Acute kidney injury in patients with COVID-19: a retrospective cohort study from Switzerland.

BACKGROUND: Data about patients in Europe with corona virus disease-2019 (COVID-19) and acute kidney injury (AKI) are scarce. We examined characteristics, presentation and risk factors of AKI in patients hospitalised with COVID-19 in a tertiary hospital in Switzerland. METHODS: We reviewed health records of patients hospitalised with a positive nasopharyngeal polymerase chain reaction test for SARS-CoV2 between 1 February and 30 June 2020, at the University Hospital of Basel. The nadir creatinine of the hospitalisation was used as baseline. AKI was defined according the KDIGO guidelines as a 1.5× increase of baseline creatinine and in-hospital renal recovery as a discharge creatinine <1.25× baseline creatinine. Least absolute shrinkage and selection operator (LASSO) regression was performed to select predictive variables of AKI. Based on this a final model was chosen. RESULTS: Of 188 patients with COVID-19, 41 (22%) developed AKI, and 11 (6%) required renal replacement therapy. AKI developed after a median of 9 days (interquartile range [IQR] 5-12) after the first symptoms and a median of 1 day (IQR 0-5) after hospital admission. The peak AKI stages were stage 1 in 39%, stage 2 in 24% and stage 3 in 37%. A total of 29 (15%) patients were admitted to the intensive care unit and of these 23 (79%) developed AKI. In-hospital renal recovery at discharge was observed in 61% of all AKI episodes. In-hospital mortality was 27% in patients with AKI and 10% in patients without AKI. Age (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI] 1.01­1.08; p = 0.024), history of chronic kidney disease (aOR 3.47, 95% CI 1.16­10.49;p = 0.026), C-reactive protein levels (aOR 1.09, 95% CI 1.03­1.06; p = 0.002) and creatinine kinase (aOR 1.03, 95% CI 1.01­1.06; p = 0.002) were associated with development of AKI. CONCLUSIONS: AKI is common in hospitalised patients with COVID-19 and more often seen in patients with severe COVID-19 illness. AKI is associated with a high in-hospital mortality.

Ultrasmall and highly biocompatible carbon dots derived from natural plant with amelioration against acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) refers to a tricky clinical disease, known by its high morbidity and mortality, with no real specific medicine for AKI. The carbonization product from Pollen Typhae (i.e., Pu-huang in China) has been extensively employed in clinic, and it is capable of relieving the renal damage and other diseases in China since acient times. RESULTS: Inspired by the carbonization process of Traditional Chinese Medicine (TCM), a novel species of carbon dots derived from Pollen Typhae (PT-CDs) was separated and then collected using a one-pot pyrolysis method. The as-prepared PT-CDs (4.85 ± 2.06 nm) with negative charge and abundant oxygenated groups exhibited high solubility, and they were stable in water. Moreover, the rhabdomyolysis (RM)-induced AKI rat model was used, and it was first demonstrated that PT-CDs had significant activity in improving the level of BUN and CRE, urine volume and kidney index, and histopathological morphology in RM-induced AKI rats. It is noteworthy that interventions of PT-CDs significantly reduced degree of inflammatory reaction and oxidative stress, which may be correlated with the basial potential mechanism of anti-AKI activities. Furthermore, cytotoxicity assay and biosafety evaluation exhibited high biocompatibility of PT-CDs. CONCLUSION: This study offers a novel relieving strategy for AKI based on PT-CDs and suggests its potential to be a related candidate for clinical applications.

De Novo Crescentic Glomerulonephritis Following COVID-19 Infection: A Pediatric Case Report.

As the global coronavirus disease 2019 (COVID-19) pandemic continues to sweep across the globe, reports of kidney involvement in adult patients infected with COVID-19 have been documented, and recently, cases in the pediatric population have also been reported. This report highlights the case of an 11-year-old boy who developed acute kidney injury presenting as gross hematuria, proteinuria, and hypertension immediately after a COVID-19 infection. A renal biopsy allowed us to diagnose the patient with post-COVID-19 infection-associated de novo crescentic immune-mediated glomerulonephritis. Oral prednisolone and cyclophosphamide treatments were initiated after methylprednisolone pulse therapy administration. Currently, the patient is receiving medical treatment for five weeks, and his renal function is gradually recovering. Previous studies have suggested that, although quite rare, a variety of kidney complications can occur after COVID-19 infection or vaccination, and it is recommended to monitor renal function through evaluation. Herein, we report a pediatric case of post-COVID-19 infection-associated de novo crescentic immune-mediated glomerulonephritis consistent with rapidly progressive glomerulonephritis.

Coronavirus disease 2019-associated nephropathy in an African American patient: a case report and review of the literature.

BACKGROUND: Acute kidney injury is now recognized as a common complication of coronavirus disease 2019, affecting up to 46% of patients, with acute tubular injury as the most common etiology. Recently, we have seen an increase in cases of collapsing glomerulonephritis in patients with coronavirus disease 2019, also known as coronavirus disease 2019-associated nephropathy. It has been noted to be seen with a higher incidence in African American patients who are carriers of the APOL1 variant allele. CASE PRESENTATION: A 47-year-old African American male with a past medical history of asthma presented to the emergency department with complaints of intermittent chest pain, shortness of breath, and worsening confusion. On admission, he was found to be hemodynamically stable, but labs were significant for elevated creatinine and blood urea nitrogen, signifying acute kidney injury. He was admitted and taken for emergent dialysis. During his hospitalization, he was found to be positive for coronavirus disease 2019. Renal biopsy was done, which showed collapsing glomerulopathy, and the patient continues to require outpatient dialysis after discharge. CONCLUSION: Collapsing glomerulonephritis has emerged as a complication in patients with coronavirus disease 2019. This condition should be particularly suspected in African American patients who present with acute kidney injury, nephrotic-range proteinuria, and who are positive for coronavirus disease 2019. Current treatment options are limited to supportive treatment and renal replacement therapy. More clinical cases and trials are needed to better understand and improve therapeutic outcomes in these patients.

SARS-CoV-2 infection of kidney tissues in some severe and fatal cases of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to diverse clinical manifestations and pathologies that involve multiple organs. Even though the disease severity is manifested mainly in the respiratory tract, which is the primary target of SARS-CoV-2 infection, acute kidney injury in the form of acute tubular necrosis has also been noted in some COVID-19 cases. It is not entirely clear whether renal cells can be infected by the virus that might be involved in acute kidney disorder. In a recent publication by Radovic and colleagues, that has been selected as the editor's choice paper published in the Journal of Medical Virology, the authors provided strong histopathological and immunofluorescence evidence of SARS-CoV-2 infection and tissue injury of renal parenchymal and tubular epithelial cells, which strongly suggest an active viral replication in the kidney of some severe and fatal COVID-19 cases, and to a lesser extent, a potential role for innate immune cells in viral infection and renal disease pathogenesis.

Foe and friend in the COVID-19-associated acute kidney injury: an insight on intrarenal renin-angiotensin system.

Since the first reported case in December of 2019, the coronavirus disease 2019 (COVID-19) has became an international public health emergency. So far, there are more than 228,206,384 confirmed cases including 4,687,066 deaths. Kidney with high expression of angiotensin-converting enzyme 2 (ACE2) is one of the extrapulmonary target organs affected in patients with COVID-19. Acute kidney injury (AKI) is one of the independent risk factors for the death of COVID-19 patients. The imbalance between ACE2-Ang(1-7)-MasR and ACE-Ang II-AT1R axis in the kidney may contribute to COVID-19-associated AKI. Although series of research have shown the inconsistent effects of multiple common RAS inhibitors on ACE2 expression and enzyme activity, most of the retrospective cohort studies indicated the safety and protective effects of ACEI/ARB in COVID-19 patients. This review article highlights the current knowledge on the possible involvement of intrarenal RAS in COVID-19-associated AKI with a primary focus on the opposing effects of ACE2-Ang(1-7)-MasR and ACE-Ang II-AT1R signaling in the kidney. Human recombinant soluble ACE2 or ACE2 variants with preserved ACE2-enzymatic activity may be the best options to improve COVID-19-associated AKI.

Urinary single-cell sequencing captures kidney injury and repair processes in human acute kidney injury.

Acute kidney injury (AKI) is a major health issue, the outcome of which depends primarily on damage and reparative processes of tubular epithelial cells. Mechanisms underlying AKI remain incompletely understood, specific therapies are lacking and monitoring the course of AKI in clinical routine is confined to measuring urine output and plasma levels of filtration markers. Here we demonstrate feasibility and potential of a novel approach to assess the cellular and molecular dynamics of AKI by establishing a robust urine-to-single cell RNA sequencing (scRNAseq) pipeline for excreted kidney cells via flow cytometry sorting. We analyzed 42,608 single cell transcriptomes of 40 urine samples from 32 patients with AKI and compared our data with reference material from human AKI post-mortem biopsies and published mouse data. We demonstrate that tubular epithelial cells transcriptomes mirror kidney pathology and reflect distinct injury and repair processes, including oxidative stress, inflammation, and tissue rearrangement. We also describe an AKI-specific abundant urinary excretion of adaptive progenitor-like cells. Thus, single cell transcriptomics of kidney cells excreted in urine provides noninvasive, unprecedented insight into cellular processes underlying AKI, thereby opening novel opportunities for target identification, AKI sub-categorization, and monitoring of natural disease course and interventions.

SARS-CoV-2 infection of kidney tissues from severe COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests diverse clinical pathologies involving multiple organs. While the respiratory tract is the primary SARS-CoV-2 target, acute kidney injury is common in COVID-19 patients, displaying as acute tubular necrosis (ATN) resulting from focal epithelial necrosis and eosinophilia, glomerulosclerosis, and autolysis of renal tubular cells. However, whether any renal cells are infected by SARS-CoV-2 and the mechanism involved in the COVID-19 kidney pathology remain unclear. METHODS: Kidney tissues obtained at autopsy from four severe COVID-19 patients and one healthy subject were examined by hematoxylin and eosin staining. Indirect immunofluorescent antibody assay was performed to detect SARS-CoV-2 spike protein S1 and nonstructural protein 8 (NSP8) together with markers of different kidney cell types and immune cells to identify the infected cells. RESULTS: Renal parenchyma showed tissue injury comprised of ATN and glomerulosclerosis. Positive staining of S1 protein was observed in renal parenchymal and tubular epithelial cells. Evidence of viral infection was also observed in innate monocytes/macrophages and NK cells. Positive staining of NSP8, which is essential for viral RNA synthesis and replication, was confirmed in renal parenchymal cells, indicating the presence of active viral replication in the kidney. CONCLUSIONS: In fatal COVID-19 kidneys, there are SARS-CoV-2 infection, minimally infiltrated innate immune cells, and evidence of viral replication, which could contribute to tissue damage in the form of ATN and glomerulosclerosis.

Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest.

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.

A Rare Case of Granulomatous Interstitial Nephritis in a Patient With COVID-19.

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.

Acute kidney injury after Pfizer COVID-19 vaccine due to crescentic fibrillary glomerulonephritis.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease manifesting with proteinuria, renal impairment, hematuria, hypertension, and in a very small proportion can be associated with rapidly progressive glomerulonephritis and, rarely, crescent formation. The main modality for diagnosis is kidney biopsy, which ultrastructurally demonstrates randomly arranged non-branching mesangial and glomerular basement membrane (GBM) fibrils and positive staining for the biomarker DNAJB9. The pathogenesis is largely unknown. It was previously hypothesized to represent an immune-complex-type glomerulonephritis, as most cases show IgG4 restriction. We present the first case of crescentic FGN after mRNA Pfizer vaccine for COVID-19. A strong temporal association between vaccination, elevated creatinine, and diffuse crescentic fibrillary process was found. Immunological, neoplastic, and infectious causes were ruled out. We hypothesized that the vaccine stimulated an immune response that triggered crescentic FGN, however, further investigations will be needed to elucidate the direct role of COVID-19 vaccination in crescentic glomerular disease.

Acute kidney injury associated to COVID-19 leads to a strong unbalance of circulant immune mediators.

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) have increased risk for acute kidney injury (AKI). The exacerbation of the immune response seems to contribute to AKI development, but the immunopathological process is not completely understood. OBJECTIVES: To analyze levels of circulant immune mediators in COVID-19 patients evolving with or without AKI. We have also investigated possible associations of these mediators with viral load and clinical outcomes. METHODS: This is a longitudinal study performed with hospitalized patients with moderate to severe COVID-19. Serum levels of 27 immune mediators were measured by a multiplex immunoassay. Data were analyzed at two timepoints during the follow-up: within the first 13 days of the disease onset (early sample) and from the 14th day to death or hospital discharge (follow-up sample). RESULTS: We studied 82 COVID-19 patients (59.5 ± 17.5 years, 54.9% male). Of these, 34 (41.5%) developed AKI. These patients presented higher SARS-CoV-2 viral load (P = 0.03), higher frequency of diabetes (P = 0.01) and death (P = 0.0004). Overall, AKI patients presented significantly higher and sustained levels (P < 0.05) of CCL-2, CCL-3, CCL-4, CXCL-8, CXCL-10, IFN-γ, IL-2, IL-6, TNF-α, IL-1Ra, IL-10 and VEGF. Importantly, higher levels of CCL-2, CXCL-10, IL-2, TNF-α, IL-10, FGFb, and VEGF were observed in AKI patients independently of death. ROC curves demonstrated that early alterations in CCL-2, CXCL-8, CXCL-10, IFN-γ, IL-6, IL-1Ra and IL-10 show a good predictive value regarding AKI development. Lastly, immune mediators were significantly associated with each other and with SARS-CoV-2 viral load in AKI patients. CONCLUSIONS: COVID-19 associated AKI is accompanied by substantial alterations in circulant levels of immune mediators, which could significantly contribute to the establishment of kidney injury.

Integrin α5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells.

BACKGROUND: Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of AKI reported during the coronavirus disease 2019 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The microRNA miR-218-5p is upregulated in endothelial progenitor cells (EPCs) after hypoxia, but microRNA regulation of Tie2 in the EPC lineage is unclear. METHODS: We isolated human kidney-derived EPCs (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. RESULTS: After ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-LoxP mammalian model (a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309+ cells), homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. CONCLUSIONS: These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.

Impact of COVID-19 on Kidney of Diabetic Patients.

Given the current state of COVID-19, it is crucial to reveal its evolving relationship with and effect on different body organ systems and their diseases. The severity and outcome of COVID-19 have a very complex relationship, especially to the vital organs including the kidney, either in their state of health or disease. Additionally, it is well known that diabetes affects the kidney, leading to diabetic nephropathy. The kidney is also affected by different pathological and immunopathological reactions with COVID-19 infection, leading to acute kidney injury. Therefore, this review intended to extract the recent advances, updates, and discoveries about the effects of COVID-19 on diabetic patients and the relationship between COVID-19 invasion and the diabetic kidney and to discuss the current state of knowledge that has not yet been proved or disproved, leading to numerous controversial issues in looking for the effect of COVID-19 associated with diabetes mellitus on the human kidney.

Acute Kidney Injury and Urinary and Histopathological Disorders in Kidney Transplant Patients with SARS-CoV-2 Infection.

BACKGROUND: Acute kidney injury (AKI) is a manifestation of SARS-CoV-2 infection. The evidence in kidney transplant (KT) is limited, as there are scarce data about the histologic features in graft biopsies of these patients. MATERIAL AND METHODS: A retrospective cohort study of KTs with SARS-CoV-2 infection from August 28, 2020, to April 23, 2021. We collected the incidence of AKI and the presence of urinary and histopathological disorders. Both groups were compared (AKI vs no AKI). Immunohistochemical and reverse transcription-polymerase chain reaction studies were performed on the anatomopathological samples. RESULTS: In our study, 72 KTs had SARS-CoV-2 infection and, among them, 27 patients (35.1%) developed AKI related to increased severity and a worse evolution of the infection, defined by a greater presence of pneumonia (P < .001), hospitalization (P < .001), admission to the intensive care unit (P < .001), the need for ventilation support (P < .001), and continuous renal replacement therapy (P < .001). In the multivariable analysis, pneumonia behaved as an independent predictor for AKI development (P = .046). No differences were observed between proteinuria a month before and after infection (P = .224). In addition, 5 patients showed microhematuria and 2 patients presented transient glycosuria without hyperglycemia. Of the 5 kidney biopsies performed, 1 biopsy (20%) showed positive reverse transcription polymerase chain reaction for SARS-CoV-2. CONCLUSIONS: AKI is a frequent and potentially serious complication in KT patients. Occasionally it could be accompanied by abnormalities in the urinary sediment. Of 5 biopsied patients, 1 patient had positive reverse transcription polymerase chain reaction in renal tissue, which suggests the systemic spread of the virus and the tropism for the renal graft.

Acute interstitial nephritis after COVID-19 vaccination.

A woman in her 70s presented to the hospital being generally unwell 8 days following the first dose of the AstraZeneca COVID-19 vaccination. She was in stage III acute kidney injury (AKI) with hyperkalaemia and metabolic acidosis. Urinalysis showed haematoproteinuria. Renal immunology screen was negative. She subsequently underwent two renal biopsies. The second biopsy showed features consistent with acute tubulointerstitial nephritis. She was commenced on oral steroids, which led to marked improvement of her renal function.There are reasons why AKI can occur post vaccination such as prerenal AKI from reduced oral intake postvaccination due to feeling unwell or developing vomiting or diarrhoea. Intravenous fluids were given to this patient but with no meaningful improvement in renal function. She developed a possible reaction to the AstraZeneca COVID-19 vaccine, which led to AKI as supported by the interstitial inflammation and presence of eosinophils on renal biopsy.

Extracellular Vesicles and Acute Kidney Injury: Potential Therapeutic Avenue for Renal Repair and Regeneration.

Acute kidney injury (AKI) is a sudden decline of renal function and represents a global clinical problem due to an elevated morbidity and mortality. Despite many efforts, currently there are no treatments to halt this devastating condition. Extracellular vesicles (EVs) are nanoparticles secreted by various cell types in both physiological and pathological conditions. EVs can arise from distinct parts of the kidney and can mediate intercellular communication between various cell types along the nephron. Besides their potential as diagnostic tools, EVs have been proposed as powerful new tools for regenerative medicine and have been broadly studied as therapeutic mediators in different models of experimental AKI. In this review, we present an overview of the basic features and biological relevance of EVs, with an emphasis on their functional role in cell-to-cell communication in the kidney. We explore versatile roles of EVs in crucial pathophysiological mechanisms contributing to AKI and give a detailed description of the renoprotective effects of EVs from different origins in AKI. Finally, we explain known mechanisms of action of EVs in AKI and provide an outlook on the potential clinical translation of EVs in the setting of AKI.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

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.