The Kidney and COVID-19: What We Know so Far

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This transcript has been edited for clarity.

Matthew Sparks, MD: Hey, everybody, this is Matt Sparks. I'm from Duke University, a nephrologist, and a member of the filtrate for Freely Filtered. I'm here with my colleague and friend, Dr Samira Farouk, to discuss acute kidney injury (AKI) and COVID-19.

Samira S. Farouk, MD, MS: Hi, everyone. I'm Samira Farouk, a transplant nephrologist at Mount Sinai Hospital in New York. I'm proud to be representing the Freely Filtered filtrate here today and am very excited to briefly talk a bit about what we know and don't know about COVID-19 and the kidneys.

Sparks: Recently you were first author on a paper in Journal of Nephrology titled "COVID-19 and the Kidney: What We Think We Know so Far and What We Don't." Can you tell us a little about the paper, its origins, and the process you went through to write this?

Farouk: I think the key to this paper is in the title. We wanted to get across a summary of the available data from clinical experiences and a small clinical research study, but we also wanted to portray the uncertainty and how little information we have, and to suggest some hypotheses and suggestions for how we might move forward. Our strategy was to cover the spectrum of kidney injury, starting first with the development of AKI. What is its prevalence? What are some potential risk factors that have emerged? Then we wanted to touch briefly on how this viral infection affects the special populations of transplant and chronic kidney disease, as well as the end-stage kidney disease population, in a different way. Finally, we had a section called "A Look to the Future," where we discuss what we can do moving forward, what we can study further, and offer some guidance for the nephrology community.

Acute Kidney Injury

Sparks: One thing that I was struck with when COVID-19 came through the United States was that it showed the importance of nephrology as a frontline healthcare workforce in all of healthcare. One of the most important things we saw was the high rates of AKI. What were those rates and how many of those individuals required kidney replacement therapy?

Farouk: It's interesting that when the pandemic first began in China, the reported rates of AKI were a bit on the lower side. Some reports coming out of China reported an AKI incidence of 0%. Over time, as the pandemic spread to the United States, we began to see increasing reports of AKI. Our center at Mount Sinai recently published in a preprint an incidence of AKI of almost 50%, with 20% of those requiring dialysis or kidney replacement therapies. There are many reasons for that disparity or difference in AKI.

One is that the reporting of AKI itself can vary and it's quite heterogeneous throughout these different studies. These patient populations may have different comorbidities, different racial and ethnic backgrounds, and different genetic factors that may predispose an injury. For example, we have seen several case reports that inheritance of the high-risk apolipoprotein L1, or APOL1, allele can be associated with the development of a severe form of kidney injury, specifically affecting the glomerulus. If we look at Figure 1 in our paper, the incidence is all over the place and ranges from zero to 50% which, for any other disease process, would be considered quite a wide range. This points to the idea that we don't fully understand this process and we don't know what is going on or the obvious risk factors.

Sparks: How many patients in the intensive care unit (ICU) who had COVID-19 and AKI would require kidney replacement therapy?

[A]t the peak, there were many more patients requiring dialysis in the ICU than we had ever seen before.

Farouk: It's hard to give a number, but it would definitely be upwards of 50%, 60%, or even 70%. As nephrology consultants, we are obviously called for the patients who require dialysis in the ICU, and at the peak there were many more patients requiring dialysis in the ICU than we had ever seen before. This required us to get a bit creative with how to ration a limited resource, to provide adequate nursing, and to provide as much dialysis as we could to the people who needed it. One way was to start the use of acute peritoneal dialysis in the ICU setting, which is something that had never been done at my institution before.

Sparks: There definitely was creativity in trying to figure out how to deploy as much kidney replacement therapy as was needed. The community came together and helped figure out how to make dialysate fluid, and how to insert these catheters in a safe manner for peritoneal dialysis. Yes, the rates were astonishing. From the reports out of China and other places, it did not initially seem like it was going to be as bad as it was.

Does COVID-19 Infect the Kidneys?

Sparks: This next topic is controversial and something we've talked about on Freely Filtered and updated on the NephJC blog. Does SARS-CoV-2 directly damage the kidney by infecting the kidney? What did your paper say on that?

Farouk: That is the million-dollar question and, like many other questions, the short answer is, we just don't know. What we found in our literature review when putting together this paper was that there is compelling evidence on both sides. There is a pretty compelling pathophysiologic hypothesis that angiotensin-converting enzyme 2 could be one potential mechanism of kidney injury by providing viral entry into the cell — as has been shown in the alveolar cells within the lung — and can potentiate nephrotoxic effects.

From a pathologic standpoint, if the virus is found in the kidney, then perhaps that is an indication that there are forms of injury. There have been conflicting reports of "viral-like" particles seen on electron microscopy. Some groups have been able to show that there is actually RNA material, which would be more confirmatory evidence that the virus is actually there. But then we have to ask ourselves, does the presence of virus necessarily mean that there is injury? A little bit of correlation vs causation: The virus is there, but what is it actually doing? We don't know so far. It would be interesting to do a study in the future to quantify serum viral load in individuals and find out whether there is any correlation of viral load and the extent of kidney injury. But that may not be a great hypothesis to pursue because we obviously are seeing high rates of AKI even though the viral loads in serum may not be high.

Sparks: I agree. When you look at SARS-CoV-2 and AKI, you see a spectrum, and most individuals will have acute tubular necrosis. And then you start to see immune hyperactivation interferon hyperactive states like collapsing glomerulopathy. And then all the way to the right, a very small minority could have direct infection of the virus. But that has not been shown very frequently. One of the biggest areas in which we got sidetracked is through electron microscopy. People were publishing papers that showed small circular structures that look like the virus. But from expert individuals in the electron microscopy field, it appeared that clathrin-coated pits can appear very similar, so we need to be very cautious. Just because we see a structure that looks like a virus does not necessarily mean that it is. In the end, I think we're not 100% sure. It's controversial. And if it does occur, it's a very rare event.

Farouk: The other component that muddies the picture is that all of these patients have severe infection. They are in a state of severe sepsis. They have high inflammatory markers. It's almost impossible to tease out what is causing this kidney injury. For example, you mentioned acute tubular injury. We know that the majority of patients who have severe sepsis, septic shock, will have acute tubular injury. Is that from the sepsis alone? Is that the virus? Is that a combination of both? It's been hard to identify that. Similarly, some urinalysis abnormalities have been reported in these patients — hematuria, proteinuria. Are those because of the virus causing some sort of damage or is that related to sepsis? It's not clear.

Risk in Special Populations

Sparks: I briefly want to mention risk in a few patient groups. One is individuals with end-stage kidney disease on dialysis or peritoneal dialysis, and the second group is those with kidney transplantation, which is the area that you practice in. What is the risk in those groups? Is it higher? Did they get a more severe form? Do we know yet?

End-Stage Kidney Disease

Farouk: Those are two interesting groups to talk about. One thing that those two groups have in common is that there is some problem with their immune system. Obviously, patients with kidney transplant are taking exogenous immunosuppressants leading to a suppressed immune system. On the other hand, there is evidence that end-stage kidney disease patients may not only have immune system suppression but also immune system activation in a certain context.

Earlier on, for the end-stage kidney disease population, there was this suggestion that perhaps the disease is not as severe in them because of their immune system abnormality or dysfunction, that maybe they cannot mount that same inflammatory or cytokine response that is seen in non-immunosuppressed individuals. And there were some reports and editorials that were suggesting that perhaps the population is protected. As we have seen the pandemic unfold a bit more, higher mortality rates have been reported, or rates similar to those of the rest of the population. Not a lot of data have been published in this area. In our institution, the inpatient mortality rate for end-stage kidney disease patients was around 20%; it was much lower for outpatients, at around 3%-4%. Those numbers are not that different from the general population.

Kidney Transplantation

Farouk: With respect to kidney transplantation, a big question that came up from our patients was, what should we do to protect ourselves? The good news is that patients with kidney transplant are somewhat accustomed to having habits or behaviors to protect themselves from different infections. They know, for the most part, that they are at higher risk. So for them, it was reinforcing those precautions that were shared with the rest of the population: wash your hands, stay home when possible. When they did develop symptoms, we would try to manage them depending on the severity: telemedicine visits for [milder] symptoms and hospital admission for more severe symptoms. Our general approach was not to cut the immunosuppression completely but lower it modestly, because there still is not great evidence that completely decreasing immunosuppression is helpful. Keeping some of that immunosuppression in the system may actually, in theory, be beneficial because it may mute some of the inflammatory response that occurs.

Data in this population are also limited. Some reports have suggested mortality and morbidity rates greater than those in the general population, close to 30%. Other groups have reported lower mortality, around 5%-7%. However, these studies are difficult to compare because they have different populations as well as follow-up times that can range anywhere from 2 weeks to a few months. I think that as time goes on, we will be able to understand this population a bit more. I'm part of a global consortium that has enrolled kidney transplant patients from around the world, from several different continents. In that cohort, we found that the mortality rates were pretty similar to those in the general population, around 20%. But again, across the world, there are different approaches in how to manage these patients. It can be different. It's difficult to compare a group of patients that had full immunosuppression maintained and another group of patients in which all of the immunosuppression was withdrawn. We're still learning about these patients. The approach at our center has been individualized: understanding the patient's immunosuppression regimen, modifying it, and observing the clinical response.

Summary

Sparks: Great. Let me summarize what we talked about with COVID-19 and the kidneys. One, it has provided an opportunity for and also showed the importance of nephrology care during a pandemic. Two, kidney injury is common, and if that develops, especially in an ICU, the need for kidney replacement therapy is high. We as a workforce, as a group, need to understand that and have the resources available. SARS-CoV-2 could impact the kidney but it's likely a rare event. Most AKI episodes are from acute tubular necrosis, which can be from a variety of things — the illness, being sick in hospital or in the ICU, hemodynamic factors, and other things. The risk in patients on dialysis or those with transplant is definitely not lower and may be comparable to that of the general population or slightly worse. We need to stay vigilant to ensure that this vulnerable group of patients socially distance, wear a mask, and do all the things that need to be done to diminish the risk.

Are Hospitals Better Prepared?

Sparks: Are hospitals in the United States better prepared for kidney complications now? What are the long-term implications for individuals who have gone through COVID-19 and have experienced AKI?

Farouk: Having been in a New York hospital that was in the epicenter, with a very high volume of patients requiring dialysis and kidney replacement therapies, I definitely think we are better prepared if we were to experience a second wave. In the initial few weeks as the peak was developing, we tried different tactics to make sure we were using our dialysis resources in the most effective way possible. We are well equipped to roll those out again. We put strategies in place to ensure that faculty and trainees were not assigned to too many patients. We could reinstitute those rescheduling plans. We had specific plans for our nursing staff to ensure safety as well as adequate patient care. We would likely bring back the utilization of acute peritoneal dialysis in the ICU. We have a plan written down and ready to go in the event of another surge. Obviously, we hope that does not happen.

The second question, about long-term effects on patients, unfortunately is something that we do not know. I think most experts would agree that there will likely be some long-standing impact on the kidneys and this will likely become an important cause of chronic kidney disease. Many institutions, including ours, have begun to build COVID-19 follow-up care centers, not only to better understand the long-term sequelae of this disease, but also to provide care for patients who may develop long-term organ damage. I know this has also been seen in the pulmonary world with persistent pulmonary symptoms like cough or shortness of breath.

I don't think the kidney is much different. We know it can be a somewhat sensitive organ. Those who had severe infection and severe AKI requiring kidney replacement therapy will likely see some long-term sequelae and perhaps, unfortunately, an increase in the prevalence of chronic kidney disease. What is important is that clinicians and researchers continue to share their data in a rigorous and robust way, with peer review and analysis. As we move forward, we can hopefully put all of the hypotheses and studies together to continue to improve our understanding of this emerging disease process.

Sparks: Thanks a lot. I appreciate the conversation, and we will see you on Freely Filtered.

Farouk: Yes, see you on Freely Filtered. Thanks, everyone, for listening.

You can follow Drs Farouk and Sparks on Twitter and catch them on Freely Filtered.

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