The Renal Manifestations of SARS-CoV-2: A Guide for Family Physicians

COVID-19 is a devastating systemic disease characterized by multisystem involvement driven by exuberant hyperinflammatory and dysregulations in coagulation. In COVID-19 patients, renal failure contributes to morbidity and mortality, and its early detection and timely management are critical to minimize such untoward and irreversible complications. In the healthcare system, family physicians constitute the first node in the management of patients, yet there is a dearth of reports and guidelines focusing on them for specific organ affection. This review provides an overview of recent studies examining the renal manifestations following SARS-CoV-2 infection. We focus on the tell-tale signs and laboratory findings of renal affection in the pediatric and adult populations with COVID-19, specifically for family practitioners to assist in their appropriate triage. Among different manifestations, urinary abnormalities and a modest increase in creatinine are the early indicators of renal affection in COVID-19 patients. Although renal transplant patients are conventionally managed by specialized teams, they may present to family physicians during a pandemic. This review provides a framework for family physicians to promptly detect early indicators of renal involvement in patients infected with SARS-CoV-2, including providing triage guidance for kidney transplant recipients.

Janus Kinase Signaling Pathway and Its Role in COVID-19 Inflammatory, Vascular, and Thrombotic Manifestations.

Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients.

SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway.

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectible human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.

Hyperthrombotic Milieu in COVID-19 Patients.

COVID-19 infection has protean systemic manifestations. Experience from previous coronavirus outbreaks, including the current SARS-CoV-2, has shown an augmented risk of thrombosis of both macrovasculature and microvasculature. The former involves both arterial and venous beds manifesting as stroke, acute coronary syndrome and venous thromboembolic events. The microvascular thrombosis is an underappreciated complication of SARS-CoV-2 infection with profound implications on the development of multisystem organ failure. The telltale signs of perpetual on-going coagulation and fibrinolytic cascades underscore the presence of diffuse endothelial damage in the patients with COVID-19. These parameters serve as strong predictors of mortality. While summarizing the alterations of various components of thrombosis in patients with COVID-19, this review points to the emerging evidence that implicates the prominent role of the extrinsic coagulation cascade in COVID-19-related coagulopathy. These mechanisms are triggered by widespread endothelial cell damage (endotheliopathy), the dominant driver of macro- and micro-vascular thrombosis in these patients. We also summarize other mediators of thrombosis, clinically relevant nuances such as the occurrence of thromboembolic events despite thromboprophylaxis (breakthrough thrombosis), current understanding of systemic anticoagulation therapy and its risk-benefit ratio. We conclude by emphasizing a need to probe COVID-19-specific mechanisms of thrombosis to develop better risk markers and safer therapeutic targets.

Hyperthrombotic Milieu in COVID-19 Patients

COVID-19 infection has protean systemic manifestations. Experience from previous coronavirus outbreaks, including the current SARS-CoV-2, has shown an augmented risk of thrombosis of both macrovasculature and microvasculature. The former involves both arterial and venous beds manifesting as stroke, acute coronary syndrome and venous thromboembolic events. The microvascular thrombosis is an underappreciated complication of SARS-CoV-2 infection with profound implications on the development of multisystem organ failure. The telltale signs of perpetual on-going coagulation and fibrinolytic cascades underscore the presence of diffuse endothelial damage in the patients with COVID-19. These parameters serve as strong predictors of mortality. While summarizing the alterations of various components of thrombosis in patients with COVID-19, this review points to the emerging evidence that implicates the prominent role of the extrinsic coagulation cascade in COVID-19-related coagulopathy. These mechanisms are triggered by widespread endothelial cell damage (endotheliopathy), the dominant driver of macro- and micro-vascular thrombosis in these patients. We also summarize other mediators of thrombosis, clinically relevant nuances such as the occurrence of thromboembolic events despite thromboprophylaxis (breakthrough thrombosis), current understanding of systemic anticoagulation therapy and its risk–benefit ratio. We conclude by emphasizing a need to probe COVID-19-specific mechanisms of thrombosis to develop better risk markers and safer therapeutic targets.

A painful lesson from the COVID-19 pandemic: the need for broad-spectrum, host-directed antivirals.

While the COVID-19 pandemic has spurred intense research and collaborative discovery worldwide, the development of a safe, effective, and targeted antiviral from the ground up is time intensive. Therefore, most antiviral discovery efforts are focused on the re-purposing of clinical stage or approved drugs. While emerging data on drugs undergoing COVID-19 repurpose are intriguing, there is an undeniable need to develop broad-spectrum antivirals to prevent future viral pandemics of unknown origin. The ideal drug to curtail rapid viral spread would be a broad-acting agent with activity against a wide range of viruses. Such a drug would work by modulating host-proteins that are often shared by multiple virus families thereby enabling preemptive drug development and therefore rapid deployment at the onset of an outbreak. Targeting host-pathways and cellular proteins that are hijacked by viruses can potentially offer broad-spectrum targets for the development of future antiviral drugs. Such host-directed antivirals are also likely to offer a higher barrier to the development and selection of drug resistant mutations. Given that most approved antivirals do not target host-proteins, we reinforce the need for the development of such antivirals that can be used in pre- and post-exposure populations.