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1.
Curr Opin Nephrol Hypertens ; 31(1): 36-46, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1612725

ABSTRACT

PURPOSE OF REVIEW: Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. RECENT FINDINGS: SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. SUMMARY: In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.


Subject(s)
Acute Kidney Injury , COVID-19 , Renal Insufficiency, Chronic , Thrombosis , Acute Kidney Injury/etiology , COVID-19/complications , Fibrosis , Humans , Inflammation , Kidney/pathology , Lipids , Renal Insufficiency, Chronic/pathology , SARS-CoV-2 , Thrombosis/pathology
2.
Mayo Clin Proc ; 96(10): 2561-2575, 2021 10.
Article in English | MEDLINE | ID: covidwho-1521396

ABSTRACT

OBJECTIVE: To compare coronavirus disease 2019 (COVID-19) acute kidney injury (AKI) to sepsis-AKI (S-AKI). The morphology and transcriptomic and proteomic characteristics of autopsy kidneys were analyzed. PATIENTS AND METHODS: Individuals 18 years of age and older who died from COVID-19 and had an autopsy performed at Mayo Clinic between April 2020 to October 2020 were included. Morphological evaluation of the kidneys of 17 individuals with COVID-19 was performed. In a subset of seven COVID-19 cases with postmortem interval of less than or equal to 20 hours, ultrastructural and molecular characteristics (targeted transcriptome and proteomics analyses of tubulointerstitium) were evaluated. Molecular characteristics were compared with archived cases of S-AKI and nonsepsis causes of AKI. RESULTS: The spectrum of COVID-19 renal pathology included macrophage-dominant microvascular inflammation (glomerulitis and peritubular capillaritis), vascular dysfunction (peritubular capillary congestion and endothelial injury), and tubular injury with ultrastructural evidence of mitochondrial damage. Investigation of the spatial architecture using a novel imaging mass cytometry revealed enrichment of CD3+CD4+ T cells in close proximity to antigen-presenting cells, and macrophage-enriched glomerular and interstitial infiltrates, suggesting an innate and adaptive immune tissue response. Coronavirus disease 2019 AKI and S-AKI, as compared to nonseptic AKI, had an enrichment of transcriptional pathways involved in inflammation (apoptosis, autophagy, major histocompatibility complex class I and II, and type 1 T helper cell differentiation). Proteomic pathway analysis showed that COVID-19 AKI and to a lesser extent S-AKI were enriched in necroptosis and sirtuin-signaling pathways, both involved in regulatory response to inflammation. Upregulation of the ceramide-signaling pathway and downregulation of oxidative phosphorylation in COVID-19 AKI were noted. CONCLUSION: This data highlights the similarities between S-AKI and COVID-19 AKI and suggests that mitochondrial dysfunction may play a pivotal role in COVID-19 AKI. This data may allow the development of novel diagnostic and therapeutic targets.


Subject(s)
Acute Kidney Injury/pathology , COVID-19/pathology , Kidney/pathology , Sepsis/pathology , Acute Kidney Injury/virology , Adult , Autopsy , Humans , Kidney Tubules, Proximal/pathology , Male , Middle Aged , Sepsis/virology
3.
ASAIO J ; 67(10): 1087-1096, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1443140

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.


Subject(s)
Acute Kidney Injury , COVID-19/complications , Kidney/pathology , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , COVID-19/pathology , Humans , Kidney Tubular Necrosis, Acute/pathology , SARS-CoV-2
4.
Sci Rep ; 11(1): 16843, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1366832

ABSTRACT

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Kidney/metabolism , Renal Insufficiency, Chronic/metabolism , SARS-CoV-2/physiology , Adenine , Angiotensin-Converting Enzyme 2/genetics , Animals , Aristolochic Acids , Disease Models, Animal , Down-Regulation , Humans , Imidazoles/administration & dosage , Kidney/pathology , Mice , Mice, Inbred C57BL , Organ Specificity , Tetrazoles/administration & dosage
5.
Pediatr Nephrol ; 36(11): 3789-3793, 2021 11.
Article in English | MEDLINE | ID: covidwho-1361293

ABSTRACT

BACKGROUND: Histological findings of kidney involvement have been rarely reported in pediatric patients with SARS-CoV-2 infection. Here, we describe clinical, laboratory, and histological findings of two pediatric cases with almost exclusive kidney involvement by SARS-CoV-2. RESULTS: A 10-year-old girl with IgA vasculitis nephritis underwent kidney biopsy, showing diffuse and segmental mesangial-proliferative glomerulonephritis, and steroid therapy was initiated. After the worsening of the clinical picture, including an atypical skin rash, she was diagnosed with SARS-CoV-2. The re-evaluation of initial biopsy showed cytoplasmatic blebs and virus-like particles in tubular cells at electron microscopy. Despite SARS-CoV-2 clearance and the intensification of immunosuppression, no improvement was observed. A second kidney biopsy showed a crescentic glomerulonephritis with sclerosis, while virus-like particles were no longer evident. The second patient was a 12-year-old girl with a 3-week history of weakness and weight loss. Rhinitis was reported the month before. No medications were being taken. Blood and urine analysis revealed elevated serum creatinine, hypouricemia, low molecular weight proteinuria, and glycosuria. A high SARS-CoV-2-IgG titre was detected. Kidney biopsy showed acute tubular-interstitial nephritis. Steroid therapy was started with a complete resolution of kidney involvement. CONCLUSION: We can speculate that in both cases SARS-CoV-2 played a major role as inflammatory trigger of the kidney damage. Therefore, we suggest investigating the potential kidney damage by SARS-CoV-2 in children. Moreover, SARS-CoV-2 can be included among infectious agents responsible for pediatric acute tubular interstitial nephritis.


Subject(s)
COVID-19/complications , Glomerulonephritis, IGA/immunology , Kidney/pathology , Nephritis, Interstitial/immunology , SARS-CoV-2/immunology , Biopsy , COVID-19/immunology , COVID-19/virology , Child , Female , Glomerulonephritis, IGA/diagnosis , Glomerulonephritis, IGA/pathology , Glomerulonephritis, IGA/virology , Humans , Kidney/immunology , Kidney/ultrastructure , Kidney/virology , Microscopy, Electron , Nephritis, Interstitial/diagnosis , Nephritis, Interstitial/pathology , Nephritis, Interstitial/virology , SARS-CoV-2/isolation & purification
6.
BMC Nephrol ; 22(1): 278, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1352651

ABSTRACT

BACKGROUND: The recent COVID-19 pandemic has raised concerns about patient diagnosis and follow-up of chronically ill patients. Patients suffering from chronic illnesses, concomitantly infected by SARS-CoV-2, globally tend to have a worse prognosis and poor outcomes. Renal tropism and acute kidney injury following SARS-CoV-2 infection has recently been described in the literature, with elevated mortality rates. Furthermore, patients with pre-existing chronic kidney disease, infected by SARS-CoV-2, should be monitored carefully. Here, we report the case of a 69-year-old patient with splenic marginal zone lymphoma, suffering from longstanding chronic kidney disease following SARS-CoV-2 infection. CASE PRESENTATION: A 69-year-old male patient previously diagnosed with pulmonary embolism and splenic marginal zone lymphoma (Splenomegaly, Matutes 2/5, CD5 negative and CD23 positive), was admitted to the hospital with shortness of breath, fever and asthenia. A nasopharyngeal swab test was performed in addition to a CT-scan, which confirmed SARS-CoV-2 infection. Blood creatinine increased following SARS-CoV-2 infection at 130 µmol/l, with usual values at 95 µmol/l. The patient was discharged at home with rest and symptomatic medical treatment (paracetamol and hydration), then readmitted to the hospital in August 2020. A kidney biopsy was therefore conducted as blood creatinine levels were abnormally elevated. Immunodetection performed in a renal biopsy specimen confirmed co-localization of SARS-CoV2 nucleocapsid and protease 3C proteins with ACE2, Lewis x and sialyl-Lewis x antigens in proximal convoluted tubules and podocytes. Co-localization of structural and non-structural viral proteins clearly demonstrated viral replication in proximal convoluted tubules in this chronically ill patient. Additionally, we observed the co-localization of sialyl-Lewis x and ACE2 receptors in the same proximal convoluted tubules. Reverse Transcriptase-Polymerase Chain Reaction test performed on the kidney biopsy was negative, with very low Ct levels (above 40). The patient was finally readmitted to the haematology department for initiation of chemotherapy, including CHOP protocol and Rituximab. CONCLUSIONS: Our case emphasizes on the importance of monitoring kidney function in immunosuppressed patients and patients suffering from cancer following SARS-CoV-2 infection, through histological screening. Further studies will be required to decipher the mechanisms underlying chronic kidney disease and the putative role of sialyl-Lewis x and HBGA during SARS-CoV-2 infection.


Subject(s)
COVID-19/complications , Kidney Tubules/virology , Renal Insufficiency, Chronic/virology , SARS-CoV-2/physiology , Virus Replication , Aged , Angiotensin-Converting Enzyme 2/analysis , Biopsy , COVID-19/blood , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/analysis , Creatinine/blood , Humans , Kidney/chemistry , Kidney/pathology , Kidney/virology , Kidney Tubules/chemistry , Kidney Tubules/pathology , Lewis X Antigen/analysis , Lymphoma, B-Cell, Marginal Zone/complications , Male , Renal Insufficiency, Chronic/pathology , Sialyl Lewis X Antigen/analysis , Splenic Neoplasms/complications
7.
Eur Rev Med Pharmacol Sci ; 25(15): 5063-5069, 2021 08.
Article in English | MEDLINE | ID: covidwho-1346861

ABSTRACT

OBJECTIVE: Vaccine-induced immune thrombocytopenia (VITT) is a new syndrome occurring primarily in healthy young adults, with a female predominance, after receiving the first dose of ChAdOx1 nCoV-19 vaccine. We describe VITT syndrome characterized by severe thrombosis and thrombocytopenia found in our patient, with fatal outcome. CASE REPORT: A 58-year-old man, after 13 days from the first administration of ChAdOx1 nCoV-19 vaccine (AstraZeneca), presented with abdominal pain, diarrhea and vomitus. Laboratory tests revealed a severe thrombocytopenia, low fibrinogen serum levels and marked increase of D-dimer serum levels. The patient quickly developed a multiple organ failure, till death, three days after the hospital admission. RESULTS: At histology, in the lungs, interalveolar septa appeared thickened with microthrombi in the capillaries and veins. Interalveolar septa appeared thickened and showed vascular proliferation. Thrombi were detected in the capillaries of glomerular tufts. In the hearth, thrombi were observed in veins and capillaries. In the liver, voluminous fibrin thrombi were diffusely observed in the branches of the portal vein. Microthrombi were also found in the vasa vasorum of the wall of abdominal aorta. In the brain, microthrombi were observed in the capillaries of the choroid plexuses. Diffuse hemorrhagic necrosis was observed in the intestinal wall with marked congestion of the venous vessels. CONCLUSIONS: In our patient, the majority of data necessary for a VITT final diagnosis were present: thrombocytopenia and thrombosis in pulmonary, portal, hepatic, renal and mesenteric veins, associated with a marked increase of D-dimer serum levels. The finding of cerebral thrombosis in choroid plexuses, is a new finding in VITT. These features are suggestive for a very aggressive form of VITT.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Purpura, Thrombocytopenic, Idiopathic/etiology , Thrombosis/etiology , Aorta/pathology , COVID-19/blood , COVID-19 Vaccines/administration & dosage , Choroid Plexus/pathology , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Ileum/pathology , Kidney/pathology , Liver/pathology , Lung/pathology , Male , Middle Aged , Myocardium/pathology , Purpura, Thrombocytopenic, Idiopathic/blood , Thrombosis/blood
8.
Brief Bioinform ; 22(2): 914-923, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343627

ABSTRACT

The novel coronavirus or COVID-19 has first been found in Wuhan, China, and became pandemic. Angiotensin-converting enzyme 2 (ACE2) plays a key role in the host cells as a receptor of Spike-I Glycoprotein of COVID-19 which causes final infection. ACE2 is highly expressed in the bladder, ileum, kidney and liver, comparing with ACE2 expression in the lung-specific pulmonary alveolar type II cells. In this study, the single-cell RNAseq data of the five tissues from different humans are curated and cell types with high expressions of ACE2 are identified. Subsequently, the protein-protein interaction networks have been established. From the network, potential biomarkers which can form functional hubs, are selected based on k-means network clustering. It is observed that angiotensin PPAR family proteins show important roles in the functional hubs. To understand the functions of the potential markers, corresponding pathways have been researched thoroughly through the pathway semantic networks. Subsequently, the pathways have been ranked according to their influence and dependency in the network using PageRank algorithm. The outcomes show some important facts in terms of infection. Firstly, renin-angiotensin system and PPAR signaling pathway can play a vital role for enhancing the infection after its intrusion through ACE2. Next, pathway networks consist of few basic metabolic and influential pathways, e.g. insulin resistance. This information corroborate the fact that diabetic patients are more vulnerable to COVID-19 infection. Interestingly, the key regulators of the aforementioned pathways are angiontensin and PPAR family proteins. Hence, angiotensin and PPAR family proteins can be considered as possible therapeutic targets. Contact: sagnik.sen2008@gmail.com, umaulik@cse.jdvu.ac.in Supplementary information: Supplementary data are available online.


Subject(s)
COVID-19/metabolism , SARS-CoV-2/pathogenicity , Algorithms , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Humans , Ileum/metabolism , Ileum/pathology , Kidney/metabolism , Kidney/pathology , Liver/metabolism , Liver/pathology , Peroxisome Proliferator-Activated Receptors/metabolism , Protein Interaction Maps , Renin-Angiotensin System/physiology , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Urinary Bladder/metabolism , Urinary Bladder/pathology
9.
Biomed Pharmacother ; 142: 111966, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1330663

ABSTRACT

Since December 2019, the world was encountered a new disease called coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 initially causes lung damage, it also affects many other organs, including the kidneys, and on average, 5-23% of people with COVID-19 develop the symptoms of acute kidney injury (AKI), including elevated blood creatinine and urea, hematuria, proteinuria, and histopathological damages. The exact mechanism is unknown, but the researchers believe that SARS-CoV-2 directly and indirectly affects the kidneys. The direct pathway is by binding the virus to ACE2 receptor in the kidney, damage to cells, the renin-angiotensin system disturbances, activating coagulation pathways, and damaging the renal vascular endothelium. The initial evidence from studying the kidney tissue in postmortem patients is more in favor of the direct pathway. The indirect pathway is created by increased cytokines and cytokine storm, sepsis, circulatory disturbances, hypoxemia, as well as using the nephrotoxic drugs. Using renal tissue biopsy and autopsy in the patients with COVID-19, recent studies found evidence for a predominant indirect pathway in AKI induction by SARS-CoV-2. Besides, some studies showed that the degree of acute tubular injury (ATI) in autopsies from COVID-19 victims is milder compared to AKI degree. We review the mechanism of AKI induction and the renal side effects of the most common drugs used to treat COVID-19 after the overview of the latest findings on SARS-CoV-2 pathogenicity.


Subject(s)
Acute Kidney Injury , COVID-19/drug therapy , Kidney/pathology , SARS-CoV-2 , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Acute Kidney Injury/virology , COVID-19/complications , COVID-19/mortality , COVID-19/physiopathology , Humans , Kidney Function Tests/methods , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology
10.
Nephrol Ther ; 17(4): 203-207, 2021 Aug.
Article in French | MEDLINE | ID: covidwho-1316598

ABSTRACT

COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.


Subject(s)
Acute Kidney Injury/virology , COVID-19/complications , Glomerulosclerosis, Focal Segmental/virology , Kidney Tubular Necrosis, Acute/virology , Biopsy , COVID-19 Vaccines/adverse effects , Humans , Kidney/pathology
11.
PLoS Pathog ; 17(7): e1009705, 2021 07.
Article in English | MEDLINE | ID: covidwho-1311291

ABSTRACT

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).


Subject(s)
COVID-19/immunology , Down-Regulation/immunology , Interferon Type I/immunology , Kidney/immunology , Myocardium/immunology , Respiratory System/immunology , SARS-CoV-2/immunology , Animals , COVID-19/pathology , Cricetinae , Disease Models, Animal , Humans , Inflammation/immunology , Inflammation/pathology , Kidney/pathology , Kidney/virology , Male , Mesocricetus , Myocardium/pathology , Respiratory System/pathology , Respiratory System/virology
12.
Front Immunol ; 12: 680567, 2021.
Article in English | MEDLINE | ID: covidwho-1304591

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. A clinical series of Kawasaki-like multisystem inflammatory syndrome (MIS), occurring after SARS-CoV-2 infection, have been described in children (MIS-C) and adults (MIS-A), but the pathophysiology remains unknown. Case Presentation: We describe a case of post-COVID-19 MIS-A in a 46-year-old man with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition with eculizumab was initiated promptly and led to a dramatic improvement of renal function. Conclusion: Our case suggests that that TMA could play a central role in the pathophysiology of post-COVID-19 MIS-A, making complement blockers an interesting therapeutic option.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/diagnosis , Complement Inactivating Agents/therapeutic use , Kidney/metabolism , SARS-CoV-2/physiology , Systemic Inflammatory Response Syndrome/diagnosis , Thrombotic Microangiopathies/diagnosis , COVID-19/drug therapy , Humans , Kidney/pathology , Male , Middle Aged , Pandemics , Recovery of Function , Systemic Inflammatory Response Syndrome/drug therapy , Thrombotic Microangiopathies/drug therapy
13.
Nat Rev Nephrol ; 17(11): 751-764, 2021 11.
Article in English | MEDLINE | ID: covidwho-1297305

ABSTRACT

Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies.


Subject(s)
Acute Kidney Injury/physiopathology , Acute Kidney Injury/virology , COVID-19/physiopathology , Adaptive Immunity/physiology , Biopsy , Complement System Proteins , Drug-Related Side Effects and Adverse Reactions , Endothelium, Vascular/physiopathology , Extracorporeal Membrane Oxygenation , Hematuria/physiopathology , Humans , Immunity, Humoral/physiology , Immunity, Innate/physiology , Immunosenescence , Inflammation/physiopathology , Inflammation/virology , Interferon Type I/physiology , Kidney/pathology , Kidney/virology , Proteinuria/physiopathology , Severity of Illness Index , Viral Load
14.
IUBMB Life ; 73(8): 1005-1015, 2021 08.
Article in English | MEDLINE | ID: covidwho-1291220

ABSTRACT

The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.


Subject(s)
COVID-19/mortality , Coronavirus Infections/mortality , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/mortality , Viral Tropism/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Gene Expression Regulation , Humans , Kidney/metabolism , Kidney/pathology , Kidney/virology , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Survival Analysis
15.
Cell Res ; 31(8): 836-846, 2021 08.
Article in English | MEDLINE | ID: covidwho-1275907

ABSTRACT

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.


Subject(s)
COVID-19/pathology , Lung/virology , SARS-CoV-2/isolation & purification , Aged , Aged, 80 and over , Autopsy , COVID-19/virology , China , Cohort Studies , Critical Illness , Female , Fibrosis , Hospitalization , Humans , Kidney/pathology , Kidney/virology , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Lung/pathology , Male , Middle Aged , RNA, Viral/metabolism , SARS-CoV-2/genetics , Spleen/pathology , Spleen/virology , Trachea/pathology , Trachea/virology
16.
J Am Soc Nephrol ; 32(9): 2242-2254, 2021 09.
Article in English | MEDLINE | ID: covidwho-1266593

ABSTRACT

BACKGROUND: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. METHODS: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids. RESULTS: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. CONCLUSIONS: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.


Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/virology , COVID-19/complications , SARS-CoV-2/pathogenicity , Spheroids, Cellular/virology , Animals , Cells, Cultured , Chlorocebus aethiops , Cohort Studies , Cytopathogenic Effect, Viral , Epithelial Cells/pathology , Epithelial Cells/virology , Host Microbial Interactions , Humans , Interferon Type I/metabolism , Kidney/immunology , Kidney/pathology , Kidney/virology , Mice , Mice, Inbred NOD , Mice, SCID , Models, Biological , Pandemics , Receptors, Virus/metabolism , Retrospective Studies , SARS-CoV-2/physiology , Spheroids, Cellular/pathology , Vero Cells , Virus Replication
17.
Crit Care ; 25(1): 202, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1266500

ABSTRACT

BACKGROUND: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. METHODS: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients. RESULTS: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. CONCLUSIONS: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.


Subject(s)
COVID-19/pathology , Gene Expression/genetics , Kidney/pathology , Kidney/physiopathology , Sepsis/pathology , Acute Kidney Injury/etiology , Acute Kidney Injury/physiopathology , Adult , Aged , Aged, 80 and over , Analysis of Variance , COVID-19/genetics , COVID-19/physiopathology , Critical Illness/therapy , Female , Humans , Intensive Care Units/organization & administration , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Sepsis/genetics , Sepsis/physiopathology , Simplified Acute Physiology Score
18.
Mamm Genome ; 32(5): 389-400, 2021 10.
Article in English | MEDLINE | ID: covidwho-1258196

ABSTRACT

Acute Kidney Injury (AKI) is a common manifestation of COVID-19 and several cases have been reported in the setting of the high-risk APOL1 genotype (common genetic variants). This increases the likelihood that African American people with the high-risk genotype APOL1 are at increased risk for kidney disease in the COVID-19 environment. Single-nucleotide polymorphisms (SNPs) are found in various microRNAs (miRNAs) and target genes change the miRNA activity that leads to different diseases. Evidence has shown that SNPs increase/decrease the effectiveness of the interaction between miRNAs and disease-related target genes. The aim of this study is not only to identify miRSNPs on the APOL1 gene and SNPs in miRNA genes targeting 3'UTR but also to evaluate the effect of these gene variations in kidney patients and their association with SARS-COV-2 infection. In 3'UTR of the APOL1 gene, we detected 96 miRNA binding sites and 35 different SNPs with 10 different online software in the binding sites of the miRNA (in silico). Also we studied gene expression of patients and control samples by using qRT-PCR (in vitro). In silico study, the binding site of miR-6741-3p on APOL1 has two SNPs (rs1288875001, G > C; rs1452517383, A > C) on APOL1 3'UTR, and its genomic sequence is the same nucleotide as rs1288875001. Similarly, two other SNPs (rs1142591, T > A; rs376326225, G > A) were identified in the binding sites of miR-6741-3p at the first position. Here, the miRSNP (rs1288875001) in APOL1 3'UTR and SNP (rs376326225) in the miR-6741-3p genomic sequence are cross-matched in the same binding region. In vitro study, the relative expression levels were calculated by the 2-ΔΔCt method & Mann-Whitney U test. The expression of APOL1 gene was different in chronic kidney patients along with COVID-19. By these results, APOL1 expression was found lower in patients than healthy (p < 0.05) in kidney patients along with COVID-19. In addition, miR-6741-3p targets many APOL1-related genes (TLR7, SLC6A19, IL-6,10,18, chemokine (C-C motif) ligand 5, SWT1, NFYB, BRF1, HES2, NFYB, MED12L, MAFG, GTF2H5, TRAF3, angiotensin II receptor-associated protein, PRSS23) by evaluating online software in the binding sites of the miR-6741-3p. miR-6741-3p has not previously shown any association with kidney diseases and SARS-COV-2 infection. It assures that APOL1 can have a significant consequence in kidney-associated diseases by different pathways. Henceforth, this study represents and demonstrates an effective association between miR-6741-3p and kidney diseases, i.e., collapsing glomerulopathy, chronic kidney disease (CKD), acute kidney injury (AKI), and tubulointerstitial lesions susceptibility to SARS-COV-2 infection via in silico and in vitro exploration and recommended to have better insight.


Subject(s)
3' Untranslated Regions/genetics , Apolipoprotein L1/genetics , COVID-19/genetics , Kidney Diseases/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide/genetics , Binding Sites/genetics , Case-Control Studies , Genotype , Humans , Kidney/pathology , SARS-CoV-2/pathogenicity
19.
Cardiorenal Med ; 11(3): 133-139, 2021.
Article in English | MEDLINE | ID: covidwho-1255729

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 has rapidly spread worldwide and resulted in the coronavirus disease 2019 (COVID-19) pandemic. The disease raised an unprecedented demand for intensive care support due to severe pulmonary dysfunction and multiorgan failure. Although the pulmonary system is the potential target of the COVID-19, recent reports have demonstrated that COVID-19 profoundly influences the cardiovascular system and the kidneys. Research studies on cadavers have shown that direct heart and kidney injury can be frequently seen in patients deceased due to COVID-19 infection. On the other hand, functional or structural dysfunction of the heart may deteriorate the renal function and vice versa. This concept is already known as the cardiorenal syndrome and may play a role in COVID-19. Proactive monitoring of micro- and macrohemodynamics could allow prompt correction of circulatory dysfunction and can be of pivotal importance in the prevention of acute kidney injury. Moreover, type and amount of fluid therapy and vasoactive drug support could help manage these patients either with or without mechanical ventilator support. This brief review outlines the current evidence regarding the COVID-19-related renal and cardiorenal complications and discusses potential hemodynamic management strategies.


Subject(s)
COVID-19 , Cardio-Renal Syndrome , COVID-19/complications , Cardio-Renal Syndrome/etiology , Cardio-Renal Syndrome/therapy , Humans , Kidney/pathology , Pandemics
20.
Int J Mol Sci ; 22(10)2021 May 20.
Article in English | MEDLINE | ID: covidwho-1244035

ABSTRACT

Previous studies have shown that COVID-19 leads to thrombotic complications, which have been associated with high morbidity and mortality rates. Neutrophils are the largest population of white blood cells and play a pivotal role in innate immunity. During an infection, neutrophils migrate from circulation to the infection site, contributing to killing pathogens. This mechanism is regulated by chemokines such as IL-8. Moreover, it was shown that neutrophils play an important role in thromboinflammation. Through a diverse repertoire of mechanisms, neutrophils, apart from directly killing pathogens, are able to activate the formation of thrombi. In COVID-19 patients, neutrophil activation promotes neutrophil extracellular trap (NET) formation, platelet aggregation, and cell damage. Furthermore, neutrophils participate in the pathogenesis of endothelitis. Overall, this review summarizes recent progress in research on the pathogenesis of COVID-19, highlighting the role of the prothrombotic action of neutrophils in NET formation.


Subject(s)
COVID-19/immunology , Extracellular Traps/immunology , Immunity, Innate , Lung/immunology , Neutrophils/immunology , Thrombosis/immunology , COVID-19/complications , COVID-19/pathology , COVID-19/therapy , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Extracellular Traps/virology , Humans , Inflammation/immunology , Inflammation/pathology , Kidney/cytology , Kidney/immunology , Kidney/pathology , Kidney/virology , Lung/cytology , Lung/pathology , Lung/virology , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/virology , SARS-CoV-2 , Thrombosis/complications , Thrombosis/pathology , Thrombosis/virology
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