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Boroojerdi MH, Al Jabry T, Mirarefin SMJ, Albalushi H. Insights into organoid-based modeling of COVID-19 pathology. Virol J 2023; 20:37. [PMID: 36841795 PMCID: PMC9959938 DOI: 10.1186/s12985-023-01996-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 02/20/2023] [Indexed: 02/27/2023] Open
Abstract
Since December 2019, various types of strategies have been applied due to the emergent need to investigate the biology and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to discover a functional treatment. Different disease modeling systems, such as mini-organ technology, have been used to improve our understanding of SARS-CoV-2 physiology and pathology. During the past 2 years, regenerative medicine research has shown the supportive role of organoid modeling in controlling coronavirus disease 2019 (COVID-19) through optimal drug and therapeutic approach improvement. Here, we overview some efforts that have been made to study SARS-CoV-2 by mimicking COVID-19 using stem cells. In addition, we summarize a perspective of drug development in COVID-19 treatment via organoid-based studies.
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Affiliation(s)
- Mohadese Hashem Boroojerdi
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Tariq Al Jabry
- Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | | | - Halima Albalushi
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
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2
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Nelson JW, Ortiz-Melo DI, Mattocks NK, Emathinger JM, Prescott J, Xu K, Griffiths RC, Wakasaki R, Piehowski PD, Hutchens MP, Coffman TM, Gurley SB. Soluble ACE2 Is Filtered into the Urine. KIDNEY360 2022; 3:2086-2094. [PMID: 36591353 PMCID: PMC9802553 DOI: 10.34067/kid.0001622022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/01/2022] [Indexed: 02/01/2023]
Abstract
Background ACE2 is a key enzyme in the renin-angiotensin system (RAS) capable of balancing the RAS by metabolizing angiotensin II (AngII). First described in cardiac tissue, abundance of ACE2 is highest in the kidney, and it is also expressed in several extrarenal tissues. Previously, we reported an association between enhanced susceptibility to hypertension and elevated renal AngII levels in global ACE2-knockout mice. Methods To examine the effect of ACE2 expressed in the kidney, relative to extrarenal expression, on the development of hypertension, we used a kidney crosstransplantation strategy with ACE2-KO and WT mice. In this model, both native kidneys are removed and renal function is provided entirely by the transplanted kidney, such that four experimental groups with restricted ACE2 expression are generated: WT→WT (WT), KO→WT (KidneyKO), WT→KO (SystemicKO), and KO→KO (TotalKO). Additionally, we used nanoscale mass spectrometry-based proteomics to identify ACE2 fragments in early glomerular filtrate of mice. Results Although significant differences in BP were not detected, a major finding of our study is that shed or soluble ACE2 (sACE2) was present in urine of KidneyKO mice that lack renal ACE2 expression. Detection of sACE2 in the urine of KidneyKO mice during AngII-mediated hypertension suggests that sACE2 originating from extrarenal tissues can reach the kidney and be excreted in urine. To confirm glomerular filtration of ACE2, we used micropuncture and nanoscale proteomics to detect peptides derived from ACE2 in the Bowman's space. Conclusions Our findings suggest that both systemic and renal tissues may contribute to sACE2 in urine, identifying the kidney as a major site for ACE2 actions. Moreover, filtration of sACE2 into the lumen of the nephron may contribute to the pathophysiology of kidney diseases characterized by disruption of the glomerular filtration barrier.
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Affiliation(s)
- Jonathan W. Nelson
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon
| | - David I. Ortiz-Melo
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Natalie K. Mattocks
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Jacqueline M. Emathinger
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Jessica Prescott
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Katherine Xu
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Robert C. Griffiths
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
| | - Rumie Wakasaki
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon
| | - Paul D. Piehowski
- Environmental and Biological Services Division, Pacific Northwest National Laboratory, Richland, Washington
| | - Michael P. Hutchens
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon
| | - Thomas M. Coffman
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
- Program in Cardiovascular and Metabolic Disorders, Duke–NUS Medical School, Singapore
| | - Susan B. Gurley
- Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon
- Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina
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Savedchuk S, Raslan R, Nystrom S, Sparks MA. Emerging Viral Infections and the Potential Impact on Hypertension, Cardiovascular Disease, and Kidney Disease. Circ Res 2022; 130:1618-1641. [PMID: 35549373 DOI: 10.1161/circresaha.122.320873] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world's population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.
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Affiliation(s)
- Solomiia Savedchuk
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
| | - Rasha Raslan
- Internal Medicine, Virginia Commonwealth University, Richmond (R.R.)
| | - Sarah Nystrom
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S., S.N., M.A.S.)
- Renal Section, Durham VA Health Care System, NC (M.A.S.)
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4
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Hollenberg MD, Epstein M. The innate immune response, microenvironment proteinases, and the COVID-19 pandemic: pathophysiologic mechanisms and emerging therapeutic targets. Kidney Int Suppl (2011) 2022; 12:48-62. [PMID: 35316977 PMCID: PMC8931295 DOI: 10.1016/j.kisu.2021.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/19/2021] [Accepted: 12/11/2021] [Indexed: 12/13/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, causing considerable mortality and morbidity worldwide, has fully engaged the biomedical community in attempts to elucidate the pathophysiology of COVID-19 and develop robust therapeutic strategies. To this end, the predominant research focus has been on the adaptive immune response to COVID-19 infections stimulated by mRNA and protein vaccines and on the duration and persistence of immune protection. In contrast, the role of the innate immune response to the viral challenge has been underrepresented. This overview focuses on the innate immune response to COVID-19 infection, with an emphasis on the roles of extracellular proteases in the tissue microenvironment. Proteinase-mediated signaling caused by enzymes in the extracellular microenvironment occurs upstream of the increased production of inflammatory cytokines that mediate COVID-19 pathology. These enzymes include the coagulation cascade, kinin-generating plasma kallikrein, and the complement system, as well as angiotensin-generating proteinases of the renin-angiotensin system. Furthermore, in the context of several articles in this Supplement elucidating and detailing the trajectory of diverse profibrotic pathways, we extrapolate these insights to explore how fibrosis and profibrotic pathways participate importantly in the pathogenesis of COVID-19. We propose that the lessons garnered from understanding the roles of microenvironment proteinases in triggering the innate immune response to COVID-19 pathology will identify potential therapeutic targets and inform approaches to the clinical management of COVID-19. Furthermore, the information may also provide a template for understanding the determinants of COVID-19-induced tissue fibrosis that may follow resolution of acute infection (so-called "long COVID"), which represents a major new challenge to our healthcare systems.
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Affiliation(s)
- Morley D. Hollenberg
- Inflammation Research Network–Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Murray Epstein
- Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida, USA
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Abstract
Patients with kidney disease are particularly vulnerable to COVID-19. In 2021, key studies demonstrated the safety of renin–angiotensin blockade in patients with kidney failure and COVID-19, and provided new data on the therapeutic potential of soluble angiotensin-converting enzyme, COVID-19 vaccine responses and the long-term effects of COVID-19 on kidney function. Renin–angiotensin system blockade is not associated with increased risk or severity of COVID-19 among patients with kidney failure3 . A truncated form of human soluble angiotensin-converting enzyme 2 (ACE2) protected kidney organoids from SARS-CoV-2 infection4 ; this protein might be a potential preventive or therapeutic agent for COVID-19. In patients with kidney failure, a third dose of the BNT162b2 COVID-19 vaccine was well tolerated and substantially increased anti-SARS-CoV-2 antibodies8 A proportion of patients (13–35%) experience a decline in estimated glomerular filtration rate in the long term following severe COVID-199 ; thus, COVID-19 should be an indication for kidney disease screening.
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Affiliation(s)
- María José Soler
- Nephrology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain.
| | - Conxita Jacobs-Cachá
- Nephrology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Barcelona, Spain
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6
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Oliveira LCG, Cruz NAN, Ricelli B, Tedesco-Silva H, Medina-Pestana JO, Casarini DE. Interactions amongst inflammation, renin-angiotensin-aldosterone and kallikrein-kinin systems: suggestive approaches for COVID-19 therapy. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20200181. [PMID: 34925477 PMCID: PMC8651214 DOI: 10.1590/1678-9199-jvatitd-2020-0181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/24/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a rapid-spread infectious disease caused by the SARS-CoV-2 virus, which can culminate in the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) systems imbalance, and in serious consequences for infected patients. This scoping review of published research exploring the RAAS and KKS was undertaken in order to trace the history of the discovery of both systems and their multiple interactions, discuss some aspects of the viral-cell interaction, including inflammation and the system imbalance triggered by SARS-CoV-2 infection, and their consequent disorders. Furthermore, we correlate the effects of continued use of the RAAS blockers in chronic diseases therapies with the virulence and physiopathology of COVID-19. We also approach the RAAS and KKS-related proposed potential therapies for treatment of COVID-19. In this way, we reinforce the importance of exploring both systems and the application of their components or their blockers in the treatment of coronavirus disease.
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Affiliation(s)
| | | | - Bruna Ricelli
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
| | - Helio Tedesco-Silva
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
| | - José Osmar Medina-Pestana
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
| | - Dulce Elena Casarini
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil
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7
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Rando HM, Wellhausen N, Ghosh S, Lee AJ, Dattoli AA, Hu F, Byrd JB, Rafizadeh DN, Lordan R, Qi Y, Sun Y, Brueffer C, Field JM, Ben Guebila M, Jadavji NM, Skelly AN, Ramsundar B, Wang J, Goel RR, Park Y, COVID-19 Review Consortium
BansalVikasBartonJohn P.BocaSimina M.BoerckelJoel D.BruefferChristianByrdJames BrianCaponeStephenDasShiktaDattoliAnna AdaDziakJohn J.FieldJeffrey M.GhoshSoumitaGitterAnthonyGoelRishi RajGreeneCasey S.GuebilaMarouen BenHimmelsteinDaniel S.HuFenglingJadavjiNafisa M.KamilJeremy P.KnyazevSergeyKollaLikhithaLeeAlexandra J.LordanRonanLubianaTiagoLukanTemitayoMacLeanAdam L.MaiDavidMangulSergheiManheimDavidMcGowanLucy D’AgostinoNaikAmrutaParkYoSonPerrinDimitriQiYanjunRafizadehDiane N.RamsundarBharathRandoHalie M.RaySandipanRobsonMichael P.RubinettiVincentSellElizabethShinholsterLamonicaSkellyAshwin N.SunYuchenSunYushaSzetoGregory L.VelazquezRyanWangJinhuiWellhausenNils, Boca SM, Gitter A, Greene CS. Identification and Development of Therapeutics for COVID-19. mSystems 2021; 6:e0023321. [PMID: 34726496 PMCID: PMC8562484 DOI: 10.1128/msystems.00233-21] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
After emerging in China in late 2019, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide, and as of mid-2021, it remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a species closely related to SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19). Building on this research, the medical and scientific communities have responded rapidly to the COVID-19 crisis and identified many candidate therapeutics. The approaches used to identify candidates fall into four main categories: adaptation of clinical approaches to diseases with related pathologies, adaptation based on virological properties, adaptation based on host response, and data-driven identification (ID) of candidates based on physical properties or on pharmacological compendia. To date, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA), while most remain under investigation. The scale of the COVID-19 crisis offers a rare opportunity to collect data on the effects of candidate therapeutics. This information provides insight not only into the management of coronavirus diseases but also into the relative success of different approaches to identifying candidate therapeutics against an emerging disease. IMPORTANCE The COVID-19 pandemic is a rapidly evolving crisis. With the worldwide scientific community shifting focus onto the SARS-CoV-2 virus and COVID-19, a large number of possible pharmaceutical approaches for treatment and prevention have been proposed. What was known about each of these potential interventions evolved rapidly throughout 2020 and 2021. This fast-paced area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals. As illustrated by the continued threat of viral epidemics during the current millennium, a rapid and strategic response to emerging viral threats can save lives. In this review, we explore how different modes of identifying candidate therapeutics have borne out during COVID-19.
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Affiliation(s)
- Halie M. Rando
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Health AI, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Nils Wellhausen
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Soumita Ghosh
- Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alexandra J. Lee
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Anna Ada Dattoli
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Fengling Hu
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James Brian Byrd
- University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Diane N. Rafizadeh
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ronan Lordan
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yanjun Qi
- Department of Computer Science, University of Virginia, Charlottesville, Virginia, USA
| | - Yuchen Sun
- Department of Computer Science, University of Virginia, Charlottesville, Virginia, USA
| | | | - Jeffrey M. Field
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Marouen Ben Guebila
- Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Nafisa M. Jadavji
- Biomedical Science, Midwestern University, Glendale, Arizona, USA
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Ashwin N. Skelly
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | | | - Jinhui Wang
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rishi Raj Goel
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - YoSon Park
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - COVID-19 Review Consortium
BansalVikasBartonJohn P.BocaSimina M.BoerckelJoel D.BruefferChristianByrdJames BrianCaponeStephenDasShiktaDattoliAnna AdaDziakJohn J.FieldJeffrey M.GhoshSoumitaGitterAnthonyGoelRishi RajGreeneCasey S.GuebilaMarouen BenHimmelsteinDaniel S.HuFenglingJadavjiNafisa M.KamilJeremy P.KnyazevSergeyKollaLikhithaLeeAlexandra J.LordanRonanLubianaTiagoLukanTemitayoMacLeanAdam L.MaiDavidMangulSergheiManheimDavidMcGowanLucy D’AgostinoNaikAmrutaParkYoSonPerrinDimitriQiYanjunRafizadehDiane N.RamsundarBharathRandoHalie M.RaySandipanRobsonMichael P.RubinettiVincentSellElizabethShinholsterLamonicaSkellyAshwin N.SunYuchenSunYushaSzetoGregory L.VelazquezRyanWangJinhuiWellhausenNils
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Health AI, University of Colorado School of Medicine, Aurora, Colorado, USA
- Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- University of Michigan School of Medicine, Ann Arbor, Michigan, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Computer Science, University of Virginia, Charlottesville, Virginia, USA
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
- Biomedical Science, Midwestern University, Glendale, Arizona, USA
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- The DeepChem Project
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA
- Early Biometrics & Statistical Innovation, Data Science & Artificial Intelligence, R & D, AstraZeneca, Gaithersburg, Maryland, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin—Madison, Madison, Wisconsin, USA
- Morgridge Institute for Research, Madison, Wisconsin, USA
- Childhood Cancer Data Lab, Alex’s Lemonade Stand Foundation, Philadelphia, Pennsylvania, USA
| | - Simina M. Boca
- Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA
- Early Biometrics & Statistical Innovation, Data Science & Artificial Intelligence, R & D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Anthony Gitter
- Department of Biostatistics and Medical Informatics, University of Wisconsin—Madison, Madison, Wisconsin, USA
- Morgridge Institute for Research, Madison, Wisconsin, USA
| | - Casey S. Greene
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, USA
- Center for Health AI, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Childhood Cancer Data Lab, Alex’s Lemonade Stand Foundation, Philadelphia, Pennsylvania, USA
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Pazoki M, Chichagi F, Hadadi A, Kafan S, Montazeri M, Kazemian S, Aminorroaya A, Ebrahimi M, Ashraf H, Hazaveh MM, Khajavi MR, Moharari RS, Sharifnia SH, Saleh SK, Rahimzadeh H, Goodarzi N, Heydarian P. Association of clinical characteristics, antidiabetic and cardiovascular agents with diabetes mellitus and COVID-19: a 7-month follow-up cohort study. J Diabetes Metab Disord 2021; 20:1545-1555. [PMID: 34778117 PMCID: PMC8573568 DOI: 10.1007/s40200-021-00901-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 09/13/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND The prognostic factors of long-term outcomes in hospitalized patients with diabetes mellitus and COVID-19 are lacking. METHODS In this retrospective cohort study, we evaluated patients aged ≥ 18-years-old with the COVID-19 diagnosis who were hospitalized between Feb 20 and Oct 29, 2020, in the Sina Hospital, Tehran, Iran. 1323 patients with COVID-19 entered in the final analysis, of whom 393 (29.7%) patients had diabetes. We followed up patients for incurring in-hospital death, severe COVID-19, in-hospital complications, and 7-month all-cause mortality. By doing univariate analysis, variables with unadjusted P-value < 0.1 in univariate analyses were regarded as the confounders to include in the logistic regression models. We made adjustments for possible clinical (model 1) and both clinical and laboratory (model 2) confounders. RESULTS After multivariable regression, it was revealed that preadmission use of sulfonylureas was associated with a borderline increased risk of severity in both models [model 1, OR (95% CI):1.83 (0.91-3.71), P-value: 0.092; model 2, 2.05 (0.87-4.79), P-value: 0.099] and major adverse events (MAE: each of the severe COVID-19, multi-organ damage, or in-hospital mortality) in model 1 [OR (95% CI): 1.86 (0.90-3.87), P-value: 0.094]. Preadmission use of ACEIs/ARBs was associated with borderline increased risk of MAE in the only model 1 [OR (95% CI):1.83 (0.96-3.48), P-value: 0.066]. CONCLUSIONS Preadmission use of sulfonylureas and ACEIs/ARBs were associated with borderline increased risk of in-hospital adverse outcomes. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s40200-021-00901-4.
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Affiliation(s)
- Marzieh Pazoki
- Department of Pulmonary Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Chichagi
- Research Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Azar Hadadi
- Department of Infectious Diseases, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Kafan
- Department of Pulmonary Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Montazeri
- Department of Infectious Diseases, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Kazemian
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center (CPPRC), Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Arya Aminorroaya
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Ebrahimi
- Department of Internal Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Ashraf
- Research Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center (CPPRC), Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Reza Khajavi
- Department of Anesthesiology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shariat Moharari
- Department of Anesthesiology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Shahrokh Karbalai Saleh
- Department of Cardiology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hormat Rahimzadeh
- Department of Internal Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Goodarzi
- Research Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Peimaneh Heydarian
- Department of Internal Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Department of Endocrinology and Metabolism, Sina Hospital, Tehran University of Medical Sciences, Hasan Abad Sq., Tehran, 11367-46911 Iran
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9
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Freundlich M, Gamba G, Rodriguez-Iturbe B. Fibroblast growth factor 23-Klotho and hypertension: experimental and clinical mechanisms. Pediatr Nephrol 2021; 36:3007-3022. [PMID: 33230698 PMCID: PMC7682775 DOI: 10.1007/s00467-020-04843-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 10/07/2020] [Accepted: 10/23/2020] [Indexed: 12/11/2022]
Abstract
Hypertension (HTN) and chronic kidney disease (CKD) are increasingly recognized in pediatric patients and represent risk factors for cardiovascular morbidity and mortality later in life. In CKD, enhanced tubular sodium reabsorption is a leading cause of HTN due to augmented extracellular fluid volume expansion. The renin-angiotensin-aldosterone system (RAAS) upregulates various tubular sodium cotransporters that are also targets of the hormone fibroblast growth factor 23 (FGF23) and its co-receptor Klotho. FGF23 inhibits the activation of 1,25-dihydroxyvitamin D that is a potent suppressor of renin biosynthesis. Here we review the complex interactions and disturbances of the FGF23-Klotho axis, vitamin D, and the RAAS relevant to blood pressure regulation and discuss the therapeutic strategies aimed at mitigating their pathophysiologic contributions to HTN.
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Affiliation(s)
- Michael Freundlich
- Department of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Gerardo Gamba
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Bernardo Rodriguez-Iturbe
- Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
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10
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Touyz RM, Boyd MO, Guzik T, Padmanabhan S, McCallum L, Delles C, Mark PB, Petrie JR, Rios F, Montezano AC, Sykes R, Berry C. Cardiovascular and Renal Risk Factors and Complications Associated With COVID-19. CJC Open 2021; 3:1257-1272. [PMID: 34151246 PMCID: PMC8205551 DOI: 10.1016/j.cjco.2021.05.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 05/28/2021] [Indexed: 01/08/2023] Open
Abstract
The current COVID-19 pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus, represents the largest medical challenge in decades. It has exposed unexpected cardiovascular vulnerabilities at all stages of the disease (pre-infection, acute phase, and subsequent chronic phase). The major cardiometabolic drivers identified as having epidemiologic and mechanistic associations with COVID-19 are abnormal adiposity, dysglycemia, dyslipidemia, and hypertension. Hypertension is of particular interest, because components of the renin-angiotensin system (RAS), which are critically involved in the pathophysiology of hypertension, are also implicated in COVID-19. Specifically, angiotensin-converting enzyme-2 (ACE2), a multifunctional protein of the RAS, which is part of the protective axis of the RAS, is also the receptor through which SARS-CoV-2 enters host cells, causing viral infection. Cardiovascular and cardiometabolic comorbidities not only predispose people to COVID-19, but also are complications of SARS-CoV-2 infection. In addition, increasing evidence indicates that acute kidney injury is common in COVID-19, occurs early and in temporal association with respiratory failure, and is associated with poor prognosis, especially in the presence of cardiovascular risk factors. Here, we discuss cardiovascular and kidney disease in the context of COVID-19 and provide recent advances on putative pathophysiological mechanisms linking cardiovascular disease and COVID-19, focusing on the RAS and ACE2, as well as the immune system and inflammation. We provide up-to-date information on the relationships among hypertension, diabetes, and COVID-19 and emphasize the major cardiovascular diseases associated with COVID-19. We also briefly discuss emerging cardiovascular complications associated with long COVID-19, notably postural tachycardia syndrome (POTS).
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Affiliation(s)
- Rhian M. Touyz
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Marcus O.E. Boyd
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Tomasz Guzik
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Sandosh Padmanabhan
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Linsay McCallum
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Christian Delles
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Patrick B. Mark
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - John R. Petrie
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Francisco Rios
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Augusto C. Montezano
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Robert Sykes
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Colin Berry
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
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11
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Soler MJ, Ribera A, Marsal JR, Mendez AB, Andres M, Azancot MA, Oristrell G, Méndez-Boo L, Cohen J, Barrabés JA, Ferreira-González I. Association of renin–angiotensin system blockers with COVID-19 diagnosis and prognosis in patients with hypertension: a population-based study. Clin Kidney J 2021; 15:79-94. [PMID: 35035939 PMCID: PMC8499934 DOI: 10.1093/ckj/sfab161] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
The effect of renin–angiotensin system (RAS) blockade either by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) susceptibility, mortality and severity is inadequately described. We examined the association between RAS blockade and COVID-19 diagnosis and prognosis in a large population-based cohort of patients with hypertension (HTN).
Methods
This is a cohort study using regional health records. We identified all individuals aged 18–95 years from 87 healthcare reference areas of the main health provider in Catalonia (Spain), with a history of HTN from primary care records. Data were linked to COVID-19 test results, hospital, pharmacy and mortality records from 1 March 2020 to 14 August 2020. We defined exposure to RAS blockers as the dispensation of ACEi/ARBs during the 3 months before COVID-19 diagnosis or 1 March 2020. Primary outcomes were: COVID-19 infection and severe progression in hospitalized patients with COVID-19 (the composite of need for invasive respiratory support or death). For both outcomes and for each exposure of interest (RAS blockade, ACEi or ARB) we estimated associations in age-, sex-, healthcare area- and propensity score-matched samples.
Results
From a cohort of 1 365 215 inhabitants we identified 305 972 patients with HTN history. Recent use of ACEi/ARBs in patients with HTN was associated with a lower 6-month cumulative incidence of COVID-19 diagnosis {3.78% [95% confidence interval (CI) 3.69–3.86%] versus 4.53% (95% CI 4.40–4.65%); P < 0.001}. In the 12 344 patients with COVID-19 infection, the use of ACEi/ARBs was not associated with a higher risk of hospitalization with need for invasive respiratory support or death [OR = 0.91 (0.71–1.15); P = 0.426].
Conclusions
RAS blockade in patients with HTN is not associated with higher risk of COVID-19 infection or with a worse progression of the disease.
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Affiliation(s)
- María José Soler
- Department of Nephrology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
| | - Aida Ribera
- Department of Cardiology, Cardiovascular Epidemiology Unit, Vall d’Hebron University Hospital Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Josep R Marsal
- Department of Cardiology, Cardiovascular Epidemiology Unit, Vall d’Hebron University Hospital Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Ana Belen Mendez
- Department of Cardiology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
| | - Mireia Andres
- Department of Cardiology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Maria Antonia Azancot
- Department of Nephrology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
| | - Gerard Oristrell
- Department of Cardiology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
| | - Leonardo Méndez-Boo
- Departament de Salut, SISAP: Sistema d′Informació dels Serveis d′Atenció Primària, Direcció de Sistemes d′Informació, Institut Català de la Salut, Generalitat de Catalunya, Barcelona, Spain
| | - Jordana Cohen
- Division of Renal-Electrolyte and Hypertension, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA
| | - Jose A Barrabés
- Department of Cardiology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Ignacio Ferreira-González
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Cardiology, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
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12
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Shimmel A, Shaikhouni S, Mariani L. Current Understanding of Clinical Manifestations of COVID-19 in Glomerular Disease. GLOMERULAR DISEASES 2021; 1:250-264. [PMID: 36747902 PMCID: PMC8450860 DOI: 10.1159/000518276] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 06/26/2021] [Indexed: 12/15/2022]
Abstract
Background The novel coronavirus disease (COVID-19), also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an evolving pandemic with significant mortality. Information about the impact of infection on glomerular disease patients in particular has been lacking. Understanding the virus's effect in glomerular disease is constantly changing. This review article summarizes the data published thus far on COVID-19 and its manifestations in pre-existing and de novo glomerular disease. Summary While patients with glomerular disease may be at higher risk of severe COVID-19 due to their immunosuppressed status, some data suggest that a low amount of immunosuppression may be helpful in mitigating the systemic inflammatory response which is associated with high mortality rates in COVID-19. There have been a few case reports on COVID-19 causing glomerular disease relapse in patients. Multiple mechanisms have been proposed for kidney injury, proteinuria, and hematuria in the setting of COVID-19. More commonly, these are caused by direct tubular injury due to hemodynamic instability and hypoxic injury. However, the cytokine storm induced by COVID-19 may trigger common post-viral glomerular disease such as IgA nephropathy, anti-GBM, and ANCA vasculitis that have also been described in COVID-19 patients. Collapsing glomerulopathy, a hallmark of HIV-associated nephropathy, is being reported SARS-CoV-2 cases, particularly in patients with high-risk APOL1 alleles. Direct viral invasion of glomerular structures is hypothesized to cause a podocytopathy due to virus's affinity to ACE2, but evidence for this remains under study. Key Messages Infection with SARS-CoV-2 may cause glomerular disease in certain patients. The mechanism of de novo glomerular disease in the setting of COVID-19 is under study. The management of patients with existing glomerular disease poses unique challenges, especially with regard to immunosuppression management. Further studies are needed to inform clinician decisions about the management of these patients during the COVID-19 pandemic.
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Affiliation(s)
- Allison Shimmel
- College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA
| | - Salma Shaikhouni
- Department of Nephrology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Laura Mariani
- Department of Nephrology, Michigan Medicine, Ann Arbor, Michigan, USA,*Laura Mariani,
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13
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Soler MJ, Noordzij M, Abramowicz D, de Arriba G, Basile C, van Buren M, Covic A, Crespo M, Duivenvoorden R, Massy ZA, Ortiz A, Sanchez JE, Petridou E, Stevens K, White C, Vart P, Gansevoort RT. Renin-Angiotensin System Blockers and the Risk of COVID-19-Related Mortality in Patients with Kidney Failure. Clin J Am Soc Nephrol 2021; 16:1061-1072. [PMID: 34088718 PMCID: PMC8425613 DOI: 10.2215/cjn.18961220] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 04/02/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVES There is concern about potential deleterious effects of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) in patients with coronavirus disease 2019 (COVID-19). Patients with kidney failure, who often use ACEis/ARBs, are at higher risk of more severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS From the European Renal Association COVID-19 database (ERACODA), we retrieved data on kidney transplant recipients and patients on dialysis who were affected by COVID-19, between February 1 and October 1, 2020, and had information on 28-day mortality. We used Cox proportional-hazards regression to calculate hazard ratios for the association between ACEi/ARB use and 28-day mortality risk. Additionally, we studied the association of discontinuation of these agents with 28-day mortality. RESULTS We evaluated 1511 patients: 459 kidney transplant recipients and 1052 patients on dialysis. At diagnosis of COVID-19, 189 (41%) of the transplant recipients and 288 (27%) of the patients on dialysis were on ACEis/ARBs. A total of 88 (19%) transplant recipients and 244 (23%) patients on dialysis died within 28 days of initial presentation. In both groups of patients, there was no association between ACEi/ARB use and 28-day mortality in both crude and adjusted models (in transplant recipients, adjusted hazard ratio, 1.12; 95% confidence interval [95% CI], 0.69 to 1.83; in patients on dialysis, adjusted hazard ratio, 1.04; 95% CI, 0.73 to 1.47). Among transplant recipients, ACEi/ARB discontinuation was associated with a higher mortality risk after adjustment for demographics and comorbidities, but the association was no longer statistically significant after adjustment for severity of COVID-19 (adjusted hazard ratio, 1.36; 95% CI, 0.40 to 4.58). Among patients on dialysis, ACEi/ARB discontinuation was not associated with mortality in any model. We obtained similar results across subgroups when ACEis and ARBs were studied separately, and when other outcomes for severity of COVID-19 were studied, e.g., hospital admission, admission to the intensive care unit, or need for ventilator support. CONCLUSIONS Among kidney transplant recipients and patients on dialysis with COVID-19, there was no significant association of ACEi/ARB use or discontinuation with mortality.
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Affiliation(s)
- Maria Jose Soler
- Department of Nephrology, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, Vall d’Hebron Barcelona Hospital Campus, Red de Investigación Renal (REDINREN), Barcelona, Spain
| | - Marlies Noordzij
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Daniel Abramowicz
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
| | - Gabriel de Arriba
- Department of Nephrology, University Hospital Guadalajara, University of Alcala, Guadalajara, Spain
| | - Carlo Basile
- Division of Nephrology, Miulli General Hospital, Acquaviva delle Fonti, Italy
| | - Marjolijn van Buren
- Department of Nephrology, University Medical Center Leiden, University of Leiden, Leiden, The Netherlands
- Department of Internal Medicine, Haga Hospital, The Hague, The Netherlands
| | - Adrian Covic
- Grigore T. Popa University of Medicine and Pharmacy, Dr. C.I. Parhon Hospital, Iasi, Romania
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Mar Institute for Medical Research, Red de Investigación Renal (REDINREN) (RD16/0009/0013), Barcelona, Spain
| | - Raphaël Duivenvoorden
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ziad A. Massy
- Department of Nephrology, Centre Hospitalier Universitaire (CHU) Ambroise Paré, Assistance Publique–Hôpitaux de Paris (AP-HP), Boulogne-Billancourt, France
- Centre for Research in Epidemiology and Population Health (CESP), Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1018, Team 5, University Versailles-Saint Quentin, University of Paris Saclay, Villejuif, France
| | - Alberto Ortiz
- Instituto de Investigación Sanitaria (IIS)–Fundación Jiménez Díaz, Autonomous University of Madrid (UAM), Red de Investigación Renal (REDINREN), Madrid, Spain
| | | | - Emily Petridou
- Representative of the European Kidney Patients’ Federation, Nicosia, Cyprus
| | - Kate Stevens
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Colin White
- Representative of the European Kidney Patients’ Federation, Dublin, Ireland
| | - Priya Vart
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Ron T. Gansevoort
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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14
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Rianto F, Sparks MA. Shining More Light on RAS Inhibition during the COVID-19 Pandemic. Clin J Am Soc Nephrol 2021; 16:1002-1004. [PMID: 34597263 PMCID: PMC8425621 DOI: 10.2215/cjn.06000521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 05/03/2021] [Indexed: 02/04/2023]
Affiliation(s)
- Fitra Rianto
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Matthew A. Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Renal Section, Durham Veterans Affairs Health Care System, Durham, North Carolina
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15
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Román JL, García-Carro C, Agraz I, Toapanta N, Vergara A, Gabaldón A, Torres I, Bury R, Baldallo C, Serón D, Soler MJ. COVID-19 in CKD Patients: Lessons from 553 CKD Patients with Biopsy-Proven Kidney Disease. Kidney Blood Press Res 2021; 46:452-459. [PMID: 34098555 PMCID: PMC8247815 DOI: 10.1159/000515714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/07/2021] [Indexed: 11/19/2022] Open
Abstract
Introduction Chronic kidney disease (CKD) patients infected with COVID-19 are at risk of serious complications such as hospitalization and death. The prognosis and lethality of COVID-19 infection in patients with established kidney disease has not been widely studied. Methods Data included patients who underwent kidney biopsy at the Vall d'Hebron Hospital between January 2013 and February 2020 with COVID-19 diagnosis during the period from March 1 to May 15, 2020. Results Thirty-nine (7%) patients were diagnosed with COVID-19 infection. Mean age was 63 ± 15 years and 48.7% were male. Hypertension was present in 79.5%, CKD without renal replacement therapy in 76.9%, and cardiovascular disease in 64.1%. Nasopharyngeal swab was performed in 26 patients; older (p = 0.01), hypertensive (p = 0.005), and immunosuppressed (p = 0.01) patients, those using RAS-blocking drugs (p = 0.04), and those with gastrointestinal symptoms (p = 0.02) were more likely to be tested for COVID-19. Twenty-two patients required hospitalization and 15.4% died. In bivariate analysis, mortality was associated with older age (p = 0.03), cardiovascular disease (p = 0.05), chronic obstructive pulmonary disease (p = 0.05), and low hemoglobin levels (p = 0.006). Adjusted Cox regression showed that low hemoglobin levels at admission had 1.81 greater risk of mortality. Conclusions Patients with COVID-19 infection and kidney disease confirmed by kidney biopsy presented a mortality of 15.4%. Swab test for COVID-19 was more likely to be performed in older, hypertensive, and immunosuppressed patients, those using RAS-blocking drugs, and those with gastrointestinal symptoms. Low hemoglobin is a risk factor for mortality.
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Affiliation(s)
- Juan León Román
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Clara García-Carro
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Irene Agraz
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Nestor Toapanta
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Ander Vergara
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Research Institute (VHIR), Nephrology Department, Nephrology Research Group, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alejandra Gabaldón
- Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Irina Torres
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Roxana Bury
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Cinthia Baldallo
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Daniel Serón
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Research Institute (VHIR), Nephrology Department, Nephrology Research Group, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Instituto Carlos IIIFEDER, Red de Investigación Renal (REDINREN), Madrid, Spain
| | - María José Soler
- Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Research Institute (VHIR), Nephrology Department, Nephrology Research Group, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Instituto Carlos IIIFEDER, Red de Investigación Renal (REDINREN), Madrid, Spain
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16
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Rubin SJS, Falkson SR, Degner NR, Blish CA. Safety of ACE-I and ARB medications in COVID-19: A retrospective cohort study of inpatients and outpatients in California. J Clin Transl Sci 2021; 5:e8. [PMID: 34611496 PMCID: PMC7605244 DOI: 10.1017/cts.2020.489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION There is significant interest in the use of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) in coronavirus disease 2019 (COVID-19) and concern over potential adverse effects since these medications upregulate the severe acute respiratory syndrome coronavirus 2 host cell entry receptor ACE2. Recent studies on ACE-I and ARB in COVID-19 were limited by excluding outpatients, excluding patients by age, analyzing ACE-I and ARB together, imputing missing data, and/or diagnosing COVID-19 by chest computed tomography without definitive reverse transcription polymerase chain reaction (RT-PCR), all of which are addressed here. METHODS We performed a retrospective cohort study of 1023 COVID-19 patients diagnosed by RT-PCR at Stanford Hospital through April 8, 2020 with a minimum follow-up time of 14 days to investigate the association between ACE-I or ARB use with outcomes. RESULTS Use of ACE-I or ARB medications was not associated with increased risk of hospitalization, intensive care unit admission, or death. Compared to patients with charted past medical history, there was a lower risk of hospitalization for patients on ACE-I (odds ratio (OR) 0.43; 95% confidence interval (CI) 0.19-0.97; P = 0.0426) and ARB (OR 0.39; 95% CI 0.17-0.90; P = 0.0270). Compared to patients with hypertension not on ACE-I or ARB, patients on ARB medications had a lower risk of hospitalization (OR 0.09; 95% CI 0.01-0.88; P = 0.0381). CONCLUSIONS These findings suggest that the use of ACE-I and ARB is not associated with adverse outcomes and may be associated with improved outcomes in COVID-19, which is immediately relevant to care of the many patients on these medications.
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Affiliation(s)
- Samuel J. S. Rubin
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Samuel R. Falkson
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Nicholas R. Degner
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Catherine A. Blish
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Chan-Zuckerberg Biohub, San Francisco, CA, USA
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17
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Raghav PK, Kalyanaraman K, Kumar D. Human cell receptors: potential drug targets to combat COVID-19. Amino Acids 2021; 53:813-842. [PMID: 33950300 PMCID: PMC8097256 DOI: 10.1007/s00726-021-02991-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 04/21/2021] [Indexed: 01/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-α subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.
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Affiliation(s)
| | - Keerthana Kalyanaraman
- Amity Institute of Biotechnology, Amity University, Sector-125, Noida, Uttar Pradesh, India
| | - Dinesh Kumar
- ICMR-National Institute of Cancer Prevention & Research, Noida, 201301, India.
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18
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Vergara A, Jacobs-Cachá C, Molina-Van den Bosch M, Domínguez-Báez P, Benito B, García-Carro C, Serón D, Soler MJ. Effect of ramipril on kidney, lung and heart ACE2 in a diabetic mice model. Mol Cell Endocrinol 2021; 529:111263. [PMID: 33811970 PMCID: PMC8010347 DOI: 10.1016/j.mce.2021.111263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/24/2021] [Accepted: 03/24/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19). The main organ affected in this infection is the lung and the virus uses the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the target cells. In this context, a controversy raised regarding the use of renin-angiotensin system (RAAS) blockers, as these drugs might increase ACE2 expression in some tissues and potentially increase the risk for SARS-CoV-2 infection. This is specially concerning in diabetic patients as diabetes is a risk factor for COVID-19. METHODS 12-week old diabetic mice (db/db) were treated with ramipril, or vehicle control for 8 weeks. Non-diabetic db/m mice were included as controls. ACE2 expression and activity were studied in lung, kidney and heart of these animals. RESULTS Kidney ACE2 activity was increased in the db/db mice as compared to the db/m (143.2% ± 23% vs 100% ± 22.3%, p = 0.004), whereas ramipril had no significant effect. In the lung, no differences were found in ACE2 when comparing db/db mice to db/m and ramipril also had no significant effect. In the heart, diabetes decreased ACE2 activity (83% ± 16.8%, vs 100% ± 23.1% p = 0.02), and ramipril increased ACE2 significantly (83% ± 16.8% vs 98.2% ± 15%, p = 0.04). CONCLUSIONS In a mouse model of type 2 diabetes, ramipril had no significant effect on ACE2 activity in either kidneys or in the lungs. Therefore, it is unlikely that RAAS blockers or at least angiotensin-converting enzyme inhibitors increase the risk of SARS-CoV-2 infection through increasing ACE2.
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Affiliation(s)
- Ander Vergara
- Nephrology Department. Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Conxita Jacobs-Cachá
- Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; REDinREN (RD16/0009/0030), Spain.
| | - Mireia Molina-Van den Bosch
- Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Pamela Domínguez-Báez
- Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Begoña Benito
- Cardiology Group, Vall d'Hebrón Research Institute (VHIR), Barcelona, Spain; Cardiology Department, Vall d'Hebrón Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Clara García-Carro
- Nephrology Department. Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; REDinREN (RD16/0009/0030), Spain
| | - Daniel Serón
- Nephrology Department. Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; REDinREN (RD16/0009/0030), Spain
| | - María José Soler
- Nephrology Department. Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Nephrology Research Group, Vall d'Hebrón Research Institute (VHIR), Vall d'Hebrón Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; REDinREN (RD16/0009/0030), Spain.
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19
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Sackin H. Hypothesis for renin-angiotensin inhibitor mitigation of COVID-19. Med Hypotheses 2021; 152:110609. [PMID: 34048987 PMCID: PMC8114589 DOI: 10.1016/j.mehy.2021.110609] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 04/11/2021] [Accepted: 05/09/2021] [Indexed: 11/30/2022]
Abstract
Preexisting hypertension is a known risk factor for severe COVID-19. Abnormal activation of RAS upregulates angiotensin II (Ang-II) and contributes to severe manifestations of COVID-19. Although RAS inhibitors (RASi) are a mainstay of antihypertensive therapy, they have been associated (in some animal studies) with an increase in angiotensin converting enzyme 2 (ACE2) receptors that facilitate cellular entry of the SARS-CoV-2 virus. Nonetheless, current medical practice does not recommend curtailing RASi to protect hypertensive patients from COVID. On the contrary, there is clinical evidence to support a beneficial effect of RASi for hypertensive patients in the midst of a COVID-19 pandemic, although the precise mechanism for this is unclear. In this paper, we hypothesize that RASi reduces the severity of COVID-19 by promoting ACE2-AT1R complex formation at the cell surface, where AT1R mediates the major vasopressor effects of Ang-II. Furthermore, we propose that the interaction between ACE2 and AT1R impedes binding of SARS-CoV-2 to ACE2, thereby allowing ACE2 to convert Ang-II to the more beneficial Ang(1–7), that has vasodilator and anti-inflammatory activity. Evidence for ACE2-AT1R complex formation during reduced Ang-II comes from receptor colocalization studies in isolated HEK293 cells, but this has not been confirmed in cells having endogenous expression of ACE2 and AT1R. Since the SARS-CoV-2 virus attacks the kidney, as well as the heart and lung, our hypothesis for the effect of RASi on COVID-19 could be tested in vitro using human proximal tubule cells (HK-2), having ACE2 and AT1 receptors. Specifically, colocalization of fluorescent labelled: SARS-CoV-2 spike protein, ACE2, and AT1R in HK-2 cells can be used to clarify the mechanism of RASi action in renal and lung epithelia, which could lead to protocols for reducing the severity of COVID-19 in both hypertensive and normotensive patients.
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Affiliation(s)
- Henry Sackin
- Department of Physiology and Biophysics & Center for Proteomics and Molecular Therapeutics, The Chicago Medical School, Rosalind Franklin University, North Chicago, IL, United States.
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20
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Derington CG, Cohen JB, Mohanty AF, Greene TH, Cook J, Ying J, Wei G, Herrick JS, Stevens VW, Jones BE, Wang L, Zheutlin AR, South AM, Hanff TC, Smith SM, Cooper-DeHoff RM, King JB, Alexander GC, Berlowitz DR, Ahmad FS, Penrod MJ, Hess R, Conroy MB, Fang JC, Rubin MA, Beddhu S, Cheung AK, Xian W, Weintraub WS, Bress AP. Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans. PLoS One 2021; 16:e0248080. [PMID: 33891615 PMCID: PMC8064574 DOI: 10.1371/journal.pone.0248080] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/19/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses. METHODS AND FINDINGS In this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73-0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86-0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30-5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93-1.38, median follow-up 30 days). CONCLUSIONS This observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials.
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Affiliation(s)
- Catherine G. Derington
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Jordana B. Cohen
- Department of Medicine, Renal-Electrolyte and Hypertension Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America
| | - April F. Mohanty
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Tom H. Greene
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - James Cook
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Jian Ying
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
| | - Guo Wei
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
| | - Jennifer S. Herrick
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
| | - Vanessa W. Stevens
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
| | - Barbara E. Jones
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Libo Wang
- Department of Medicine, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Alexander R. Zheutlin
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Andrew M. South
- Department of Pediatrics, Section of Nephrology, Brenner Children’s Hospital, Wake Forest School of Medicine, Winston Salem, NC, United States of America
- Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston Salem, NC, United States of America
| | - Thomas C. Hanff
- Department of Medicine, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Steven M. Smith
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, United States of America
| | - Rhonda M. Cooper-DeHoff
- Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, United States of America
- Department of Medicine, University of Florida, College of Medicine, Gainesville, FL, United States of America
| | - Jordan B. King
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- Institute for Health Research, Kaiser Permanente Colorado, Aurora, CO, United States of America
| | - G. Caleb Alexander
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Dan R. Berlowitz
- Department of Public Health; University of Massachusetts Lowell, Lowell, MA, United States of America
- Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, United States of America
| | - Faraz S. Ahmad
- Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - M. Jason Penrod
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Rachel Hess
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Molly B. Conroy
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - James C. Fang
- Department of Medicine, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Michael A. Rubin
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Srinivasan Beddhu
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Alfred K. Cheung
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America
| | - Weiming Xian
- Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, United States of America
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States of America
| | | | - Adam P. Bress
- Department of Population Health Sciences, Division of Health System Innovation and Research, University of Utah School of Medicine, Salt Lake City, UT, United States of America
- George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America
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21
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Ali FEM, Mohammedsaleh ZM, Ali MM, Ghogar OM. Impact of cytokine storm and systemic inflammation on liver impairment patients infected by SARS-CoV-2: Prospective therapeutic challenges. World J Gastroenterol 2021; 27:1531-1552. [PMID: 33958841 PMCID: PMC8058655 DOI: 10.3748/wjg.v27.i15.1531] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/17/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a devastating worldwide pandemic infection caused by a severe acute respiratory syndrome namely coronavirus 2 (SARS-CoV-2) that is associated with a high spreading and mortality rate. On the date this review was written, SARS-CoV-2 infected about 96 million people and killed about 2 million people. Several arguments disclosed the high mortality of COVID-19 due to acute respiratory distress syndrome or change in the amount of angiotensin-converting enzyme 2 (ACE2) receptor expression or cytokine storm strength production. In a similar pattern, hepatic impairment patients co-infected with SARS-CoV-2 exhibited overexpression of ACE2 receptors and cytokine storm overwhelming, which worsens the hepatic impairment and increases the mortality rate. In this review, the impact of SARS-CoV-2 on hepatic impairment conditions we overviewed. Besides, we focused on the recent studies that indicated cytokine storm as well as ACE2 as the main factors for high COVID-19 spreading and mortality while hinting at the potential therapeutic strategies.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Zuhair M Mohammedsaleh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Mahmoud M Ali
- Pre-graduated students, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Osama M Ghogar
- Pre-graduated students, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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22
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Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Van Beusecum JP, Patrick DM, Smart CD, Kleyman TR, Kingery J, Peck RN, Laffer CL, Kirabo A. Hypertension: Do Inflammation and Immunity Hold the Key to Solving this Epidemic? Circ Res 2021; 128:908-933. [PMID: 33793336 PMCID: PMC8023750 DOI: 10.1161/circresaha.121.318052] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.
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Affiliation(s)
- Meena S. Madhur
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center
- Department of Molecular Physiology and Biophysics, Vanderbilt University
| | - Fernando Elijovich
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Matthew R. Alexander
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center
| | - Ashley Pitzer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jeanne Ishimwe
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Justin P. Van Beusecum
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - David M. Patrick
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center
| | - Charles D. Smart
- Department of Molecular Physiology and Biophysics, Vanderbilt University
| | - Thomas R. Kleyman
- Departments of Medicine, Cell Biology, Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Justin Kingery
- Center for Global Health, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania
| | - Robert N. Peck
- Center for Global Health, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania
- Mwanza Intervention Trials Unit (MITU), Mwanza, Tanzania
| | - Cheryl L. Laffer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University
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23
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Cohen JB, D'Agostino McGowan L, Jensen ET, Rigdon J, South AM. Evaluating sources of bias in observational studies of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use during COVID-19: beyond confounding. J Hypertens 2021; 39:795-805. [PMID: 33186321 PMCID: PMC8164085 DOI: 10.1097/hjh.0000000000002706] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Concerns over ACE inhibitor or ARB use to treat hypertension during COVID-19 remain unresolved. Although studies using more robust methodologies provided some clarity, sources of bias persist and it remains critical to quickly address this question. In this review, we discuss pernicious sources of bias using a causal model framework, including time-varying confounder, collider, information, and time-dependent bias, in the context of recently published studies. We discuss causal inference methodologies that can address these issues, including causal diagrams, time-to-event analyses, sensitivity analyses, and marginal structural modeling. We discuss effect modification and we propose a role for causal mediation analysis to estimate indirect effects via mediating factors, especially components of the renin--angiotensin system. Thorough knowledge of these sources of bias and the appropriate methodologies to address them is crucial when evaluating observational studies to inform patient management decisions regarding whether ACE inhibitors or ARBs are associated with greater risk from COVID-19.
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Affiliation(s)
- Jordana B Cohen
- Renal-Electrolyte and Hypertension Division, Department of Medicine
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Elizabeth T Jensen
- Department of Epidemiology and Prevention, Division of Public Health Sciences
| | - Joseph Rigdon
- Department of Biostatistics and Data Science, Division of Public Health Sciences
| | - Andrew M South
- Department of Epidemiology and Prevention, Division of Public Health Sciences
- Section of Nephrology, Department of Pediatrics, Brenner Children's Hospital
- Department of Surgery-Hypertension & Vascular Research
- Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
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24
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Smolander J, Bruchfeld A. The COVID-19 Epidemic: Management and Outcomes of Hemodialysis and Peritoneal Dialysis Patients in Stockholm, Sweden. Kidney Blood Press Res 2021; 46:250-256. [PMID: 33774645 PMCID: PMC8089452 DOI: 10.1159/000514268] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/04/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The COVID-19 outbreak has been associated with a high morbidity, mortality, and a risk of long-term sequelae, and patients with severe COVID-19 are at increased risk of acute kidney injury. CKD patients are at high risk of being exposed to COVID-19 and suffer complications and poor outcome. In Sweden, mitigation strategies did not include lockdown. During March-April of 2020, wide-spread infection occurred in Stockholm. METHODS Management and outcomes in forty hemodialysis (HD) patients and 4 peritoneal dialysis (PD) patients, with symptomatic COVID-19 in greater Stockholm during March and April of 2020 are reported. RESULTS Twenty-four HD patients (60%) required medical care and hospitalization, whereas 16 patients (40%) were treated at home. Nine patients died (mortality rate of 22.5%), of whom 8 were men. The median age in non-survivors (78 years) was significantly higher than in survivors (p = 0.003). The median time in dialysis (11.5 years) was also significantly longer in non-survivors (p = 0.01). C-reactive protein (CRP) at diagnosis in 7 of non-survivors (median 213 mg/L, range 86-329 mg/L) was significantly higher than the CRP in 25 survivors (median 87 mg/L, range 1-328 mg/L) (p = 0.0003). Maximum CRP also indicated poorer outcome among hospitalized patients (p = 0.0004). The gender imbalance was striking with only men dying apart from 1 elderly woman. Only 4 PD patients were hospitalized with symptomatic COVID-19. One patient died, 2 were discharged, and 1 was treated at the intensive care unit and survived. CONCLUSION HD patients >70 years were reported with longer dialysis vintage, higher CRP, and males were at an increased risk of dying from COVID-19, whereas those <70 years seemed to have a milder disease. Mitigation strategies to reduce rates of infection in high-risk populations remain essential. Follow-up focusing on long-term prognosis for extrapulmonary manifestations is likely to be important also in dialysis patients.
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Affiliation(s)
| | - Annette Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Renal Medicine, Karolinska University Hospital and CLINTEC KI, Stockholm, Sweden
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25
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Soler MJ, Batlle D. COVID-19 and its impact on the kidney and the nephrology community. Clin Kidney J 2021; 14:i1-i5. [PMID: 33815779 PMCID: PMC7995518 DOI: 10.1093/ckj/sfab039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 10/09/2020] [Indexed: 01/08/2023] Open
Affiliation(s)
- María José Soler
- Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain
| | - Daniel Batlle
- Department of Medicine, Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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26
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From confusion to clarity: RAS blockade in patients hospitalized with COVID-19. Kidney Int 2021; 99:1059-1061. [PMID: 33753072 PMCID: PMC7973333 DOI: 10.1016/j.kint.2021.02.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 11/21/2022]
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27
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Rando HM, Wellhausen N, Ghosh S, Lee AJ, Dattoli AA, Hu F, Byrd JB, Rafizadeh DN, Lordan R, Qi Y, Sun Y, Brueffer C, Field JM, Guebila MB, Jadavji NM, Skelly AN, Ramsundar B, Wang J, Goel RR, Park Y, Boca SM, Gitter A, Greene CS. Identification and Development of Therapeutics for COVID-19. ARXIV 2021:arXiv:2103.02723v3. [PMID: 33688554 PMCID: PMC7941644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Revised: 09/10/2021] [Indexed: 11/23/2022]
Abstract
After emerging in China in late 2019, the novel coronavirus SARS-CoV-2 spread worldwide and as of mid-2021 remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a closely related species of SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19). Building on this research, the medical and scientific communities have responded rapidly to the COVID-19 crisis to identify many candidate therapeutics. The approaches used to identify candidates fall into four main categories: adaptation of clinical approaches to diseases with related pathologies, adaptation based on virological properties, adaptation based on host response, and data-driven identification of candidates based on physical properties or on pharmacological compendia. To date, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA), while most remain under investigation. The scale of the COVID-19 crisis offers a rare opportunity to collect data on the effects of candidate therapeutics. This information provides insight not only into the management of coronavirus diseases, but also into the relative success of different approaches to identifying candidate therapeutics against an emerging disease.
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Affiliation(s)
- Halie M Rando
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America; Center for Health AI, University of Colorado School of Medicine, Aurora, Colorado, United States of America · Funded by the Gordon and Betty Moore Foundation (GBMF 4552)
| | - Nils Wellhausen
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Soumita Ghosh
- Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Alexandra J Lee
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America · Funded by the Gordon and Betty Moore Foundation (GBMF 4552)
| | - Anna Ada Dattoli
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Fengling Hu
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - James Brian Byrd
- University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America · Funded by NIH K23HL128909; FastGrants
| | - Diane N Rafizadeh
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaFunded by NIH Medical Scientist Training Program T32 GM07170
| | - Ronan Lordan
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5158, USA
| | - Yanjun Qi
- Department of Computer Science, University of Virginia, Charlottesville, VA, United States of America
| | - Yuchen Sun
- Department of Computer Science, University of Virginia, Charlottesville, VA, United States of America
| | | | - Jeffrey M Field
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marouen Ben Guebila
- Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America
| | - Nafisa M Jadavji
- Biomedical Science, Midwestern University, Glendale, AZ, United States of America; Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada · Funded by the American Heart Association (20AIREA35050015)
| | - Ashwin N Skelly
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America · Funded by NIH Medical Scientist Training Program T32 GM07170
| | | | - Jinhui Wang
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Rishi Raj Goel
- Institute for Immunology, University of Pennsylvania, Philadelphia, PA, United States of America
| | - YoSon Park
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America · Funded by NHGRI R01 HG10067
| | - Simina M Boca
- Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, District of Columbia, United States of America; Early Biometrics & Statistical Innovation, Data Science & Artificial Intelligence, R & D, AstraZeneca, Gaithersburg, Maryland, United States of America
| | - Anthony Gitter
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America; Morgridge Institute for Research, Madison, Wisconsin, United States of America · Funded by John W. and Jeanne M. Rowe Center for Research in Virology
| | - Casey S Greene
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Philadelphia, Pennsylvania, United States of America; Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America; Center for Health AI, University of Colorado School of Medicine, Aurora, Colorado, United States of America · Funded by the Gordon and Betty Moore Foundation (GBMF 4552); the National Human Genome Research Institute (R01 HG010067)
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Gnanenthiran SR, Borghi C, Burger D, Charchar F, Poulter NR, Schlaich MP, Steckelings UM, Stergiou G, Tomaszewski M, Unger T, Wainford RD, Williams B, Rodgers A, Schutte AE. Prospective meta-analysis protocol on randomised trials of renin-angiotensin system inhibitors in patients with COVID-19: an initiative of the International Society of Hypertension. BMJ Open 2021; 11:e043625. [PMID: 33593784 PMCID: PMC7887864 DOI: 10.1136/bmjopen-2020-043625] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 12/24/2020] [Accepted: 01/26/2021] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION Whether ACE inhibitors (ACEi) or angiotensin II receptor blocker (ARB) therapy should be continued, initiated or ceased in patients with COVID-19 is uncertain. Given the widespread use of ACEi/ARBs worldwide, guidance on the use of these drugs is urgently needed. This prospective meta-analysis aims to pool data from randomised controlled trials (RCTs) to assess the safety and efficacy of ACEi/ARB therapy in adults infected with SARS-CoV-2. METHODS AND ANALYSIS RCTs will be eligible if they compare patients with COVID-19 randomised to ACEi/ARB continuation or commencement versuss no ACEi/ARB therapy; study duration ≥14 days; recruitment completed between March 2020 and May 2021. The primary outcome will be all-cause mortality at ≤30 days. Secondary outcomes will include mechanical ventilation, admission to intensive care or cardiovascular events at short-term follow-up (≤30 days) and all-cause mortality at longer-term follow-up (>1 month). Prespecified subgroup analyses will assess the effect of sex; age; comorbidities; smoking status; ethnicity; country of origin on all-cause mortality. A search of ClinicalTrials.gov has been performed, which will be followed by a formal search of trial registers, preprint servers, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify RCTs that meet inclusion criteria. To date, a search of ClinicalTrials.gov identified 21 potentially eligible trials for this meta-analysis. We will request trial investigators/sponsors to contribute standardised grouped tabular outcome data. ETHICS AND DISSEMINATION Ethics approval and informed consent will be the responsibility of the individual RCTs. Dissemination of results will occur by peer-reviewed publication. The results of our analysis can inform public health policy and clinical decision making regarding ACEi/ARB use in patients with COVID-19 on a global scale.
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Affiliation(s)
| | - Claudio Borghi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Dylan Burger
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Fadi Charchar
- School of Health and Life Sciences, Federation University Australia, Ballarat, Victoria, Australia
| | - Neil R Poulter
- Imperial Clinical Trials Unit, Imperial College London, London, UK
| | - Markus P Schlaich
- Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
| | | | - George Stergiou
- Third Department of Medicine, Hypertension Center STRIDE-7, School of Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maciej Tomaszewski
- Division of Medicine and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust Manchester, Manchester, UK
| | - Thomas Unger
- CARIM-School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Richard D Wainford
- Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Bryan Williams
- Institute of Cardiovascular Science, University College London and National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK
| | - Anthony Rodgers
- The George Institute for Global Health; University of New South Wales, Sydney, New South Wales, Australia
| | - Aletta E Schutte
- The George Institute for Global Health; University of New South Wales, Sydney, New South Wales, Australia
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Cohen JB, South AM, Shaltout HA, Sinclair MR, Sparks MA. Renin-angiotensin system blockade in the COVID-19 pandemic. Clin Kidney J 2021; 14:i48-i59. [PMID: 33796285 PMCID: PMC7929063 DOI: 10.1093/ckj/sfab026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 01/08/2023] Open
Abstract
In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin–angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.
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Affiliation(s)
- Jordana B Cohen
- Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew M South
- Section of Nephrology, Department of Pediatrics, Brenner Children's Hospital, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Surgery, Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC, USA.,Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Hossam A Shaltout
- Department of Surgery, Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC, USA.,Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Pharmacology and Toxicology, School of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Matthew R Sinclair
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.,Duke Clinical Research Institute, Durham, NC, USA
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.,Renal Section, Durham VA Health Care System, Durham, NC, USA
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30
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Bolotova O, Yoo J, Chaudhri I, Marcos LA, Sahib H, Koraishy FM, Skopicki H, Ahmad S, Mallipattu SK. Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study. PLoS One 2020; 15:e0244708. [PMID: 33378401 PMCID: PMC7773257 DOI: 10.1371/journal.pone.0244708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 12/15/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension. METHODS AND FINDINGS This is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort. CONCLUSION In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.
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Affiliation(s)
- Olena Bolotova
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Jeanwoo Yoo
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Imran Chaudhri
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Luis A. Marcos
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Haseena Sahib
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Farrukh M. Koraishy
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Hal Skopicki
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Sahar Ahmad
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
| | - Sandeep K. Mallipattu
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America
- Renal Section, Northport VA Medical Center, Northport, NY, United States of America
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Liu P, Xie X, Gao L, Jin J. Designed variants of ACE2-Fc that decouple anti-SARS-CoV-2 activities from unwanted cardiovascular effects. Int J Biol Macromol 2020; 165:1626-1633. [PMID: 33080267 PMCID: PMC7568492 DOI: 10.1016/j.ijbiomac.2020.10.120] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 10/12/2020] [Accepted: 10/14/2020] [Indexed: 12/13/2022]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2, and recombinant ACE2 decoys are being evaluated as new antiviral therapies. We designed and tested an antibody-like ACE2-Fc fusion protein, which has the benefit of long pharmacological half-life and the potential to facilitate immune clearance of the virus. Out of a concern that the intrinsic catalytic activity of ACE2 may unintentionally alter the balance of its hormonal substrates and cause adverse cardiovascular effects in treatment, we performed a mutagenesis screening for inactivating the enzyme. Three mutants, R273A, H378A and E402A, completely lost their enzymatic activity for either surrogate or physiological substrates. All of them remained capable of binding SARS-CoV-2 and could suppress the transduction of a pseudotyped virus in cell culture. This study established new ACE2-Fc candidates as antiviral treatment for SARS-CoV-2 without potentially harmful side effects from ACE2's catalytic actions toward its vasoactive substrates.
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Affiliation(s)
- Pan Liu
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Xinfang Xie
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Li Gao
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Jing Jin
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Abstract
Acute kidney injury (AKI) is a frequent complication in coronavirus disease 2019 (COVID-19). It is often linked to progressive respiratory failure and is associated with increased morbidity and mortality. The AKI is presumably of multifactorial origin, whereby direct viral infestation of the kidneys also seems to be involved. Specific treatment procedures for AKI associated with COVID-19 are currently missing. In addition, the role of extracorporeal procedures in the treatment of COVID-19 could so far not be clarified. Latest data indicate persistent loss of renal function following COVID-19-associated AKI. Therefore, a re-evaluation of renal function following recovery from COVID-19 should be recommended.
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Affiliation(s)
- A. Gäckler
- Klink für Nephrologie, Universitätsmedizin Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Deutschland
| | - H. Rohn
- Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie, Universitätsmedizin Essen, Universität Duisburg-Essen, Essen, Deutschland
| | - O. Witzke
- Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie, Universitätsmedizin Essen, Universität Duisburg-Essen, Essen, Deutschland
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33
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Bhalla V, Blish CA, South AM. A historical perspective on ACE2 in the COVID-19 era. J Hum Hypertens 2020; 35:935-939. [PMID: 33318644 PMCID: PMC7735396 DOI: 10.1038/s41371-020-00459-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 10/26/2020] [Accepted: 11/25/2020] [Indexed: 12/31/2022]
Affiliation(s)
- Vivek Bhalla
- Stanford Hypertension Center, Stanford University School of Medicine, Stanford, CA, USA. .,Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA. .,Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
| | - Catherine A Blish
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.,Division of Infectious Diseases and Geographical Medicine, Stanford University School of Medicine, Stanford, CA, USA.,Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Andrew M South
- Section of Nephrology, Department of Pediatrics, Brenner Children's Hospital, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA
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34
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Koshy AN, Murphy AC, Farouque O, Ramchand J, Burrell LM, Yudi MB. Renin-angiotensin system inhibition and risk of infection and mortality in COVID-19: a systematic review and meta-analysis. Intern Med J 2020; 50:1468-1474. [PMID: 33191600 PMCID: PMC7753674 DOI: 10.1111/imj.15002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, enters human cells by binding of its viral protein to the aminopeptidase angiotensin-converting enzyme 2 (ACE2). This has led to speculation whether treatment with renin-angiotensin system (RAS) inhibitors was associated with an increased likelihood of a positive test for COVID-19 and risk of mortality. AIMS We performed a systematic review and meta-analysis to investigate whether RAS inhibitors increased the likelihood of a positive test or death/severe illness in patients with COVID-19. METHODS A systematic search of MEDLINE, PubMed and EMBASE was conducted for studies stratified by the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Pooled analysis was performed using a random-effects model. RESULTS Seven trials of 73 122 patients were included. Overall, 16 624 (22.7%) patients had a positive COVID-19 test and 7892 (10.8%) were on a RAS inhibitor. RAS inhibitors were not associated with higher likelihood of a positive COVID-19 test result (odds ratio (OR) 0.97 (95% CI 0.97-1.05, P = 0.48) with low heterogeneity. This was comparable when stratifying by use of each medication class. The use of RAS inhibitors was also not associated with mortality or severe illness (OR 0.89, 95% CI 0.73-1.07, P = 0.21) with moderate heterogeneity. CONCLUSION Use of ACEI or ARB was not associated with a heightened susceptibility for a positive diagnosis of COVID-19. Furthermore, they were not associated with increased illness severity or mortality due to COVID-19. Randomised controlled trials are needed to address definitively the potential benefits or harms of RAS inhibitors in patients with COVID-19.
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Affiliation(s)
- Anoop N. Koshy
- Department of CardiologyAustin HealthMelbourneVictoriaAustralia
- Department of MedicineThe University of Melbourne, MelbourneVictoriaAustralia
| | - Alexandra C. Murphy
- Department of CardiologyAustin HealthMelbourneVictoriaAustralia
- Department of MedicineThe University of Melbourne, MelbourneVictoriaAustralia
| | - Omar Farouque
- Department of CardiologyAustin HealthMelbourneVictoriaAustralia
- Department of MedicineThe University of Melbourne, MelbourneVictoriaAustralia
| | - Jay Ramchand
- Department of CardiologyAustin HealthMelbourneVictoriaAustralia
- Department of MedicineThe University of Melbourne, MelbourneVictoriaAustralia
- Heart and Vascular InstituteCleveland Clinic Miller Family Heart and Vascular InstituteClevelandOhioUSA
| | - Louise M. Burrell
- Department of CardiologyAustin HealthMelbourneVictoriaAustralia
- Department of MedicineThe University of Melbourne, MelbourneVictoriaAustralia
| | - Matias B. Yudi
- Department of CardiologyAustin HealthMelbourneVictoriaAustralia
- Department of MedicineThe University of Melbourne, MelbourneVictoriaAustralia
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Teoh CW, Gaudreault-Tremblay MM, Blydt-Hansen TD, Goldberg A, Arora S, Feber J, Langlois V, Ruhl M, Phan V, Morgan C, Acott P, Hamiwka L. Management of Pediatric Kidney Transplant Patients During the COVID-19 Pandemic: Guidance From the Canadian Society of Transplantation Pediatric Group. Can J Kidney Health Dis 2020; 7:2054358120967845. [PMID: 33240516 PMCID: PMC7672730 DOI: 10.1177/2054358120967845] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022] Open
Abstract
PURPOSE OF THE PROGRAM To provide guidance on the management of pediatric kidney transplant patients during the COVID-19 pandemic. SOURCES OF INFORMATION Program-specific documents, preexisting, and related to COVID-19; documents from provincial, national, and international kidney transplant societies/agencies and organ procurement agencies; national and international webinars, including webinars that we hosted for input and feedback; with additional information from formal and informal review of published academic literature. METHODS Challenges in the care of pediatric kidney transplant patients during the COVID-19 pandemic were highlighted within the Canadian Society of Transplantation (CST) Pediatric Group. It identified pediatric kidney transplant nephrologists (including a pediatric nephrologist ethicist) across the country and formed a workgroup. The initial guidance document was drafted and members of the workgroup reviewed and discussed all suggestions in detail via e-mail and virtual meetings. Disagreements were resolved by consensus. The document was reviewed by the CST Kidney Transplant Working Group, by the Canadian Society of Nephrology (CSN) COVID-19 Rapid Response Team (RRT), and an infectious disease expert. The suggestions were presented at an interactive webinar sponsored by CSN in collaboration with the CST and Canadian Association of Pediatric Nephrologists (CAPN), and attended by pediatric kidney health care professionals for further peer input. Final revisions were made based on feedback received. CJKHD editors reviewed the parallel process peer review and edited the manuscript for clarity. KEY FINDINGS We identified 8 key areas of pediatric kidney transplant care that may be affected by the COVID-19 pandemic: (1) transplant activity, (2) outpatient clinic activity, (3) monitoring, (4) multidisciplinary care, (5) medications (immunosuppression and others), (6) patient/family education/support, (7) school and employment, and (8) management of pediatric kidney transplant patients who are COVID-19 positive. We make specific suggestions for each of these areas. LIMITATIONS A full systematic review of available literature was not undertaken for the sake of expediency in development of this guideline. There is a paucity of literature to support evidence-based recommendations at this time. Instead, these guidelines were formulated based on expert opinion derived from available knowledge/experience and are subject to the biases associated with this level of evidence. The parallel review process that was created to expedite the publication of this work may not be as robust as standard arms' length peer review processes. IMPLICATIONS These recommendations are meant to serve as a guide to pediatric kidney transplant directors, clinicians, and administrators for providing the best patient care in the context of limited resources while protecting patients and health care providers wherever possible by limiting exposure to COVID-19. We recognize that recommendations may not be applicable to all provincial/local health authority practices and that they may not be delivered to all patients given the time and resource constraints affecting the individual provincial/local health jurisdiction.
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Affiliation(s)
- Chia Wei Teoh
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada
- Transplant & Regenerative Medicine Centre, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, ON, Canada
| | | | - Tom D. Blydt-Hansen
- Division of Nephrology, BC Children’s Hospital, Vancouver, Canada
- Department of Paediatrics, The University of British Columbia, Vancouver, Canada
| | - Aviva Goldberg
- Division of Nephrology, The Children’s Hospital of Winnipeg, MB, Canada
- Department of Paediatrics and Child Health, University of Manitoba, Winnipeg, Canada
| | - Steven Arora
- Division of Nephrology, McMaster Children’s Hospital, Hamilton, ON, Canada
- Department of Paediatrics, McMaster University, Hamilton, ON, Canada
| | - Janusz Feber
- Division of Nephrology, Children’s Hospital of Eastern Ontario, Ottawa, Canada
- Department of Paediatrics, University of Ottawa, ON, Canada
| | - Valerie Langlois
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada
- Transplant & Regenerative Medicine Centre, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, ON, Canada
| | - Michelle Ruhl
- Division of Nephrology, Jim Pattison Children’s Hospital, Saskatoon, SK, Canada
- Department of Paediatrics, University of Saskatchewan, Saskatoon, Canada
| | - Veronique Phan
- Division of Nephrology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Paediatrics, University de Montreal, QC, Canada
| | - Catherine Morgan
- Division of Nephrology, Stollery Children’s Hospital, Edmonton, AB, Canada
- Department of Paediatrics, University of Alberta, Edmonton, Canada
| | - Philip Acott
- Division of Nephrology, IWK Health Centre, Halifax, NS, Canada
- Department of Paediatrics, Dalhousie University, Halifax, NS, Canada
| | - Lorraine Hamiwka
- Division of Nephrology, Alberta Children’s Hospital, Calgary, Canada
- Department of Paediatrics, University of Calgary, AB, Canada
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Abstract
Die SARS(„severe acute respiratory syndrome“)-CoV(„coronavirus“)-2-Pandemie hat sich zu einer der größten globalen Herausforderungen unserer Zeit entwickelt. Recht schnell wurde klar, dass im Rahmen einer COVID-19(„coronavirus disease 2019“)-Erkrankung neben der Lunge auch andere Organe in unterschiedlichem Maße betroffen sind. Besonders häufig sind dies auch die Nieren. So weisen viele zuvor nierengesunde Patienten bereits zu Beginn einer COVID-19-Erkrankung Urinauffälligkeiten auf, und bei schweren Verläufen entwickelt sich oft eine akute Nierenschädigung.
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Affiliation(s)
- H Rohn
- Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie (WZI) Universitätsmedizin Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Deutschland
| | - T Feldkamp
- Klinik für Nieren- und Hochdruckkrankheiten, Innere Medizin IV, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - O Witzke
- Klinik für Infektiologie, Westdeutsches Zentrum für Infektiologie (WZI) Universitätsmedizin Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Deutschland
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Chirinos JA, Cohen JB, Zhao L, Hanff T, Sweitzer N, Fang J, Corrales-Medina V, Anmar R, Morley M, Zamani P, Bhattacharya P, Brandimarto J, Jia Y, Basso MD, Wang Z, Ebert C, Ramirez-Valle F, Schafer PH, Seiffert D, Gordon DA, Cappola T. Clinical and Proteomic Correlates of Plasma ACE2 (Angiotensin-Converting Enzyme 2) in Human Heart Failure. Hypertension 2020; 76:1526-1536. [PMID: 32981365 PMCID: PMC10681288 DOI: 10.1161/hypertensionaha.120.15829] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against ≈5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies.
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Affiliation(s)
- Julio A. Chirinos
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jordana B. Cohen
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Lei Zhao
- Bristol Myers Squibb Company, Princeton, New Jersey, USA
| | - Thomas Hanff
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Nancy Sweitzer
- Sarver Heart Institute, University of Arizona, Tuscon, AZ
| | - James Fang
- University of Utah, Salt Lake City, Utah
| | | | - Ron Anmar
- Bristol Myers Squibb Company, Princeton, New Jersey, USA
| | - Michael Morley
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Payman Zamani
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Priyanka Bhattacharya
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jeff Brandimarto
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Yi Jia
- SomaLogic Inc., Boulder, CO, USA
| | | | - Zhaoqing Wang
- Bristol Myers Squibb Company, Princeton, New Jersey, USA
| | | | | | | | | | | | - Thomas Cappola
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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38
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Sparks MA, South AM, Badley AD, Baker-Smith CM, Batlle D, Bozkurt B, Cattaneo R, Crowley SD, Dell’Italia LJ, Ford AL, Griendling K, Gurley SB, Kasner SE, Murray JA, Nath KA, Pfeffer MA, Rangaswami J, Taylor WR, Garovic VD. Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices. Hypertension 2020; 76:1350-1367. [PMID: 32981369 PMCID: PMC7685174 DOI: 10.1161/hypertensionaha.120.15948] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.
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Affiliation(s)
- Matthew A. Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC
- Renal Section, Durham VA Health Care System, Durham, NC
- American Heart Association, Council on Kidney in Cardiovascular Disease
| | - Andrew M. South
- American Heart Association, Council on Kidney in Cardiovascular Disease
- American Heart Association, Council on Hypertension
- Section of Nephrology, Department of Pediatrics, Brenner Children’s Hospital, Wake Forest School of Medicine, Winston Salem, NC
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC
- Department of Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC
- Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC
| | - Andrew D. Badley
- Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN
| | - Carissa M. Baker-Smith
- Director of Preventive Cardiology, Division of Pediatric Cardiology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- American Heart Association, Council on Lifelong Congenital Heart Disease and Heart Health in the Young
| | - Daniel Batlle
- Division of Nephrology and Hypertension, Northwestern University Feinberg Medical School, Chicago, IL
- American Heart Association, Council on Hypertension
| | - Biykem Bozkurt
- Section of Cardiology, Department of Internal Medicine, Baylor College of Medicine, Houston, TX
- Michael E. DeBakey VA Medical Center, Houston, TX
- American Heart Association, Council on Clinical Cardiology
| | - Roberto Cattaneo
- Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN
| | - Steven D. Crowley
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC
- Renal Section, Durham VA Health Care System, Durham, NC
- American Heart Association, Council on Kidney in Cardiovascular Disease
| | - Louis J. Dell’Italia
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL
- Department of Veterans Affairs Medical Center, Birmingham, AL
- American Heart Association, Council on Basic Cardiovascular Sciences
| | - Andria L. Ford
- Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO
- American Heart Association, Stroke Council
| | - Kathy Griendling
- American Heart Association, Council on Basic Cardiovascular Sciences
- Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA
| | - Susan B. Gurley
- American Heart Association, Council on Kidney in Cardiovascular Disease
- Department of Medicine, Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR
| | - Scott E. Kasner
- Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
- American Heart Association, Stroke Council
| | - Joseph A. Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Karl A. Nath
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN
| | - Marc A. Pfeffer
- American Heart Association, Council on Clinical Cardiology
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Janani Rangaswami
- American Heart Association, Council on Kidney in Cardiovascular Disease
- Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA
- Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA
| | - W. Robert Taylor
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA
- Division of Cardiology, Atlanta VA Medical Center, Decatur, GA
- American Heart Association, Council on Arteriosclerosis, Thrombosis and Vascular Biology
| | - Vesna D. Garovic
- American Heart Association, Council on Hypertension
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN
- Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN
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Kant S, Menez SP, Hanouneh M, Fine DM, Crews DC, Brennan DC, Sperati CJ, Jaar BG. The COVID-19 nephrology compendium: AKI, CKD, ESKD and transplantation. BMC Nephrol 2020; 21:449. [PMID: 33109103 PMCID: PMC7590240 DOI: 10.1186/s12882-020-02112-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/19/2020] [Indexed: 01/08/2023] Open
Abstract
The pandemic of coronavirus disease 2019 (CoVID-19) has been an unprecedented period. The disease afflicts multiple organ systems, with acute kidney injury (AKI) a major complication in seriously ill patients. The incidence of AKI in patients with CoVID-19 is variable across numerous international studies, but the high incidence of AKI and its associated worse outcomes in the critical care setting are a consistent finding. A multitude of patterns and mechanisms of AKI have been elucidated, and novel strategies to address shortage of renal replacement therapy equipment have been implemented. The disease also has had consequences on longitudinal management of patients with chronic kidney disease and end stage kidney disease. Kidney transplant recipients may be especially susceptible to CoVID-19 as a result of immunosuppression, with preliminary studies demonstrating high mortality rates. Increased surveillance of disease with low threshold for testing and adjustment of immunosuppression regimen during acute periods of illness have been recommended.
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Affiliation(s)
- Sam Kant
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
| | - Steven P Menez
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
| | - Mohamed Hanouneh
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
- Nephrology Center of Maryland, Baltimore, MD, USA
| | - Derek M Fine
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
| | - Deidra C Crews
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
- Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD, USA
| | - Daniel C Brennan
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
| | - C John Sperati
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA
| | - Bernard G Jaar
- Department of Medicine, Johns Hopkins School of Medicine, 5601 Loch Raven Boulevard, Suite 3 North, Baltimore, MD, 21205, USA.
- Nephrology Center of Maryland, Baltimore, MD, USA.
- Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD, USA.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
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40
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Zheng WJ, Yan Q, Ni YS, Zhan SF, Yang LL, Zhuang HF, Liu XH, Jiang Y. Examining the effector mechanisms of Xuebijing injection on COVID-19 based on network pharmacology. BioData Min 2020; 13:17. [PMID: 33082858 PMCID: PMC7563914 DOI: 10.1186/s13040-020-00227-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 10/04/2020] [Indexed: 12/15/2022] Open
Abstract
Background Chinese medicine Xuebijing (XBJ) has proven to be effective in the treatment of mild coronavirus disease 2019 (COVID-19) cases. But the bioactive compounds and potential mechanisms of XBJ for COVID-19 prevention and treatment are unclear. This study aimed to examine the potential effector mechanisms of XBJ on COVID-19 based on network pharmacology. Methods We searched Chinese and international papers to obtain the active ingredients of XBJ. Then, we compiled COVID-19 disease targets from the GeneCards gene database and via literature searches. Next, we used the SwissTargetPrediction database to predict XBJ’s effector targets and map them to the abovementioned COVID-19 disease targets in order to obtain potential therapeutic targets of XBJ. Cytoscape software version 3.7.0 was used to construct a “XBJ active-compound-potential-effector target” network and protein-protein interaction (PPI) network, and then to carry out network topology analysis of potential targets. We used the ClueGO and CluePedia plugins in Cytoscape to conduct gene ontology (GO) biological process (BP) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of XBJ’s effector targets. We used AutoDock vina and PyMOL software for molecular docking. Results We obtained 144 potential COVID-19 effector targets of XBJ. Fourteen of these targets-glyceraldehyde 3-phosphate dehydrogenase (GAPDH), albumin (ALB), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), Caspase-3 (CASP3), signal transducer and activator of transcription 3 (STAT3), MAPK8, prostaglandin-endoperoxide synthase 2 (PTGS2), JUN, interleukin-2 (IL-2), estrogen receptor 1 (ESR1), and MAPK14 had degree values > 40 and therefore could be considered key targets. They participated in extracellular signal–regulated kinase 1 and 2 (ERK1, ERK2) cascade, the T-cell receptor signaling pathway, activation of MAPK activity, cellular response to lipopolysaccharide, and other inflammation- and immune-related BPs. XBJ exerted its therapeutic effects through the renin-angiotensin system (RAS), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), MAPK, phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt)-vascular endothelial growth factor (VEGF), toll-like receptor (TLR), TNF, and inflammatory-mediator regulation of transient receptor potential (TRP) signaling pathways to ultimately construct a “drug-ingredient-target-pathway” effector network. The molecular docking results showed that the core 18 effective ingredients had a docking score of less than − 4.0 with those top 10 targets. Conclusion The active ingredients of XBJ regulated different genes, acted on different pathways, and synergistically produced anti-inflammatory and immune-regulatory effects, which fully demonstrated the synergistic effects of different components on multiple targets and pathways. Our study demonstrated that key ingredients and their targets have potential binding activity, the existing studies on the pharmacological mechanisms of XBJ in the treatment of sepsis and severe pneumonia, could explain the effector mechanism of XBJ in COVID-19 treatment, and those provided a preliminary examination of the potential effector mechanism in this disease.
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Affiliation(s)
- Wen-Jiang Zheng
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qian Yan
- The First Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong-Shi Ni
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shao-Feng Zhan
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liu-Liu Yang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hong-Fa Zhuang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Hong Liu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong Jiang
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China
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41
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Affiliation(s)
- Jay Ramchand
- Section of Cardiovascular Imaging, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia.
| | - Louise M Burrell
- Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia
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42
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Lano G, Braconnier A, Bataille S, Cavaille G, Moussi-Frances J, Gondouin B, Bindi P, Nakhla M, Mansour J, Halin P, Levy B, Canivet E, Gaha K, Kazes I, Noel N, Wynckel A, Debrumetz A, Jourde-Chiche N, Moal V, Vial R, Scarfoglière V, Bobot M, Gully M, Legris T, Pelletier M, Sallee M, Burtey S, Brunet P, Robert T, Rieu P. Risk factors for severity of COVID-19 in chronic dialysis patients from a multicentre French cohort. Clin Kidney J 2020; 13:878-888. [PMID: 33354330 PMCID: PMC7743188 DOI: 10.1093/ckj/sfaa199] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is an emerging infectious disease, related to severe acute respiratory syndrome coronavirus 2 infection. Few data are available in patients with end-stage renal disease (ESRD). METHODS We conducted an observational cohort study of COVID-19 patients at 11 dialysis centres in two distinct districts of France to examine the epidemiological and clinical characteristics of COVID-19 in this population, and to determine risk factors of disease severity (defined as a composite outcome including intensive care unit admission or death) and mortality. RESULTS Among the 2336 patients enrolled, 5.5% had confirmed COVID-19 diagnosis. Of the 122 patients with a follow-up superior to 28 days, 37% reached the composite outcome and 28% died. Multivariate analysis showed that oxygen therapy on diagnosis and a decrease in lymphocyte count were independent risk factors associated with disease severity and with mortality. Chronic use of angiotensin II receptor blockers (ARBs) (18% of patients) was associated with a protective effect on mortality. Treatment with azithromycin and hydroxychloroquine (AZT/HCQ) (46% of patients) were not associated with the composite outcome and with death in univariate and multivariate analyses. CONCLUSIONS COVID-19 is a severe disease with poor prognosis in patients with ESRD. Usual treatment with ARBs seems to be protective of critical evolution and mortality. There is no evidence of clinical benefit with the combination of AZT/HCQ.
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Affiliation(s)
- Guillaume Lano
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
| | - Antoine Braconnier
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
| | - Stanislas Bataille
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
- Elsan, Phocean Institute of Nephrology, Clinique Bouchard, Marseille, France
| | | | | | - Bertrand Gondouin
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Association des Dialysés Provence et Corse (ADPC), Marseille, France
| | - Pascal Bindi
- Department of Nephrology, Verdun Hospital, Verdun, France
| | - Magued Nakhla
- Department of Nephrology, Laon Hospital, Laon, France
| | - Janette Mansour
- Department of Nephrology, Soissons Hospital, Soissons, France
| | - Pascale Halin
- Department of Nephrology, Charleville-Mézières Hospital, Charleville-Mézières, France
| | - Bénédicte Levy
- Department of Nephrology, Troyes Hospital, Troyes, France
| | - Eric Canivet
- Association Régionale pour la Promotion de la Dialyse à Domicile (ARPDD), Reims, France
| | - Khaled Gaha
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
| | - Isabelle Kazes
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
| | - Natacha Noel
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
| | - Alain Wynckel
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
| | - Alexandre Debrumetz
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
| | - Noemie Jourde-Chiche
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
| | - Valerie Moal
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Romain Vial
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Violaine Scarfoglière
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Mickael Bobot
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
| | - Marion Gully
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Tristan Legris
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Marion Pelletier
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Marion Sallee
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
| | - Stephane Burtey
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
| | - Philippe Brunet
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
- Aix-Marseille University, C2VN, INSERM 1263, INRAe 1260, Marseille, France
| | - Thomas Robert
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, La Conception Hospital, Marseille, France
| | - Philippe Rieu
- Department of Nephrology and Renal Transplantation, Maison Blanche Hospital, University Hospital of Reims, Reims, France
- Laboratory of Nephrology, UMR CNRS URCA 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France
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Grace JA, Casey S, Burrell LM, Angus PW. Proposed mechanism for increased COVID-19 mortality in patients with decompensated cirrhosis. Hepatol Int 2020; 14:884-885. [PMID: 32886332 PMCID: PMC7471588 DOI: 10.1007/s12072-020-10084-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/17/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Josephine A Grace
- Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia.
| | - Stephen Casey
- Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Louise M Burrell
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Peter W Angus
- Department of Gastroenterology and Hepatology, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia
- Department of Medicine and Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia
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Shah S, Sparks MA. COVID-19 and the Kidney Community: Coalescing in Crisis. Adv Chronic Kidney Dis 2020; 27:362-364. [PMID: 33308500 PMCID: PMC7586923 DOI: 10.1053/j.ackd.2020.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/23/2020] [Indexed: 01/08/2023]
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Vlasschaert C, Topf JM, Hiremath S. Proliferation of Papers and Preprints During the Coronavirus Disease 2019 Pandemic: Progress or Problems With Peer Review? Adv Chronic Kidney Dis 2020; 27:418-426. [PMID: 33308508 PMCID: PMC7409832 DOI: 10.1053/j.ackd.2020.08.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 12/23/2022]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has spread exponentially throughout the world in a short period, aided by our hyperconnected world including global trade and travel. Unlike previous pandemics, the pace of the spread of the virus has been matched by the pace of publications, not just in traditional journals, but also in preprint servers. Not all publication findings are true, and sifting through the firehose of data has been challenging to peer reviewers, editors, as well as to consumers of the literature, that is, scientists, healthcare workers, and the general public. There has been an equally exponential rise in the public discussion on social media. Rather than decry the pace of change, we suggest the nephrology community should embrace it, making deposition of research into preprint servers the default, encouraging prepublication peer review more widely of such preprint studies, and harnessing social media tools to make these actions easier and seamless.
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Affiliation(s)
| | - Joel M Topf
- Department of Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI
| | - Swapnil Hiremath
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
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Ng JH, Bijol V, Sparks MA, Sise ME, Izzedine H, Jhaveri KD. Pathophysiology and Pathology of Acute Kidney Injury in Patients With COVID-19. Adv Chronic Kidney Dis 2020; 27:365-376. [PMID: 33308501 PMCID: PMC7574722 DOI: 10.1053/j.ackd.2020.09.003] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 02/08/2023]
Abstract
Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease or end-stage kidney disease. An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.
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MESH Headings
- Acute Kidney Injury/etiology
- Acute Kidney Injury/metabolism
- Acute Kidney Injury/pathology
- Acute Kidney Injury/physiopathology
- Anti-Bacterial Agents/adverse effects
- Antiviral Agents/adverse effects
- Apolipoprotein L1/genetics
- Ascorbic Acid/adverse effects
- Azotemia/metabolism
- Azotemia/pathology
- Azotemia/physiopathology
- COVID-19/metabolism
- COVID-19/pathology
- COVID-19/physiopathology
- Cytokines/metabolism
- Disease Progression
- Glomerulonephritis/metabolism
- Glomerulonephritis/pathology
- Glomerulonephritis/physiopathology
- Glomerulonephritis, Membranous/metabolism
- Glomerulonephritis, Membranous/pathology
- Glomerulonephritis, Membranous/physiopathology
- Hospital Mortality
- Humans
- Kidney Tubules, Proximal/injuries
- Length of Stay
- Myoglobin/metabolism
- Nephritis, Interstitial/metabolism
- Nephritis, Interstitial/pathology
- Nephritis, Interstitial/physiopathology
- Nephrosis, Lipoid/metabolism
- Nephrosis, Lipoid/pathology
- Nephrosis, Lipoid/physiopathology
- Renal Insufficiency, Chronic
- Rhabdomyolysis/metabolism
- SARS-CoV-2
- Severity of Illness Index
- Thrombotic Microangiopathies/metabolism
- Thrombotic Microangiopathies/pathology
- Thrombotic Microangiopathies/physiopathology
- Vitamins/adverse effects
- COVID-19 Drug Treatment
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Affiliation(s)
- Jia H Ng
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, NY.
| | - Vanesa Bijol
- Department of Pathology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, NY
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC; Renal Section, Durham Veterans Affairs Health Care System, Durham, NC
| | - Meghan E Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Hassane Izzedine
- Department of Nephrology, Peupliers Private Hospital, Ramsay Générale de Santé, Paris, France
| | - Kenar D Jhaveri
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, NY
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Abstract
Purpose of Review Angiotensin-converting enzyme 2 (ACE2), a specific high-affinity angiotensin II-hydrolytic enzyme, is the vector that facilitates cellular entry of SARS-CoV-1 and the novel SARS-CoV-2 coronavirus. SARS-CoV-2, which crossed species barriers to infect humans, is highly contagious and associated with high lethality due to multi-organ failure, mostly in older patients with other co-morbidities. Recent Findings Accumulating clinical evidence demonstrates that the intensity of the infection and its complications are more prominent in men. It has been postulated that potential functional modulation of ACE2 by estrogen may explain the sex difference in morbidity and mortality. Summary We review here the evidence regarding the role of estrogenic hormones in ACE2 expression and regulation, with the intent of bringing to the forefront potential mechanisms that may explain sex differences in SARS-CoV-2 infection and COVID-19 outcomes, assist in management of COVID-19, and uncover new therapeutic strategies.
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Toner L, Koshy AN, Ko J, Driscoll A, Farouque O. Clinical Characteristics and Trends in Heart Failure Hospitalizations: An Australian Experience During the COVID-19 Lockdown. JACC-HEART FAILURE 2020; 8:872-875. [PMID: 33004116 PMCID: PMC7418698 DOI: 10.1016/j.jchf.2020.05.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 12/04/2022]
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Teng S, Tang Q. ACE2 enhance viral infection or viral infection aggravate the underlying diseases. Comput Struct Biotechnol J 2020; 18:2100-2106. [PMID: 32832038 PMCID: PMC7409731 DOI: 10.1016/j.csbj.2020.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/26/2020] [Accepted: 08/01/2020] [Indexed: 12/14/2022] Open
Abstract
ACE2 plays a critical role in SARS-CoV-2 infection to cause COVID-19 and SARS-CoV-2 spike protein binds to ACE2 and probably functionally inhibits ACE2 to aggravate the underlying diseases of COVID-19. The important factors that affect the severity and fatality of COVID-19 include patients' underlying diseases and ages. Therefore, particular care to the patients with underlying diseases is needed during the treatment of COVID-19 patients.
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Key Words
- ACE2, Angiotensin converting enzyme 2
- ACEI, ACE inhibitor
- Angiotensin converting enzyme 2
- COVID-19, Coronavirus Infectious Disease-19
- CVD, cardiovascular disease
- Coronavirus Infectious Disease-19
- Health disparity
- PAH, pulmonary artery hypertension
- R0, Reproductive number
- RAS, Renin-angiotensin system
- RBD, Receptor binding domain
- S, Spike: TMPRSS2, Transmembrane protease, serine 2
- SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus −2 SARS-CoV-2, Middle East Respiratory Syndrome 2: MERS-2
- SNP, Single Nucleotide Polymorphism
- Severe Acute Respiratory Syndrome Coronavirus −2
- Single Nucleotide Polymorphism
- Underlying diseases
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Affiliation(s)
- Shaolei Teng
- Department of Biology, Howard University, 415 College St. NW, Washington, DC 20059 USA
| | - Qiyi Tang
- Howard University College of Medicine, 520 W Street NW, Washington, DC 20059 USA
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Batlle D, Soler MJ, Welling PA, Swaminathan S, on behalf of the COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group*. Authors’ Reply. J Am Soc Nephrol 2020; 31:1918-1919. [DOI: 10.1681/asn.2020060799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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