Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 ...receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.
Cardiorenal syndrome (CRS) type 1 is characterized as the development of acute kidney injury (AKI) and dysfunction in the patient with acute cardiac illness, most commonly acute decompensated heart ...failure (ADHF). There is evidence in the literature supporting multiple pathophysiological mechanisms operating simultaneously and sequentially to result in the clinical syndrome characterized by a rise in serum creatinine, oliguria, diuretic resistance, and in many cases, worsening of ADHF symptoms. The milieu of chronic kidney disease has associated factors including obesity, cachexia, hypertension, diabetes, proteinuria, uremic solute retention, anemia, and repeated subclinical AKI events all work to escalate individual risk of CRS in the setting of ADHF. All of these conditions have been linked to cardiac and renal fibrosis. In the hospitalized patient, hemodynamic changes leading to venous renal congestion, neurohormonal activation, hypothalamic-pituitary stress reaction, inflammation and immune cell signaling, systemic endotoxemic exposure from the gut, superimposed infection, and iatrogenesis all contribute to CRS type 1. The final common pathway of bidirectional organ injury appears to be cellular, tissue, and systemic oxidative stress that exacerbate organ function. This review explores in detail the pathophysiological pathways that put a patient at risk and then effectuate the vicious cycle now recognized as CRS type 1.
It is becoming increasingly clear that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like most human viral infections, will require multiple drugs in combination to treat COVID-19 ...illness. In this issue of the Journal, Doi and colleagues describe successful treatment of patients with early COVID-19 with favipiravir, an oral polymerase inhibitor, to rapidly and substantially clear SARS-CoV-2 from nasal secretions irrespective if it was started relatively early or later within the first week of infection. These data support the concept that favipiravir could be paired with at least one more off-target antiviral agent (doxycycline, azithromycin, or ivermectin) followed by corticosteroids and antithrombotics to prevent COVID-19 hospitalization and death in those over age 50 and/or those with one or more comorbidities. Clinical trials and advanced practice should immediately pivot to combination/sequential drug therapy for ambulatory COVID-19 illness.
The mRNA SARS-CoV-2 vaccines were brought to market in response to the public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease has no precedent. The ...many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein. However, the immune response to the vaccine is very different from that to a SARS-CoV-2 infection. In this paper, we present evidence that vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. Immune cells that have taken up the vaccine nanoparticles release into circulation large numbers of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell's palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis. We show evidence from the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines questions them as positive contributors to public health.
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•mRNA vaccines promote sustained synthesis of the SARS-CoV-2 spike protein.•The spike protein is neurotoxic, and it impairs DNA repair mechanisms.•Suppression of type I interferon responses results in impaired innate immunity.•The mRNA vaccines potentially cause increased risk to infectious diseases and cancer.•Codon optimization results in G-rich mRNA that has unpredictable complex effects.
Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other ...organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.
Cardiorenal Syndrome Type 1 Ronco, Claudio, MD; Cicoira, Mariantonietta, MD; McCullough, Peter A., MD, MPH
Journal of the American College of Cardiology,
09/2012, Letnik:
60, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Cardiorenal syndrome (CRS) type 1 is characterized as the development of acute kidney injury (AKI) and dysfunction in the patient with acute cardiac illness, most commonly acute decompensated heart ...failure (ADHF). There is evidence in the literature supporting multiple pathophysiological mechanisms operating simultaneously and sequentially to result in the clinical syndrome characterized by a rise in serum creatinine, oliguria, diuretic resistance, and in many cases, worsening of ADHF symptoms. The milieu of chronic kidney disease has associated factors including obesity, cachexia, hypertension, diabetes, proteinuria, uremic solute retention, anemia, and repeated subclinical AKI events all work to escalate individual risk of CRS in the setting of ADHF. All of these conditions have been linked to cardiac and renal fibrosis. In the hospitalized patient, hemodynamic changes leading to venous renal congestion, neurohormonal activation, hypothalamic-pituitary stress reaction, inflammation and immune cell signaling, systemic endotoxemic exposure from the gut, superimposed infection, and iatrogenesis all contribute to CRS type 1. The final common pathway of bidirectional organ injury appears to be cellular, tissue, and systemic oxidative stress that exacerbate organ function. This review explores in detail the pathophysiological pathways that put a patient at risk and then effectuate the vicious cycle now recognized as CRS type 1.
In this study, patients with type 2 diabetes, albuminuria, and mild-to-moderate renal dysfunction received losartan followed by lisinopril or placebo. The study was stopped early because of increased ...risks of hyperkalemia and acute kidney injury with combination therapy.
Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in the United States.
1
Persons with diabetes and proteinuria are at high risk for progression to ESRD.
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Blockade of the renin–angiotensin system decreases the progression of proteinuric kidney disease,
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–
5
and the degree of reduction in proteinuria correlates with the extent to which the decrease in the glomerular filtration rate (GFR) is slowed.
2
,
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Given these observations, it has been hypothesized that interventions that further lower proteinuria will further reduce the risk of progression.
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Combination therapy with an angiotensin-converting–enzyme (ACE) inhibitor and an angiotensin II–receptor blocker (ARB) results in . . .
Heart failure (HF) is a major comorbidity in patients with end-stage kidney disease (ESKD). The pathogenesis of HF in patients on renal replacement therapy represents the confluence of several ...traditional and nontraditional vascular risk factors, unique to the milieu of chronic kidney disease and the dialysis modality. The diagnosis of HF with ESKD is complicated by the background of frequent inevitable fluid shifts superimposed on underlying myocardial pump abnormalities and dialysis-induced myocardial stunning. A careful temporal assessment of symptoms and physical findings, cardiac imaging, hemodynamic data, and biomarkers help establish an accurate diagnosis of HF in ESKD. Accurate volume assessment and its tight management remains the cornerstone of treatment in HF in patients on dialysis. A multidisciplinary approach between the cardiologist and nephrologist in optimizing pharmacologic strategies for HF in this population, and dialysis-based options such as frequent dialysis, may help reduce the burden of HF in this vulnerable population. Finally, including patients with ESKD in clinical trials for HF therapies, and designing pragmatic trials that bring targeted strategies for HF into the daily clinical practice of dialysis, will shed light on the optimal management of the dual burden of cardiomyopathy and advanced kidney disease.
Arterial Stiffness in the Heart Disease of CKD Zanoli, Luca; Lentini, Paolo; Briet, Marie ...
Journal of the American Society of Nephrology,
06/2019, Letnik:
30, Številka:
6
Journal Article
Recenzirano
Odprti dostop
CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the ...pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (
, uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.
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