays improves GFR estimations with P30 ≥90% in adults. Reporting estimates of both single and combined marker equations in clinical settings makes it possible to assess the validity of the combined equation based on the agreement between the single marker equations.</p>
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9.
  • Björk, Jonas, et al. (författare)
  • Accuracy of GFR estimating equations combining standardized cystatin C and creatinine assays: a cross-sectional study in Sweden
  • 2015
  • Ingår i: Clinical Chemistry and Laboratory Medicine. - De Gruyter. - 1434-6621. ; 53:3, s. 403-414
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The recently established international cystatin C calibrator makes it possible to develop non-laboratory specific glomerular filtration rate (GFR) estimating (eGFR) equations. This study compares the performance of the arithmetic mean of the revised Lund-Malmo creatinine and CAPA cystatin C equations (MEAN(LM-REV+CAPA)), the arithmetic mean of the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) creatinine and cystatin C equations (MEAN(CKD-EPI)), and the composite CKD-EPI equation (CKD-EPICREA+CYSC) with the corresponding single marker equations using internationally standardized calibrators for both cystatin C and creatinine. Methods: The study included 1200 examinations in 1112 adult Swedish patients referred for measurement of GFR (mGFR) 2008-2010 by plasma clearance of iohexol (median 51 mL/min/1.73 m(2)). Bias, precision (interquartile range, IQR) and accuracy (percentage of estimates +/- 30% of mGFR; P-30) were compared. Results: Combined marker equations were unbiased and had higher precision and accuracy than single marker equations. Overall results of MEAN(LM-REV+CAPA)/MEAN(CKD-EPI)/CKD-EPICREA+CYSC were: median bias -2.2%/-0.5%/-1.6%, IQR 9.2/9.2/8.8 mL/min/1.73 m(2), and P-30 91.3%/91.0%/91.1%. The P-30 figures were about 7-14 -percentage points higher than the single marker equations. The combined equations also had a more stable performance across mGFR, age and BMI intervals, generally with P-30 >= 90% and never <80%. Combined equations reached P-30 of 95% when the difference between eGFR(CREA) and eGFR(CYSC) was <10% but decreased to 82% at a difference of >= 40%. Conclusions: Combining cystatin C and creatinine assays improves GFR estimations with P-30 >= 90% in adults. Reporting estimates of both single and combined marker equations in clinical settings makes it possible to assess the validity of the combined equation based on the agreement between the single marker equations.
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10.
  • Björk, Jonas, et al. (författare)
  • GFR estimation based on standardized creatinine and cystatin C : A European multicenter analysis in older adults
  • 2018
  • Ingår i: Clinical Chemistry and Laboratory Medicine. - De Gruyter. - 1437-4331. ; 56:3, s. 422-435
  • Tidskriftsartikel (refereegranskat)abstract
    • Although recommended by the Kidney Disease Improving Global Outcomes, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICR) creatinine equation was not targeted to estimate glomerular filtration rate (eGFR) among older adults. The Berlin Initiative Study (BIS1CR) equation was specifically developed in older adults, and the Lund-Malmö revised (LMRCR) and the Full Age Spectrum (FASCR) equations have shown promising results in older adults. Our aim was to validate these four creatinine equations, including addition of cystatin C in a large multicenter cohort of Europeans ≥70 years. A total of 3226 individuals (2638 with cystatin C) underwent GFR measurement (mGFR; median, 44 mL/min/1.73 m2) using plasma iohexol clearance. Bias, precision (interquartile range [IQR]), accuracy (percent of estimates ±30% of mGFR, P30), eGFR accuracy diagrams and probability diagrams to classify mGFR<45 mL/min/1.73 m2 were compared. The overall results of BIS1CR/CKD-EPICR/FASCR/LMRCR were as follows: median bias, 1.7/3.6/0.6/-0.7 mL/min/1.73 m2; IQR, 11.6/12.3/11.1/10.5 mL/min/1.73 m2; and P30, 77.5%/76.4%/80.9%/83.5% (significantly higher for LMR, p<0.001). Substandard P30 (<75%) was noted for all equations at mGFR<30 mL/min/1.73 m2, and at body mass index values <20 and ≥35 kg/m2. LMRCR had the most stable performance across mGFR subgroups. Only LMRCR and FASCR had a relatively constant small bias across eGFR levels. Probability diagrams exhibited wide eGFR intervals for all equations where mGFR<45 could not be confidently ruled in or out. Adding cystatin C improved P30 accuracy to 85.7/86.8/85.7/88.7 for BIS2CR+CYS/CKD-EPICR+CYS/FASCR+CYS/MEANLMR+CAPA. LMRCR and FASCR seem to be attractive alternatives to CKD-EPICR in estimating GFR by creatinine-based equations in older Europeans. Addition of cystatin C leads to important improvement in estimation performance.
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