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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. [ABSTRACT FROM AUTHOR]

Objective: In a combination of in vivo and in vitro studies, we investigated mechanisms via which α-tocopherol, a lipid soluble form of vitamin E, can directly affect endothelial activation as induced by H2O2 and TNFα. Methods: We measured effects of α-tocopherol on H2O2-induced lipid peroxidation as determined with a fluorescent C-11 BODIPY581/591 probe and on adhesion molecule expression in cultured endothelial cells. In 20 healthy volunteers treated with increasing doses of α-tocopherol up to 800 IU/ml for 12 weeks, plasma levels of soluble cell adhesion molecules (sCAMs) and C-reactive protein were measured. Results: We showed that α-tocopherol protects cultured endothelial cells against H2O2-induced lipid peroxidation, while TNFα did not induce lipid peroxidation. Moreover, α-tocopherol attenuated H2O2-, but not TNFα-induced increases in adhesion molecule expression. In healthy persons, α-tocopherol decreased plasma levels of sE-selectin from 65±6 to 60±6 ng/ml (P=0.002), sVCAM from 893±31 to 853±23 ng/ml (P=0.022), and sICAM from 483±21 to 463±16 ng/ml (P=0.048). C-Reactive protein, as a sensitive marker of low grade inflammation, was not significantly affected. Conclusion: α-Tocopherol specifically inhibits lipid peroxidation-induced endothelial activation in vitro. The observed vitamin E-induced decrease in sCAMs in control subjects suggests that lipid peroxidation can take place in healthy individuals. Although vitamin E supplementation may be especially effective in specific groups of patients exposed to increased oxidative stress, our study suggests that vitamin E supplementation can be of benefit in healthy individuals as well. [Copyright &y& Elsevier]

Nitric oxide (NO) may play an important role in the pathogenesis of diabetic microangiopathy. However, arteriolar changes in NO activity and sensitivity to NO may be dependent on both the type of arteriole and the duration of diabetes. Therefore, we assessed, in the in situ spinotrapezius muscle preparation of streptozotocin-diabetic rats and of controls, inside diameters of A2–A4 arterioles and the reactivity to topically applied acetylcholine and nitroprusside, before and after NG-nitro-l-arginine (l-NNA) at 2, 4, 6 and 12 weeks of diabetes. In A2 arterioles, basal diameters and the contribution of NO to basal diameter were not affected during the course of streptozotocin-induced diabetes. However, the maximal response to acetylcholine in these arterioles was attenuated after 2 until 4 weeks, and from 4 weeks on a sustained decrease in reactivity to sodium nitroprusside was observed. In A3 arterioles, both the basal diameter and the contribution of NO to basal diameter were decreased after 2 weeks and increased after 6 weeks, while the response to sodium nitroprusside was unaffected. In A4 arterioles, a significant increase in basal diameter was observed after 6 weeks only. Thus, this study shows that streptozotocin-induced diabetes causes microvascular changes in NO activity and sensitivity that depend on the type of arteriole. For each order of arteriole, these changes show a specific pattern during the course of diabetes. [Copyright &y& Elsevier]

In patients treated with peritoneal dialysis (PD), lowering the calcium level in PD fluids results in lower serum calcium levels and higher parathyroid hormone (PTH) levels. It is hypothesized that this effect is attenuated when patients are using icodextrin 7.5% for the once-daily long dwell (containing high calcium concentration). In this case series, we included 8 stable PD patients (mean age 68 ± 13 years, 7 male), all using icodextrin 7.5% (containing 1.75 mmol/L calcium) for the once-daily long dwell. The calcium content of the PD fluids for the remaining dwells was lowered from 1.75 mmol/L to 1.25 mmol/L. Bone mineral parameters and phosphate prescription at baseline, 6 weeks after this change, and after 6 months were compared. After lowering calcium concentration of the PD fluids – except for the icodextrin 7.5% – from 1.75 mmol/L to 1.25 mmol/L, calcium levels changed from 2.32 ± 0.11 to 2.29 ± 0.12 (p = NS); intact PTH (iPTH) from 39.6 ± 28.3 to 64.9 ± 34.5 pmol/L (p = 0.045); and alkaline phosphatase from 104.13 ± 48.75 to 101.38 ± 32.39 (p = NS). After 6 months, all bone mineral parameters were similar to baseline levels; however, slightly higher calcium-based phosphate binders were prescribed. Lowering calcium content from 1.75 mmol/L to 1.25 mmol/L in PD fluids in patients on icodextrin resulted in stable calcium values, a temporal increase in iPTH and a modest increase in calcium-based phosphate binder prescription. Using icodextrin for the long once-daily dwell appears to attenuate the effects on bone mineral parameters when lowering the calcium concentration of the short dwells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several investigators have reported discrepancies between the bromocresol-purple (BCP), bromocresol-green (BCG) and immunonephelometric (INP) assays in dialysis patients. This study compared the abovementioned assays and investigated whether hemodialysis itself or carbamylation of albumin is the cause for this discrepancy. Methods: Samples obtained from hemodialysis patients were analyzed by BCP, BCG and INP. Furthermore, albumin was carbamylated in vitro using isocyanate. Isocyanate converts lysine to homocitrulline. Results: No differences were observed between samples of the pre- and post-hemodialysis groups for BCP. In the control group, BCG averaged 6g/L higher than INP. BCP did not statistically deviate from INP. In the dialysis group BCG averaged 5g/L higher when compared to INP, whereas BCP averaged 2g/L lower. BCP was affected by carbamylation of albumin. BCG and INP measurements were affected to a much lesser extent. Homocitrulline content of hydrolysates was increased in both the carbamylated albumin as well as in the dialysis population. Conclusion: In a hemodialysis population albumin concentrations are not consistently estimated by both BCG and BCP methods. Relative to INP measurements BCG overestimates the albumin concentration (4–10g/L), whereas BCP leads to an underestimation (0–4g/L). Carbamylation of albumin is the main attributor to the discrepancy found with BCP. [Copyright &y& Elsevier]

We describe the characterization of a new hemoglobin (Hb) variant found in a 77-year-old Dutch woman, suspected of hypoxia-mediated erythrocytosis. The typical blood parameters (Hb 17.3 g/dL; PCV 0.525 L/L; RBC 5.82 × 1012/L) could not be explained by any of the pathological or physiological conditions causing erythrocytosis. The patient was preventively phlebotomized because of intermittent claudication and erythrocytosis. At the hematological and biochemical levels, no anemia or hemolysis were present and no abnormal Hb fractions were detectable on alkaline electrophoresis or high performance liquid chromatography (HPLC). Molecular analysis revealed intact α-globin genes and a heterozygosity for a GTI→GCT transition at codon 23 of the β-globin gene, causing a Val→Ala amino acid substitution. The P50 measured in full blood indicated that this mutant has an elevated oxygen affinity. This is the fourth single nucleotide substitution at codon 23 of the β gene and the second associated with erythrocytosis. Because the family was not available for investigation no information was obtained as to whether the mutation represents a de novo event or was inherited, and might be a more common cause of erythrocytosis in Dutch patients. Considering the relatively high frequency of β-thalassemia (thal) in the large allochthonous population in The Netherlands, combinations of Hb Zoeterwoude and β-thal traits may lead to hemizygosity, with severe hypoxia and erythrocytosis from a few months after birth. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) has been recognized as a highly prevalent risk factor for both the severity of coronavirus disease 2019 (COVID-19) and COVID-19 associated adverse outcomes. In this multicenter observational cohort study, we aim to determine mortality and readmission rates of patients hospitalized for COVID-19 across varying CKD stages. We performed a multicenter cohort study among COVID-19 patients included in the Dutch COVIDPredict cohort. The cohort consists of hospitalized patients from March 2020 until July 2021 with PCR-confirmed SARS-CoV-2 infection or a highly suspected CT scan-based infection with a CORADS score ≥ 4. A total of 4151 hospitalized COVID-19 patients were included of who 389 had a history of CKD before admission. After adjusting for all confounding covariables, in patients with CKD stage 3a, stage 3b, stage 4 and patients with KTX (kidney transplantation), odds ratios of death and readmission compared to patients without CKD ranged from 1.96 to 8.94. We demonstrate an evident increased 12-week mortality and readmission rate in patients with chronic kidney disease. Besides justified concerns for kidney transplant patients, clinicians should also be aware of more severe COVID-19 outcomes and increased vulnerability in CKD patients. [ABSTRACT FROM AUTHOR]

Background: Patients with end-stage renal disease who are undergoing dialysis are reported to be at high risk of sudden cardiac death (SCD), and to date, no therapy has been shown to be effective in reducing this risk. The feasibility and value of prophylactic implantable cardioverter-defibrillator (ICD) implantation to prevent SCD is uncertain.Methods: We conducted the ICD2 trial (Implantable Cardioverter-Defibrillator in Dialysis Patients), a prospective, randomized, controlled study investigating the value and safety of ICD implantation to prevent SCD in 200 patients on dialysis with a left ventricular ejection fraction ≥35%, after adequate screening and optimization of other treatments. The primary end point was SCD. Secondary end points were all-cause mortality and ICD-related complications.Results: The trial was stopped as per the recommendation of the data and safety monitoring board for futility reasons after inclusion of 188 patients, 97 in the ICD group and 91 in the control group. The median duration of follow-up was 6.8 years (interquartile range, 3.8-8.8 years). SCD occurred in 19 of 188 cases (10.1%), 11 of 97 in the ICD group and 8 of 91 in the control group. The cumulative SCD incidence at 5 years was 9.7% (95% CI, 3.3%-16.2%) in the ICD group and 7.9% (95% CI, 1.7-14.0%) in the control group, resulting in a hazard ratio of 1.32 (95% CI, 0.53-3.29; P=0.55). Overall, 99 of 188 patients died (52.7%), 52 in the ICD group and 47 in the control group. Five-year survival probability was 50.6% (95% CI, 39.8%-61.5%) in the ICD group and 54.5% (95% CI, 43.0-66.0%) in the control group, resulting in a hazard ratio of 1.02 (95% CI, 0.69-1.52; P=0.92). Among 80 patients who received an ICD, 25 adverse events related to ICD implantation occurred.Conclusions: In a well-screened and well-treated population undergoing dialysis, prophylactic ICD therapy did not reduce the rate of SCD or all-cause mortality, which remained high.Clinical Trial Registration: URL: http://www.controlled-trials.com . Unique identifier: ISRCTN20479861. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of a young woman who had severe Anti-glomerular basement membrane (GBM) nephritis with high level anti-body titres, going through successful antibody suppression following the addition of rituximab to her therapy.