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1.
J Am Soc Nephrol ; 33(2): 326-341, 2022 02.
Article in English | MEDLINE | ID: covidwho-2141035

ABSTRACT

BACKGROUND: Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). METHODS: The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. RESULTS: Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. CONCLUSIONS: Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1ß via NLRP3 inflammasome signaling and Na+-K+-ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.


Subject(s)
Acute Kidney Injury/drug therapy , Hypoxanthine Phosphoribosyltransferase/metabolism , Organic Anion Transporters/deficiency , Urate Oxidase/deficiency , Xanthine Dehydrogenase/antagonists & inhibitors , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Allopurinol/pharmacology , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Hypoxanthine Phosphoribosyltransferase/genetics , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Nitriles/pharmacology , Organic Anion Transporters/genetics , Physical Exertion , Pyridines/pharmacology , Renal Tubular Transport, Inborn Errors/drug therapy , Renal Tubular Transport, Inborn Errors/etiology , Renal Tubular Transport, Inborn Errors/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Urate Oxidase/genetics , Urinary Calculi/drug therapy , Urinary Calculi/etiology , Urinary Calculi/metabolism
2.
Adv Chronic Kidney Dis ; 29(6): 520-525, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2115727

ABSTRACT

Kidney pathology education is a critical component in training of nephrology fellows, as well as for continuing medical education for practicing nephrologists. Kidney pathology images are included on nephrology fellow board exams, and clinicopathologic correlation of kidney biopsy findings is critical in everyday clinical practice. Nephropathology training is a requirement by the American College of Graduate Medical Education within nephrology fellowship curricula. However, greater than one-third of fellowship program directors believe that nephropathology training for their fellows is not sufficient. During the Coronavirus Disease-19 pandemic, the use of digital learning has become commonplace with virtual conferences (local, national, and international) and online meetings becoming the norm for education. Nephrology has become a leader in free open-access online medical education, both prior to and, to even a greater extent, during the pandemic. Here, we review available resources to nephrology fellows and other learners to supplement nephropathology training, which includes medical blogs, journal clubs, interactive quizzes and games, online conferences, podcasts, and mentorship opportunities. These resources are archived and provide durable content to learners of all stages of training, even beyond the pandemic.


Subject(s)
COVID-19 , Nephrology , Humans , United States , Nephrology/education , COVID-19/epidemiology , Fellowships and Scholarships , Education, Medical, Graduate/methods , Kidney/pathology , Curriculum
3.
Ter Arkh ; 94(6): 769-771, 2022 Aug 04.
Article in Russian | MEDLINE | ID: covidwho-2044339

ABSTRACT

The presented clinical observation reflects the difficulties of differential diagnosis of progressive kidney damage in a patient with sarcoidosis who has undergone a new coronavirus infection. The differential circle included interstitial nephritis as an exacerbation of the underlying disease, acute drug-induced kidney injury, acute glomerulonephritis. Nephrobiopsy confirmed the diagnosis of acute sarcoid tubulointerstitial nephritis with acute tubular necrosis. Timely administration of corticosteroids led to the control of the sarcoidosis process, restoration of kidney function.


Subject(s)
COVID-19 , Nephritis, Interstitial , Sarcoidosis , Humans , COVID-19/diagnosis , Nephritis, Interstitial/diagnosis , Nephritis, Interstitial/drug therapy , Nephritis, Interstitial/etiology , Sarcoidosis/complications , Sarcoidosis/diagnosis , Sarcoidosis/drug therapy , Adrenal Cortex Hormones/therapeutic use , Kidney/pathology
4.
Front Immunol ; 13: 950076, 2022.
Article in English | MEDLINE | ID: covidwho-2022732

ABSTRACT

Renal injury secondary to COVID-19 is an important factor for the poor prognosis of COVID-19 patients. The pathogenesis of renal injury caused by aberrant immune inflammatory of COVID-19 remains unclear. In this study, a total of 166 samples from 4 peripheral blood transcriptomic datasets of COVID-19 patients were integrated. By using the weighted gene co-expression network (WGCNA) algorithm, we identified key genes for mild, moderate, and severe COVID-19. Subsequently, taking these genes as input genes, we performed Short Time-series Expression Miner (STEM) analysis in a time consecutive ischemia-reperfusion injury (IRI) -kidney dataset to identify genes associated with renal injury in COVID-19. The results showed that only in severe COVID-19 there exist a small group of genes associated with the progression of renal injury. Gene enrichment analysis revealed that these genes are involved in extensive immune inflammation and cell death-related pathways. A further protein-protein interaction (PPI) network analysis screened 15 PPI-hub genes: ALOX5, CD38, GSF3R, LGR, RPR1, HCK, ITGAX, LYN, MAPK3, NCF4, SELP, SPI1, WAS, TLR2 and TLR4. Single-cell sequencing analysis indicated that PPI-hub genes were mainly distributed in neutrophils, macrophages, and dendritic cells. Intercellular ligand-receptor analysis characterized the activated ligand-receptors between these immune cells and parenchyma cells in depth. And KEGG enrichment analysis revealed that viral protein interaction with cytokine and cytokine receptor, necroptosis, and Toll-like receptor signaling pathway may be potentially essential for immune cell infiltration leading to COVID-19 renal injury. Finally, we validated the expression pattern of PPI-hub genes in an independent data set by random forest. In addition, we found that the high expression of these genes was correlated with a low glomerular filtration rate. Including them as risk genes in lasso regression, we constructed a Nomogram model for predicting severe COVID-19. In conclusion, our study explores the pathogenesis of renal injury promoted by immunoinflammatory in severe COVID-19 and extends the clinical utility of its key genes.


Subject(s)
COVID-19 , Computational Biology , Biomarkers, Tumor/genetics , COVID-19/genetics , Computational Biology/methods , Humans , Kidney/pathology , Ligands
5.
PLoS One ; 17(8): e0272237, 2022.
Article in English | MEDLINE | ID: covidwho-2002304

ABSTRACT

OBJECTIVE: By analyzing the pathological characteristics and clinical data of renal biopsy in our hospital in the past 20 years, to further understand the epidemic characteristics and pathological changes of primary glomerular disease, and to provide regional data for the big data of kidney disease in my country. METHODS: A retrospective analysis of 9448 patients with primary glomerular disease who were hospitalized in our hospital from January 1, 2000 to December 31, 2019, aged 18 years or older, and undergoing renal biopsy. Divided every 5 years into a group, a total of 4 groups (first group 2000.1.1-2004.12.31, second groups 2005.1.1-2009.12.31; third groups 2010.1.1-2014.12.31, fourth groups 2015.1.1-2019.12.31). RESULTS: ① There were more males than females, and male: female vs 1.53:1. The proportion of men in the past five years has increased compared with the previous 15 years. ② Mostly middle-aged, with a median age of 41.39 years old. The age is increasing over time. There are differences between the four groups, P <0.001; ③ The most common clinical manifestations are nephrotic syndrome, followed by chronic glomerulonephritis. Occult glomerulonephritis, the proportion of patients with nephrotic syndrome increases over time, first to fourth group (40.08%< 42.64% < 47.08%< 53.69%); ④ The most common pathology type from 2000 to 2009 was mesangial proliferative glomerulonephritis. IgA nephropathy was the most common type from 2010 to 2014, but the proportion of membranous nephropathy increased year by year, and it became the most common pathological type from 2015 to 2019; ⑤ The clinical and pathological manifestations of different genders are different, but there is no statistical difference. CONCLUSION: In the past 20 years, the primary glomerular disease is mainly middle-aged. There are more men than women. The most common type of clinical manifestation is nephrotic syndrome. The pathological type is mesangial proliferative glomerulonephritis. Over time, the average age is increasing, and the proportion of patients with renal syndrome is increasing. IgA nephropathy is the most common pathological type from 2010 to 2014, and membranous nephropathy has become the main pathological type in the past 5 years.


Subject(s)
Glomerulonephritis, IGA , Glomerulonephritis, Membranous , Glomerulonephritis , Nephrotic Syndrome , Vascular Diseases , Adult , Biopsy , Female , Glomerulonephritis/epidemiology , Glomerulonephritis/pathology , Glomerulonephritis, IGA/epidemiology , Glomerulonephritis, IGA/pathology , Glomerulonephritis, Membranous/epidemiology , Glomerulonephritis, Membranous/pathology , Humans , Kidney/pathology , Male , Middle Aged , Nephrotic Syndrome/epidemiology , Nephrotic Syndrome/pathology , Retrospective Studies , Vascular Diseases/pathology
6.
J Nephrol ; 35(9): 2387-2389, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2000171

ABSTRACT

Due to the many implemented restrictions, the SARS-CoV-2 pandemic has rendered some tasks more difficult, for instance, the evaluation of outpatients. Panama's tertiary care hospital for kidney biopsy referral was transformed into a COVID-only hospital in order to assist the large number of COVID-19 patients. In order to face the impossibility of following patients with nephrotic or nephritic syndrome, a biopsy program was implemented in a southern province in Panama. Thirty kidney biopsies were carried out over a 1-year period. This experience shows that kidney biopsy programs, that are usually run only in large referral centers, can also be implemented in small nephrology centers, allowing to obtain accurate diagnoses and to guide correct treatment.


Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Pandemics , Kidney/pathology , SARS-CoV-2 , Biopsy , Panama/epidemiology
7.
Saudi J Kidney Dis Transpl ; 32(6): 1523-1544, 2021.
Article in English | MEDLINE | ID: covidwho-1975051

ABSTRACT

The major targets of coronavirus disease 2019 (COVID-19) are the respiratory and immune systems. However, a significant proportion of hospitalized patients had kidney dysfunction. The histopathological surveys have principally focused on respiratory, hematopoietic, and immune systems, whereas histopathologic data of kidney injury are lacking. Our study aimed to summarize the renal histopathological findings in COVID-19 from the published case report and case series. We conducted a systematic searching of databases such as MEDLINE, EMBASE, and Cochrane Library for published reports of COVID-19 patients with renal histopathological changes from autopsy studies and from "for cause" indication biopsies. Included in our study are case reports and case series with extractable quantitative data on patient demographics such as age, sex, ethnicity, as well as data on renal function tests, their comorbidities, and biopsy to study the histopathological changes. Data were analyzed with Microsoft Excel. To evaluate the methodological quality, we chose the framework for appraisal, synthesis, and application of evidence suggested by Murad et al. Systematic searches of literature found 31 studies that fulfilled the eligibility criteria. These studies included a total of 139 cases, where individual case details including clinical and histopathological findings were available. The median age of the cases was 62 years with a male:female ratio of 2.5:1. Associated comorbidities were noted in 78.4% of cases. The majority of the cases had renal dysfunction with proteinuria which was documented in more than two-thirds of the cases. The histopathological findings observed the frequent tubular involvement manifested by acute tubular injury. Regarding glomerular pathology, collapsing glomerulopathy emerged as a distinct lesion in these patients and was noted among 46.8% of cases with glomerular lesions. A small subset of cases (4.3%) had thrombotic microangiopathy. Collapsing glomerulopathy emerged as a hallmark of glomerular changes among COVID-19 patients. Tubular damage is common and is linked to multiple factors including ischemia, sepsis among others. In the form of thrombotic microangiopathy seen in a subset of patients, vascular damage hints toward the hyper-coagulable state associated with the infection. The demonstration of viral particles in renal tissue remains debatable and requires further study.


Subject(s)
COVID-19 , Kidney Diseases , Thrombotic Microangiopathies , Female , Humans , Kidney/pathology , Kidney/physiology , Kidney Diseases/pathology , Kidney Glomerulus/pathology , Male , Middle Aged , Proteinuria/etiology , Thrombotic Microangiopathies/complications
8.
J Investig Med High Impact Case Rep ; 10: 23247096221114517, 2022.
Article in English | MEDLINE | ID: covidwho-1968530

ABSTRACT

Acute kidney injury (AKI) in patients with coronavirus disease 2019 (COVID-19) is common, especially among severely ill patients. While acute tubular necrosis (ATN) is one of the most common findings in published kidney biopsy series for patients with COVID-19 infections, a number of glomerular pathologies have been described as well. Among glomerular pathologies in COVID-19, COVID-19-Associated Collapsing Glomerulopathy (COVAN) remains the most common pattern of injury. Patients with 2 high-risk APOL1 alleles appear to be at increased risk for COVAN, similar to other forms of collapsing glomerulopathy such as HIV-Associated Nephropathy. Acute interstitial nephritis (AIN) is a less common finding in patients with COVID-19 and reported cases have been mild. Reports of a subtype of AIN, granulomatous interstitial nephritis (GIN), among COVID-19 patients are extremely rare and have not been reported in association with COVAN. Here, we report a case of COVAN associated with severe GIN.


Subject(s)
Acute Kidney Injury , COVID-19 , Nephritis, Interstitial , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Apolipoprotein L1 , COVID-19/complications , Granuloma/complications , Humans , Kidney/pathology , Nephritis, Interstitial/etiology , Nephritis, Interstitial/pathology
9.
Front Immunol ; 13: 835156, 2022.
Article in English | MEDLINE | ID: covidwho-1902991

ABSTRACT

Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19.


Subject(s)
COVID-19/immunology , Complement Pathway, Alternative/immunology , Lectins/immunology , Aged , Aged, 80 and over , Autopsy , COVID-19/pathology , COVID-19/virology , Complement System Proteins/immunology , Female , Humans , Kidney/immunology , Kidney/pathology , Kidney/virology , Lung/immunology , Lung/pathology , Lung/virology , Male , Middle Aged , Neutrophils/immunology , Peroxidase/immunology , SARS-CoV-2/immunology
10.
Front Cell Infect Microbiol ; 12: 865283, 2022.
Article in English | MEDLINE | ID: covidwho-1822357

ABSTRACT

Nephropathogenic infectious bronchitis virus (NIBV) is one of the most important viral pathogens in the world poultry industry. Here, we used RT-qPCR, WB and immunofluorescence to explore the interaction between NIBV and the host innate immune system of the kidney. Multiple virions were found in the kidney tissues of the disease group under electron microscopy, and pathological changes such as structural damage of renal tubules and bleeding were observed by HE staining. In addition, we found that the mRNA levels of TLR7, TRAF6, and IKKß were upregulated after NIBV infection. IRF7 mRNA levels decreased significantly at 5 dpi and increased significantly at 11 to 18 dpi. The NF-κB P65 mRNA level increased significantly at 5 to 18 dpi and decreased at 28 dpi. However, NIBV infection-induced NF-κB P65 protein levels were downregulated at multiple time points. Moreover, we demonstrated that the cytokine (IFN-γ, IL-8, and IL-6) mRNA and protein expression levels were increased significantly at multiple time points after NIBV infection. Furthermore, immunofluorescence analysis showed that NF-κB P65 and IFN-γ were mainly located in the nuclear or perinuclear region. The positive signal intensity of NF-κB P65 was significantly lower than that of the normal group at 1 to 5 dpi, and there was no significant change in the subsequent time period. The positive signal intensity of IFN-γ decreased significantly at 5 dpi, and increased significantly at 11 to 28 dpi. In conclusion, we found that NIBV promoted cytokine release through the TLR7/NF-κB signaling axis, thus causing kidney injury.


Subject(s)
Infectious bronchitis virus , Animals , Chickens , Cytokines/metabolism , Infectious bronchitis virus/metabolism , Kidney/pathology , NF-kappa B/metabolism , RNA, Messenger/metabolism , Toll-Like Receptor 7/genetics
11.
Medicine (Baltimore) ; 101(7): e28754, 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1746192

ABSTRACT

RATIONALE: Kidney involvement with COVID-19 infection is a well-known complication, and the majority of kidney involvement is related to ischemic injury/acute tubular injury. However, there are some cases of glomerulonephritis, the etiology of which is not yet known, but an immune process is likely to be the trigger. PATIENT CONCERNS: A 27-year-old man presented to our hospital with facial puffiness and lower-limb swelling. DIAGNOSIS: Laboratory assessment revealed features of impaired kidney function with proteinuria and hematuria; COVID-19 polymerase chain reaction was positive, which was consistent with pauci-immune crescentic focal segmental glomerulonephritis. INTERVENTION: After renal biopsy, the patient was started on methylprednisolone and rituximab. Due to worsening kidney parameters, he underwent intermittent hemodialysis as needed. OUTCOME: Kidney function tests partially improved; he was discharged on oral steroids with follow-up in the nephrology clinic to observe for the need for further hemodialysis. LESSONS: We conducted a literature review of cases of glomerulonephritis associated with COVID-19 and described numerous types of glomerulonephritis. This report highlights the importance of recognizing emerging glomerulonephritis with COVID-19, the different pathological patterns of renal biopsies, and management interventions and responses.


Subject(s)
COVID-19 , Glomerulonephritis, Membranoproliferative , Glomerulonephritis , Acute Disease , Adult , COVID-19/complications , Glomerulonephritis/complications , Glomerulonephritis, Membranoproliferative/pathology , Humans , Kidney/pathology , Male
12.
Transplant Proc ; 54(6): 1465-1470, 2022.
Article in English | MEDLINE | ID: covidwho-1713002

ABSTRACT

BACKGROUND: Collapsing glomerulopathy (CGN) secondary to HIV or COVID-19 infection mainly occurs in patients of African American descent due to APOL-1 gene mutations, but CGN is occasionally reported in white patients. CGNs are rarely reported in renal transplant biopsies and their association with idiopathic focal segmental glomerulosclerosis (FSGS) is unclear. METHODS AND RESULTS: Patient #1 was a 48-year-old Caucasian white man who had a renal transplant 8 years ago and was recently diagnosed with COVID-19 infection. Two weeks post infection, his serum creatinine (SCr) increased to 2.01 mg/dL from a baseline of 1.40 mg/dL, and he developed concomitant nephrotic range proteinuria. The first renal transplant biopsy showed FSGS. Four weeks later, his sCr level increased to 2.65 mg/dL with worsening proteinuria, and a second renal transplant biopsy revealed CGN. Patient #2 was a 32-year-old African American man whose native renal biopsy revealed primary FSGS. He received a renal transplant with initial post-transplant sCr level at 1.17 mg/dL. Four months later, his sCr and protein-to-creatinine ratio began to rise. Sequential biopsies revealed that the patient had developed recurrent FSGS, which progressed to show features of CGN. The CGN was further confirmed in his transplant kidney graft at autopsy later. CONCLUSIONS: This is the first case report of CGN in a white renal recipient with COVID-19 infection. The pathologic presentations of FSGS progressing to collapsing FSGS in our 2 renal transplant recipients suggest that FSGS and GGN may share a common pathophysiologic mechanism of podocytopathy.


Subject(s)
COVID-19 , Glomerulosclerosis, Focal Segmental , Kidney Diseases , Kidney Transplantation , Adult , Creatinine , Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kidney/pathology , Kidney Diseases/pathology , Kidney Transplantation/adverse effects , Male , Middle Aged , Proteinuria/complications
13.
Adv Clin Exp Med ; 31(3): 317-326, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1709668

ABSTRACT

Acute kidney injury occurs in about 30% of patients hospitalized with coronavirus disease 2019 (COVID-19) and is one of the most common extrapulmonary complications of this disease. The highest risk of acute kidney injury is found in hospitalized patients who require mechanical ventilation. The pathogenesis of acute kidney injury in COVID-19 is multifactorial and seems to not be fully understood. Both direct and indirect mechanisms of kidney injury caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be considered. The histological picture of kidney specimens obtained from patients with acute kidney injury in the course of COVID-19 is dominated by acute tubular necrosis. Some patients also have acute interstitial nephritis, blood clots in the kidney vessels and focal segmental glomerulosclerosis (the variant with collapsing vascular loops). Acute kidney injury in COVID-19 is primarily caused not by direct viral effect, but by indirect pathophysiological mechanisms. The histopathological findings in these patients does not differ from the majority of the other patients with acute kidney injury. The main pathophysiological mechanisms underlying acute kidney injury in COVID-19 are: hemodynamic abnormalities, hypoxia and cytokine storm. The methods of treating the underlying disease, i.e., COVID-19 in patients with acute kidney injury and those without acute kidney injury are similar. However, it should be stressed that in the treatment of COVID-19 accompanied by acute kidney injury, the contraindication to remdesivir is estimated using glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. The general principles of management in patients with both, COVID-19 and acute kidney injury do not differ from the principles of management in patients with acute kidney injury due to the other causes.


Subject(s)
Acute Kidney Injury , COVID-19 , Nephritis, Interstitial , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , COVID-19/complications , COVID-19/epidemiology , Humans , Kidney/pathology , Nephritis, Interstitial/complications , Nephritis, Interstitial/pathology , SARS-CoV-2
14.
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
15.
Biomolecules ; 12(2)2022 02 12.
Article in English | MEDLINE | ID: covidwho-1686604

ABSTRACT

The onset of coronavirus disease (COVID-19) as a pandemic infection, has led to increasing insights on its pathophysiology and clinical features being revealed, such as a noticeable kidney involvement. In this study, we describe the histopathological, immunofluorescence, and ultrastructural features of biopsy-proven kidney injury observed in a series of SARS-CoV-2 positive cases in our institution from April 2020 to November 2021. We retrieved and retrospectively reviewed nine cases (two pediatric and seven adults) that experienced nephrotic syndrome (six cases), acute kidney injury (two cases), and a clinically silent microhematuria and leukocyturia. Kidney biopsies were investigated by means of light microscopy, direct immunofluorescence, and electron microscopy. The primary diagnoses were minimal change disease (four cases), acute tubular necrosis (two cases), collapsing glomerulopathy (two cases), and C3 glomerulopathy (one case). None of the cases showed viral or viral-like particles on ultrastructural analysis. Novel and specific histologic features on kidney biopsy related to SARS-CoV-2 infection have been gradually disclosed and reported, harboring relevant clinical and therapeutic implications. Recognizing and properly diagnosing renal involvement in patients experiencing COVID-19 could be challenging (due to the lack of direct proof of viral infection, e.g., viral particles) and requires a proper integration of clinical and pathological data.


Subject(s)
COVID-19/complications , Kidney Diseases/complications , Kidney Diseases/virology , Kidney/injuries , Kidney/virology , Adolescent , Aged , Aged, 80 and over , Biopsy , COVID-19/pathology , COVID-19/virology , Female , Humans , Italy , Kidney/pathology , Kidney/ultrastructure , Kidney Diseases/pathology , Male , Middle Aged , Retrospective Studies
16.
Pediatr Nephrol ; 37(10): 2375-2381, 2022 10.
Article in English | MEDLINE | ID: covidwho-1680823

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.


Subject(s)
Acute Kidney Injury , COVID-19 , IgA Vasculitis , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Adolescent , Adult , COVID-19/complications , Child , Humans , Kidney/pathology , SARS-CoV-2
17.
Arthritis Res Ther ; 24(1): 6, 2022 01 03.
Article in English | MEDLINE | ID: covidwho-1590005

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) has been recommended as a basic treatment for lupus nephritis (LN) during this decade based on its ability to improve LN-related renal immune-mediated inflammatory lesions. As a classical lysosomal inhibitor, HCQ may inhibit lysosomal degradation and disrupt protective autophagy in proximal tubular epithelial cells (PTECs). Therefore, the final renal effects of HCQ on LN need to be clarified. METHOD: HCQ was administered on spontaneous female MRL/lpr LN mice with severe proteinuria daily for 4 weeks. Moreover, the MRL/lpr mice with proteinuric LN were subjected to cisplatin-induced or unilateral ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) after 2 weeks of HCQ preadministration. RESULTS: As expected, HCQ treatment increased the survival ratio and downregulated the levels of serum creatinine in the mice with LN, ameliorated renal lesions, and inhibited renal interstitial inflammation. Unexpectedly, HCQ preadministration significantly increased susceptibility to and delayed the recovery of AKI complicated by LN, as demonstrated by an increase in PTEC apoptosis and expression of the tubular injury marker KIM-1 as well as the retardation of PTEC replenishment. HCQ preadministration suppressed the proliferation of PTECs by arresting cells in G1/S phase and upregulated the expression of cell cycle inhibitors. Furthermore, HCQ preadministration disrupted the PTEC autophagy-lysosomal pathway and accelerated PTEC senescence. CONCLUSION: HCQ treatment may increase susceptibility and delay the recovery of AKI complicated by LN despite its ability to improve LN-related renal immune-mediated inflammatory lesions. The probable mechanism involves accelerated apoptosis and inhibited proliferation of PTECs via autophagy-lysosomal pathway disruption and senescence promotion.


Subject(s)
Acute Kidney Injury , Lupus Nephritis , Acute Kidney Injury/chemically induced , Animals , Female , Hydroxychloroquine/pharmacology , Kidney/pathology , Mice , Mice, Inbred MRL lpr
18.
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
19.
J Nephrol ; 35(2): 381-395, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1536386

ABSTRACT

Elderly individuals with chronic disorders tend to develop inflammaging, a condition associated with elevated levels of blood inflammatory markers, and increased susceptibility to chronic disease progression. Native and adaptive immunity are both involved in immune system senescence, kidney fibrosis and aging. The innate immune system is characterized by a limited number of receptors, constantly challenged by self and non-self stimuli. Circulating and kidney resident myeloid and lymphoid cells are all equipped with pattern recognition receptors (PRRs). Recent reports on PRRs show kidney overexpression of toll-like receptors (TLRs) in inflammaging autoimmune renal diseases, vasculitis, acute kidney injury and kidney transplant rejection. TLR upregulation leads to proinflammatory cytokine induction, fibrosis, and chronic kidney disease progression. TLR2 blockade in a murine model of renal ischemia reperfusion injury prevented the escape of natural killer cells and neutrophils by inflammaging kidney injury. Tumor necrosis factor-α blockade in endothelial cells with senescence-associated secretory phenotype significantly reduced interleukin-6 release. These findings should encourage experimental and translational clinical trials aimed at modulating renal inflammaging by native immunity blockade.


Subject(s)
Acute Kidney Injury , Endothelial Cells , Acute Kidney Injury/pathology , Aged , Animals , Humans , Immune System , Immunity, Innate , Kidney/pathology , Mice
20.
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
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