| 1. |
- Brage, M, et al.
(författare)
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Different cysteine proteinases involved in bone resorption and osteoclast formation.
- 2005
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:6, s. 439-47
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Tidskriftsartikel (refereegranskat)abstract
- Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.
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| 2. |
- Grubb, Anders, et al.
(författare)
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Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation.
- 2011
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71, s. 145-149
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background. The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery. Methods. Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days. Results. Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period. Conclusion. The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR.
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| 3. |
- Björk, Jonas, et al.
(författare)
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A new tool for predicting the probability of chronic kidney disease from a specific value of estimated GFR.
- 2010
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; Jul 1, s. 327-333
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. To demonstrate how patients' probability of having chronic kidney disease (CKD) stage 3-5 (measured GFR <60 mL/min/1.73 m(2)) can be predicted from a specific value of estimated glomerular filtration rate (eGFR). Material and methods. The probability of CKD stage 3-5 was predicted from a logistic regression model (n = 850) using three different eGFR prediction equations: Lund-Malmö, MDRD and CKD-EPI. Population weighting was used to illustrate how this probability varies in three different populations: original sample (55% true prevalence of CKD stage 3-5), a screening (6.7% prevalence) and a CKD population (84% prevalence). Results. All three eGFR-equations had high classification ability (area under the receiver-operating-characteristic curve = 97%). The probability of CKD stage 3-5 increased with decreasing eGFR, varied substantially among the populations studied and to some extent between the eGFR-equations. Using the Lund-Malmö equation as illustration, the probability of CKD stage 3-5 is > 90% only when eGFR is <38 mL/min/1.73 m(2) in a screening population, whereas it is > 90% already when eGFR is <51 mL/min/1.73 m(2) in a CKD population. Conversely, the probability of CKD stage 3-5 is <10% if eGFR > 59 mL/min/1.73 m(2) in a screening population, whereas it is <10% only when eGFR is > 88 mL/min/1.73 m(2) in a CKD population. Conclusion. Instead of reporting diagnostic accuracy as sensitivity, specificity, and predictive values, actual eGFR supplemented with the probability that it represents a true GFR <60 mL/min/1.73 m(2) may be more valuable for physicians. Clinical (pre-test) probability in the population must be considered when predicting this probability.
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| 4. |
- Björk, Jonas, et al.
(författare)
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Revised equations for estimating glomerular filtration rate based on the Lund-Malmö Study cohort.
- 2011
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71, s. 232-239
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. To increase the accuracy of estimated GFR (eGFR) from creatinine overall and at measured GFR ≥90 mL/min per 1.73 m(2) by revising the Lund-Malmö (LM) equations, to elaborate on more complex forms to improve the LM and CKD-EPI equations further, and to assess benefits of adding lean body mass (LBM). Material and methods. Swedish Caucasians (n = 850, 376 women; median 60, range 18-95 years) referred for GFR measurement (plasma iohexol-clearance: median 55, range 5-173 mL/min/1.73 m(2)) constituted the Lund-Malmö Study cohort. Bias, precision, accuracy, expressed as median absolute percentage difference and percentage of estimates ±10% (P(10)) and ±30% (P(30)) of measured GFR, and classification ability with respect to five GFR stages were compared with the original LM, CKD-EPI and MDRD equations. Results. LM Revised overall performed better than LM Original without LBM due to increased accuracy at measured GFR ≥90 mL/min/1.73 m(2). Further extensions of the CKD-EPI or LM equations did not substantially improve overall performance. In particular, the performance of LM Revised at measured GFR ≥90 mL/min/1.73 m(2) could not be improved further without decreasing accuracy and classification ability at lower GFR-levels. Adding LBM to the equations had no strong effect on accuracy. Conclusion. Comparisons with the CKD-EPI and MDRD equations suggest that the LM equations are superior for the present Swedish population, due to markedly higher accuracy of the LM equations at measured GFR <30 mL/min/1.73 m(2). However, the LM equations cannot be recommended for use in general clinical practice until validated in other populations.
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| 5. |
- Tyrefors, Niklas, et al.
(författare)
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Two new types of assays to determine protein concentrations in biological fluids using mass spectrometry of intact proteins with cystatin C in spinal fluid as an example
- 2014
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 74:6, s. 546-554
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Tidskriftsartikel (refereegranskat)abstract
- There is no reference method that is generally acknowledged to be unbiased for the determination of the concentration of any protein in biological fluids. This is probably because mass spectrometry (MS) methods acknowledged as reference methods for determination of low molecular mass substances in biological fluids, e.g. creatinine, have been difficult to adapt for proteins. Here we suggest two tentative MS methods, which might be used as reference methods for the determination of protein concentrations in biological fluids. One is based upon the addition to the fluid of a non-proteome reference protein, very similar to the one to be measured, and analyzing the ratio between the corresponding peaks in a selected ion monitoring (SIM) chromatogram. We call this method LC-MS-NPRP (NPRP, Non-Proteome Reference Protein). The other method is based upon the classical standard addition assay for low molecular mass substances. The results of these assays for cystatin C in spinal fluid were compared to those obtained by an immunoassay. Both methods indicated lower concentration than the immunoassay. This was found to be due to the presence of a significant fraction of monohydroxylated cystatin C in spinal fluid. It turned out that the sum of the unhydroxylated and hydroxylated cystatin C concentrations, determined by either of the two MS methods, were close to the results obtained by the immunoassay. These MS-based methods analyze intact proteins and therefore seem more suitable for the determination of protein concentrations in biological fluids than other MS-based methods requiring proteolytic degradation with its inherent lack of precision.
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| 6. |
- Pesonen, Erkki, et al.
(författare)
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Elevated infection parameters and infection symptoms predict an acute coronary event.
- 2008
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Ingår i: Therapeutic Advances in Cardiovascular Disease. - : SAGE Publications. - 1753-9447 .- 1753-9455. ; 2:6, s. 419-424
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The etiology and significance of flu-like symptoms often appearing before myocardial infarction should be clarified. METHODS: In a case-control study of 323 matched controls and a random sample of 110 out of 351 cases the presence of infection symptoms during the preceding four weeks before admission were asked and blood samples taken. RESULTS: Enterovirus (EV), herpes simplex virus (HSV), and Chlamydia pneumoniae IgA titers were significantly higher in cases than in controls (p<0.001, 0.008 and 0.046, respectively). Flu-like symptoms appeared significantly more often in patients than in controls the most common one being fatigue (p<0.001). In controls with fatigue, EV and HSV titers showed a trend to be higher (1.50 vs 1.45 and 4.29 vs 3.73) than in controls without fatigue but only HSV titers were statistically significantly higher (3.47 vs 3.96, p = 0.02). Even CRP and amyloid A concentrations (3.49 vs 2.08, p<0.0001 and 5.70 vs 3.77 mg/l, p = 0.003, respectively) as well as C4 (0.40 vs 0.44, p = 0.02) were higher in controls with fatigue. CONCLUSIONS: Odds ratios for a coronary event in a logistic regression model were 4.79 for fatigue and 2.72 for EV antibody levels in their fourth quartile. A linear-by-linear association test showed increasing number of single symptoms with higher EV titer quartiles (p = 0.004).
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| 7. |
- Nyman, Ulf, et al.
(författare)
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The Lund-Malmo creatinine-based glomerular filtration rate prediction equation for adults also performs well in children
- 2008
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 68:7, s. 568-576
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Tidskriftsartikel (refereegranskat)abstract
- Objective . To evaluate the clinical performance in a paediatric population of the Lund-Malmo creatinine-based glomerular filtration rate (GFR) prediction equations, primarily developed for adults. Material and methods . Iohexol clearance was used as the gold standard in 85 paediatric Caucasian patients (0.3-17 years; 37 F/48 M). One Lund-Malmo equation was based on age and gender (LM) and one included lean body mass (LM-LBM). Comparisons focused on correlation (adjusted R-2), bias (median percent error) and accuracy (proportions of predicted GFR differing <= 30 % from measured GFR) (mL/min/1.73 m(2)). The performances were compared with those of the Modification of Diet in Renal Disease (MDRD) Study equation, a dedicated paediatric creatinine equation, Counahan-Barratt (CB) and a cystatin C-based equation. Results . The MDRD equation performed poorly with a median bias of 96 %. Of the remaining equations, only the LM-LBM produced significant bias (+10 % in median) according to line of identity regression analysis. The LM equation yielded marginally higher accuracy (76 %) than the LM-LBM equation (74 %) and the CB (73 %), but lower than the cystatin C-based equation (82 %). However, the estimated accuracy figures for these four equations were generally imprecise and none of the differences compared with the LM equation was statistically significant. Conclusion . In contrast to most creatinine-based GFR prediction equations, the LM equation performs adequately for both children and adults. This may be due to the unique model-building principles used when the LM equation was established. Further validation in a larger paediatric population is necessary.
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| 8. |
- Christensson, Anders, et al.
(författare)
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Serum cystatin C advantageous compared with serum creatinine in the detection of mild but not severe diabetic nephropathy.
- 2004
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 256:6, s. 510-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether serum cystatin C is more accurate than serum creatinine in the detection of diabetic nephropathy, also after adjustment for age.METHODS: Forty-one patients with type 1 and 82 patients with type 2 diabetes were evaluated with serum creatinine, serum cystatin C, and (51)Cr-EDTA clearance (reference method). Cystatin C was measured by a particle-enhanced turbidimetric method and creatinine by an enzymatic method. Statistical estimations were performed both without and with age adjustment created by z-scores for (51)Cr-EDTA clearance, creatinine, and cystatin C. The cut-off levels for glomerular filtration rate (GFR) ((51)Cr-EDTA clearance) were 60 and 80 mL min(-1) 1.73 m(-2), respectively, in absolute values and 80, 90 and 95% CIs, respectively, in age-adjusted values (z-scores).RESULTS: Estimations without age adjustment showed significantly (P = 0.0132) closer correlation for cystatin C (r = 0.817) versus (51)Cr-EDTA clearance as compared with creatinine (r = 0.678). However, when using age-adjusted values, the correlation for cystatin C and creatinine, respectively, versus (51)Cr-EDTA clearance did not differ. When comparing the diagnostic utilities for serum cystatin C versus serum creatinine in manifest renal impairment (GFR < 60 mL min(-1) 1.73 m(-2) or z-scores <-1.28 SD), there were no significant differences between the two markers whether age adjusted or not. However, for diagnosing mild nephropathy (GFR < 80 mL min(-1) 1.73 m(-2) or z-score -0.84 SD), serum cystatin C is significantly more useful.CONCLUSIONS: Serum cystatin C performed better compared with serum creatinine even when measured enzymatically, to detect mild diabetic nephropathy. However, serum creatinine was as efficient as serum cystatin C to detect advanced diabetic nephropathy.
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| 9. |
- Nyman, Ulf, et al.
(författare)
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Different equations to combine creatinine and cystatin C to predict GFR. Arithmetic mean of existing equations performs as well as complex combinations
- 2009
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 69:5, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To test various ways of combining creatinine and cystatin C in equations to predict glomerular filtration rate (GFR). Material and methods: Performance of the following expressions to predict GFR was compared with measured GFR (iohexol clearance, mL/min/1.73 m(2)) in 857 patients: (i) Lund-Malmo creatinine equation, (ii) Grubb cystatin C equation, (iii) arithmetic mean of (1) and (2), (iv) geometric mean of (1) and (2), (v) linear regression on (1) and (2), (vi) regression on (1) and cystatin C, and (vii) regression on creatinine, cystatin C, age and gender. Results: For the entire cohort median percent error (bias) was <5% for all expressions, though all expressions tended to underestimate (<8.3 to <15.8%) GFR at levels <90 mL/min/1.73 m(2). The five expressions combining creatinine and cystatin C significantly improved correlation and accuracy (p < 0.001) within 15 and 30% of measured GFR compared with the equations based on the separate analytes and with no significant difference between the five expressions. In a subgroup of patients with neurological disease and muscle atrophy the cystatin C equation performed better than the expressions combining creatinine and cystatin C. Conclusion: Simply calculating the arithmetic mean of predicted GFR based on separate creatinine and cystatin C equations performs equally well as more complex equations. Reporting GFR based on separate creatinine and cystatin C equations, and their arithmetic mean also has the definite advantage that the physician can choose the estimated GFR, most appropriate depending on the clinical setting and patient characteristics.
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| 10. |
- Nyman, Ulf, et al.
(författare)
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The CKD-EPI and MDRD equations to estimate GFR. Validation in the Swedish Lund-Malmo Study cohort
- 2011
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71:2, s. 129-138
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To compare the recently developed CKD-EPI equation to estimate GFR in adult Swedish-Caucasians with the MDRD equation. Material and methods. Swedish-Caucasians (N = 850, 376 females; median age 60, range 5-95 years) referred for plasma iohexol-clearance (median 55, range 5-223 mL/min/1.73 m(2)) constituted the Lund-Malmo Study cohort. Bias, precision (interquartile range, IQR, of the differences between estimated and measured GFR), accuracy expressed as percentage of estimates +/- 10% (P-10) and +/- 30% (P-30) of measured GFR, and classification ability for five GFR stages < 15, 15-29, 30-59, 60-89 and >= 90 mL/min/1.73 m(2) were compared. Results. Overall there were no important differences between the equations; CKD-EPI/MDRD median values of bias +5.4%/+3.4%, IQR both 14 mL/min/1.73 m(2), P-10 36%/34%, P-30 both 80%, and correctly classified GFR stages 68%/67%. P-30 for the CKD-EPI equation was substantially higher than for MDRD at GFR >= 90 mL/min/1.73 m(2) (93% versus 79%). The MDRD equation performed better in the GFR interval 30-89 mL/min/1.73 m(2), while accuracy was limited for both equations at GFR < 30 mL/min/1.73 m(2) (P-30 < 75% in both females and males). The CKD-EPI/MDRD equations caused a +22%/ +14% bias in the 18-39 year interval and the MDRD equation a + 18% bias >= 80 years. Both equations performed poorly in males with BMI < 20 kg/m(2) (CKD-EPI/MDRD median bias +36%/46%). Conclusion. Overall the recently developed CKD-EPI equation performed well but was not superior to the MDRD equation. The CKD-EPI equation may be preferred in screenings of general populations and in the elderly. None of the equations appeared reliable among patients with markedly decreased GFR, young adults and underweight males.
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