COVID-19 Pandemic Waves and Mortality Among Patients on Kidney Replacement Therapy

COVID-19; Dialysis; MortalityCOVID-19; Diálisis: MortalidadCOVID-19; Diàlisi; MortalitatThis work was supported with unrestricted grants from European Renal Association (ERA), Nierstichting (Dutch Kidney Foundation), Baxter, and Sandoz unrestricted research grants

Pitfalls when comparing COVID-19-related outcomes across studies-lessons learnt from the ERACODA collaboration

Reported outcomes, such as incidence rates of mortality and intensive care unit admission, vary widely across epidemiological coronavirus disease 2019 (COVID-19) studies, including in the nephrology field. This variation can in part be explained by differences in patient characteristics, but also methodological aspects must be considered. In this review, we reflect on the methodological factors that contribute to the observed variation in COVID-19-related outcomes and their risk factors that are identified in the various studies. We focus on issues that arose during the design and analysis phase of the European Renal Association COVID-19 Database (ERACODA), and use examples from recently published reports on COVID-19 to illustrate these issues

Relationship of Serum Inflammatory Biomarkers With Plaque Inflammation Assessed by FDG PET/CT The dal-PLAQUE Study

ObjectivesThis study sought to longitudinally investigate the relationship between a broad spectrum of serum inflammatory biomarkers and plaque inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).BackgroundBoth plaque inflammation and serum biomarkers of inflammation are associated with atherothrombotic events; however, the relationship between them is unclear.MethodsWe conducted a post hoc analysis of the dal-PLAQUE (A Randomized Placebo-Controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors), a randomized, placebo-controlled study of dalcetrapib, a cholesteryl ester transfer protein inhibitor, in 130 patients with coronary heart disease, or coronary heart disease risk equivalents on stable lipid-lowering therapy. Baseline and change after 3-month follow-up in inflammatory biomarker levels and baseline and change after 3-month follow-up in aorta and carotid 18F-FDG PET/CT (mean maximum target-to-background ratio of the most diseased segment [TBRmds]) were analyzed.ResultsBaseline myeloperoxidase positively correlated with baseline carotid TBRmds (rho = 0.25, p = 0.02). This correlation remained at the 3-month follow-up and was independent of traditional cardiovascular disease risk factors. Baseline lipoprotein-associated phospholipase A2 mass correlated with aorta TBRmds (rho = 0.21, p = 0.03). However, this correlation disappeared at the 3-month follow-up and was not independent of cardiovascular disease risk factors. There was no association between change from baseline in myeloperoxidase or lipoprotein-associated phospholipase A2 mass and change from baseline in aorta and carotid TBRmds. Baseline and change from baseline in high sensitivity C-reactive protein, interleukin 6, soluble P-selectin, soluble E-selectin, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and matrix-metalloproteinase 3 and 9 did not correlate with baseline or change from baseline in carotid or aorta TBRmds.ConclusionsOur data show that, in patients with coronary heart disease or at high risk of coronary heart disease on stable lipid-lowering therapy, circulating myeloperoxidase levels are associated with carotid plaque inflammation. (A Randomized, Placebo-controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors [dal-PLAQUE]; NCT00655473

Sex differences in COVID-19 mortality risk in patients on kidney function replacement therapy

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A Statin-Loaded Reconstituted High-Density Lipoprotein Nanoparticle Inhibits Atherosclerotic Plaque Inflammation

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation

Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs

Acid ceramidase regulates innate immune memory

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.</p

Acid ceramidase regulates innate immune memory

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.</p