Is the Kidney Merely a 'Bystander' When it Comes to COVID-19?

Pam Harrison

August 11, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

A new Canadian study has found increased expression of angiotensin-converting enzyme 2 (ACE2) receptors in the kidneys of patients with diabetic nephropathy, which may help explain why such patients are at higher risk of COVID-19 and have severe outcomes, say the researchers.

However, the findings — which suggests the SARS-CoV-2 virus directly infects the kidneys — flies in the face of many other studies, which instead indicate kidney damage may be the by-product of the novel coronavirus wreaking havoc elsewhere in the body.  

The new study has been published as a journal preproof in the Canadian Journal of Diabetes by Richard Gilbert, MD, Canada Research Chair in Diabetes Complications, St Michael's Hospital, Toronto, Ontario, and colleagues.

Asked to comment, Jamie Hirsch, MD, says that although it is well-established that SARS-CoV-2 uses the ACE2 receptor to invade the lungs, where it causes direct viral injury, it is less clear whether this is what happens in the kidneys.

Hirsch is a nephrologist and assistant professor of medicine, Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York.

Early conjecture was that the renin-angiotensin-aldosterone system (RAAS) blocking medications — notably ACE inhibitors and angiotensin II receptor blockers (ARBs) — might exacerbate the impact of COVID-19 in patients taking these antihypertensive agents. Both classes of drugs block ACE1 (referred to simply as ACE), which could lead to increased ACE2 expression, he explained to Medscape Medical News.

"Speculation was that if a patient had more ACE2 around, then perhaps there would be a greater ability for the virus to invade the host and, in turn, lead to worse outcomes," Hirsch said.

This theory has not panned out, however.

Levels of ACE2 Doubled in Patients With Diabetic Kidney Disease

In their new work, the Canadian researchers hypothesized there would be an abundance of ACE2 in the kidney and the presence, or at least the amount, of ACE2 in that organ might be affected by either diabetes, drugs that block the RAAS, or both.

They found that mean ACE2 levels of messenger RNA (mRNA) were approximately twofold higher in archival kidney biopsies from patients with diabetic kidney disease — at 13.2 reads per million compared with a mean of 7.7 reads per million for healthy living controls (P = .001).

"The augmented kidney ACE2 expression demonstrated in the present study may signify a greater propensity to renal complications of COVID-19 among individuals with diabetes," they say.

But they did not find a significant difference in mRNA for ACE2 between patients with diabetic kidney disease who had been taking a RAAS-blocking agent, at 12.2 reads per million, and those who had not, at 16.2 reads per million.

In fact, these results are not that surprising, says Hirsch, given that they have already been supported by several large observational studies looking at the impact of real-world ACE inhibitor and ARB use on COVID-19 outcomes.

In one of these studies, there was no association between any single medication class and either a propensity to become infected, or an increased risk of severe illness, with COVID-19, which is why guidelines continue to recommend patients taking ACE inhibitors and ARBs remain on them.

And in fact, there are now studies exploring whether ACE inhibitors or ARBs might help patients with hypertension and COVID-19 through the disease course. Preliminary evidence shows those maintained on a RAAS blocker during treatment for COVID-19 were significantly less likely to die from the infection compared with matched patients with hypertension not taking an ACE inhibitor or ARB.

Does the Novel Coronavirus Directly Infect the Kidneys?

It remains unclear whether SARS-CoV-2 directly invades the kidney and then causes damage, as seems to be the case with the lungs, or whether kidney damage is a knock-on effect from the effects of the coronavirus elsewhere in the body.

In one of many studies, pathologic analysis of biopsied kidneys taken from patients who had died of COVID-19 showed varying degrees of acute tubular necrosis in the kidneys of all patients, but no immunohistochemical evidence of the virus itself — not even viral particles. Whether SARS-CoV-2 directly infects the kidney is, indeed, "the $64 million question," said Samira S. Farouk, MD, of the Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York City.

Farouk has also published work in the field, and in a discussion on Medscape, she acknowledged that it "is almost impossible to tease out what is causing kidney injury" in COVID-19 infection.

At Hirsch's own institution, approximately 40% of patients hospitalized for COVID-19 develop some degree of acute kidney injury — but it may be related to widespread thrombosis often seen in severe COVID-19.

Or it could be due to profound immune system dysregulation caused by the virus, or extensive inflammation that leaves in its wake multisystem organ failure, Hirsch believes.

"On infection, there is this overwhelming inflammatory cascade, and I think it could be that the kidneys may just be a 'bystander' where all this is happening, so it's not the virus itself infecting the kidneys [but] the virus is infecting the lungs where it causes a whole cascade of inflammation leading to subsequent kidney injury," he speculated.

Jury Still Out on Kidney/COVID-19 Story: Most Taking the Middle Road

The other important aspect to the COVID-19/kidney story centers around the balance between ACE and ACE2 expression the body needs to achieve.

"If systems become overactive, they end up leading to fibrosis and scarring and worsening end-organ damage, and the ACE pathway is what causes all this damage, which is why we use blockers of that enzyme to stop it from happening," Hirsch explained.

ACE2, on the other hand, actually counterbalances ACE such that when ACE2 is overexpressed, "it can actually reduce inflammation and be beneficial," he added.

Unlike the latest Canadian study where ACE2 was overexpressed in diabetic kidney tissue, other researchers have shown a reduction in ACE2 expression in patients with diabetic kidney disease.

By not countering the damaging effects of unchecked ACE activity, a reduction in the expression of ACE2 may explain why patients with diabetes have more inflammation and worse outcomes in general, although not necessarily in relation to COVID-19, Hirsch suggested.

Commenting further on the new Canadian study, Hirsch admitted that he doesn't quite know what to make of it.

"On the one hand, we're not seeing direct viral invasion in the kidney in virtually all studies at this point," he said.

But on the other hand, prior studies have shown a reduction in ACE2 expression in patients with diabetes so this [new Canadian] study clearly differs from some others, Hirsch added.

"The only thing that I can say is the jury is still very much out on the COVID-19/kidney story and that most people are taking a very middle road."

"If patients are taking these RAAS medications for high blood pressure, they should continue taking them," Hirsch emphasized, reaffirming current guidelines.

Gilbert has reported receiving research grants to his institution from AstraZeneca and Boehringer Ingelheim. He has also reported serving on advisory panels and receiving speaker honoraria for AstraZeneca, Boehringer Ingelheim, and Janssen. He is a shareholder in Certa Therapeutics, OccuRx, and Fibrocor Therapeutics. Hirsch and Farouk have reported no relevant financial relationships.

Can J Diabetes. Published July 18, 2020. Full text

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