COVID-19 And Kidney Disease

Keywords COVID-19, kidney, chronic kidney disease, end-stage kidney disease, ESKD, dialysis, kidney transplant, SARS-CoV-2, kidney failure requiring replacement therapy, KFRT 

Abstract COVID-19 can cause acute kidney injury and may cause or exacerbate chronic kidney diseases, including glomerular diseases. SARS-CoV-2 infection of kidney cells has been reported, but it remains unclear if viral infection of kidney cells causes disease. The most important causes of kidney injury in patients with COVID-19 include impaired renal perfusion and immune dysregulation. Chronic kidney disease, especially kidney failure with kidney replacement therapy and kidney transplant, is associated with markedly increased COVID-19 mortality. Persons with severe kidney disease have been excluded from most clinical trials of COVID-19 therapies, so therapeutic approaches must be extrapolated from studies of patients without kidney disease. Some medications used to treat COVID-19 should be avoided or used at reduced dosages in patients with severe kidney disease and in kidney transplant recipients. Additional research is needed to determine the optimal strategies to prevent and treat COVID-19 in patients with kidney disease.

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INTRODUCTION 

Though respiratory failure is the most common cause of death in persons with COVID-19 (coronavirus disease 2019), acute kidney injury (AKI) is a frequent complication of severe COVID-19, and AKI and chronic kidney disease (CKD) are strongly associated with increased mortality in persons with COVID-19. Immune activation/dysregulation occurring in patients with COVID-19 and, rarely, after vaccination against SARS-CoV-2, can also cause kidney disease. COVID-19 disproportionately affects patients with CKD, especially those with kidney failure receiving kidney replacement therapy (KFRT) and kidney transplant recipients (KTRs). In this article, we review the mechanisms by which COVID-19 causes kidney disease, important kidney-related complications of COVID-19, and strategies to optimize the management of patients with kidney disease and COVID-19.

PATHOPHYSIOLOGY OF KIDNEY INJURY IN COVID-19 Viral Life Cycle 

COVID-19 is caused by infection by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) virus. Coronaviruses are enveloped, single-stranded RNA viruses with tropism for humans, other mammals, and nonmammalian species (1). SARS-CoV-2 primarily enters cells via binding of the viral spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The S protein is then primed by cleavage by the Type 2 transmembrane serine protease (TMPRSS2) or by other proteases, which initiates the formation of the fusion pore (2). Entry into host cells by SARS-CoV- 2 activates innate immune responses, which can be effective in limiting viral replication and the severity of disease. However, excessive immune activation can promote cytokine storm and tissue injury, leading to tissue and organ dysfunction (3).

Does SARS-CoV-2 Infection of Kidney Cells Cause Kidney Disease? 

Renal parenchymal cells, especially proximal tubular cells, express high levels of ACE2 (4). These cells also express TMPRSS2 and other proteases that may promote S protein cleavage and viral entry (2), suggesting that the kidney may be susceptible to SARS-CoV-2 infection. Several studies have reported the detection of SARS-CoV-2 RNA and protein in the kidneys of patients with COVID-19 (5–7) and visualization of SARS-CoV-2 virions by electron microscopy (8, 9). However, these reports may have been confounded by false positives due to the lack of specificity of assays, and normal intracellular organelles may have been misidentified as virions (10, 11). It remains controversial whether the kidney is a target of SARS-CoV-2 infection (12, 13). Even if SARS-CoV-2 does infect kidney cells, it is unclear whether infection can cause clinically evident kidney injury. Also, since it is difficult to detect SARS-CoV-2 in the blood of patients with COVID-19, it is uncertain how kidney cells would be exposed to infectious viruses. In a recent study of kidney specimens from 62 patients with COVID-19, reverse transcriptase polymerase chain reaction (RT-PCR) testing detected SARS-CoV-2 in all kidney specimens, and nucleocapsid protein was detected in 6 of 6 specimens (14). SARS-CoV-2 RNA was detected in kidney tubular cells and podocytes, and cells expressing viral RNA had increased expression of genes involved in injury, inflammation, and fibrosis (14). Though this study and others suggest a role for direct viral infection of kidney cells in the pathogenesis of kidney disease, there remains a lack of consensus regarding the prevalence of kidney infection in COVID-19 (12).

ACUTE KIDNEY INJURY Clinical Presentation, Epidemiology, and Risk Factors 

AKI is a common complication of COVID-19, particularly in hospitalized patients. In addition to acute reductions of estimated glomerular filtration rate (eGFR) and/or urine output, proteinuria, and hematuria are common in patients with COVID-19 and AKI (15, 16). Studies from early in the pandemic when the rates of severe COVID-19 illness were high reported that the pooled incidence of AKI was 28.6% in studies from the United States and Europe but was much lower (5.5%) in studies from China (17, 18). Risk factors for AKI include older age, male sex, acute respiratory distress syndrome (ARDS) and/or requirement for mechanical ventilation, and comorbidities including CKD, hypertension, and diabetes mellitus (17). Higher serum levels of C-reactive protein, ferritin, and D-dimers are also associated with an increased risk of COVID-19 AKI (19).

Pathogenesis of Acute Kidney Injury in Patients with COVID-19 

Patients with severe COVID-19 often have multiple factors that can contribute to kidney injury, including impaired renal perfusion, exposure to nephrotoxic agents, increased systemic and local cytokine production, and endothelial injury (20, 21). Reduced renal perfusion may occur due to systemic hypotension caused by septic shock, volume depletion, or cardiac dysfunction. Acute lung injury increases systemic levels of cytokines and the release of damage-associated molecular patterns (DAMPs) from injured cells. Cytokines and DAMPs can bind cytokine receptors and DAMPsensing receptors in the kidneys, including Toll-like receptors, which then activate innate immune responses, amplifying kidney inflammation and injury (21). Major factors contributing to AKI are summarized in

Figure 1. In COVID-19 patients, microvascular occlusion and endothelial injury are important contributors to lung injury and biomarkers of coagulation and endothelial injury are associated with increased kidney injury and with mortality (19, 22). There are also reports of acute renal thrombosis (23). However, histologic examination of kidney autopsy and biopsy specimens demonstrated that most patients with COVID-19 and kidney injury do not have microvascular thrombosis (13).

Treatment Considerations and Clinical Outcomes

In a large US cohort study, 20.6% of patients with COVID-19 requiring ICU admission required kidney replacement therapy (KRT) (19). The optimal modality for KRT is unknown, and the choice may be guided by provider expertise and availability of supplies. Hemodynamically unstable patients who require prone positioning may benefit from continuous KRT, whereas peritoneal dialysis may be preferable in patients with dialysis circuit clotting and/or contraindications to anti-coagulation (24, 25). Fluid management can be complex in patients with COVID-19 and AKI, and clinicians should correct volume depletion while avoiding excessive volume resuscitation, which can worsen oxygenation in patients with ARDS (25, 26).

Though most patients with COVID-19 and AKI have an eventual improvement in kidney function, AKI persists for >7 days in 35–40% of patients, and 30% of survivors with AKI requiring KRT remain dialysis-dependent at the time of hospital discharge (16, 27). The severity of AKI is associated with the risk of new and progressive CKD and with mortality (18, 25, 28, 29). Since a significant proportion of patients with COVID-19 and AKI subsequently develop CKD (30), kidney function should be monitored after AKI resolves to assess for the presence of CKD.

The severity of AKI and the need for KRT in patients with COVID-19 decreased during the first year of the pandemic, even before vaccination was available, likely due to improvements in care for patients with COVID-19 (31, 32). The incidence and severity of AKI in patients with COVID-19 will continue to evolve with an increased prevalence of immunity due to vaccination and infections, emerging SARS-CoV-2 variants, and the development of new therapies.

Figure 1 Schematic representation of the major factors contributing to acute kidney injury and collapsing glomerulosclerosis in patients with COVID-19. Abbreviation: DAMPs, damage-associated molecular patterns. 

COVID-19-ASSOCIATED GLOMERULAR DISEASES

Numerous glomerular diseases have been reported in persons with COVID-19 and/or after vaccination against SARS-CoV-2. Below, we discuss COVID-19-associated glomerular diseases manifesting primarily as proteinuria (predominant podocyte injury) and those presenting with proteinuria and hematuria of glomerular origin (glomerulonephritis).

Podocytopathies 

Glomerular diseases characterized primarily by podocyte injury include focal segmental glomerulosclerosis, minimal change disease, and membranous nephropathy. Podocytopathies as reported in the context of COVID-19 disease and/or vaccination are summarized below.

Focal segmental glomerulosclerosis.

Early in the pandemic, reports emerged describing a syndrome of severe proteinuria, often with AKI, in patients with COVID-19. Biopsy results revealed severe podocyte injury, often with the collapse of glomerular capillary tufts [collapsing variant of focal segmental glomerulosclerosis (FSGS)] and acute tubular injury. This syndrome of acute podocytopathy occurring in the setting of COVID-19 has been termed COVID-19-associated nephropathy (COVAN) (33–37). Another common histologic finding in COVAN is endothelial tubuloreticular inclusions, which are a hallmark of glomerular diseases associated with high systemic interferon levels, including systemic lupus erythematosus (SLE) and HIV-associated nephropathy (HIVAN). Most patients with biopsy-proven COVAN are Black, and most who have undergone genotyping have been found to have high-risk APOL1 genotypes (34, 35, 37–39). APOL1 high-risk genotypes are predominantly found in persons with African ancestry and are associated with a markedly increased risk of collapsing glomerulopathy occurring after interferon treatment and in SLE and HIVAN, diseases associated with high systemic interferon levels (40). Since interferons increase APOL1 expression, COVID-19 may precipitate COVAN in genetically susceptible individuals by increasing the expression of toxic APOL1 variants (Figure 1).

Kidney function eventually improves in most patients with COVAN, even those who are dialysis-dependent at the time of diagnosis (41). However, a significant proportion progress to kidney failure requiring replacement therapy (KFRT). Though some clinicians have treated patients with COVAN with steroids, the lack of controlled studies prevents evidence-based treatment recommendations.

Rare cases of COVAN have also been reported after vaccination against SARS-CoV-2 (38, 42). Since vaccination can increase systemic interferons, it is likely that the pathogenesis of COVAN occurring after vaccination is similar to COVAN in persons with COVID-19. Though there have also been case reports of non-collapsing variants of FSGS occurring in patients with COVID-19 or after vaccination against SARS-CoV-2 (43–45), it remains unclear whether there is a causal relationship between COVID-19 or vaccination and non-collapsing variants of FSGS.

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