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1.
J Ayurveda Integr Med ; 13(1): 100380, 2022.
Article in English | MEDLINE | ID: covidwho-1838951

ABSTRACT

The world is facing a global crisis and health emergency of COVID-19. Understanding of COVID-19 pathophysiology in ayurvedic host centric framework is prerequisite for apt use of Ayurveda. This paper reviews COVID-19 pathophysiology, clinical presentations and prognosis in ayurvedic perspective. Concept of exogenous pathogenic diseases can be traced in fever, microbes, toxins, epidemics and seasonal regimens chapters of Ayurveda. Such exogenous diseases later manifest multi-system presentation according to involvement of different 'Dosha' and derangement of 'Agni'. The pathology of COVID-19 is primarily that of Sannipata Jwara (fever) with involvement of respiratory system. Secondary manifestations include coagulopathies, cardiovascular, neural, and renal complications. Gastrointestinal system is closely associated with respiratory mechanism in ayurvedic pathophysiological conceptualization of Srotas. Abnormal immune responses in COVID-19 are result of abnormalities of Tridosha, Rakta (blood) and Ojus (Vital nectar). The initial phase is Vata-Kapha dominant whereas later stage of aggravated immune response is Vata-Pitta dominant. Alveolar damage, coagulopathies indicate Rakta dhatu vitiation. With this integrative understanding of COVID-19, we propose novel strategies for therapeutics and prophylaxis. Measures for 'Conservation of Agni-bala', 'Attainment of Rakta- Pitta-Prana homeostasis and 'Protection of Tri-Marma i.e. vital organs' can be important Host based strategies for reduction in the mortality in COVID-19 and for better clinical outcomes. This host centric approach can make paradigm shift in management of this epidemic.

2.
Exp Physiol ; 2021 May 31.
Article in English | MEDLINE | ID: covidwho-1807292

ABSTRACT

NEW FINDINGS: What is the topic of this review? Lactate is considered an important substrate for mitochondria in the muscles, heart and brain during exercise and is the main gluconeogenetic precursor in the liver and kidneys. In this light, we review the (patho)physiology of lactate metabolism in sepsis and coronavirus disease 2019 (COVID-19). What advances does it highlight? Elevated blood lactate is strongly associated with mortality in septic patients. Lactate seems unrelated to tissue hypoxia but is likely to reflect mitochondrial dysfunction and high adrenergic stimulation. Patients with severe COVID-19 exhibit near-normal blood lactate, indicating preserved mitochondrial function, despite a systemic hyperinflammatory state similar to sepsis. ABSTRACT: In critically ill patients, elevated plasma lactate is often interpreted as a sign of organ hypoperfusion and/or tissue hypoxia. This view on lactate is likely to have been influenced by the pioneering exercise physiologists around 1920. August Krogh identified an oxygen deficit at the onset of exercise that was later related to an oxygen 'debt' and lactate accumulation by A. V. Hill. Lactate is considered to be the main gluconeogenetic precursor in the liver and kidneys during submaximal exercise, but hepatic elimination is attenuated by splanchnic vasoconstriction during high-intensity exercise, causing an exponential increase in blood lactate. With the development of stable isotope tracers, lactate has become established as an important energy source for muscle, brain and heart tissue, where it is used for mitochondrial respiration. Plasma lactate > 4 mM is strongly associated with mortality in septic shock, with no direct link between lactate release and tissue hypoxia. Herein, we provide evidence for mitochondrial dysfunction and adrenergic stimulation as explanations for the sepsis-induced hyperlactataemia. Despite profound hypoxaemia and intense work of breathing, patients with severe coronavirus disease 2019 (COVID-19) rarely exhibit hyperlactataemia (> 2.5 mM), while presenting a systemic hyperinflammatory state much like sepsis. However, lactate dehydrogenase, which controls the formation of lactate, is markedly elevated in plasma and strongly associated with mortality in severe COVID-19. We briefly review the potential mechanisms of the lactate dehydrogenase elevation in COVID-19 and its relationship to lactate metabolism based on mechanisms established in contracting skeletal muscle and the acute respiratory distress syndrome.

3.
J Am Soc Nephrol ; 32(9): 2242-2254, 2021 09.
Article in English | MEDLINE | ID: covidwho-1702796

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
4.
Curr Pharm Biotechnol ; 23(2): 307-315, 2022.
Article in English | MEDLINE | ID: covidwho-1633212

ABSTRACT

Exposure to environmental toxicants such as Arsenic (As) can result in As-induced alterations in immune regulators. Consequently, people who are more prone to viral infections like influenza A or B, H1N1, SARS CoV (Severe Acute Respiratory Syndrome Coronavirus), and SARS CoV2 may develop a susceptibility to immune responses in their lungs because our previous reports delineated the ability of QIAPI 1®, a melanin precursor, to dissociate water molecules with simultaneous therapeutic efficacy against central nervous system (CNS) diseases, retinopathy, and As-induced renal toxicity. Considering the commonalitie of lung pathology of SARS CoV and As-induced toxicity, the aim of this study is to decipher the efficacy of QIAPI 1® against pentavalent As-induced lung toxicity by examining the pulmonary pathology. Hematoxylin & Eosin (H&E) staining was used for ascertaining the lung pathology in Wistar rat models. Animals were divided into 3 groups: control group, group treated with pentavalent As, and a group treated with pentavalent As and QIAPI 1®. There were no significant changes in lung histopathology in the control group as indicated by intact morphology. The As-treated group revealed damage to the histoarchitecture with pulmonary edema, interstitial fibrosis, diffuse alveolar damage, Bronchiolitis obliterans organizing pneumonia (BOOP)-lesions, formation of hyaline membrane, multinucleated giant pneumocytes, atypical pneumocytes, inflammatory cell infiltration, and interstitial edema. The group treated with As and QIAPI 1® significantly associated with mitigated histological signs of lung inflammation induced by Arsenic. Therefore, QIAPI 1® can be recommended as antagonistic to Asinduced lung toxicity. In conclusion, this model could be preferred as a hypothetical model to examine the efficacy of QIAPI 1® in SARS CoV2-induced pulmonary damage. Future studies are warranted to delineate the efficacy of QIAPI 1® against SARS CoV and SARS CoV2 lung pathology.


Subject(s)
Arsenic , COVID-19 , Influenza A Virus, H1N1 Subtype , Animals , Arsenic/toxicity , Humans , Lung , Rats , Rats, Wistar , SARS-CoV-2
6.
J Bras Nefrol ; 43(4): 551-571, 2021.
Article in English, Portuguese | MEDLINE | ID: covidwho-1575271

ABSTRACT

Acute kidney injury (AKI) in hospitalized patients with COVID-19 is associated with higher mortality and a worse prognosis. Nevertheless, most patients with COVID-19 have mild symptoms, and about 5% can develop more severe symptoms and involve hypovolemia and multiple organ dysfunction syndrome. In a pathophysiological perspective, severe SARS-CoV-2 infection is characterized by numerous dependent pathways triggered by hypercytokinemia, especially IL-6 and TNF-alpha, leading to systemic inflammation, hypercoagulability, and multiple organ dysfunction. Systemic endotheliitis and direct viral tropism to proximal renal tubular cells and podocytes are important pathophysiological mechanisms leading to kidney injury in patients with more critical infection, with a clinical presentation ranging from proteinuria and/or glomerular hematuria to fulminant AKI requiring renal replacement therapies. Glomerulonephritis, rhabdomyolysis, and nephrotoxic drugs are also associated with kidney damage in patients with COVID-19. Thus, AKI and proteinuria are independent risk factors for mortality in patients with SARS-CoV-2 infection. We provide a comprehensive review of the literature emphasizing the impact of acute kidney involvement in the evolutive prognosis and mortality of patients with COVID-19.


Subject(s)
Acute Kidney Injury , COVID-19 , Acute Kidney Injury/therapy , Humans , Proteinuria , Renal Replacement Therapy , SARS-CoV-2
7.
PLoS One ; 16(3): e0248956, 2021.
Article in English | MEDLINE | ID: covidwho-1574916

ABSTRACT

PURPOSE: Heterogeneity has been observed in outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of clinical phenotypes may facilitate tailored therapy and improve outcomes. The purpose of this study is to identify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes. METHODS: This is a retrospective analysis of COVID-19 patients from March 7, 2020 to August 25, 2020 at 14 U.S. hospitals. Ensemble clustering was performed on 33 variables collected within 72 hours of admission. Principal component analysis was performed to visualize variable contributions to clustering. Multinomial regression models were fit to compare patient comorbidities across phenotypes. Multivariable models were fit to estimate associations between phenotype and in-hospital complications and clinical outcomes. RESULTS: The database included 1,022 hospitalized patients with COVID-19. Three clinical phenotypes were identified (I, II, III), with 236 [23.1%] patients in phenotype I, 613 [60%] patients in phenotype II, and 173 [16.9%] patients in phenotype III. Patients with respiratory comorbidities were most commonly phenotype III (p = 0.002), while patients with hematologic, renal, and cardiac (all p<0.001) comorbidities were most commonly phenotype I. Adjusted odds of respiratory, renal, hepatic, metabolic (all p<0.001), and hematological (p = 0.02) complications were highest for phenotype I. Phenotypes I and II were associated with 7.30-fold (HR:7.30, 95% CI:(3.11-17.17), p<0.001) and 2.57-fold (HR:2.57, 95% CI:(1.10-6.00), p = 0.03) increases in hazard of death relative to phenotype III. CONCLUSION: We identified three clinical COVID-19 phenotypes, reflecting patient populations with different comorbidities, complications, and clinical outcomes. Future research is needed to determine the utility of these phenotypes in clinical practice and trial design.


Subject(s)
COVID-19/complications , COVID-19/epidemiology , Phenotype , Aged , Comorbidity , Female , Humans , Male , Middle Aged , Retrospective Studies
8.
Clin J Am Soc Nephrol ; 16(11): 1755-1765, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526737

ABSTRACT

Despite evidence of multiorgan tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV2 can directly infect the kidney is relevant to the understanding of pathogenesis of AKI and collapsing glomerulopathy in patients with COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, RT-PCR, in situ hybridization, and electron microscopy. In our review of studies to date, we found that SARS-CoV-2 in the kidneys of patients with COVID-19 was detected in 18 of 94 (19%) by immunohistochemistry, 71 of 144 (49%) by RT-PCR, and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed because many other studies have been negative for SARS-CoV-2 and it should be noted that when detected, it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19-associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a noninvasive way to evaluate SARS-CoV-2 infection during the evolution of COVID-19-associated kidney disease.


Subject(s)
COVID-19/virology , Kidney Diseases/virology , Kidney/virology , SARS-CoV-2/pathogenicity , Animals , Biopsy , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , COVID-19 Testing , Host-Pathogen Interactions , Humans , Kidney Diseases/diagnosis , Kidney Diseases/mortality , Predictive Value of Tests , Prognosis , Risk Assessment , Risk Factors
9.
Pediatr Nephrol ; 36(9): 2627-2638, 2021 09.
Article in English | MEDLINE | ID: covidwho-1520348

ABSTRACT

BACKGROUND AND OBJECTIVES: COVID-19 is responsible for the 2019 novel coronavirus disease pandemic. Despite the vast research about the adult population, there has been little data collected on acute kidney injury (AKI) epidemiology, associated risk factors, treatments, and mortality in pediatric COVID-19 patients admitted to the ICU. AKI is a severe complication of COVID-19 among children and adolescents. METHODS: A comprehensive literature search was conducted in PubMed/MEDLINE and Cochrane Center Trials to find all published literature related to AKI in COVID-19 patients, including incidence and outcomes. RESULTS: Twenty-four studies reporting the outcomes of interest were included. Across all studies, the overall sample size of COVID positive children was 1,247 and the median age of this population was 9.1 years old. Among COVID positive pediatric patients, there was an AKI incidence of 30.51%, with only 0.56% of these patients receiving KRT. The mortality was 2.55% among all COVID positive pediatric patients. The incidence of multisystem inflammatory syndrome in children (MIS-C) among COVID positive patients was 74.29%. CONCLUSION: AKI has shown to be a negative prognostic factor in adult patients with COVID-19 and now also in the pediatric cohort with high incidence and mortality rates. Additionally, our findings show a strong comparison in epidemiology between adult and pediatric COVID-19 patients; however, they need to be confirmed with additional data and studies.


Subject(s)
Acute Kidney Injury/epidemiology , COVID-19/complications , Intensive Care Units/statistics & numerical data , Renal Replacement Therapy/statistics & numerical data , Systemic Inflammatory Response Syndrome/complications , Acute Kidney Injury/immunology , Acute Kidney Injury/therapy , Acute Kidney Injury/virology , Adult , Age Factors , COVID-19/diagnosis , COVID-19/immunology , COVID-19/mortality , Child , Hospital Mortality , Humans , Incidence , Pandemics/statistics & numerical data , Risk Factors , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/mortality
10.
J Clin Med ; 10(8)2021 Apr 08.
Article in English | MEDLINE | ID: covidwho-1526823

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to 5% to 16% hospitalization in intensive care units (ICU) and is associated with 23% to 75% of kidney impairments, including acute kidney injury (AKI). The current work aims to precisely characterize the renal impairment associated to SARS-CoV-2 in ICU patients. Forty-two patients consecutively admitted to the ICU of a French university hospital who tested positive for SARS-CoV-2 between 25 March 2020, and 29 April 2020, were included and classified in categories according to their renal function. Complete renal profiles and evolution during ICU stay were fully characterized in 34 patients. Univariate analyses were performed to determine risk factors associated with AKI. In a second step, we conducted a logistic regression model with inverse probability of treatment weighting (IPTW) analyses to assess major comorbidities as predictors of AKI. Thirty-two patients (94.1%) met diagnostic criteria for intrinsic renal injury with a mixed pattern of tubular and glomerular injuries within the first week of ICU admission, which lasted upon discharge. During their ICU stay, 24 patients (57.1%) presented AKI which was associated with increased mortality (p = 0.007), hemodynamic failure (p = 0.022), and more altered clearance at hospital discharge (p = 0.001). AKI occurrence was associated with lower pH (p = 0.024), higher PaCO2 (CO2 partial pressure in the arterial blood) (p = 0.027), PEEP (positive end-expiratory pressure) (p = 0.027), procalcitonin (p = 0.015), and CRP (C-reactive protein) (p = 0.045) on ICU admission. AKI was found to be independently associated with chronic kidney disease (adjusted OR (odd ratio) 5.97 (2.1-19.69), p = 0.00149). Critical SARS-CoV-2 infection is associated with persistent intrinsic renal injury and AKI, which is a risk factor of mortality. Mechanical ventilation settings seem to be a critical factor of kidney impairment.

11.
Kidney Med ; 3(3): 426-432, 2021.
Article in English | MEDLINE | ID: covidwho-1525989

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented and historic public health crisis that continues to expand and evolve. The National Kidney Foundation held a 2-part continuing medical education live virtual symposium on July 16 and July 24, 2020, to address the multiple challenges of COVID-19 in the context of advanced chronic kidney disease. Faculty addressed the pathophysiology, impact, risks, and management of COVID-19 as it relates to advanced kidney disease. Testing, risk mitigation, and inpatient and outpatient management were also addressed. This concise review addresses major findings of the symposium along with certain updates regarding vaccinations since then. These findings include: (1) severe COVID-19 infection has been associated with acute kidney injury, (2) it is essential to prevent and actively manage acute kidney injury to decrease mortality in these critically ill patients, (3) management of patients with advanced kidney disease should be geared toward minimizing their risk for exposure while making sure they are receiving adequate treatments, and (4) patients with kidney disease, especially ones in advanced stages, should be prioritized for vaccination.

12.
J Am Soc Nephrol ; 2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1496674

ABSTRACT

BACKGROUND: Although zebrafish embryos have been used to study ciliogenesis and model polycystic kidney disease (PKD), adult zebrafish remain unexplored. METHODS: Transcription activator-like effector nucleases (TALEN) technology was used to generate mutant for tmem67, the homolog of the mammalian causative gene for Meckel syndrome type 3 (MKS3). Classic 2D and optical-clearing 3D imaging of an isolated adult zebrafish kidney were used to examine cystic and ciliary phenotypes. A hypomorphic mtor strain or rapamycin was used to inhibit mTOR activity. RESULTS: Adult tmem67 zebrafish developed progressive mesonephric cysts that share conserved features of mammalian cystogenesis, including a switch of cyst origin with age and an increase in proliferation of cyst-lining epithelial cells. The mutants had shorter and fewer distal single cilia and greater numbers of multiciliated cells (MCCs). Absence of a single cilium preceded cystogenesis, and expansion of MCCs occurred after pronephric cyst formation and was inversely correlated with the severity of renal cysts in young adult zebrafish, suggesting a primary defect and an adaptive action, respectively. Finally, the mutants exhibited hyperactive mTOR signaling. mTOR inhibition ameliorated renal cysts in both the embryonic and adult zebrafish models; however, it only rescued ciliary abnormalities in the adult mutants. CONCLUSIONS: Adult zebrafish tmem67 mutants offer a new vertebrate model for renal cystic diseases, in which cilia morphology can be analyzed at a single-nephron resolution and mTOR inhibition proves to be a candidate therapeutic strategy.

13.
J Am Soc Nephrol ; 32(1): 41-51, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496668

ABSTRACT

BACKGROUND: Mutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood. METHODS: Unbiased transcriptional profiling in an adult-onset Pkd2 mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in Pkd2 single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. In vivo studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and Pkd2/Ift88 double-knockout mice that are protected from cyst growth served as controls. RESULTS: The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. Cdk1 appeared as a central component in this analysis. Cdk1 expression was similarly dysregulated in Pkd1 models of ADPKD, and conditional inactivation of Cdk1 with Pkd1 markedly improved the cystic phenotype and kidney function compared with inactivation of Pkd1 alone. The Pkd1/Cdk1 double knockout blocked cyst cell proliferation that otherwise accompanied Pkd1 inactivation alone. CONCLUSIONS: Dysregulation of Cdk1 is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of Pkd1.


Subject(s)
CDC2 Protein Kinase/metabolism , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/metabolism , TRPP Cation Channels/metabolism , Animals , Apoptosis , CDC2 Protein Kinase/genetics , Catalytic Domain , Cell Proliferation , Crosses, Genetic , DNA Replication , Female , Gene Expression Profiling , Gene Expression Regulation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Phenotype , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , RNA-Seq , TRPP Cation Channels/genetics , Transcription, Genetic , Whole Exome Sequencing
14.
J Am Soc Nephrol ; 32(1): 115-126, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496665

ABSTRACT

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.


Subject(s)
Biomarkers/blood , Diabetic Nephropathies/genetics , Kidney Failure, Chronic/genetics , Renal Insufficiency, Chronic/genetics , Adult , Aged , Chemokine CCL2/blood , Chitinase-3-Like Protein 1/blood , Cohort Studies , Diabetic Nephropathies/blood , Disease Progression , Female , Glomerular Filtration Rate , Hepatitis A Virus Cellular Receptor 1/blood , Humans , Kidney Failure, Chronic/blood , Male , Middle Aged , Phenotype , Prevalence , Receptors, Tumor Necrosis Factor, Type I/blood , Receptors, Tumor Necrosis Factor, Type II/blood , Receptors, Urokinase Plasminogen Activator/blood , Renal Insufficiency, Chronic/blood , Risk , Young Adult
15.
J Am Soc Nephrol ; 32(1): 69-85, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496661

ABSTRACT

BACKGROUND: In children, the acute pyelonephritis that can result from urinary tract infections (UTIs), which commonly ascend from the bladder to the kidney, is a growing concern because it poses a risk of renal scarring and irreversible loss of kidney function. To date, the cellular mechanisms underlying acute pyelonephritis-driven renal scarring remain unknown. METHODS: We used a preclinical model of uropathogenic Escherichia coli-induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis. We used cell-specific monoclonal antibodies to eliminate neutrophils, monocytes, or both. Bacterial ascent and the cell dynamics of phagocytic cells were assessed by biophotonic imaging and flow cytometry, respectively. We used quantitative RT-PCR and histopathologic analyses to evaluate inflammation and renal scarring. RESULTS: We found that neutrophils are critical to control bacterial ascent, which is in line with previous studies suggesting a protective role for neutrophils during a UTI, whereas monocyte-derived macrophages orchestrate a strong, but ineffective, inflammatory response against uropathogenic, E. coli-induced, acute pyelonephritis. Experimental neutropenia during acute pyelonephritis resulted in a compensatory increase in the number of monocytes and heightened macrophage-dependent inflammation in the kidney. Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium. CONCLUSIONS: These findings reveal a previously unappreciated outcome for neutrophil-macrophage imbalance in promoting host susceptibility to acute pyelonephritis and the development of permanent renal damage. This suggests targeting dysregulated macrophage responses might be a therapeutic tool to prevent renal scarring during acute pyelonephritis.


Subject(s)
Cicatrix/physiopathology , Kidney/physiopathology , Macrophages/cytology , Neutrophils/cytology , Pyelonephritis/metabolism , Animals , Escherichia coli , Female , Fibrosis/microbiology , Fibrosis/physiopathology , Inflammation , Kidney/microbiology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Neutrophils/metabolism , Phagocytosis , Pyelonephritis/microbiology , Pyelonephritis/physiopathology , Urinary Tract Infections/microbiology , Urinary Tract Infections/physiopathology
16.
J Am Soc Nephrol ; 32(2): 375-384, 2021 02.
Article in English | MEDLINE | ID: covidwho-1496655

ABSTRACT

BACKGROUND: Recent clinical studies report that women with a history of AKI have an increased incidence of maternal and fetal adverse outcomes during pregnancy, despite fully recovering renal function prior to conception. The mechanisms contributing to such adverse outcomes in pregnancy after AKI are not yet understood. METHODS: To develop a rodent model to investigate fetal and maternal outcomes in female animals with a history of AKI, we used ischemia-reperfusion injury as an experimental model of AKI in female Sprague Dawley rats. The 12-week-old animals underwent warm bilateral ischemia-reperfusion surgery involving clamping of both renal arteries for 45 minutes or sham surgery (control). Rats were allowed to recover for 1 month prior to mating. Recovery from ischemia-reperfusion injury was confirmed by measurements of plasma creatinine and urinary protein excretion. We assessed maternal and fetal outcomes during late pregnancy on gestational day 20. RESULTS: After recovery from ischemia-reperfusion injury, compared with healthy sham-surgery controls, dams exhibited pregnancy-induced renal insufficiency with increases in plasma creatinine and urea, along with increased urinary protein excretion. Additionally, recovered ischemia-reperfusion dams experienced worse fetal outcomes compared with controls, with intrauterine growth restriction leading to higher rates of fetal demise and smaller pups. CONCLUSIONS: In this rat model, despite biochemical resolution of ischemia-reperfusion injury, subsequent pregnancy resulted in maternal renal insufficiency and significant impairments in fetal growth. This mirrors findings in recent reports in the clinical population, indicating that this model may be a useful tool to further explore the alterations in kidney function after AKI in women.


Subject(s)
Acute Kidney Injury/etiology , Pregnancy Complications/etiology , Reperfusion Injury/etiology , Animals , Disease Models, Animal , Female , Kidney Function Tests , Ligation , Pregnancy , Rats , Rats, Sprague-Dawley , Renal Artery/surgery
17.
Antimicrob Agents Chemother ; 65(7): e0009721, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1486469

ABSTRACT

Efforts to mitigate the coronavirus disease 2019 (COVID-19) pandemic include the screening of existing antiviral molecules that could be repurposed to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Although SARS-CoV-2 replicates and propagates efficiently in African green monkey kidney (Vero) cells, antivirals such as nucleos(t)ide analogs (NUCs) often show decreased activity in these cells due to inefficient metabolization. SARS-CoV-2 exhibits low viability in human cells in culture. Here, serial passages of a SARS-CoV-2 isolate (original-SARS2) in the human hepatoma cell clone Huh7.5 led to the selection of a variant (adapted-SARS2) with significantly improved infectivity in human liver (Huh7 and Huh7.5) and lung cancer (unmodified Calu-1 and A549) cells. The adapted virus exhibited mutations in the spike protein, including a 9-amino-acid deletion and 3 amino acid changes (E484D, P812R, and Q954H). E484D also emerged in Vero E6-cultured viruses that became viable in A549 cells. Original and adapted viruses were susceptible to scavenger receptor class B type 1 (SR-B1) receptor blocking, and adapted-SARS2 exhibited significantly less dependence on ACE2. Both variants were similarly neutralized by COVID-19 convalescent-phase plasma, but adapted-SARS2 exhibited increased susceptibility to exogenous type I interferon. Remdesivir inhibited original- and adapted-SARS2 similarly, demonstrating the utility of the system for the screening of NUCs. Among the tested NUCs, only remdesivir, molnupiravir, and, to a limited extent, galidesivir showed antiviral effects across human cell lines, whereas sofosbuvir, ribavirin, and favipiravir had no apparent activity. Analogously to the emergence of spike mutations in vivo, the spike protein is under intense adaptive selection pressure in cell culture. Our results indicate that the emergence of spike mutations will most likely not affect the activity of remdesivir.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/pharmacology , Chlorocebus aethiops , Humans , Pandemics , Spike Glycoprotein, Coronavirus , Virus Replication
18.
Phytother Res ; 35(10): 5417-5426, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1479439

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first occurred in China in December 2019 and subsequently spread all over the world with cardiovascular, renal, and pulmonary symptoms. Therefore, recognizing and treating the cardiovascular sign and symptoms that caused by coronavirus disease 2019 (COVID-19) can be effective in reducing patient mortality. To control the COVID-19-related cardiovascular symptoms, natural products are considered one of the promising choices as complementary medicine. Scientists are struggling to discover new antiviral agents specific to this virus. In this review, the natural products for management of cardiovascular symptoms of COVID-19 are categorized into three groups: (a) natural products with an impact on angiotensin II type 1 receptor; (b) natural products that inhibit angiotensin-converting enzyme activity; and (c) natural products that mimic adenosine activity. All these natural products should undergo clinical investigations to test their efficacy, safety, and toxicity in the treatment of cardiovascular symptoms of COVID-19. This article summarizes agents with potential efficacy against COVID-19-related cardiovascular symptoms.


Subject(s)
Biological Products , COVID-19 , Angiotensin-Converting Enzyme Inhibitors , Antiviral Agents/therapeutic use , Biological Products/therapeutic use , Humans , SARS-CoV-2
19.
Adv Nutr ; 11(4): 1002-1015, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-1455233

ABSTRACT

The prevalence of chronic kidney disease (CKD) is increasing and dietary interventions may be a strategy to reduce this burden. In the general population, higher potassium intake is considered protective for cardiovascular health. Due to the risk of hyperkalemia in CKD, limiting potassium intake is often recommended. However, given that poor cardiovascular function can cause kidney damage, following a low-potassium diet may be deleterious for patients with CKD. The aim of this systematic review was to summarize the evidence on dietary potassium intake and CKD progression. Multiple databases were searched on 7 June 2019 and data were managed with Covidence. No intervention trials met the inclusion criteria. Eleven observational studies met the inclusion criteria (10 post hoc analyses, 1 retrospective cohort), representing 49,573 stage 1-5 predialysis patients with CKD from 41 different countries. Of the 11 studies, 6 studies reported exclusively on early CKD (stage 1-2), 4 studies separately reported analyses on both early and late (stage 3-5) CKD, and 2 studies reported exclusively on late CKD. A total of 9 studies reported risk of disease progression in early CKD; in 4 studies high potassium intake was associated with lower risk, while in 2 studies the low intake showed a higher progression of risk, and 3 studies reported no relation. In late CKD, results are mixed: 2 studies suggested benefit of higher potassium intake and 1 suggested benefit of lower potassium intake, whereas 3 studies were neutral. These results should be interpreted with caution, as considerations preventing firm conclusions include 1) the overall low range of dietary potassium intake, with all studies reporting an average intake below the 2004 Kidney Disease Outcomes Quality Initiatives guidelines, and 2) the method used to assess potassium intake in most studies (i.e., urine) in late stages of CKD. Ideally, well-controlled intervention studies are needed to understand how dietary potassium intake is linked to CKD progression.


Subject(s)
Potassium, Dietary , Renal Insufficiency, Chronic , Humans , Kidney , Nutritional Status , Retrospective Studies
20.
Biochem Biophys Res Commun ; 2020 Feb 17.
Article in English | MEDLINE | ID: covidwho-1454030

ABSTRACT

2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.

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