Blueprint for a european calciphylaxis registry initiative. the european calciphylaxis network (eucalnet)

Calcific uraemic arteriolopathy (CUA) is a rare disease and continues to be a clinical challenge. The typical course of CUA is characterized by painful skin discolouration and induration evolving to necrotic ulcerations. Medial calcification of cutaneous arterioles and extensive extracellular matrix remodelling are the hallmarks of CUA. The epidemiology and risk factors associated with this disease are still not fully understood. Moreover, CUA treatment strategies vary significantly among centres and expert recommendations are heterogeneous. Registries may provide important insights and information to increase our knowledge about epidemiology and clinical aspects of CUA and may help to optimize its therapeutic management. In 2006, we established an internet-based registry in Germany (www.calciphylaxie.de) to allow online notification of patients with established or suspected CUA. The registry includes a comprehensive database with questions covering >70 parameters and items regarding patient-related and laboratory data, clinical background and presentation as well as therapeutic strategies. The next phase will be to allow international patient registration via www.calciphylaxis.net as part of the multinational EuCalNet (European Calciphylaxis Network) initiative, which is supported by the ERA-EDTA scientific working group 'CKD-MBD'. Based on the valuable experience with the previous German CUA registry, EuCalNet will be a useful tool to collect data on the rare disease CUA and may become a basis for prospective controlled trials in the near future

Distribution of Matrix Metalloproteinases in Human Atherosclerotic Carotid Plaques and Their Production by Smooth Muscle Cells and Macrophage Subsets

In this study, the potential of matrix metalloproteinase (MMP) sense for detection of atherosclerotic plaque instability was explored. Secondly, expression of MMPs by macrophage subtypes and smooth muscle cells (SMCs) was investigated. Twenty-three consecutive plaques removed during carotid endarterectomy were incubated in MMPSense (TM) 680 and imaged with IVISA (R) Spectrum. mRNA levels of MMPs, macrophage markers, and SMCs were determined in plaque specimens, and in in vitro differentiated M1 and M2 macrophages. There was a significant difference between autofluorescence signals and MMPSense signals, both on the intraluminal and extraluminal sides of plaques. MMP-9 and CD68 messenger RNA (mRNA) expression was higher in hot spots, whereas MMP-2 and alpha SMA expression was higher in cold spots. In vitro M2 macrophages had higher mRNA expression of MMP-1, MMP-9, MMP-12, and TIMP-1 compared to M1 macrophages. MMP-9 is most dominantly MMP present in atherosclerotic plaques and is produced by M2 rather than M1 macrophages

Switching iron sucrose to ferric carboxymaltose associates to better control of iron status in hemodialysis patients

Background: Although the efficacy of iron sucrose (IS) and ferric carboxymaltose (FCM) in treating anemia in hemodialysis (HD) patients has been studied individually, a comparison of these two intravenous iron formulations has not yet been performed in HD patients. Methods: We performed a retrospective audit on records of 221 stable HD patients from different HD centers in the Netherlands, who were switched from IS to FCM on a 1: 1 ratio. To assess the effect of the switch on iron status parameters, data from 3 time points before and 3 time points after the switch were analyzed using linear mixed effects models. Subanalyses were done in 2 subgroups of patients anemic or iron deficient at baseline. Results: Hemoglobin increased in all groups (anemic [1.4 g/dL, P <0.001] iron deficient [0.6 g/dL, P <0.001]), while the weekly iron dose was significantly lower when patients received FCM compared to IS (48 vs 55 mg/week, P = 0.04). Furthermore, serum ferritin and transferrin saturation increased in all groups (anemic [64 mu g/L, 5.0%, P <0.001] iron deficient [76 mu g/L, 3.6%, P <0.001]). Finally, the darbepoetin a dose decreased significantly in all groups (anemic [- 16 mu g/wk., P = 0.01] iron deficient [- 11 mu g/wk., P <0.001]). Conclusions: In this real-life study in HD patients, a switch from IS to FCM resulted in an improvement of iron status parameters despite a lower weekly dose of FCM. Furthermore, the ESA dose was reduced during FCM, while hemoglobin levels increased

Fluorescence-guided imaging for resection margin evaluation in head and neck cancer patients using cetuximab-800CW:A quantitative dose-escalation study

Tumor-positive resection margins are present in up to 23% of head and neck cancer (HNC) surgeries, as intraoperative techniques for real-time evaluation of the resection margins are lacking. In this study, we investigated the safety and potential clinical value of fluorescence-guided imaging (FGI) for resection margin evaluation in HNC patients. We determined the optimal cetuximab-800CW dose by quantification of intrinsic fluorescence values using multi-diameter single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy. Methods: Five cohorts of three HNC patients received cetuximab-800CW systemically: three single dose cohorts (10, 25, 50 mg) and two cohorts pre-dosed with 75 mg unlabeled cetuximab (15 or 25 mg). Fluorescence visualization and MDSFR/SFF spectroscopy quantification was performed and were correlated to histopathology. Results: There were no study-related adverse events higher than Common Terminology Criteria for Adverse Events grade-II. Quantification of intrinsic fluorescence values showed a dose-dependent increase in background fluorescence in the single dose cohorts (p<0.001, p<0.001), which remained consistently low in the pre-dosed cohorts (p=0.6808). Resection margin status was evaluated with a sensitivity of 100% (4/4 tumor-positive margins) and specificity of 91% (10/11 tumor-negative margins). Conclusion: A pre-dose of 75 mg unlabeled cetuximab followed by 15 mg cetuximab-800CW was considered the optimal dose based on safety, fluorescence visualization and quantification of intrinsic fluorescence values. We were able to use a lower dose cetuximab-800CW than previously described, while remaining a high sensitivity for tumor detection due to application of equipment optimized for IRDye800CW detection, which was validated by quantification of intrinsic fluorescence values

The Urokinase Receptor (uPAR) Facilitates Clearance of Borrelia burgdorferi

The causative agent of Lyme borreliosis, the spirochete Borrelia burgdorferi, has been shown to induce expression of the urokinase receptor (uPAR); however, the role of uPAR in the immune response against Borrelia has never been investigated. uPAR not only acts as a proteinase receptor, but can also, dependently or independently of ligation to uPA, directly affect leukocyte function. We here demonstrate that uPAR is upregulated on murine and human leukocytes upon exposure to B. burgdorferi both in vitro as well as in vivo. Notably, B. burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored significantly higher Borrelia numbers compared to WT controls. This was associated with impaired phagocytotic capacity of B. burgdorferi by uPAR knock-out leukocytes in vitro. B. burgdorferi numbers in vivo, and phagocytotic capacity in vitro, were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in uPAR knock-out mice partially backcrossed to a B. burgdorferi susceptible C3H/HeN background, higher B. burgdorferi numbers were associated with more severe carditis and increased local TLR2 and IL-1β mRNA expression. In conclusion, in B. burgdorferi infection, uPAR is required for phagocytosis and adequate eradication of the spirochete from the heart by a mechanism that is independent of binding of uPAR to uPA or its role in the fibrinolytic system

Associations between depressive symptoms and disease progression in older patients with chronic kidney disease: results of the EQUAL study

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease; however, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (&gt;= 65 years; estimated glomerular filtration rate &lt;= 20 mL/min/1.73 m(2)) were included from a European multicentre prospective cohort between 2012 and 2019. Depressive symptoms were measured by the five-item Mental Health Inventory (cut-off &lt;= 70; 0-100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73 m(2)/month. A total of 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (P = 0.08). Unlike women, men with depressive symptoms had an increased mortality rate compared with those without symptoms [adjusted hazard ratio 1.41 (95% confidence interval 1.03-1.93)]. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, or with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men

Mevastatin increases eNO synthase expression and inhibits lipid peroxidation in human endothelial cells

Statins can protect endothelial activation independent from their lipid-lowering effects. To gain more insight in mechanisms via which HMG-CoA inhibition may attenuate endothelial activation, we assessed the effects of mevastatin on eNOS expression of non- and modified-LDL treated endothelial cells and on basal and hydrogen peroxide-induced lipid peroxidation. Oxidized-LDL (Ox-LDL), but not glycated or acylated LDL decreased eNOS expression in human endothelial cells. The extent to which Ox-LDL decreases eNOS expression depends on the extent of modification of Ox-LDL. Mevastatin increased eNOS-expression, both in the presence and absence of Ox-LDL. In addition, mevastatin decreased the H2O2-induced (100 μM) lipid peroxidation in endothelial cells. This study shows that mevastatin has protective effects on endothelial cells by inducing eNOS and by inhibiting lipid peroxidation

Influence of four different PTH methods on the classification of chronic kidney disease patients according to the new KDIGO guideline

Secondary hyperparathyroidism develops frequently with chronic kidney disease (CKD) and is associated with poor outcome. The new CKD-MBD guideline, Kidney Disease: Improving Global Outcomes (KDIGO), recommends a target range for PTH which is based on the locally used, upper reference range limit (URL). We examined the impact of the KDIGO guideline on the classification of dialysis patients in two different hospitals using 4 different intact-PTH assays. Blood samples from 76 consecutive hemodialysis CKD patients were measured for PTH concentration. Classification of the patients was performed according to the previous KDOQI and the KDIGO guideline using the manufacturers' and laboratory determined URLs. Classification of patients based on 3 different PTH methods (Siemens ADVIA Centaur, Siemens Immulite 2000, and Beckman Coulter Unicel DxI) was compared with the classification found in another hospital using the Roche Modular E170 PTH assay. Depending on the PTH assay used, between 9 (12%) to 14 (18%) of the patients were classified differently in the two hospitals if the KDOQI guideline was followed. Application of the KDIGO-PTH target range resulted in a similar or decreased number of differently classified patients if the PTH concentration was measured using the Advia Centaur and Immulite assays. With the Beckman Coulter PTH assay, however, the number of differently KDIGO-classified patients increased if the manufacturers' URL (9.3 pmol/L) was used to calculate the PTH-target range. Application of the laboratory determined URL (7.0 pmol/L) improved concordance in classification, although the number of differently classified patients was still higher than with the other PTH assays. The best concordance in classification for the Beckman Coulter assay was found at a PTH value of 6.0 pmol/L. Regarding the Roche and Siemens assays, no significant difference was found in the classification using the URL either determined by the laboratory or the manufacturers. Compared with the KDOQI guideline, the new KDIGO guideline may increase the number of discrepancies in the classification of CKD patients if the Access Beckman Coulter PTH assay is used in conjunction with the calculated target range based on the manufacturers' URL. The best concordance in the classification for the Beckman Coulter assay was found at a PTH value below the manufacturers' and laboratory determined UR