Pathophysiology of COVID-19- associated acute kidney injury

Citation: Legrand M, Bell S, Forni L, Joannidis M, Koyner JL, Liu K, Cantaluppi V. Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol. 2021 Jul 5:1–14. doi: 10.1038/s41581-021-00452-0. Epub ahead of print. PMID: 34226718; PMCID: PMC8256398.

https://pubmed.ncbi.nlm.nih.gov/34226718/

• The pulmonary manifestations of COVID-19 are most prominent, but acute kidney injury (AKI) is also now recognized as a common complication of the disease and is often evident at hospital admission.
• Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid‐19 is necessary to develop management strategies and design effective therapies
• Age, history of hypertension and diabetes mellitus have been repeatedly associated with a higher risk of AKI in patients with COVID-19 as well as chronic kidney disease
• In this clinical scenario, the high mortality observed in comorbid and elderly patients may be related to a reduction in renal functional reserve (RFR), an impaired capacity of the kidney to increase GFR in response to stress and reduced functioning nephron mass
• According to one meta-analysis from 2020, the pooled incidence of AKI among hospitalized patients with COVID-19 was 28.6% (95% CI 19.8–39.5) in the USA and Europe and 5.5% (95% CI 4.1–7.4) in China
• These data are mirrored in a separate large cohort of New York-based patients, of whom 3,854 (39.9%) had inpatient COVID-19 AKI
• Early reports of COVID-19 AKI noted the presence of hematuria and/or proteinuria
• The proteinuria detected in patients with COVID-19 AKI is of low molecular weight rather than albuminuria, suggesting a tubular origin rather than glomerular injury, and can be used to identify patients with early-stage AKI
• Evidence from a study of biopsy data from 47 patients in France demonstrated that kidney injury seen in cases with the most severe respiratory disease in the ICU is predominantly tubular (66.7%); by contrast, collapsing glomerulopathy and focal segmental glomerulosclerosis were not seen in critically ill patients but were observed in 70.6% of cases not in the ICU (cases with less severe pulmonary manifestations)
• The pathophysiology of COVID-19 AKI is thought to involve local and systemic inflammatory and immune responses, endothelial injury and activation of coagulation pathways and the renin–angiotensin system
• Non-specific factors that are common in critically ill patients, such as mechanical ventilation, hypoxia, hypo- tension, low cardiac output and nephrotoxic agents, might also contribute to kidney injury and/or functional decline in the most severely affected patients
• Current data from renal histology also reveals a genetic component of Covid-associated AKI, which is a promising finding that will hopefully bring more clarity to the pathophysiology, and, therefore, treatment of the condition

Treatment

Specific strategies for the treatment or prevention of COVID AKI are currently lacking.  However, a few strategies are having been currently explored

1. Steroids

• The subsequently published RECOVERY trial demonstrated that use of dexamethasone resulted in lower 28-day mortality in patients with COVID-19 requiring ventilation or oxygen
  • Among patients who did not require KRT at randomization, those who received dexamethasone were less likely than those in the control group to receive KRT (4.4% versus 7.5%, RR 0.61; 95% CI 0.48–0.76) suggesting a protective effect of dexamethasone on the kidney.

2. Monoclonal Antibodies

• Tocilizumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that inhibits the binding of IL-6 and its receptors and thereby blocks IL-6 signalling and associated inflammation. Preliminary results from the RECOVERY trial suggest that administration of tocilizumab to hospitalized patients with COVID-19, hypoxia and evidence of inflammation improved survival and chances of hospital discharge at 28 days.
• Furthermore, the preliminary report demonstrates a significant reduction in the requirement for KRT, suggesting the beneficial effects of tocilizumab on preventing AKI and/or promoting renal recovery

3. Interferon therapy

• Interferon therapy is one of the most promising approaches to improving viral clearance in the early stages of COVID-19. However, although small interventional trials have reported encouraging results with interferon therapy, more robust trials are needed

In conclusion, acute tubular injury seems to be a common occurrence in patients with COVID-19 AKI, but is often mild, despite severely altered kidney function. Endothelial injury, microvascular thrombi, local inflammation and immune cell infiltration have been repeatedly observed in patients with COVID-19 AKI; however, differences and similarities in the pathophysiology of COVID-19 AKI and non-COVID sepsis-associated AKI remain to be established. A high incidence of thrombi and intravascular coagulation might be one striking difference.

Given the interactions between lung and kidney, treatment and strategies that prevent progression of the disease and need for mechanical ventilation are very likely to protect the kidney. For example, Human recombinant sACE2 has been shown to prevent viral infection of kidney cells in vitro, and might represent a promising specific treatment for COVID-19 AKI in the future.