COVID-19 and the Kidney

By Mohamed Hassanein, MD, Yeshwanter Radhakrishnan, MD, John Sedor, MD, Tushar Vachharajani, MD, Vidula T. Vachharajani, MD, Joshua Augustine, MD, Sevag Demirjian, MD, and George Thomas, MD

COVID-19 is primarily considered a respiratory illness, but the kidney may be one of the targets of SARS-CoV-2 infection, since the virus enters cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is found in abundance in the kidney. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), gains entry into target cells through the ACE2 receptors. ACE2 receptors are present in the kidneys as well as the lungs, heart, and intestinal cells.1-8 This article discusses the pathogenesis and optimal management of acute kidney injury (AKI) in COVID-19.

SARS-CoV-2 can damage the kidneys in several ways

The renin-angiotensin system plays an important role in human physiology. Angiotensin I is cleaved from angiotensinogen by renin and converted to angiotensin II by ACE. Angiotensin II causes systemic vasoconstriction and also enhances inflammation, endothelial cell dysfunction, oxidative stress, collagen synthesis in fibroblasts, and fibrosis in target organs.7-9 ACE2 is a counter-regulatory enzyme that breaks down angiotensin II to form angiotensin 1–7, which mediates vasodilation and attenuates angiotensin II-mediated inflammation.7

SARS-CoV, the virus that caused the SARS epidemic in 2003, downregulates expression of ACE2 after it enters the cell, and without the counter-regulatory effects of ACE2, the deleterious effects of angiotensin II are believed to lead to lung disease, including severe acute respiratory distress syndrome (ARDS).7-10

The kidney has an abundance of ACE2 receptors and therefore may be one of the primary targets of SARS-CoV-2 infection.7 ACE2 is expressed in the kidney much more than in the lungs, specifically on the brush border apical membrane of the proximal tubule and also at lower levels in the podocytes.11 Virus particles were observed in the tubular epithelium and in podocytes in an autopsy series of COVID-19 patients.12 TMPRSS2 is robustly expressed in the distal nephron but not the proximal tubule; it is unclear if other transmembrane serine proteases in the proximal tubule can mediate the priming step.8

AKI with COVID-19 results in higher mortality rate

AKI in COVID-19 is also associated with a higher risk of death.13-21 A systematic review and meta-analysis23 of six studies from China found that severe AKI in COVID-19 (defined as AKI stage 3 and AKI requiring kidney replacement therapy) was associated with a three-fold higher risk of death.

A U.S. study17 reported a mortality rate of 35% in patients with AKI; of those who died, 91% had stage 3 AKI. The mortality rate was 55% in those needing kidney replacement therapy. Another study19 showed an in-hospital mortality rate of 33.7% in those with COVID-19-associated AKI compared with 13.4% in those with AKI without COVID-19. Those with stage 3 AKI and COVID-19 had a 2.6-fold higher mortality rate than those with stage 3 AKI who did not have COVID-19.

There are limited data on the long-term prognosis of COVID-19 patients with AKI. A single-center study from China reported that although the mortality rate was high in patients with AKI, nearly half of the patients recovered from AKI within three weeks of onset of infection.21 A U.S. study17 reported a median creatinine level of 1.70 mg/dL (interquartile range 0.96, 3.50) at the time of discharge in patients with AKI, and 91% of hospitalized patients who needed kidney replacement therapy were still on it at the time of study censoring. Another study from the U.S. showed that fewer COVID-19 AKI patients recovered renal function than AKI patients without COVID-19 (42.3% vs 68.5%).19

Proteinuria and hematuria have been reported in patients with COVID-19, but their significance and impact on mortality are not yet known. An early report from China13 found proteinuria in 43.9% and hematuria in 26.7% of patients. Subsequent studies from the U.S. reported 2+ or 3+ blood in 46% of patients, and 2+ or 3+ protein in 42% of patients on urine dipstick analysis. Another study showed proteinuria in 87% of patients.17-20

While the effects of ACE2 expression and viral entry on proteinuria are unknown, it is speculated that proteinuria could be related to viral replication, particularly in the podocytes.11

Pathophysiology of acute kidney injury in COVID-19 (ACE2 = angiotensin-converting enzyme 2; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2).

Causes of AKI in COVID-19 patients

Selected therapies for COVID-19*

*This information is subject to change as new findings are published.

Please note: This is an abridged version of an article originally published in the Cleveland Clinic Journal of Medicine. The article in its entirety, including a complete list of references can be found here.