Jaime Landman: Hi, my name is Jamie Landman. I'm a Chair of the Department of Urology at UC Irvine and I'm here with my more than better half, Dr. Monty Pal.

Monty Pal: Hello, everyone. Monty Pal here. I'm a medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles.

Jaime Landman: And today on Kidney Cancer Today, we're addressing a bit of an unusual topic, what we would normally not see as a kidney cancer topic, but it's become incredibly salient and important. One of our guests today, Ms. Dena Battle, whose president of KCCure, a wonderful advocate for patients with kidney cancer out of Washington DC brought to our attention that people are suffering because of their concerns of kidney-associated complications with COVID. And after reviewing the literature and what's online and the information available, it's clear that this is another disaster with perhaps not what is fake news, but terrible quality news out there.

So today we assembled a panel of remarkable experts to help us sort through this a bit. Along with Dena Battle, we have what is now a regular on Kidney Cancer Today, Professor Michael Staehler, he's the founder and Chief of the Interdisciplinary Center for Kidney Tumors in Munich, as well as two of my great partners from University of California Irvine.

We have Dr. Kam Kalantar-Zadeh, whose Professor of Medicine, he's the Chief of the Division of Urology and in my mind and in many people's minds, one of the most distinguished nephrologists in the world, either being the president or past president of most organizations in nephrology.

And of course, Dr. Connie Rhee, whose Assistant Professor of Medicine and in the end in the School of Public Health, by the way. And she is one of those consummate physician-scientists. Her work on endocrine arrangements and chronic kidney disease is magnificent. She's both won awards from the NIH as well as awarded from the NIH. So with this panel, I'm really hoping that we can clarify a bit about what we know about COVID and chronic kidney disease acute kidney disease.

So Dena, do you mind framing the problem since you were really kind to bring it to our attention?

Dena Battle: Absolutely. And thanks, Jamie and Monty, for having us back on again. As you know, we talked previously about anxiety that kidney cancer patients have related to COVID-19 and as a result of that, we put together some guidance using expert advice from scientific advisors as well as information out there. One of the most common questions we got was does COVID attack the kidneys and am I at higher risk having one kidney as a result of having kidney cancer? And all the information that we had showed that there really wasn't evidence yet to show that COVID attacks the kidneys.

The International Society of Nephrologists put out guidance saying that right now the evidence doesn't show that. But, unfortunately, there were some news headlines, and these were coming from very credible sources, The New York Times, The Washington Post, talking about shortages of dialysis because all these patients with COVID-19 are going into renal failure and it really caused us some concern and we felt like a lot of patients in our communities were concerned seeing these headlines. A lot of them asked, "Hey, is this information that you're putting out accurate?" A lot of people being much more concerned, very worried about kidney function and COVID-19. So we really appreciate experts coming together to help clarify this for patients.

Jaime Landman: You brought this to our attention. I actually had our Kidney Cancer Today team do some homework, looked at the National Kidney Foundation, American Kidney Fund, a bunch of things online, and basically most of the advice is to wash your hands and keep six feet away from people. Which is not bad advice. It's great advice, but not particularly helpful when it comes to this question. I looked at what you pointed out some ABC news article where they talked about a patient, it was a one-off patient. They did not follow up with the hospital, the doctors, citing HIPAA regulations.

Let's start off with doctors Rhee and Kalanter-Zadeh. You guys know more about kidney and kidney function than probably anyone on the planet. Can you help us out? Is there some terrible association? Is there any association? What do you know?

Kamyar Kalantar-Zadeh: Thank you, Dr. Landman, Jaime, thank you for also the introduction and I think the world needs to know that you, Jaime, are among the most renowned and recognized experts in urology and kidney cancer. I'm a nephrologist. It's quite interesting that I always tell my patients kidneys are so important that they have two dedicated areas of expertise in medicine, urology and nephrology.

So in terms of nephrology, which pertains to the function of the kidneys and what kidneys do for the body. So data suggest that COVID-19, actually there is mixed data, but most studies have not identified a direct involvement of kidneys with the COVID-19 infection, known as coronavirus. However, there are several things to say. Number one is that when the patient goes to that more severe stage, this cytokine release, these are patients whose lungs are essentially eaten from inside or torn apart. When that happens, when the lungs are completely or to a great extent are damaged by the virus, through that. And when these patients require intubation and mechanical ventilation because of that and because of other reasons including additional infections and sepsis, chances are that that patient goes to what is called acute kidney injury, AKI.

And these patients, not infrequently, while they're intubated and mechanically ventilated, they require support for kidney failure in form of dialysis or extended dialysis, which is called CRRT, continuous renal replacement therapy. So we have that challenge and according to some data, up to 20% or more or a high proportion of patients who are intubated with COVID-19 require renal replacement therapy in the form of dialysis. Hence, so we can say that five to 20% of all patients who are COVID-19 positive and intubated and mechanically ventilated, in critical condition, they have kidney failure and they require kidney replacement therapy in form of dialysis. And that's why, for example, you hear in the reports from New York that patients are intubated in ICUs and they need dialysis. So I'm going to stop here to see if Dr. Connie Rhee who is also a world-recognized expert would like to add anything.

Connie Rhee: Okay, thank you Dr. Kalantar and I'd like to thank Dr. Landman, Dr. Pal, and Dena and Kourtney for the opportunity to participate in this UroToday discussion. So I think with respect to COVID-19 and the impact upon kidney health and function, I completely agree with Dr. Kalantar and the estimates that he's citing and I think there are really three main distinct populations that one has to consider when thinking about this novel coronavirus.

So first there are the patients who develop acute kidney injury in the context of COVID-19, which will be the main focus of my discussion. And then number two, patients with chronic kidney disease who include those who had a partial nephrectomy in the context of kidney malignancy. And this is a population that is in fact at higher risk of complications overall from COVID-19.

And then third, which I won't talk too much about, but that's also a really dominant population that we take care of is patients with end-stage renal disease on dialysis and patients with kidney transplantation and these patients are at particularly high-risk from the more severe disease from COVID-19 because both of these populations have suppressed immune systems and dialysis patients, in particular, have multiple risk factors. They're older age, they have multiple comorbidities, they tend to be more of minority racial-ethnic background which we've seen worse outcomes with respect to COVID-19, and they have frequent travels to dialysis and have frequent clustering on dialysis shifts. All placing that heightened risk for getting COVID-19 and also having more severe manifestations.

But I think in terms of the area in which it sounds like many of the audience members have, I think particular interest in is how COVID-19 actually affects kidney function. So I wholeheartedly agree with Dr. Kalantar that, at this point, the data is very mixed and it's really too preliminary to be able to definitively know. And one of the big issues that's been cited from a number of epidemiologic studies and reviews is that we don't know what the denominator is and a lot of these studies are done in very heterogeneous and distinct populations.

So we definitely need more research to better understand the scope of disease. But exactly as Dr. Kalantar pointed out, the data is very mixed. So to provide some epidemiologic context, in Italy in roughly half of the patients have been reported to be hospitalized about 47% and roughly 6% have actually required ICU admission. And then looking at data from Wuhan, in a very high impact kidney journal, Kidney International, about 25 to 29% of patients who experienced critical illness or who died developed acute kidney injury. But the overall incidence of acute kidney injury among patients irrespective of critical illness status, so those who are critically ill, but those who are not critically ill was actually only 5%. And then there was another high impact publication early on in the New England Journal of Medicine, also looking at a Chinese observational cohort of about 1,100 patients and that actually showed that in this cohort among whom 91% had pneumonia, 5%, I think, were admitted to the ICU, 3% developed ARDS. Actually only half a percent, 0.5% developed acute kidney injury.

And there's been some pretty well-written emerging reviews have been coming out in terms of the histopathology of acute kidney injury in COVID-19. So there was a nice autopsy case series about 26 patients who developed respiratory failure or had respiratory death from COVID-19. Among these, 11 patients had pre-existing, high-risk factors for acute kidney injury like diabetes, hypertension, and also chronic kidney disease. And among these 26 cases, nine developed acute kidney injury. And this study and also other reports have been citing that it appears to be that acute tubular injury, so acute tubular damage or ATN, is the dominant pathology that we're seeing in terms of kidney failure in these patients. But there were also some other histopathology finds that are somewhat interesting, they saw clusters of red blood cells, they saw some pigmented casts and then they actually sampled, in this autopsy series, I think nine cases. And out of those nine cases, seven out of nine actually had particles of COVID-19 within the histopathology.

And then I think just rounding this out in terms of proposed potential mechanisms of acute kidney injury, there's also been a very nice review published in Kidney International by the Editor in Chief, Pierre Ronco, and also co-author, Dr. Reese. And what they have described is exactly what Dr. Kalantar cited, is that there are multiple co-existing mechanisms that could be contributing to acute kidney injury in COVID-19. So first, there's that cytokine release syndrome in which you see this upregulation of IL-6. And not just the virus, but a lot of therapies are getting for this can increase IL-6 and cause kidney damage. So this could be being on the vent. This could be getting continuous hemodiafiltration and what happens with this cytokine release syndrome as you guys know, is that it causes a systemic endothelial injury then that's going to lead to fluid leakage.

Some people are going to get fluid in their lungs, poor perfusions, they will get edema, they'll get increased third spacing of fluid and increased abdominal pressures, low intravascular pressures and subsequent hypotension and all this can cause kidney injury through multiple pathways. It can cause intrarenal inflammation, increased vascular permeability, you'll get volume-depleted and then they also can get cardiotoxicity leading to cardiac damage. So that's one mechanism, cytokine release syndrome.

And the second proposed mechanism is also there could be an organ crosstalk between multiple organs that are affected by COVID-19, such as the lung and the heart then affecting the kidneys. So the kidneys, sometimes they stay subservient to a lot of the other organs in the body and certainly the heart and the lungs play a dominant role. So acute respiratory distress syndrome that we are seeing in the COVID-19 patients can lead to hypoxia in the kidneys, a low oxygen content.

Also, the high peak airway pressures that may lead to insure abdominal hypertension. I think the ventilated patients can also lead to increased abdominal pressures and cause kidney injury. And then again some cases that we've had experience with, Dr. Kalantar actually published a case report on this in The American Journal of Nephrology, may develop cardiomyopathy and viral myocarditis and then patients can get cardiorenal damage from this.

And then finally, probably the third pathway or mechanism by which we may see COVID-19 leading to kidney injury, is just the systemic effects of being critically ill. So this could be because of volume overload that patients are getting either from fluid leakage with a systemic inflammation and then endothelial damage or just getting fluids as part of the treatment and they'll get increased abdominal pressures and that will compress on the renal veins and cause kidney injury.

They could get all this third space fluid that can cause them to get renal ischemia. Again, the heart can be damaged and that can lead to kidney injury because of poor renal perfusion. And then finally, I think the last two entities, there've been cases of rhabdomyolysis and that can cause damage to the kidney tubules and cause pigment nephropathy and acute tubular injury. And finally, just the inflammation and endotoxins that patients get can cause sepsis-associated acute kidney injury as well. So there are many factors at play that may or may actually not be specific to COVID-19, just being critically ill. But I think in terms of the scope of disease, I think that's, I think a big question right now and a lot of research still needs to be done.

Monty Pal: Thank you, Connie, that was a fantastic overview. I'm going to throw this question to both you and Kam. In terms of looking at this gigantic pool of data that you just outlined for us, what would you say the bottom line, on the one hand, Kam cited the fact that about 20% of patients going into the ICU are requiring dialysis. On the other hand, you cited this 1,100 patients, Chinese theories where only 0.5% of patients required dialysis. Under those circumstances, are patients really at a higher risk necessarily for kidney damage for COVID-19 in your opinion? And how does this differ versus the flu, right?

Connie Rhee: So I think you're exactly right. The data that you and Dr. Kalantar citing, it really looks like according to some nice reviews that have looked at that in the immunologic data, we're seeing estimates ranging from about five to 30% but it's very hard to draw inference or conclusions from this data because the populations are so heterogeneous, the practice patterns are so different. The populations are so different even within the cohorts. But I would say I think the bottom line is that I think patients with underlying kidney disease, so be it from a partial nephrectomy or having chronic kidney disease from diabetes or hypertension, which we commonly see. I'd say in general they're risk of acute kidney injury. The magnitude I think the jury is still out with respect to COVID-19, but I think in seeing the overall complications of COVID-19 that we have to be a little bit weary because of issues with immune system suppression, that may make them more vulnerable to COVID-19 effects.

Kamyar Kalantar-Zadeh: Yeah. Also, if I could add that this also depends on the background population. For example, if you're talking about an area where there are more patients on dialysis or more patients with chronic kidney disease, which makes them more vulnerable to a worsening kidney function, further worsening of kidney function, then the data suggests, or that's at least what we hypothesize, that these are studies suggesting higher level of or a high proportion of patients requiring dialysis therapy. For example, in New York, there are anecdotal data and the studies are being published soon that, as I said, up to 20% of patients who are in ICU, they require dialysis. It's because New York deals with the patients who are in ICUs and critical care units in New York, in the city of New York and surrounding.

These are more susceptible to the ravages of COVID-19 towards the kidneys because they have underlying kidney disease. They have CKD, chronic kidney disease, and already dialysis patients or not. We are not sure, but that these are data suggesting that probably in the United States we may expect to see a higher proportion of patients requiring dialyses compared to data coming from China. Now I think, this is a segue towards talking about patients with kidney cancer or patients who have one kidney, also known as solitary kidney. So I'm going to stop here to see what, where the discussion is going. 

Jaime Landman: Well, I got to be honest in a sea of poor quality news and even maybe fake news, it's great to hear some real news. One thing that you all brought up with some geographic differences and I heard that may be due to different strains of the virus. We are privileged to have Michael on the line. Just out of curiosity, you heard this conversation, any differences from the European perspective?

Michael Staehler: So actually, I just checked here in Munich, how many patients actually are on dialysis if they have COVID and if they are on an ICU, we have about 10 to 20% of the patients on an ICU and even being on dialysis, and actually almost nobody who is just on a regular ward there. So I think the numbers are not as high. And the question here to me is not is it cause for dying from that or is it just a consequence of the systemic inflammatory response that those patients have? And there has, as you mentioned, been an autopsy series being presented, and as horrible as autopsy series are, what we see is there is endotheliitis and this endotheliitis is throughout the body. And that causes heart problems, it causes the kidneys to fail and it causes the lungs to fail.

So, in the beginning, we have the massive inflammatory reaction through a virus in some patients and we still have not understood which patients are the ones that actually are having a more severe course of the disease versus patients who stay completely asymptomatic. And I want to put that a little bit into perspective. Right now we have a chance of one in 500 of being infected with COVID, you have a chance of one in 5,000 to have a more severe course of the disease and you have a chance a one in 15,000 to have kidney failure in that setting. So we're looking at something that might be rare and it's not like because you have an impaired kidney function, you're at a higher risk of acquiring COVID-19, and I think we have to be clear here for everyone that it's the other way around. If you have COVID, you have a low chance of having a kidney failure. And interestingly enough, we don't see a lot of cancer patients actually having COVID. I don't know why and I don't know what's going on there. And we see 1,500 patients with kidney cancer and I haven't had a single case of them having COVID-19. I don't know why. It's interesting.

This is, in general, a population that doesn't have a lot of infections, which I think is unique to kidney cancer itself and we haven't really had a lot of information so far on cancer patients and COVID. And I think if you look at the data from the JAMA journal that just have been published, we see that a third of the patients who died and are elderly had a kidney replacement therapy at the end, which just reflects on how severely sick they are, the patients who do survive or are still hospitalized, that's only two to 4% of the patients. So I don't think that the infection of the kidney itself is the reason for those patients being so horrifically sick?

Jaime Landman: Well, I think we're going to start to bring this to a close. What a remarkable database view on this topic. Thanks to Miss Dena Battle for bringing this really important topic to our attention. Michael Staehler, thank you so much. It was great to have Dr. Connie Rhee and Dr. Kam Kalantar-Zadeh, world-renowned nephrologist, and of course, my wonderful partner, Monty Pal, thank you so much for this really informative episode and with that, we'll close it out.