While most SARS-CoV-2 infections and reinfections in the era of widespread population immunity with omicron subsub-lineage variants are mild for immunocompetent individuals, any manifestation previously seen during the pandemic phase is still possible. COVID-19 may affect any organ system. Previous infections and prior vaccines protect against symptomatic future SARS-CoV-2 infections, though this protection wanes over time.

Hypokalemia is a prevalent complication of COVID-19 patients with acute kidney injury (AKI); however, mechanisms have yet to be fully understood. By single-nucleus RNA sequencing, we found that COVID-19 patients with AKI were associated with a marked upregulation of the epithelial sodium channel (ENaC) in the renal tubular epithelial cells (TECs). By using a mouse model of AKI induced by kidney-specific overexpressing SARS-CoV-2 N protein, we detected that overexpression of renal SARS-CoV-2 N protein could induce hypokalemia and AKI, which was associated with the upregulation of ENaC, ROMK, and BK proteins. Functionally, a patch-clamp study revealed that the overexpression of SARS-CoV-2 N protein largely increased the ENaC current in the TECs. Mechanically, we uncovered that kidney-specific overexpressing SARS-CoV-2 N protein could activate ENaC to cause hypokalemia and AKI directly by binding to the ENaCα and ENaCγ subunits and indirectly by activating the p38 MAPK pathway. Importantly, treatment with an ENaC specific inhibitor could protect against SARS-CoV-2 N-induced hypokalemia and AKI, revealing a regulatory role and therapeutic target of ENaC in SARS-CoV-2 N-induced hypokalemia and AKI. In conclusion, hypokalemia in COVID-19 AKI is induced by SARS-CoV-2 N protein via the ENaC-dependent mechanism. Targeting ENaC may offer a novel therapy for COVID-19 patients with AKI.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to a significant burden on global healthcare systems. COVID-19-induced acute kidney injury (AKI) is among one of the complications, that has emerged as a critical and frequent condition in COVID-19 patients. This AKI among COVID-19 patients is associated with poor outcomes, and high mortality rates, especially in those with severe AKI or requiring renal replacement therapy. COVID-19-induced AKI represents a significant complication with complex pathophysiology and multifactorial risk factors. Indeed, several pathophysiological mechanisms, including direct viral invasion of renal cells, systemic inflammation, endothelial and thrombotic abnormalities as well as nephrotoxic drugs and rhabdomyolysis are believed to underlie this condition. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include acute tubular necrosis, glomerular injury, and the presence of viral particles within renal tissue and urine. Identified risk factors for developing AKI vary among studies, depending on regions, underlying conditions, and the severity of the disease. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include show acute tubular necrosis, glomerular injury, and viral particles within renal tissue and urine. While, identified risk factors for developing AKI vary among studies, according to regions, underlying conditions, and the gravity of the disease. This narrative review aims to synthesize current knowledge on the incidence, pathophysiology, risk factors, histopathology, and outcomes of AKI induced by COVID-19.

Negative- and positive-staining transmission electron microscopy (ns/psTEM) is a cornerstone of research and diagnostics, enabling nanometer-resolution analysis of organic specimens from nanoparticles to cells without requiring costly cryo-equipment. For nearly 70 years, uranyl salts like uranyl acetate (UA) have been the gold-standard ns/psTEM-stains. However, mounting safety concerns due to their high toxicity and radioactivity have led to stricter regulations and expensive licensing requirements. Consequently, there is an urgent global demand for safer, more sustainable stains that deliver uranyl-comparable, high-quality ns/psTEM. Here, the commercially available stain-alternatives UranyLess, UAR, UA-Zero, PTA, STAIN 77, Nano-W, NanoVan, and lead citrate are systematically assessed against UA. The stains are evaluated regarding their contrast, resolution, stain-distribution, and ease-of-use in ns/psTEM across a diverse sample set, including polymethylmethacrylate-nanoplastics, phosphatidylcholine-liposomes, Influenza-A viruses, globular ferritin, fibrillar pyruvate kinase amyloids, and human lung-carcinoma cell-sections. It is shown that for this variety of samples, a ready-to-use uranyl-alternative is commercially available with comparable or even superior ns/psTEM-performance to UA using an efficient staining-protocol. Furthermore, the GUIDE4U tool is developed for the fast identification of the appropriate uranyl-replacements for each sample of interest, saving ns/psTEM-users time and costs while ensuring excellent staining results for ultrastructural analysis, thereby further catalyzing the use of safer stains.

Over the past 3 years, several kidney complications in children with severe involvement by SARS-CoV-2 have been described. However, literature data are still lacking regarding possible kidney injury in children with paucisymptomatic SARS-CoV-2 infection. Thus, we retrospectively evaluated renal function in those patients. Children between 3 and 18 years, without any renal disease, with previous paucisymptomatic SARS-CoV-2 infection from May 2020 to March 2022, were recruited at our post-COVID-19 outpatient clinic. We retrospectively collected: Glomerular filtration rate, Fractional-excretion-of-sodium (FENa), tubular-reabsorption-of-phosphate (TRP), calcium-creatinine-urine ratio (CaU/CrU); proteinuria/m2/day and microhematuria by urine cytofluorometry. A total of 148 children were enrolled after a median period of 3 (IQR 6) months after infection. Twenty-six patients (17.6%) had reduced GFR, fifty (33.9%) had hyperfiltration, eleven (7.4%) had abnormal FENa and/or TRP, twenty-two (14.9%) had hypercalciuria, seventy-eight (52.7%) had pathological daily proteinuria. Microhematuria was found in sixteen (10.9%) subjects. Hyperfiltration was more prevalent among males (38.9% vs. 22.4%, p = 0.027); CaU/CrU [median 0.08 (IQR 0.09) vs. 0.13 (IQR 0.13) p = 0.003] was significantly higher in females. Our data suggest that SARS-CoV-2 could determine, in a significant proportion of children, kidney damage characterized by hyperfiltration, proteinuria, and hematuria, warranting strict follow-up in these patients.

Background/Objectives: Although kidney transplant recipients (KTRs) who are immune-compromised have been shown to be at high risk of adverse acute COVID-19 outcomes (i.e., mortality and critical illness), the long-term outcomes of KTRs with a history of SARS-CoV-2 infection are unknown. We aimed to compare long-term outcomes of KTRs with and without exposure to SARS-CoV-2. Methods: This study retrospectively evaluated 1815 KTRs in the Montefiore Health System from 4 January 2001 to 31 January 2024. The final cohorts consisted of KTRs who survived COVID-19 (n = 510) and matched KTRs without COVID-19 (n = 510, controls). Outcomes were defined as all-cause mortality and changes in estimated glomerular filtration rate (eGFR) and urine protein to creatinine ratio (UPCR) from 30 days up to four years post index date. Kaplan-Meier survival analysis and Cox proportional modeling were performed for mortality. Generalized estimating equations were used to analyze changes in eGFR and UPCR across time. Results: There was no significant group difference in long-term all-cause mortality (adjusted hazard ratio = 0.66, [0.43, 1.01] p = 0.057). eGFR in controls and COVID-19 patients before infection similarly decreased -0.98 units/year [-1.50, -0.46]. By contrast, eGFR declined at a significantly greater rate (-1.80 units/year [-2.45, -1.15]) in KTRs after COVID-19 compared to KTRs without COVID-19. This association was only seen among male and not female KTRs. COVID-19 status was not significantly associated with rate of change in UPCR or acute kidney rejection rate. Conclusions: SARS-CoV-2 infection was associated with an accelerated decline in eGFR up to four years post infection, suggesting potential long-term implications for graft health. These findings underscore the importance of vigilant monitoring and management of kidney function post SARS-CoV-2 infection in this vulnerable population.

Patients surviving coronavirus disease of 2019 (COVID-19) often complain of skeletal muscle weakness that may be very limiting and long-lasting. There are almost no studies on the skeletal muscle of these patients, and electron microscopic data are scarce. We assessed the ultrastructural changes in the quadriceps of eight patients with COVID-19 and found a combination of features different from those reported in corticosteroid myopathy and acute relaxant-steroid myopathy. The most remarkable and constant changes involved the endothelial cells and consisted of massive amounts of pinocytotic vesicles, degenerative changes, platelet aggregates and, most characteristic of all, an increase in the external lamina thickness that seems to stem from reduplication due to successive bouts of endothelial cell damage and subsequent regeneration. Viral particles were not found in any of the cases. This distinct and quite common set of alterations defines the myopathy associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This association seems to be the result of an inflammatory process that would arise in infected cells but could damage non-infected endomysial blood vessels, thus resulting in persistent changes of the microvasculature that would be related to long-standing myopathic clinical features.

Coronavirus 2019 (COVID-19) is an infectious disease caused by a novel coronavirus, SARS-CoV-2. Acute kidney injury (AKI) affects approximately 20-40% of patients with COVID-19 admitted to the intensive care unit (ICU), and it is a complication that has been linked to increased morbidity and mortality. Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury.

Articles were searched from databases such as PubMed, Google Scholar, and Cochrane Library till June 2023. Pooled sensitivity, specificity, area under the curve (AUC), diagnostic odds ratio (DOR), and summery receiver operating curve (SROC) were calculated with 95% confidence interval. I2 statistics and Chi-square test were used to look for the heterogeneity in between studies. Meta-regression was conducted to look for the source of heterogeneity and GRADE analysis was performed to look for the certainty of evidence.

Altogether, eight studies were selected (4 serum/5 urine), out of which one study had both serum and urine NGAL data. The total sample size was 1,067 (349 serum/718 urine). For serum and urine NGAL, the pooled sensitivity was 0.79 (95% CI: 0.72-0.84) and 0.75 (95% CI: 0.68-0.80), pooled specificity was 0.87 (95% CI: 0.81-0.91) and 0.85 (95% CI: 0.77-0.91), DOR was 24 (95% CI: 14-43), and 17 (95% CI: 9-32) and AUC was 0.90 (95% CI: 0.87-0.92) and 0.80 (95% CI: 0.76-0.83), respectively.

Both serum and urine NGAL have favourable pooled sensitivity, specificity, DOR and AUC for the diagnosis of AKI in COVID-19 infection, however, with low certainty of evidence.

The risk factors for Henoch-Schönlein purpura nephritis (HSPN) remain largely unclear, particularly in family environment and vaccination. This study aimed to develop a predictive framework to quantify the risk of HSPN by examining family environmental factors and COVID-19 vaccination outcomes in children with Henoch-Schönlein purpura (HSP) in Anhui, China.

This study retrospectively analyzed 362 children diagnosed with HSP at Anhui Children's Hospital between January 2020 and February 2024. A questionnaire was designed to collect information from enrolled children. For patients with incomplete medical records, parents were contacted via phone or the questionnaire was sent to them to complete the survey. After data collection, the patients were split randomly into a training group and a validation group at a 7:3 ratio, univariate and multivariate logistic regression analyses were performed to identify risk factors for nephritis, and a nomogram was constructed from these factors to provide a visual prediction of the likelihood of nephritis in HSP. The nomogram's performance was evaluated in both the training and validation groups using the area under the receiver operating characteristic (AUC) curve, calibration plots, and decision curve analysis (DCA).

The study identified family income/month, age of onset, BMI, number of recurrences, and COVID-19 vaccination status as independent risk factors for HSPN. A nomogram was subsequently developed afterward using these factors. In the training group, the nomogram achieved an area under the curve (AUC) of 0.83 (95% CI: 0.78-0.88), while in the validation group, the AUC was 0.90 (95% CI: 0.84-0.96), demonstrating strong predictive performance. The calibration curve showed that the nomogram's predictions were well-aligned with the actual outcomes. Additionally, DCA indicated that the nomogram provided considerable clinical net benefit.

The nomogram offers accurate risk prediction for nephritis in children with HSP, helping healthcare professionals identify high-risk patients early and make informed clinical decisions.

Multisystem Inflammatory Syndrome in Children: A Comprehensive Review over the Past Five Years This review explores many facets of Multisystem Inflammatory Syndrome in Children (MIS-C) over the previous 5 years. In the time since the COVID 19 pandemic gripped our medical systems, we can now explore the data that has been collected from the previous years. The literature has allowed us to better understand the impact of COVID 19 and the post illness occurrence of a severe systemic inflammatory disease on our youngest patient populations. This paper will outline the pathophysiology of MIS-C, the treatments utilized, short and long-term patient outcomes including epidemiological factors.

To evaluate hospital outcomes and their predictors during the pandemic for patients with and without COVID-19, stratified by the presence of acute kidney injury (AKI).

Retrospective observation study using the Hospital Episodes Statistics database for England.

2 385 337 unique hospital admissions of adult patients from March 2020 to March 2021 in England.

COVID-19 cases were identified by the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code of U07.1. Patients with suspected COVID-19 (U07.2 code) and patients with end-stage kidney disease on chronic dialysis (N18.6 and Z99.2) were excluded. AKI cases were identified by the ICD10 code. Patients were categorised into four groups based on COVID-19 and AKI diagnoses: Group 1-neither; Group 2-COVID-19 only; Group 3-AKI only; Group 4-both. A multivariable logistic regression model was created with in-hospital mortality as the outcome, including diagnostic groups, demographics, admission methods, comorbidity severity, deprivation index and intensive therapy unit (ITU) admission.

Among 2 385 337 admissions involving 663 628 patients, 856 544 had AKI (N17 codes) and 1 528 793 did not. Among patients without AKI, there were 1,008,774 admissions among 133,988 individuals without COVID-19 (Group 1) and 520,019 admissions among 256,037 individuals with COVID-19 (Group 2). Among patients with AKI, there were 630,342 admissions among 218,270 individuals without COVID-19 (Group 3) and 226,202 admissions among 55,333 individuals with COVID-19 (Group 4). Patients in group 4 were older (75.4 ± 13.8 years) and had greater length of stay (17.1 ± 17 days) than all other groups. They also had and had a greater proportion of males, ethnic minorities and comorbidities than other groups. Mortality was highest in Group 4 (28.7%) and lowest in Group 1 (1.1%). The increased risk of death persisted after controlling for multiple baseline factors (OR for death vs Group 1: Group 4-22.28, Group 2-9.67, Group 3-6.44). ITU admission was least required in Group 1 (1.2%) and most in Group 4 (10.9%), with mortality at 4.8% versus 47.8%, respectively.

Patients with COVID-19 and AKI have a high risk of mortality and should be recognised early and provided with optimal support. Planning for future pandemics should ensure adequate critical care and acute dialysis capacity.

NCT04579562.

The COVID-19 pandemic has significantly impacted global healthcare systems, revealed vulnerabilities and prompted a re-evaluation of medical practices. Acute complications from the virus, including cardiovascular and neurological issues, have underscored the necessity for timely medical interventions. Advances in diagnostic methods and personalized therapies have been pivotal in mitigating severe outcomes. Additionally, Long COVID has emerged as a complex challenge, affecting various body systems and leading to respiratory, cardiovascular, neurological, psychological, and musculoskeletal problems. This broad spectrum of complications highlights the importance of multidisciplinary management approaches that prioritize therapy, rehabilitation, and patient-centered care. Vulnerable populations such as paediatric patients, pregnant women, and immunocompromised individuals face unique risks and complications, necessitating continuous monitoring and tailored management strategies to reduce morbidity and mortality associated with COVID-19.

Background/Objectives: Acute kidney injury (AKI) is a serious and prevalent complication of COVID-19. This study examines the prevalence, risk factors, and outcomes of AKI in hospitalized COVID-19 patients. Methods: We analyzed the data of 1223 adult COVID-19 hospitalized patients from a single district hospital during three pandemic periods: 3 November 2020-31 December 2020, 17 March 2021-8 May 2021, and 4 November 2021-21 February 2022. The analysis included demographic data, comorbidities, laboratory results, chest radiographs (CT lung scans), and outcomes. Results: We found an overall AKI incidence of 29.02%. AKI patients versus non-AKI ones were significantly older (median age 76.0 vs. 71.0, p < 0.001) and had more comorbidities, especially previous renal diseases, heart failure, coronary artery disease, and hypertension; they also significantly more often used diuretics, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACE-Is). AKI patients more frequently presented with abnormal CT lung scans and had higher white blood cell counts, lower lymphocytes percentages, higher C-reactive protein (CRP) levels, and lower platelet counts. They more often required oxygen therapy, more days of hospitalization, and had higher mortality rates. Conclusions: Older age, comorbidities, the use of diuretics, and renin-angiotensin system inhibitors (RASI) are key risk factors for AKI, which is consequently linked to a more severe disease course and poorer prognosis.

SARS-CoV-2 infection has led to a range of long-lasting symptoms, collectively referred to as long COVID. Current research highlights the critical role of angiotensin-converting enzyme 2 (ACE2) in regulating gut microbiota diversity, vascular function, and homeostasis within the renin-angiotensin system (RAS). ACE2 is utilized by the SARS-CoV-2 virus to enter host cells, but its downregulation following infection contributes to gut microbiota dysbiosis and RAS disruption. These imbalances have been linked to a range of long COVID symptoms, including joint pain, chest pain, chronic cough, fatigue, brain fog, anxiety, depression, myalgia, peripheral neuropathy, memory difficulties, and impaired attention. This review investigates the dysregulation caused by SARS-CoV-2 infection and the long-term effects it has on various organ systems, including the musculoskeletal, neurological, renal, respiratory, and cardiovascular systems. We explored the bidirectional interactions between the gut microbiota, immune function, and these organ systems, focusing on how microbiota dysregulation contributes to the chronic inflammation and dysfunction observed in long COVID symptoms. Understanding these interactions is key for identifying effective therapeutic strategies and interventional targets aimed at mitigating the impact of long COVID on organ health and improving patient outcomes.

The biological effects of SARS-CoV-2 infection in transplanted kidneys are uncertain with little pathological information.

This single-center, prospective observational study evaluated kidney transplant biopsies from recipients of deceased donors with COVID-19, current recipients contracting SARS-CoV-2 Omicron variant in 2022, against prior BK virus (BKV) infection and uninfected (without SARS-CoV-2 or BKV) samples, as respective positive and negative comparators (n = 503 samples).

We demonstrated nonvirus tubular injury in implanted tissue from infected donors and prevalent recipients with mild acute COVID-19 and acute kidney injury, excluding direct viral infection as a cause of kidney damage. COVID particles were absent in 4116 ultrastructural images of 295 renal tubules from 4 patients with acute COVID-19. No viral cytopathic effect, viral allograft nephropathy, or SARS-CoV-2 RNA was detected in acute tissues, nor in 128 sequential samples from infected donors or recipients with COVID-19. Following recipient COVID-19 (mean 16.8 ± 12.0 wk post-infection), the biopsy-prevalence of rejection was 33.0% (n = 100 biopsies) versus 13.4% for contemporaneous uninfected controls (n = 337; P  < 0.001). Prior COVID-19 was an independent risk factor for incident rejection using multivariable generalized estimating equation adjusted for competing risks (odds ratio, 2.195; 95% confidence interval, 1.189-4.052; P  = 0.012). Landmark and matched-pair analyses confirmed an association of SARS-CoV-2 with subsequent transplant rejection, with a similar pattern following BKV infection.

Transplantation from COVID-19+ deceased donors yielded good recipient outcomes without evidence of viral tissue transmission. Acute kidney injury during COVID-19 was mediated by archetypical tubular injury and infection correlated with an increased risk of subsequent rejection.

This study aims to identify the risk factors associated with clinical outcomes and the proteomic changes in organs related to fatal SARS-CoV-2 infection within the super-elderly population. This retrospective analysis included all elderly individuals with COVID-19 admitted to the Second Medical Center of PLA General Hospital from December 2022 to January 2023. The follow-up period ended on March 30, 2023. During this time, epidemiological, demographic, laboratory, and outcome data were analyzed descriptively. Proteomic sequencing was performed on super-elderly patients who died from COVID-19 at different stages of the disease. A total of 352 elderly COVID-19 patients, with a mean age of 89.84 ± 8.54 years, were included in this study. During a median follow-up period of 98 days, 79 patients died. Deceased patients were older and more likely to have cardiovascular and cerebrovascular diseases, with a lower prevalence of lipid-lowering therapy. The number of deaths in the acute and post-acute phases were 34 and 45, respectively. Proteomics data suggest that the immune systems of patients who died in the acute phase underwent a more rapid and severe onslaught. Patients in the post-acute phase showed higher levels of viral genome replication and a more robust immune response. However, the over-activation of the immune system led to systemic organ dysfunction. Effective management of comorbidities may improve the prognosis of COVID-19 in super-elderly patients. The continuous replication of the SARS-CoV-2 virus and its subsequent impact on the immune system are critical determinants of survival time in this demographic.

Acute kidney injury (AKI) is common in critically ill patients and is associated with increased morbidity and mortality. Its complications often require renal replacement therapy (RRT). Invasive mechanical ventilation (IMV) and infections are considered risk factors for the occurrence of AKI. The use of IMV and non-invasive ventilation (NIV) has changed over the course of the pandemic. Concomitant with this change in treatment a reduction in the incidences of AKI and RRT was observed. We aimed to investigate the impact of IMV on RRT initiation by comparing critically ill patients with and without COVID-19. Furthermore, we wanted to investigate the rates and timing of RRT as well as the outcome of patients, who were treated with RRT.

A total of 8,678 patients were included, of which 555 (12.8%) in the COVID-19 and 554 (12.8%) in the control group were treated with RRT. In the first week of ICU stay the COVID-19 patients showed a significantly lower probability for RRT initiation (day 1: p < 0.0001, day 2: p = 0.021). However, after day 7 a reversed HR was found. In mechanically ventilated patients the risk was significantly higher for the initiation of RRT over the entire stay. While in non-COVID-19 patients this was a non-significant trend, in COVID-19 patients the risk for RRT was significantly increased. The median delay between initiation of IMV and requirement of RRT was observed to be longer in COVID-19 patients (5 days [IQR: 2-11] vs. 2 days [IQR: 1-5]). The analysis restricted to patients with RRT showed a significantly higher risk for ICU death in patients requiring IMV compared to patients without IMV.

The analysis demonstrated that IMV as well as COVID-19 are associated with an increased risk for initiation of RRT. The association between IMV and risk of RRT initiation was given for all investigated time intervals. Additionally, COVID-19 patients showed an increased risk for RRT initiation during the entire ICU stay within patients admitted to an ICU due to respiratory disease. In COVID-19 patients treated with RRT, the risk of death was significantly higher compared to non-COVID-19 patients.

Early reports have indicated that the Omicron variant of coronavirus disease 2019 (COVID-19) may be associated with low mortality. However, the mortality rate of critical patients in Taiwan with COVID-19 caused by different variants has not been well described.

This retrospective cohort study was conducted at the Linkou Branch of Chang Gung Memorial Hospital, Taiwan, from April 2020 to September 2022. Critically ill patients who had confirmed SARS-CoV-2 infection and were on mechanical ventilation (MV) were enrolled. Demographic data, laboratory results, and treatment information were collected and analyzed. In addition, clinical outcomes for different SARS-CoV-2 variants were analyzed.

This study included 110 critical patients with COVID-19 who required intubation and intensive care unit (ICU) admission. Among these patients, 46 (41.8%) required intensive care during Alpha predominance period and 64 (58.2%) during the Omicron predominance period. The Alpha group had a higher body mass index, had a longer ICU stay, and included more patients with acute respiratory distress syndrome, and the Omicron group included more active smokers, had more comorbidities, had worse initial laboratory data (including higher white blood cell counts, prothrombin time [PT], activated partial prothrombin time, blood urine nitrogen levels, and creatine levels), and had higher in-hospital mortality rates (40.6% vs 15.2%, p = 0.004). The independent risk factors for in-hospital mortality, were Charlson Comorbidity Index (CCI) ≥ 3 and higher PT and creatine levels.

Our study discovered that CCI ≥ 3, elevated serum creatine levels, and prolonged PT were independently associated with a high mortality rate in patients with critical COVID-19. Patients with those risk factors may require intensive monitoring during their treatment course.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mainly affects the respiratory tract, but different organs may be involved including the kidney. Data on acute kidney injury (AKI) in critical forms of coronavirus disease 2019 (COVID-19) are scarce. We aimed to assess the incidence, risk factors and prognostic impact of AKI complicating critical forms of COVID-19.

A retrospective descriptive case/control monocentric study conducted in a medical intensive care unit of a tertiary teaching hospital over a period of 18 months.

We enrolled 144 patients, with a mean age of 58±13 years old and a male predominance (sex-ratio: 1.25). Forty-one (28%) developed AKI within a median of 4 days (Q1: 3, Q3: 8.5) after hospitalization. It was staged KDIGO class 3, in about half of the cases. Thirteen patients underwent renal replacement therapy and renal function improved in seven cases. Diabetes (OR: 6.07; 95% CI: (1,30-28,4); p: 0.022), nephrotoxic antibiotics (OR: 21; 95% CI: (3,2-146); p: 0.002), and shock (OR: 12.21; 95% CI: (2.87-51.85); p: 0.031,) were the three independent risk factors of AKI onset. Mortality was significantly higher in AKI group (HR:12; 95% CI: (5.81-18.18); p:0.041) but AKI didn't appear to be an independent risk factor of poor outcome. In fact, age > 53 years (p: 0.018), septic shock complicating hospital acquired infection (p: 0.003) and mechanical ventilation (p<0.001) were the three prognostic factors in multivariate analysis.

The incidence of AKI was high in this study and associated to an increased mortality. Diabetes, use of nephrotoxic antibiotics and shock contributed significantly to its occurrence. This underlines the importance of rationalizing antibiotic prescription and providing adequate management of patients with hemodynamic instability in order to prevent consequent AKI.

Recent studies have found that a link between people with type 1 diabetes mellitus (T1DM) are at higher risk of morbidity as well as mortality from COVID-19 infection, indicating a need for vaccination. T1DM appears to impair innate and adaptive immunity. The overabundance of pro-inflammatory cytokines produced in COVID-19 illness that is severe and potentially fatal is known as a "cytokine storm." Numerous cohorts have revealed chronic inflammation as a key risk factor for unfavorable COVID-19 outcomes. TNF-α, interleukin (IL)-1a, IL-1, IL-2, IL-6, and other cytokines were found in higher concentrations in patients with T1DM. Even more importantly, oxidative stress contributes significantly to the severity and course of COVID- 19's significant role in the progression and severity of COVID-19 diseases. Severe glucose excursions, a defining characteristic of type 1 diabetes, are widely recognized for their potent role as mediating agents of oxidative stress via several routes, such as heightened production of advanced glycation end products (AGEs) and activation of protein kinase C (PKC). Furthermore, persistent endothelial dysfunction and hypercoagulation found in T1DM may impair microcirculation and endothelium, which could result in the development of various organ failure and acute breathing syndrome.

To assess incidence, risk factors and impact of acute kidney injury(AKI) within 48 h of intensive care unit(ICU) admission on ICU mortality in patients with SARS-CoV-2 pneumonia. To assess ICU mortality and risk factors for continuous renal replacement therapy (CRRT) in AKI I and II patients.

Retrospective observational study.

Sixty-seven ICU from Spain, Andorra, Ireland.

5399 patients March 2020 to April 2022.

Demographic variables, comorbidities, laboratory data (worst values) during the first two days of ICU admission to generate a logistic regression model describing independent risk factors for AKI and ICU mortality. AKI was defined according to current international guidelines (kidney disease improving global outcomes, KDIGO).

Of 5399 patients included 1879 (34.8%) developed AKI. These patients had higher ICU mortality and AKI was independently associated with a higher ICU mortality (HR 1.32 CI 1.17-1.48; p < 0.001). Male gender, hypertension, diabetes, obesity, chronic heart failure, myocardial dysfunction, higher severity scores, and procalcitonine were independently associated with the development of AKI. In AKI I and II patients the need for CRRT was 12.6% (217/1710). In these patients, APACHE II, need for mechanical ventilation in the first 24 h after ICU admission and myocardial dysfunction were associated with risk of needing CRRT. AKI I and II patients had a high ICU mortality (38.5%), especially if CRRT were required (64.1% vs. 34,8%; p < 0.001).

Critically ill patients with SARS-CoV-2 pneumonia and AKI have a high ICU mortality. Even AKI I and II stages are associated with high risk of needing CRRT and ICU mortality.

SARS-CoV-2 virus infects cells by engaging with ACE2 requiring protease TMPRSS2. ACE2 is highly expressed in kidneys. Predictors for severe disease are high age and male sex. We hypothesized that ACE2 and TMPRSS2 proteins are more abundant (1) in males and with increasing age in kidney and (2) in urine and extracellular vesicles (EVs) from male patients with COVID-19 and (3) SARS-CoV-2 is present in urine and EVs during infection. Kidney cortex samples from patients subjected to cancer nephrectomy (male/female; < 50 years/˃75 years, n = 24; ˃80 years, n = 15) were analyzed for ACE2 and TMPRSS2 protein levels. Urine from patients hospitalized with SARS-CoV-2 infection was analyzed for ACE2 and TMPRSS2. uEVs were used for immunoblotting and SARS-CoV-2 mRNA and antigen detection. Tissue ACE2 and TMPRSS2 protein levels did not change with age. ACE2 was not more abundant in male kidneys in any age group. ACE2 protein was associated with proximal tubule apical membranes in cortex. TMPRSS2 was observed predominantly in the medulla. ACE2 was elevated significantly in uEVs and urine from patients with COVID-19 with no sex difference compared with urine from controls w/wo albuminuria. TMPRSS2 was elevated in uEVs from males compared to female. ACE2 and TMPRSS2 did not co-localize in uEVs/apical membranes. SARS-CoV-2 nucleoprotein and mRNA were not detected in urine. Higher kidney ACE2 protein abundance is unlikely to explain higher susceptibility to SARS-CoV-2 infection in males. Kidney tubular cells appear not highly susceptible to SARS-CoV-2 infection. Loss of ACE2 into urine in COVID could impact susceptibility and angiotensin metabolism.

In this study, we examined preexisting systemic inflammation before COVID-19 (SIC), as assessed through C-reactive protein (CRP) levels, to gain insights into the origins of acute kidney injury (AKI) in adults with comorbidities affected by COVID-19. Although aging is not categorized as a disease, it is characterized by chronic inflammation, and older individuals typically exhibit higher circulating levels of inflammatory molecules, particularly CRP, compared to younger individuals. Conversely, elevated CRP concentrations in older adults have been linked with the development of comorbidities. Simultaneously, these comorbidities contribute to the production of inflammatory molecules, including CRP. Consequently, older adults with comorbidities have higher CRP concentrations than their counterparts without comorbidities or those with fewer comorbidities. Given that CRP levels are correlated with the development and severity of AKI in non-COVID-19 patients, we hypothesized that individuals with greater SIC are more likely to develop AKI during SARS-CoV-2 infection than those with less SIC.

This study aimed to examine the impact of APS on acute kidney injury induced by rhabdomyolysis (RIAKI), exploring its association with macrophage M1 polarization and elucidating the underlying mechanisms.

C57BL/6J mice were randomly assigned to one of three groups: a normal control group, a RIAKI model group, and an APS treatment group. Techniques such as flow cytometry and immunofluorescence were employed to demonstrate that APS can inhibit the transition of renal macrophages to the M1 phenotype in RIAKI. Furthermore, the raw264.7 macrophage cell line was chosen and induced into the M1 phenotype to further examine the impact of APS on this model and elucidate the underlying mechanism.

Administration of APS led to a significant decrease in UREA levels by 25.2% and CREA levels by 60.9% within the model group. Also, APS exhibited an inhibitory effect on the infiltration of M1 macrophages and the cGAS-STING pathway in kidneys within the RIAKI, subsequently leading to decreased serum concentrations of IL-1β, IL-6 and TNF-α by 44.5%, 12.9%, and 10.3%, respectively, consistent with the results of in vitro experiments. Furthermore, APS exhibited an anti-apoptotic effect on MPC5 cells when co-cultured with M1 macrophages.

Astragalus polysaccharide (APS) potentially mitigated rhabdomyolysis-induced renal damage by impeding the M1 polarization of macrophages. This inherent mechanism might involve the suppression of the cGAS-STING pathway activation within macrophages. Furthermore, APS could endow protective effects on podocytes through the inhibition of apoptosis.

During the COVID-19 pandemic, it has been observed that acute kidney injury (AKI) especially requiring intervention support of hemodialysis has notably increased mortality rates among COVID-19-positive critically ill patients; however, comprehensive data regarding this from India, especially the eastern territory, remains sparse. This study aims to outline the demographic, clinical, and biochemical characteristics, along with the outcomes, of these patients.

A retrospective study was performed at the All India Institute of Medical Sciences (AIIMS), Patna, from March 1, 2020, to March 31, 2021. Included were patients diagnosed with COVID-19 and AKI necessitating hemodialysis during their intensive care unit (ICU) stay. These patients tested positive for COVID-19 and met the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI stages 1-3, requiring ICU admission and hemodialysis. Medical history, clinical features, laboratory results, comorbidities, and demographic data were collected and analyzed. Patients were tracked from admission to discharge or death. Gaussian-distributed values were compared using the unpaired t-test or Pearson's test, while non-Gaussian continuous variables were analyzed using the Mann-Whitney test or Spearman's test. The study employed the Kolmogorov-Smirnov test to assess Gaussian distribution, while categorical data were compared using the Chi-square test.

Among 773 patients with positive COVID-19 tests who were admitted to the ICU, 236 patients developed AKI, and among them, 139 patients required hemodialysis. The total mortality rate was 167 (70.7%) among people who had AKI and 102 (77%) in patients with AKI who required hemodialysis. AKI was also a risk factor associated with higher mortality rates in older patients (>45 years) (n=150 (73.2%)), those needing invasive ventilation (n=163 (88.1%)), and patients with elevated total leucocyte count (TLC) (n=130 (79.3%)), lactate dehydrogenase (LDH) (n=159 (72.9%)), interleukin-6 (IL-6) (n=153 (72.2%)), and serum ferritin (n=51 (73.7%)) and hypoalbuminemia (n=152 (73.1%)).

AKI requiring hemodialysis significantly increases mortality risk in COVID-19 patients. Other risk factors for mortality with AKI in COVID-19-positive patients include age, elevated leucocyte count, invasive ventilation, and deranged inflammatory markers.

Kidney involvement occurs in almost one third of patients hospitalised with coronavirus disease 2019 (COVID-19) and is associated with increased disease severity. This review aims to outline the spectrum of kidney pathology involved in COVID-19. Literature was reviewed systematically on the databases Medline OVID and Scopus in search of case reports, case series, cohort studies and autopsy studies of patients with COVID-19 who underwent kidney biopsies. Studies were published between August 2020 and November 2021. Fourteen studies consisting of 159 patients were included in this review. Acute tubular necrosis is the most common pathology followed by collapsing glomerulopathy, occurring in 40.1% and 28.9% of patients respectively. Of the 46 patients with collapsing glomerulopathy, 44 were of African descent with high-risk apolipoprotein L1 genotypes. Less common glomerular diseases include membranous nephropathy, secondary focal segmental glomerulosclerosis, minimal change disease and primary focal segmental glomerulosclerosis occurring in 5%, 4.4%, 3.1% and 2.5% of patients respectively. Glomerulonephritis occurred in a minority of patients. Direct viral infection has not been found as a definitive aetiology. Acute kidney injury occurs frequently in hospitalised COVID-19 patients and is associated with increased morbidity and mortality. The mechanisms underpinning acute kidney injury are multifactorial. Acute tubular necrosis is the most common. Collapsing glomerulopathy is the most common glomerular injury and is strongly linked to apolipoprotein L1 genotypes. Improved understanding of COVID-19-related kidney pathologies can guide treatment to improve patient outcomes and reduce progression of chronic kidney disease. The longitudinal impact of COVID-19-related kidney disease requires further research.

Persistent severe acute kidney injury (PS-AKI) is associated with poor clinical outcomes. Our study attempted to evaluate the diagnostic value of chemokines for early-stage PS-AKI prediction.

According to the KDIGO criteria, 115 COVID-19 patients diagnosed with stage 2/3 AKI were recruited from the intensive care unit between December 2022 and February 2023. Primary clinical outcomes included detecting PS-AKI in the first week (≥ KDIGO stage 2 ≥ 72 h). Cytometric Bead Array was used to detect patient plasma levels (interleukin-8 (IL-8), C-C chemokine ligand 5 (CCL5), chemokine (C-X-C Motif) ligand 9 (CXCL9), and interferon-inducible protein 10 (IP-10)) of chemokines within 24 h of enrollment.

Of the 115 COVID-19 patients with stage 2/3 AKI, 27 were diagnosed with PS-AKI. Among the four measured chemokines, only the IL-8 level was significantly elevated in the PS-AKI group than in the Non-PS-AKI group. IL-8 was more effective as a biomarker while predicting PS-AKI with an area under the curve of 0.769 (0.675-0.863). This was superior to other biomarkers related to AKI, including serum creatinine. Moreover, plasma IL-8 levels of >32.2 pg/ml on admission could predict PS-AKI risk (sensitivity = 92.6%, specificity = 51.1%). Additionally, the IL-8 level was associated with total protein and IL-6 levels.

Plasma IL-8 is a promising marker for the early identification of PS-AKI among COVID-19 patients. These findings should be validated in further studies with a larger sample size.

The Coronavirus Disease 2019 (COVID-19) pandemic, driven by the novel coronavirus and its variants, has caused over 518 million infections and 6.25 million deaths globally, leading to a significant health crisis. Beyond its primary respiratory impact, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been implicated in various extra-pulmonary complications. Research studies reveal that the virus affects multiple organs, including the kidneys, liver, pancreas, and central nervous system (CNS), largely due to the widespread expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors. Clinical evidence shows that the virus can induce diabetes by disrupting pancreatic and liver functions as well as cause acute kidney injury. Additionally, neurological complications, including cognitive impairments and neuroinflammation, have been observed in a significant number of COVID-19 patients. This review discusses the mechanisms linking SARS-CoV-2 to acute kidney injury, Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM), emphasizing its effects on pancreatic beta cells, insulin resistance, and the regulation of gluconeogenesis. We also explore how SARS-CoV-2 induces neurological complications, detailing the intricate pathways of neuro-invasion and the potential to trigger conditions such as Alzheimer's disease (AD). By elucidating the metabolic and neurological manifestations of COVID-19 and the underlying pathogenic mechanisms, this review underscores the imperative for continued research and the development of effective therapeutic interventions to mitigate the long-term and short-term impacts of SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) infection is well established as a systemic disease including kidney damage. The entry point into the renal cell remains the angiotensin-converting enzyme 2 (ACE-2) receptor and the spectrum of renal lesions is broad, with a clear predominance of structural and functional tubular lesions. The most common form of glomerular injury is collapsing glomerulopathy (CG), which is strongly associated with apolipoprotein L1(APOL-1) risk variants. These acute lesions, which are secondary to the direct or indirect effects of SARS-CoV-2, can progress to chronicity and are specific to long COVID-19 in the absence of any other cause. Residual inflammation associated with SARS-CoV-2 infection, in addition to acute kidney injury (AKI) as a transitional state with or without severe histological lesions, may be responsible for greater kidney function decline in mild-to-moderate COVID-19. This review discusses the evidence for renal histological markers of chronicity in COVID-19 patients and triggers of low-grade inflammation that may explain the decline in kidney function in the post-COVID-19 period.

Coronavirus disease 2019 (COVID-19) has been recognised as a risk factor for acute kidney injury (AKI). Our aim was to investigate the risk factors contributing to hospitalised and outpatient paediatric COVID-19-associated AKI.

A retrospective observational study was conducted on patients aged 1 month to 18 years with diagnosed COVID-19-associated AKI applied to a tertiary paediatric referral hospital between March 1, 2020 and March 1, 2022.

A total of 6683 patients were evaluated and 486 patients were included in the study. Acute kidney injury was observed in 3.7% of outpatients and 23.9% of hospitalised patients. Multivariate logistic regression analysis showed that, on admission, a history of contact with a COVID-19 positive person (p < 0.001), age below 12 months (p = 0.004), presence of comorbidities (p < 0.001), abdominal pain (p = 0.008), anorexia (p = 0.003), dyspnoea (p = 0.005), higher lactate dehydrogenase values (p = 0.004), neutrophilia (p < 0.001), higher neutrophil-to-lymphocyte ratio (NLR) (p = 0.003), higher white blood cell counts (p = 0.006), elevated C-reactive protein (CRP) levels (p = 0.002), anaemia (p = 0.015), hypoalbuminaemia (p < 0.001), hyperglycaemia (p = 0.006), and presence of proteinuria (p = 0.003) were independent predictors of AKI. Higher rates of hospitalisation (p < 0.001) and admission to the paediatric intensive care unit (PICU) (p < 0.001), longer length of hospitalisation (p < 0.001), and greater need for mechanical ventilation (p < 0.001) were associated with AKI.

This study reveals that not only hospitalised children, but also paediatric patients are at risk for AKI. The presence of comorbidities, abdominal pain, anorexia, dyspnoea, anaemia, inflammation, hypoalbuminaemia, proteinuria and history of contact with a COVID-19 positive person were the main risk factors for AKI. COVID-19-associated AKI was associated with worse outcomes.

The primary challenge posed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19-related mortality, often exacerbated by additional medical complications, such as COVID-19-associated kidney injuries (CAKIs). Up to half of COVID-19 patients experience kidney complications, with those facing acute respiratory failure and kidney injury having the worst overall prognosis. Despite the significant impact of CAKI on COVID-19-related mortality and its enduring effects in long COVID, the underlying causes and molecular mechanisms of CAKI remain elusive. In this study, we identified a functional relationship between the expression of the SARS-CoV-2 ORF3a protein and inflammation-driven apoptotic death of renal tubular epithelial cells in patients with CAKI. We demonstrate in vitro that ORF3a independently induces renal cell-specific apoptotic cell death, as evidenced by the elevation of kidney injury molecule-1 (KIM-1) and the activation of NF-kB-mediated proinflammatory cytokine (TNFα and IL-6) production. By examining kidney tissues of SARS-CoV-2-infected K18-ACE2 transgenic mice, we observed a similar correlation between ORF3a-induced cytopathic changes and kidney injury. This correlation was further validated through reconstitution of the ORF3a effects via direct adenoviral injection into mouse kidneys. Through medicinal analysis, we identified a natural compound, glycyrrhizin (GL4419), which not only blocks viral replication in renal cells, but also mitigates ORF3a-induced renal cell death by inhibiting activation of a high mobility group box 1 (HMGB1) protein, leading to a reduction of KIM-1. Moreover, ORF3a interacts with HMGB1. Overproduction or downregulation of hmgb1 expression results in correlative changes in renal cellular KIM-1 response and respective cytokine production, implicating a crucial role of HMGB1 in ORF3a-inflicted kidney injuries. Our data suggest a direct functional link between ORF3a and kidney injury, highlighting ORF3a as a unique therapeutic target contributing to CAKI.

The major challenge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the pandemic is COVID-19-related mortality, which has tragically claimed millions of lives. COVID-19-associated morbidity and mortality are often exacerbated by pre-existing medical conditions, such as chronic kidney diseases (CKDs), or the development of acute kidney injury (AKI) due to COVID-19, collectively known as COVID-19-associated kidney injuries (CAKIs). Patients who experience acute respiratory failure with CAKI have the poorest clinical outcomes, including increased mortality. Despite these alarming clinical findings, there is a critical gap in our understanding of the underlying causes of CAKI. Our study establishes a direct correlation between the expression of the SARS-CoV-2 viral ORF3a protein and kidney injury induced by ORF3a linking to CAKI. This functional relationship was initially observed in our clinical studies of COVID-19 patients with AKI and was further validated through animal and in vitro cellular studies, either by expressing ORF3a alone or in the context of viral infection. By elucidating this functional relationship and its underlying mechanistic pathways, our research deepens the understanding of COVID-19-associated kidney diseases and presents potential therapeutic avenues to address the healthcare challenges faced by individuals with underlying conditions.

Recent reports have revealed that nephropathy leading to kidney injury (KI) is a prevalent complication of COVID-19 and is linked to high mortality and morbidity in diabetes mellitus type II (DM-T-II) patients. This systematic literature review and meta-analysis aimed to critically analyze existing studies and evidence on the impact of COVID-19 on nephropathy and kidney injury in diabetes mellitus type II (DM-T-II) patients.

A systematic search was conducted in the Web of Science (WoS), PubMed and Cochrane databases for relevant studies published between March 2020 and July 2023. To ensure the integrity of the systematic literature review and meta-analysis, observational studies that specifically reported post-COVID-19 kidney injury in DM-T2 patients were included, whereas we did not include articles in the press, meta-analyses, case reports, case series, Diabetes Type-I articles or non-English papers. The primary outcome was kidney injury in patients with type II diabetes after contracting COVID-19. The protocol for this study was published on PROSPERO (registration number CRD42023413887).

Initially, 6,339 articles were included in the search, from which only 6 observational studies were selected by following the 2020 PRISMA statement. The quality of the evidence was assessed by a tool provided by the National Institutes of Health (observational studies). The total number of participants included in the studies was 14,723. Our systematic literature review and meta-analysis provide compelling evidence that kidney injury is a prevalent complication of COVID-19 infection in the type II diabetes population, with a pooled odds ratio of 2.27 (95% CI: 2.05-2.51; p < 0.00001), often necessitating hospitalization and hemodialysis in severe cases.

Covid-19 is associated with a two-fold increase in nephropathy and acute kidney injury in diabetes mellitus type 2 patients compared to non-diabetic patients. This implies that kidney injury is more likely to occur in diabetes mellitus type 2 patients post Covid infection.

COVID-19 has been reported to be associated with the occurrence and recurrence of membranous nephropathy (MN). The clinicopathological characteristics and complement system activation of MN after COVID-19 are unclear.

A total of 38 patients with biopsy-proven MN who developed new-onset proteinuria after COVID-19 were enrolled in this study. One hundred patients with primary MN diagnosed before the COVID-19 pandemic were the control. Renal immunohistochemical staining for SARS-CoV-2 nucleocapsid protein was performed in 38 patients with MN after COVID-19. Serum membrane attack complex (MAC) was detected by enzyme-linked immunosorbent assay. Glomerular staining for the complement proteins in different pathways were detected by immunohistochemistry.

Thirteen of 38 patients had positive staining for SARS-CoV-2 nucleocapsid protein. Compared with the control patients, the clinical manifestations were more severe in patients after COVID-19. Patients with positive SARS-CoV-2 staining had a higher proportion of nephrotic syndrome, lower level of serum albumin, and greater severity of renal interstitial fibrosis than those of patients with negative SARS-CoV-2 staining. Serum MAC level and renal MAC staining intensity of MN after COVID-19 were significantly higher than those of the control patients. MAC expression in MN patients with positive SARS-CoV-2 staining was stronger than that in both control patients and MN after COVID-19 with negative SARS-CoV-2 staining. The expression trend of factor H was consistent with that of MAC.

Excessive activation of the complement system aggravated symptoms in MN after COVID-19. Therapeutic strategy targeting the complement system may need to be considered.

The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19.

Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment.

IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules.

SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19.

Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.