COVID-19 associated acute transplant failure after AB0-incompatible living donor kidney transplantation - a case report.

INTRODUCTION: Immunosuppressive therapy is associated with an increased risk of severe courses of SARS-CoV-2 infection, with frequently delayed viral clearance. We report a case of an acute kidney transplant failure in persistent SARS-CoV-2 infection in a patient with absolute B-cell depletion after administration of rituximab for AB0-incompatible living donor kidney transplantation. CASE PRESENTATION: A 34-year-old unvaccinated patient is diagnosed with SARS-CoV-2 infection four months after kidney transplantation. With only mild symptoms and an estimated glomerular filtration rate (eGFR) of 44 ml/min/1.73 m2, therapy with molnupiravir was initially given. Within the next eight weeks, transplant biopsies were performed for acute graft failure. These showed acute T-cell rejection with severe acute tubular epithelial damage with only mild interstitial fibrosis and tubular atrophy (BANFF cat. 4 IB), and borderline rejection (BANFF cat. 3). A therapy with prednisolone and intravenous immunoglobulins was performed twice. With unchanged graft failure, the third biopsy also formally showed BANFF cat. 4 IB. However, fluorescence in situ hybridization detected SARS-CoV-2 viruses in large portions of the distal tubules. After nine weeks of persistent COVID-19 disease neither anti-SARS-CoV-2 IgG nor a SARS-CoV-2-specific cellular immune response could be detected, leading to the administration of sotrovimab and remdesivir. Among them, SARS-CoV-2 clearance, detection of IgG, and improvement of graft function were achieved. CONCLUSION: Lack of viral clearance can lead to complications of SARS-CoV-2 infection with atypical manifestations. In kidney transplant patients, before initiating therapy, the differential diagnoses of "rejection" and "virus infection" should be weighed against each other in an interdisciplinary team of nephrologists, infectious diseases specialists and pathologists.

Possible kidney-lung cross-talk in COVID-19: in silico modeling of SARS-CoV-2 infection.

BACKGROUND: Publicly available genomics datasets have grown drastically during the past decades. Although most of these datasets were initially generated to answer a pre-defined scientific question, their repurposing can be useful when new challenges such as COVID-19 arise. While the establishment and use of experimental models of COVID-19 are in progress, the potential hypotheses for mechanisms of onset and progression of COVID-19 can be generated by using in silico analysis of known molecular changes during COVID-19 and targets for SARS-CoV-2 invasion. METHODS: Selecting condition: COVID-19 infection leads to pneumonia and mechanical ventilation (PMV) and associated with acute kidney injury (AKI). There is increasing data demonstrating mechanistic links between AKI and lung injury caused by mechanical ventilation. Selecting targets: SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) for cell entry. We hypothesized that expression of ACE2 and TMPRSS2 would be affected in models of AKI and PMV. We therefore evaluated expression of ACE2 and TMPRSS2 as well as other novel molecular players of AKI and AKI-lung cross-talk in the publicly available microarray datasets GSE6730 and GSE60088, which represent gene expression of lungs and kidneys in mouse models of AKI and PMV, respectively. RESULTS: Expression of COVID-19 related genes ACE2 and TMPRSS2 was downregulated in lungs after 6 h of distant AKI effects. The expression of ACE2 decreased further after 36 h, while expression of TMPRSS2 recovered. In kidneys, both genes were downregulated by AKI, but not by distant lung injury. We also identified 53 kidney genes upregulated by PMV; and 254 lung genes upregulated by AKI, 9 genes of which were common to both organs. 3 of 9 genes were previously linked to kidney-lung cross-talk: Lcn2 (Fold Change (FC)Lung (L) = 18.6, FCKidney (K) = 6.32), Socs3 (FCL = 10.5, FCK = 10.4), Inhbb (FCL = 6.20, FCK = 6.17). This finding validates the current approach and reveals 6 new candidates, including Maff (FCL = 7.21, FCK = 5.98). CONCLUSIONS: Using our in silico approach, we identified changes in COVID-19 related genes ACE2 and TMPRSS2 in traditional mouse models of AKI and kidney-lung cross-talk. We also found changes in new candidate genes, which could be involved in the combined kidney-lung injury during COVID-19.

TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling.

BACKGROUND: Injury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 (TrkC) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. METHODS: Nephron-specific TrkC knockout (TrkC-KO) and nephron-specific TrkC-overexpressing (TrkC-OE) mice were generated to dissect the role of TrkC in nephron development and maintenance. RESULTS: Both TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)-associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. CONCLUSIONS: Our results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.

Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.

Changes in glomerular filtration rate and metabolomic differences in severely ill coronavirus disease survivors 3 months after discharge.

To explore the recovery of renal function in severely ill coronavirus disease (COVID-19) survivors and determine the plasma metabolomic profile of patients with different renal outcomes 3 months after discharge, we included 89 severe COVID-19 survivors who had been discharged from Wuhan Union Hospital for 3 months. All patients had no underlying kidney disease before admission. At patient recruitment, renal function assessment, laboratory examination, chest computed tomography (CT) were performed. Liquid chromatography-mass spectrometry was used to detect metabolites in the plasma. We analyzed the longitudinally change in the estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin-c levels using the CKD-EPI equation and explored the metabolomic differences in patients with different eGFR change patterns from hospitalization to 3 months after discharge. Lung CT showed good recovery; however, the median eGFR significantly decreased at the 3-month follow-up. Among the 89 severely ill COVID-19 patients, 69 (77.5%) showed abnormal eGFR (<90 mL/min per 1.73 m2) at 3 months after discharge. Age (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.08-1.47, p = 0.003), body mass index (OR = 1.97, 95% CI = 1.20-3.22, p = 0.007), and cystatin-c level (OR = 1.22, 95% CI = 1.07-1.39, p = 0.003) at discharge were independent risk factors for post-discharge abnormal eGFR. Plasma metabolomics at the 3-months follow-up revealed that ß-pseudouridine, uridine, and 2-(dimethylamino) guanosine levels gradually increased with an abnormal degree of eGFR. Moreover, the kynurenine pathway in tryptophan metabolism, vitamin B6 metabolism, cysteine and methionine metabolism, and arginine biosynthesis were also perturbed in survivors with abnormal eGFR.

Overview of acute kidney manifestations and management of patients with COVID-19.

Since the start of the COVID-19 pandemic, several manifestations of kidney involvement associated with infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been described, including proteinuria, hematuria, and acute kidney injury. A growing body of literature has explored the risk factors and pathogenesis of COVID-19-associated acute kidney injury (AKI), including direct and indirect mechanisms, as well as early postdischarge outcomes that may result from various manifestations of kidney involvement. In this review, we explore the current state of knowledge of the epidemiology of COVID-19-associated AKI, potential mechanisms and pathogenesis of AKI, and various management strategies for patients in the acute setting. We highlight how kidney replacement therapy for patients with COVID-19-associated AKI has been affected by the increasing demand for dialysis and how the postacute management of patients, including outpatient follow-up, is vitally important. We also review what is presently known about long-term kidney outcomes after the initial recovery from COVID-19. We provide some guidance as to the management of patients hospitalized with COVID-19 who are at risk for AKI as well as for future clinical research in the setting of COVID-19 and the significance of early identification of patients at highest risk for adverse kidney outcomes.

Obesity is independently associated with septic shock, renal complications, and mortality in a multiracial patient cohort hospitalized with COVID-19.

BACKGROUND: Obesity has emerged as a risk factor for severe coronavirus disease 2019 (COVID-19) infection. To inform treatment considerations the relationship between obesity and COVID-19 complications and the influence of race, ethnicity, and socioeconomic factors deserves continued attention. OBJECTIVE: To determine if obesity is an independent risk factor for severe COVID-19 complications and mortality and examine the relationship between BMI, race, ethnicity, distressed community index and COVID-19 complications and mortality. METHODS: A retrospective cohort study of 1,019 SARS-CoV-2 positive adult admitted to an academic medical center (n = 928) and its affiliated community hospital (n-91) in New York City from March 1 to April 18, 2020. RESULTS: Median age was 64 years (IQR 52-75), 58.7% were men, 23.0% were Black, and 52.8% were Hispanic. The prevalence of overweight and obesity was 75.2%; median BMI was 28.5 kg/m2 (25.1-33.0). Over the study period 23.7% patients died, 27.3% required invasive mechanical ventilation, 22.7% developed septic shock, and 9.1% required renal replacement therapy (RRT). In the multivariable logistic regression model, BMI was associated with complications including intubation (Odds Ratio [OR]1.03, 95% Confidence Interval [CI]1.01-1.05), septic shock (OR 1.04, CI 1.01-1.06), and RRT (OR1.07, CI 1.04-1.10), and mortality (OR 1.04, CI 1.01-1.06). The odds of death were highest among those with BMI ≥ 40 kg/m2 (OR 2.05, CI 1.04-4.04). Mortality did not differ by race, ethnicity, or socioeconomic distress score, though Black and Asian patients were more likely to require RRT. CONCLUSIONS AND RELEVANCE: Severe complications of COVID-19 and death are more likely in patients with obesity, independent of age and comorbidities. While race, ethnicity, and socioeconomic status did not impact COVID-19 related mortality, Black and Asian patients were more likely to require RRT. The presence of obesity, and in some instances race, should inform resource allocation and risk stratification in patients hospitalized with COVID-19.

Renal manifestations, incidence, pathogenesis and implications on prognosis and mortality in COVID-19 patients: A review of current evidence and the potential for future directions.

Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has now spread into a worldwide pandemic. The pulmonary manifestations of this disease have been well described in literature, however COVID-19 can also cause severe and lasting harm in other organs including the kidneys, heart, and pancreas. Emerging evidence suggests that COVID-19 has multiple renal manifestations which impact the prognosis and mortality of this disease. Here we present a literature review of the current evidence of renal involvement in COVID-19 patients and the potential for future directions in management.

Coronavirus disease 2019 and kidney injury.

PURPOSE OF REVIEW: In this paper, we seek to review coronavirus disease 2019 (COVID-19) associated kidney injury with a focus on what is known about pathophysiology. RECENT FINDINGS: Kidney injury is a common complication of SARS-CoV-2 infection and is associated with increased morbidity and mortality. Acute tubular necrosis and glomerular injury are two common findings. Direct viral effect, endothelial dysfunction, and podocyte and tubular epithelial injury have been described. COVID-19-related glomerular injury may also be associated with high-risk APOL1 genotype. SUMMARY: Data on COVID-19 renal involvement have suggested novel mechanisms of kidney injury that need to be further elucidated. More data are needed on renal involvement in milder disease, renal-specific therapeutic interventions, and long-term sequelae.

Effects of dapagliflozin on prevention of major clinical events and recovery in patients with respiratory failure because of COVID-19: Design and rationale for the DARE-19 study.

AIMS: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19. MATERIALS AND METHODS: DARE-19 (NCT04350593) is an investigator-initiated, collaborative, international, multicentre, randomized, double-blind, placebo-controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all-cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID-19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID-19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all-cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID-19 will be assessed. CONCLUSIONS: DARE-19 will evaluate whether dapagliflozin can prevent COVID-19-related complications and all-cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE-19 is the first large randomized controlled trial investigating use of sodium-glucose cotransporter 2 inhibitors in patients with COVID-19.

A case of neglected hepatorenal dysfunction during the COVID pandemic.

As the world fights with the Coronavirus, most of the hospitals are gearing up for the care of these patients. As most of the attention these days is being given on Coronavirus, the patients suffering from other clinical infections are being neglected. SARS-CoV-2 is being kept as the top differential in patients presenting with fever and respiratory distress. We hereby present a case of patient returning from Indonesia during the pandemic presenting with a history of hepatic, renal dysfunction with fever and cough. Due to the pandemic, the patient's fever and cough outweighed the hepatic and renal dysfunction, and the patient had to undergo dialysis before the final diagnosis of leptospirosis could be made.

The COVID-Kidney Controversy: Can SARS-CoV-2 Cause Direct Renal Infection?

CONTEXT: Determining whether SARS-CoV-2 causes direct infection of the kidneys is challenging due to limitations in imaging and molecular tools. Subject of Review: A growing number of conflicting kidney biopsy and autopsy reports highlight this controversial issue. Second Opinion: Based on the collective evidence, therapies that improve hemodynamic stability and oxygenation, or dampen complement activation, are likely to ameliorate acute kidney injury in COVID-19. At this time, whether inhibition of viral infection and replication directly modulates kidney damage is inconclusive.

SARS-CoV-2 Infection in the Central and Peripheral Nervous System-Associated Morbidities and Their Potential Mechanism.

The recent outbreak of SARS-CoV-2 infections that causes coronavirus-induced disease of 2019 (COVID-19) is the defining and unprecedented global health crisis of our time in both the scale and magnitude. Although the respiratory tract is the primary target of SARS-CoV-2, accumulating evidence suggests that the virus may also invade both the central nervous system (CNS) and the peripheral nervous system (PNS) leading to numerous neurological issues including some serious complications such as seizures, encephalitis, and loss of consciousness. Here, we present a comprehensive review of the currently known role of SARS-CoV-2 and identify all the neurological problems reported among the COVID-19 case reports throughout the world. The virus might gain entry into the CNS either through the trans-synaptic route via the olfactory neurons or through the damaged endothelium in the brain microvasculature using the ACE2 receptor potentiated by neuropilin-1 (NRP-1). The most critical of all symptoms appear to be the spontaneous loss of breathing in some COVID-19 patients. This might be indicative of a dysfunction within the cardiopulmonary regulatory centers in the brainstem. These pioneering studies, thus, lay a strong foundation for more in-depth basic and clinical research required to confirm the role of SARS-CoV-2 infection in neurodegeneration of critical brain regulatory centers.

Coronavirus infection and kidney disease: a review of current and emerging evidence.

In November 2009, an outbreak of a new strain of coronavirus (later named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was first noticed in the city of Wuhan in China, rapidly spreading to assume pandemic proportions within a short period of time. The disease was subsequently designated as coronavirus disease-19 (COVID-19). The death toll has continued to rise with grave health and socio-economic implications for individuals, families and nations globally. Although the respiratory tract is primarily involved in this disease, kidney affectation is increasingly reported and has been shown to worsen the prognosis of the disease. Current evidence shows that kidney disease is not uncommon in patients with coronavirus infection especially in those with COVID-19 and may arise from a constellation of factors such as hypotension, sepsis, rhabdomyolysis, multi-organ failure, use of nephrotoxic medications as well as direct infection in some cases. Factors associated with acute kidney injury in coronavirus infected patients may include elderly age, male sex, presence of co-morbidities as well as pre-existing chronic kidney disease and end stage renal disease. Although, there is presently no effective treatment for COVID-19, there is room for conservative management, extracorporeal therapy and renal replacement therapy. The aim of this review was to integrate current and emerging evidences on renal disease resulting from COVID-19 and the previous epidemics of coronavirus infections including the Middle East Respiratory Syndrome (MERS) and the Severe Acute Respiratory Syndrome (SARS) caused by other strains of the virus.

Manifestaciones extrapulmonares de la infección por SARS-CoV-2.

The disease caused by a new coronavirus, which started in 2019, was named COVID-19 and declared a pandemic on March 11, 2020 by the World Health Organization. Although it is true that the first reports emphasized the respiratory manifestations of this disease as an initial clinical presentation, little by little cases with different initial manifestations began to appear, involving other systems. In cases where central nervous system involvement was identified, the most frequent findings were dizziness, headache, and alteration of alertness. Regarding the cardiovascular system, elevation of cardiac biomarkers and myocarditis are one of the most frequent findings. The main gastrointestinal symptoms described so far are: anorexia, nausea, vomiting, diarrhea, abdominal pain and/or discomfort. Venous thromboembolism is a frequent complication and a public health problem. Skin manifestations remain a field of investigation. Maculopapular rashes, reticular livedo, acral gangrene, among others, have been identified. Health personnel must be updated on new clinical findings and the forms of presentation of this partially known disease, which will make it possible to make more accurate and timely diagnoses, thus impacting the prognosis of these patients.

La enfermedad causada por un nuevo coronavirus, que inició en 2019, fue denominada COVID-19 y declarada pandemia el 11 de marzo de 2020 por la Organización Mundial de la Salud. Si bien es cierto que los primeros reportes enfatizaron las manifestaciones respiratorias de esta enfermedad como presentación clínica inicial, poco a poco empezaron a aparecer casos con manifestaciones iniciales distintas, involucrando otros sistemas. En los casos en los que se identificó afectación del sistema nervioso central, los hallazgos más frecuentes fueron mareo, cefalea y alteración del estado de alerta. Respecto al sistema cardiovascular, la elevación de biomarcadores cardiacos y la miocarditis son unos de los hallazgos más frecuentes. Los principales síntomas gastrointestinales descritos hasta el momento son anorexia, náuseas, vómitos, diarrea y dolor o disconfort abdominal. La tromboembolia venosa es una complicación frecuente y un problema de salud pública. Las manifestaciones cutáneas siguen siendo un campo de investigación. Se han identificado exantemas maculopapulares, livedo reticular y gangrena acral, entre otros. El personal sanitario debe estar actualizado sobre los nuevos hallazgos clínicos y las formas de presentación de esta enfermedad solo parcialmente conocida, lo que permitirá hacer diagnósticos más precisos y oportunos, y así impactar en el pronóstico de estos enfermos.

Detection and analysis of clinical features of patients with different types of coronavirus disease 2019.

This study was designed to investigate the change of various indexes in patients with different types of coronavirus disease 2019 (COVID-19). Seventy-five patients with COVID-19 were collected from the First Affiliated Hospital, Zhejiang University School of Medicine, and they were classified into moderate, severe and critically severe types according to the disease severity. The basic information, blood routine, pneumonia-related blood indexes, immune-related indexes along with liver, kidney and myocardial indexes in patients with different types were analyzed. The analysis of immune-related indexes showed that the proportions of critically severe patients with abnormal interleukin-2 (IL-2) and IL-4 were higher than those of severe and moderate patients. In addition, the proportion of patients with abnormal total cholesterol increased as the severity of disease increased, and the proportion in critically severe patients was significantly higher than that in moderate patients. The patients with a more severe COVID-19 are older and more likely to have a history of hypertension. With the progression of COVID-19, the abnormal proportion of total white blood cell, neutrophils, lymphocytes, IL-2, IL-4, and total cholesterol increased. The change of these indexes in patients with different COVID-19 types could provide reference for the disease severity identification and diagnosis of COVID-19. In addition, the change in the total cholesterol level suggested that COVID-19 would induce some liver function damage in patients.

Gastrointestinal and renal complications in SARS-CoV-2-infected patients: Role of immune system.

The recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease has been accompanied by various gastrointestinal (GI) and renal manifestations in significant portion of infected patients. Beside studies on the respiratory complications of coronavirus infection, understanding the essential immunological processes underlying the different clinical manifestations of virus infection is crucial for the identification and development of effective therapies. In addition to the respiratory tract, the digestive and urinary systems are the major sources of virus transmission. Thus, knowledge about the invasion mechanisms of SARS-CoV-2 in these systems and the immune system responses is important for implementing the infection prevention strategies. This article presents an overview of the gut and renal complications in SARS-CoV-2 infection. We focus on how SARS-CoV-2 interacts with the immune system and the consequent contribution of immune system, gut, and renal dysfunctions in the development of disease.