Kidney Pathology & Donor Management

00:00:00:01
Laura Carroll
Hello, everyone. Thanks again for joining us. On behalf of the entire CompuMed team. Welcome to another presentation in our management webinar series. The topic today, Kidney Pathology, has been our most requested subject matter from all of the surveys we get from all of you. So we do listen, and here we are to present this. So just want to emphasize that the polls and the surveys that you all complete for us are really valuable as we continue to explore different topics to present to all of you.

00:00:33:18
So today, we are really thrilled to have Dr. Mohammed El Hag to share his expert insight about kidney pathology and the importance of having a renal pathology specialist reading the studies. Dr. El Hag, is a certified pathologist with extensive experience and pathology, as you read in all the invites, he’s highly published and very passionate about this topic. So I’m just going to let him take it away.

00:01:01:02
Thanks, Dr. El Hag. We’re excited.

00:01:06:12
Dr. El Hag
Thank you, Laura, for the introduction. And let me share my screen here. We just go back and again, you know, meetings, everybody. And thank you for joining us today for this talk of kidney transplantation pathologists. My name is Mohammed El Hag. I’m a practicing pathologist with training and experience in transplantation pathologists. If any of you are from the Pittsburgh area, they probably know me from if you’re from Cairo or from or probably interacted at some level before.

00:01:35:22
Where we met when I was in Pittsburgh, we used to do a high volume kidney transplantation donor evaluation, and we used digital technology as well as other technologies and methods for evaluating kidney, liver, as well as other biopsies from potential organ donors.

00:01:57:13
So the primary objective from today’s talk is really to discuss the role of pathology in the world of organ procurement. I have something here that perhaps I’m just going to get this little bit in the world of organ procurement, organ allocation, and also post procurement as well. So there is a role for pathology in kidney biopsies and kidney sampling in these environments as well.

00:02:20:16
We’ll also discuss some of the challenges that face us as pathologists, OPOs, as coordinators and companies like CompuMed who are trying to provide a solution for this, will also touch briefly on the history of transplantation challenges of doing things online. Right. So I’m also going to touch briefly in the history of transplantation. It’s more interesting than know you might think.

00:02:43:05
We’ll discuss a little bit about the usual things that are common that we see kidney biopsies, what the problems are, what the pitfalls are, what mistakes can happen, what discrepancies happen. And then we’ll talk a little bit about to produce ability and prognostication, things that kind of might plague a little bit donor biopsy, validation of the kidney and the liver as well.

00:03:05:01
All right. So let’s go in here. So organ transplantation is actually way older than we think as it was back maybe millennia. Some of the earliest and most interesting accounts, possible myths about organ transplantation go back to 1600 B.C., where skin autogenous skin grafts was talked about. Right but the most or the first thing that that is from one human to the other human was elect transplantation performed by Cosmos and Damien.

00:03:35:04
Both Syrian born physicians and surgeons who were well known were sainted physicians and are well known for treating their patients for free. Now that immortalized with this beautiful basilica in Rome, I think it’s around the stadium forum in Rome. It’s a beautiful place to go and see. Their work is also immortalized in a lot of things and beautiful depictions throughout Italy as well as in the Middle East.

00:04:00:24
So Holzman Damiano known or the myth goes, that they have transplanted and Ethiopian like into one of their patients, and its work, I would say, exists now. More scientific and scientific error, however, relied heavily on animal studies. The cornerstone of transplantation is the vascular. Mr. Moses and I’m not mistaken, the people who do follow these for a person as the battle this has actually don’t prize.

00:04:28:22
This is truly a huge landmark in organ transplantation. That is all followed by a lot of xenotransplantation experiments or taking one organ from one animal to another animal. So human zero transplantation has, of course, failed throughout and continues to be a challenge to perform. The most recent, I think well documented is a heart that has been beating for about a month, I think, and the University of Maryland, and that was xenotransplantation.

00:05:01:12
But after a month, that heart has failed. So we’re still not successful with that. So we only rely on human to human transplantation as well as of course, it is a future for artificial organs. The first human to human transplantation in the modern era has been performed by Dr. in Russia and that was a deceased kidney donor, one deceased kidney donor into a sibling.

00:05:22:20
Now, this was done across ABO barriers and at the time I don’t think they had a full grasp of the analogy underlying successful transplantation course. That transplantation procedure has failed. The first successful transplantation was a kidney, and that was done in around 1954 in Boston by Dr. Joe Murray, who passed away about ten years ago, if I’m not mistaken.

00:05:46:03
So what he did was he took it in a living donor, a twin, an identical twin, and transplanted the kidney from one identical twin to the other. Of course, there are no immunological barriers. This procedure, the procedural part of the vascular anastomosis, the surgical parts of the procedures have been perfected for many years. Of course, there’s always there’s always been room for more protection, for more difficult procedures, but the surgical part of it has been perfected.

00:06:12:12
And now with identical twins who are very similar genetically, this organ has actually found the function for many, many, many years now. This has given us insight that there are mismatches between donors and between recipients that we need to be on the lookout for. Of course, ABO blood grouping is the first barrier for transplantation. But even in this day and age, we have ways across this transplantation order to increase the donor pool and allow the sickest to get organs first.

00:06:48:11
In the 1960s, a giant of a man by the name Thomas Starzl started and feel it was one of the few to first describe chemical immunosuppression by adding prednisone to his protocols. Prior to that very aggressive protocols that included all body irradiation usually of the donors have been tried. They have failed miserably. Of course, in some cases, in others they have worked.

00:07:11:20
So the descriptions are still there. But prednisone, other forms of chemical immunosuppression have been introduced and they have shown success. And he’s shown tremendous success in explaining to the world the importance of immunology in the world of organ transplantation. And he has been able to fundamentally change the field. He is one of the pioneers of tolerance.

00:07:36:12
Tolerance remains the holy grail of transplantation in which organs to be transferred from one recipient to the donor without having to give them immunosuppression. Now that he has been able to achieve that from the nineties in very, very a few patients who remain, some of them remain completely tolerant and some of them remain operation tolerant is also among the first, of course, to perform liver transplantation, as well as among the leading developers of current tacrolimus and FK506 and cyclosporine medications that we currently use for immune suppression.

00:08:15:03
Of course, Strazl and our physicians and scientists have worked diligently on the field of organ transplantation for us to reach the current status that we are in right now. We know very well that kidney transplantation truly saves lives. One, it improves the quality of life, recipients with end-stage liver disease, and two, and improves their survival. One may survive more with a transplant kidney than with dialysis alone.

00:08:41:05
So it offers hope and improved lifestyle, as well as hopefully prolong survival for these patients. The problem is that the majority of patients with end stage kidney disease are going to be in a awake and they will not receive a kidney. You guys know better than me with the average length of our waitlist is for kidney transplantation. The problem that we face now is that the demand far exceeds the supply.

00:09:08:04
So of course, as we always do, human ingenuity, we have to get creative. What are we going to do? We’re going to expand the donor. How are we going to do that? We’re going to expect we’re going to expand the criteria, right? So we’re going to take what is known as ECD donors or extended or expanded criteria donors.

00:09:25:04
And I will talk a little bit about what that means. We have experimented with hepatitis C virus positive donors. We call these HCV mismatched in which we take an organ from a hepatitis C virus infected donor and place that in recipient who is HCV negative. So we’re able to do that now because we have indications to treat hepatitis C virus infection.

00:09:48:01
Other things that have expanded the donor pool include the use of actually kidneys from COVID positive donors. Those have actually also been shown to work. But this, of course, is probably done in a very limited number of large volume centers. And unfortunately, despite all of this, the largest contribution to the donor pool has actually come from the opioid epidemic.

00:10:09:23
And that is a very unfortunate thing. Kidney Donor Profile index is a clinical method for evaluating these donors. To get a donor. You have their age, you have their medical history, know what is going on with them. So we’ve developed a kidney donor profile index or a KDPI as a method to evaluate these donors with that ECD donors with the regular donors, and we give them a percentage score.

00:10:37:23
And that percentage score tells us how good an organ might be and how well it may function. Right now, there are multiple scores and parameters that go into this, and we’ll also talk about it. But I want you to know that. High KDPI in the introduction of these standard practice donors has probably increased the number of biopsies due to performance because some of these high KDPI patients will need a biopsy in order to fully investigate the kidney.

00:11:07:09
I’ll talk a little bit more about that. A huge problem in the transplantation world, especially in kidney, is the rate of discard in the United States. Our rate of discard is extremely high. It’s probably around 40% right? 38% of those discarded kidneys organs are discarded because of results on their pathology reports. So we need to take that into consideration that these pathology reports that we are generating for organ transplantation centers to be able to accept or reject an organ collectively have resulted or contributed significantly to the rejection of about 38% of all discarded kidneys.

00:11:49:23
Now, that is a huge number. And as a pathologist, I want to improve that number and decrease it. So organ and donor evaluation, I apologize. So organ and donor evaluation is done at multiple levels at the OPO level, is done at the at the centers, that are accepting these organs, transplantation centers as well, and is tailored towards specific patients.

00:12:22:01
One organ might not be good for patient E, but this organ is probably to improve the lifestyle of patient B, for example. So when we talk about extended criteria donors or expanded criteria donors, we’re talking about individuals who are older than the age of 60 or those who are older than the age of 50, but have hypertension. And those with high get anything over 1.5 milligrams is considered to be an extended practice, as well as those who did not die from cerebrovascular accident of course, with very visible and clear reason that they have vascular disease that is affected them and actual death.

00:13:00:03
So by proxy that means that kidneys are probably also might be affected by this vascular disease as well. Now, the KDPI is a very helpful tool that clinicians use to evaluate the donors and the kidneys. Right. So that factors in age, height, weight, ethnicity, diabetes, hypertension, creatinine, their history of hepatitis C virus infection as well as a DCD donor at a DCD donor.

00:13:26:20
As you all know, this donation, that’s a circulatory death. Those are less than ideal donors. And those donors also usually are a little bit riskier and their organs are less than ideal because of the ischemia that they have to go through one way for them to pass away. Unfortunately, as well as the cause of death, things like cerebrovascular accident, things that are not included in these evaluations, of course, are unfavorable pump parameters, abnormal anatomy, history of malignancy and transmission risk, as well as other infectious etiologies.

00:13:58:05
Now, we’re not going to talk a lot about malignancy transmission risk, but those are very clear and we have charts. We know which types of cancers we would never touch the patient. The patient is just now considered a donor. And what type of cancers that we allow a certain time to elapse before we accept them as donors. These are clear and we can and this can be a subject of talk for other presentations as well as clarity’s felt to be needed, at least.

00:14:23:07
Now let’s go back to the KDPI system and talk about it and how we can use it appropriately. But no KDPI the KDPI system, things are sometimes placed in it, but not necessarily the full context. It doesn’t reflect the full context. For example, when they apologize. So I’m having my Marco Rubio moment, so I’m going to have a sip of water.

00:14:54:17
An African-American doctor, for example, will have a an eight these in the KDPI 17% percent at respective with other risk factors. Now, what we do with the biopsy, if you take a biopsy this door and you look at the kidney, this guy does not have FSGS. There are no other glomeraular B. So that means I’m a clinician and I’m looking at this and I’m saying, you know what, That 70%, they did a kidney biopsy and they don’t see glomeruli, look, I might take this patient and let’s look at the other factors.

00:15:29:19
This donor has a history of hepatitis C virus infection increase my KDPI by up to 23%, irrespective of renal function. As a clinician, I will look at the renal function out saying that’s good, it’s a good renal function, but that increased my KDPI. Are there any correlates hepatitis C virus and some of the other viral infection since are known to cause renal disease.

00:15:56:13
And that’s why you see virus infection is indicating that if you do a kidney biopsy and you look at I’m not seeing any kind of globulin, I’m not seeing any other leaders, I’m not seeing any damage that is associated with hepatitis C virus in the kidney biopsy serum creatinine, for example, you have an increased serum creatinine in your donor that increase your KDPI

00:16:19:13
I now whether this increase is from a chronic disease or just from acute tubular injury due to the hospitalization and the circumstances surrounding the brain death, for example, we do not know. So you do a kidney biopsy. Pathologists like me, it looks like they said you guys have acute tubular injury here that is reversible versus when I say, yes, this actually this guy has chronic renal disease with a high number of sclerosis glomeruli.

00:16:47:02
Eli And interstitial fibrosis and tubular atrophy. That makes a huge difference as the cause of the increase, whether it’s an acute reversible event or is it chronic irreversible damage to the kidney. Other factors that we can see as well and help in kidney biopsies that are factored into the KDPI. I include things like diabetes mellitus, hypertension and other chronic diseases, which we can also see on kidney biopsy.

00:17:17:18
So we can diagnose hypertensive nephropathy, we can diagnosed diabetic. And I will show you guys some images and how we do this and what that looks like on a donor kidney biopsy. Now, biopsies in general, we call them procurement biopsies. They can also be called donor biopsies. But for us, let’s call them procurement biopsies. Roughly 50% of donors will get a kidney biopsy.

00:17:43:08
And with the current OPTN guidelines which recommend that anyone with a KDPI of 85% gets a biopsy, as well as our expanded criteria, as many of them will get a biopsy. And that’s the recommendation by OPTN. And now the recommendation also recommends a ten by five millimeter sized wedge biopsy. And we’ll talk about differences in terms of pathology between wedge biopsy and core biopsy and which one is better.

00:18:10:17
They are very equivalent. The wedge gives you more information and certain things. The core gives you more information about certain things. I personally love the wedge biopsy. They are harder to read for pathologists, but it always gives us consistently gives us a decent number of glomeruli that we can look at and allow us to really look at interstitial fibrosis and blood and tubular atrophy.

00:18:34:17
And all of these factors will definitely increase the number of perform apps. So the need is for certain things. One, these are done in non-ideal circumstances, right? Was ideal. You’re in a time crunch. Everyone wants the results. Everyone wants to place the kidneys. Right? You’re getting wedge biopsies. Some pathologists may not like your presenting definitely in these which biopsies things like glomeruli sclerosis because maybe a biopsy is something that is cut.

00:19:05:01
You’re doing the frozen section which is full of artifacts and is a lot harder to read. The regular pathology section. The quality is just different. There is no question you show a pathologist a section that’s a permanent or well process section, which is a frozen section, will always be able to tell the difference. We don’t even need to look at it under the microscope.

00:19:23:03
We can just look at the slides and we can definitely tell the difference. We were only relying on H&E that is performed manually rather than a one hour process to perform proper H&E stain, as well as a number of other specialists like Silver stain, PAS, Trichrome. You’re asking a pathologist looking at the middle of the night, Kidney transplantation always need somebody at night to read these biopsies.

00:19:48:15
Many times it’s unknown. Pathologists, some of them may or may not have a special training kidney pathologist. They might not even know the the important parameters due to be reported in these. Of course, those training in ecology are very good at treating this virus to be able to give you a consistent, consistent results all the time. Now, I want to touch base very quickly about the big differences between a postperfusion biopsy which is performed during transplantation.

00:20:17:21
But after the organ is connected to the to the recipient and after it is perfused with the recipient’s blood. And between the procurement biopsy, which we do, it basically to place the organ. So there is no room, there is no way we can do a pulse perfusion biopsy and usually it’s done after that. But I want you to know the differences and the differences are the procurement biopsies are always wedge biopsies most of the time, are wedge biopsy this are popular type of biopsies, and we can suture that area in nicely in a neatly nobody needle biopsy to perform a proposed perfusion biopsy.

00:20:52:22
We freeze or computed biopsy. We do a single stain and depending on where it’s done and who’s reading it, the reporting parameters are very good. There are some centers that will only report a total number of glomerular sclerosis versus the total number of glomeruli and do not. Of course, there is always the availability of an expert pathologist to review these once they are scanned through a whole slide image scanner.

00:21:25:18
But that is also not available anywhere close to it. Postperfusion biopsies are always read almost by exclusively well-trained pathologists, usually with good renal pathology fellowship training, as well as multiple years of experience. In some cases, the reported elements are standardized by Banff. Everybody does the same exact report. So these are very valuable in terms of prognosis of the city perfused or just decently perfused organs.

00:21:57:06
Now let’s talk about pathology findings in these biopsies. Let’s see what we’re looking for as pathologist with images like, with, like different compartments look like. So you guys always collect these biopsies, put them in nice little containers labeled with the patient’s name, usual birthdate, as well as UNOS number. It depends, but we at least need to identify do not place them in saline, feel free to place them in a University of Wisconsin preserve, for example, or any other organ preservative.

00:22:31:16
But not saline, because saline creates a lot of artifacts which make it very hard to because what is the tissue makes it very hard to actually evaluate these organs. Now we use this machine. This is called a cryostat which freezes the tissue. And then to really find microdroplets, we’re able to cut them, generate slides that we use a microscope to look at them.

00:22:57:14
Now, there are different compartments that will look at these once a slide is made. Looking at the microscope, there are various compartments that we look at. One of them is the glomerular compartment. Two is the vascular compartment, three is the interstitial compartment, and four is the tubular. Now, I look at the slide at least four times because I look at each compartment separately and maybe a fifth time just to look at everything together.

00:23:30:04
I give you a score for each compartment. I tell you what is going on with each of that is what the Banff has suggested, and we’ll go over what the patterns suggest and how we try to standardize the reading of these biopsies. Now, each compartment has a set of parameters that we look at some of them are very easy to see.

00:23:48:16
Some of them are more difficult and some of them are extremely challenging. Now, this is how that ten by five millimeter biopsy that you guys took from the donor kidney and delivered to us pathology. We section it in the cryostat. That is my contemplate very thin section, usually about four four microns in thickness. We placed in a glass test line and their stain it with an H and E stain.

00:24:18:04
Now this is how it looks like on glass, right? It retains the same size. Maybe it expands a little bit because of the freezing, but it’s 1.5 ten millimeters by five millimeters. Now, that’s a lot of real estate to look at. A high bar because we look at it at around 40 times up to 400 times the size using the microscope.

00:24:45:06
Now, this is a scan image, meaning I don’t have to sit under a microscope to look at it. I can look at it through a computer screen and drive it as if I’m sitting at a microscope. It’s actually much easier, quicker for a pathologist, and I can do it from anywhere. Instead of having to come into the hospital and look at it under my microscope.

00:25:06:06
Now, the glomerular compartment is probably the most important compartment that we need to look at. One of the evaluating these donor biopsies, I’ll give you a total number of normal glomeruli with it that is clean nose disease or they’re healthy. I’ll just give you a total number. I count them. This is how a normal glomerulus looks like. It has this nice groups of cavities.

00:25:28:02
These are cavities through which through which blood comes in, infiltrates and goes out into the space, and then through the tubules go all the way out and into the black, and then it comes out right. This is how I expect a normal gliomas to look like. This is another example of a normal glomerulus. Now, granted, this is this appears a little bit cellular.

00:25:52:15
However, again, this is the challenger. I cannot take this out of context and I cannot do what I do with the post perfusion biopsy of this biopsy. So most of the time, unless we have significant disease, we’re going to let them go as part of the spectrum of what is normal as well as in a patient who is undergoing the process of death or brain death.

00:26:13:13
Now, we also count the number of globally sclerotic glomeruli, meaning they go from this and become obsolescent, meaning they’re not functioning, they’re not helping us produce urine. They’re not helping us get rid of toxins at all. So they’re useless. So we count them because it gives us an idea about how much damage the kidney has sustained. Again, this is the most important parameter.

00:26:38:11
But I don’t just we don’t just give you a number of the global sclerosis glomeruli as a percentage of the total number. We also look for other things, right? This is the easy part, especially if we have enough glomeruli. Like this is really the easy part now for all pathologists. Sometimes we ask you what is the creatinine?

00:26:58:24
What is the age? They have hepatitis C, Do they have hepatitis B? How did they die? We ask these questions because we want to cheat a little bit. We want to know what to look for very carefully. Right. If you tell me this is a 60 year old African woman, I’m going to be looking very hard for lesions like focal seg glom segmental sclerosis.

00:27:16:23
And I’m going to tell you about this. This is going to affect how you place this kidney or if you place this kidney at all, if I know that this is an average patient, I will look for evidence of diabetes in the kidney. If I see things like Kimmelstiel-Wilson nodules, this is called nodular glomerulosclerosis.

00:27:33:16
If I see that, I will tell you I’m going to comment. I do see pockets of nodular glomerulosclerosis. And I will tell you what the differential is. Most clinicians now and if I see elements of their nephropathy and also tell you most of the time when we see KW diabetic legions or someone with a long history of diabetes and we verify that on the biopsy, most of the time, that’s not the most perfect biopsy to give to somebody who can afford to wait a little bit longer, who’s who is younger.

00:27:58:19
And we can expect to keep that kidney for many, many years. Right. If it’s a functioning kidney, might give it to somebody else with the donor list or it might end up being discarded. Other legions that we look for are things like glomerular thrombi, as well as necrosis and other regions of activity. Right? So glomerular thrombi important because it just it’s secluding this completely.

00:28:22:00
So these glomerular functioning at 100%. We think we need to take that into consideration. Usually we see that in the context sometimes of head trauma. So if you hear me ask you, oh, how did this patient actually have a trauma, that is maybe I’m looking to see if they’re thrombi. Usually the cutoff is about 10 to 20%.

00:28:40:07
So anything less than ten or 20%, usually most of the time we don’t you know, they clean out. That is fine. But once you see it’s widespread, then, you know, the decision becomes a little bit more difficult because the kidney might not actually work once it’s transplant. Now, this is one of the more challenging things when it comes to glomeruli.

00:28:58:10
The easiest thing in the domain compartment is really to account for this. Global sclerosis is what’s not so sclerosed Now, the vascular compartment is also challenging. We give you a score based on the percentage of atherosclerosis involving the most significant, the affected arteries. So I’m looking for the most significant constricted artery and I misquoting meaning if it’s occluded by only less than 10%, I’m going to call it mild atherosclerosis.

00:29:29:06
If it’s more less than 50%, but maybe more than 10%, 25%, maybe I’ll call that more than half sclerosis and things that are completely put in more than 50% we call the CCB atherosclerosis. Now, this is not as easy every year because this arteries are tubular structures. And if we cut it this way or this way or additionally, it will look weird and it’ll be very hard to tell if this is mild, moderate, that is any disease at all.

00:29:58:23
So you need a certain level of expertise in order to figure to these we’re cut are now arteriolar hyalinosis. This is one of the most difficult things to appreciate on a frozen section, mainly small arterials entering or leaving the glomeruli. It very hard to find locate because again that you have to get that perfect section in order to see them.

00:30:22:10
And the other thing is that the frozen artifact makes it very hard to see if I see one arterial with hyaline. That’s by definition, mild arteriolar hyalinosis for to see more, I’ll get into moderate and severe. Now these things do not occur in isolation. If I’m seeing severe arterial sclerosis or hyalinosis, that means there is an element of vascular arterial disease as well.

00:30:44:00
So it’s probably more that arterial sclerosis. That also means my my glomeruli are going to be affected. So all of these things, elements are going to move together, they’re going to get severe together. We’re going to lose them together. Right? So you’re not going to find 100% glomeruli like with severe vascular disease unless the biopsy is not right or it’s not representing their interstitial compartment.

00:31:06:05
We’ll look for a number of things. One is the interstitial inflammation, but it’s not a major determinate function. We talk about that. But the most important thing is, meaning interstitial fibrosis. Now, this is very challenging because in frozen sections we produce this space in interstitial which can be edema, an artifact which can make it very hard to identify interstitial fibrosis.

00:31:30:21
The other problem with interstitial fibrosis, it’s really very overemphasized, kind of presented on which biopsies. Sometimes there are some capsular scars. Mr. Otherwise perfectly well functioning really well. And if we do to biopsy and we see maybe the fibrosis sort of minimal, nonexistent, but when you only look at a scar area under the capsule, I might tell you that severe remember, I’m not looking at the whole kidney.

00:31:56:19
I’m looking at that one centimeter piece from under the capsule that might actually have been scarred. And that’s why it was biopsied because of that little scar. But remember, that little scar may not present the entire kidneys. When you’re biopsy in the kidney, you see a scar. You can biopsy it just to see what’s going on with the scar, but try to biopsied it.

00:32:16:06
It looks healthy. So I can give you something that because the not an entire kidney’s scar, it’s only a small area. So it gives you something that presents the entire thing. You’re not talking about that little area. It might be inconsequential to the kidney function. The other compartment is tubular compartment. Now, there are two things in the tubule acute change.

00:32:37:08
The chronic changes. Now tubular atrophy. The chronic change, it goes hand in hand, usually with interstitial fibrosis. Most of the time we consider them to be the same compartment and the transfer protocol. This if the I for interstitial and f for fibrosis, t is for tubular a for atrophy so we call it IFTA so we refer to them as one thing because they are really great and they go hand in hand with the fibrosis, you’re going to have atrophy, you’re going to have fibrosis.

00:33:06:16
Now, the other more acute thing that happens there and pathologists are not the best are telling it at in a frozen section because it’s not that specific and we don’t necessarily agree all the time. Is tubular injury, maybe a tubular injury or dislodging of the juvenile epithelium, which again is reversible and that will be physically active at the time of death.

00:33:26:23
Maybe that is the only problem is patient. Right. But we know it’s reversible. So this is a transplantable kidney. Sometimes it can go for mild. When it’s moderate, it is a lot of it very clear and probably correlates with a more severe elevation of creatinine kidney function. Now, depending on the amount of cortical infarction, which can be challenging to verify, it might be a little bit hard to place this kidney.

00:33:55:14
But again, remember, if the area on the biopsy is just that area that has been hypo profuse and fighting, but the rest of the kidney healthy. But you biopsied that in fact that area, the results are going to look bad. Right. So maybe again provide another biopsy for looks up usually with infarction it’s not like that it’s more with with a scar.

00:34:17:24
The other challenges that we see with evaluation of disposal, section of piece artifacts that are being introduced by the frozen section, meaning things there’s actually ice in here which kind of expands things, which doesn’t let me see tubular atrophy very well might see interstitial fibrosis very well prevents me from scoring the tubular injury very well. All right. The other thing that can occur as well are things that can be introduced at

00:34:45:07
Remember, for me to be able to see into the tissue, I need to cover it with something that is transparent, like a piece of glass or a piece of plastic that is really transparent. And in between them we have something called the mounting media. Now is the cover sleeping introduces air into this. It will look like this, it’ll blacken this piece of tissue and they won’t be able to see into it very well.

00:35:07:21
I might give you the rest of this, but I won’t be able to read this for you. But that’s fine if I can get them decent number of glomeruli on three quarters, it’s the biopsy that is actually all right. Course, sometimes the challenges to get enough glomeruli, sometimes we get to that is not a very common thing to happen, especially to read with those ten by five millimeter biopsies.

00:35:29:02
There are some capsule really well done. That is not usually the challenge that we face, although it does happen from time to now, is all of this stuff that we have described, does it actually correlate with graph function? That is a very good question. Why are we doing it? Basically, for something to be useful clinically, it has to show prognostic value, meaning Is this actually going to work and how long is it going to work and how long is it going to last?

00:35:59:00
Tried to. It has to be useful, right? If it’s set by me or by another pathologist or my third pathologist, we have to be able to reproduce these results too, so that we can give the same prognostic value. Now, there is a lot of ambiguity, ambiguity about the utility. Sometimes donor biopsies, especially when we do a lot, but hear me out,

00:36:21:03
Right people, This can be a very valuable tool, not by itself, but when you consider KDPI by the elements of the KDPI, by the elements of your biopsy results, especially betrayed by well-trained as well as their clinical parameters, instead of discarding a kidney based or KDPI maybe the biopsy would inform the decision not to discard, But maybe the biopsy would also tell you how this kidney isn’t treated good.

00:36:48:09
It needs to be discarded, or maybe it needs to be allocated to somebody else who might take a couple of years out of it. But they’re also really sick of it. Right? So there’s a lot of ambiguity. There’s a number of studies out there. The methodologies have been different. The sample have been different, and the sampling variability has.

00:37:07:04
But the most important elements that have always been determinants of prognosis between different various types has been global glomerular sclerosis as a percentage of the total number of glomeruli, like interstitial fibrosis and its brother Tubular atrophy, as well as the presence or lack of the presence of disease. Now many centers rely only on the glomerular sclerosis other might look at other parameters.

00:37:35:07
There are other centers. So then a very smart thing which we’re not going to look at glomerular sclerosis alone. We’re not going to going to look at if now we’re going to combine that field or even show you some really clear examples here. The score that will give us the sum of all of these chronic parameters is much more helpful than use.

00:37:54:06
And I’ll show you very good examples here. Now, we know very well that these procurement biopsies, the results have been ambiguous, both clearly clarified outcomes, but compared to post perfusion biopsies which consistently show correlation with how the kidney function. Now we want to do that as well with procurement biopsy, but we have to do it the same way that we do post perfusion biopsy, meaning standardization.

00:38:26:21
And the people who look at these biopsies right that way you would get your produce ability as well as prognostic data. So again, I keep emphasizing this, that the glomerular sclerosis score, the number of glomeruli, has been really the most important value that we provide. Usually the cutoff value is 20%, but of course that can be in it and that can change from one center to the other.

00:38:57:13
You have to remember that these where these cutoffs were developed many, many years ago. And I would remind you that some of the regional studies, the eight cases, the eight biopsies that showed more than 20% and that were transplanted, only three of them lost their kidneys with that within three months, that means those other six patients who might not get these kidneys because there is a greater than 20%.

00:39:21:18
glomerular Sclerosis. Many of these can be transplanted as some of these kidneys can actually benefit. And what a nice group did in Spain was they said, okay, we’re not going to rely on a single parameter, right. We’re going to get all of these factors. GTS means global sclerosis. CI is a chronic interstitial fibrosis CT or chronic tubular atrophy, as well as arteriosclerosis, which is referred to as CV as well are arterial hyalinosis.

00:39:51:10
We’re going to combine them together and we’re going to form a score. And based on that score, they were able to lower their discard rate from 11.5% successfully. Only 5.5% right now. To start with, Europeans have a lower rate for many reasons that we can discuss later, but they do have a much lower significant, you know, in this country than we do.

00:40:15:07
But remember, the US is very high volume when it comes to transplantation. We transplant more than many of these other European countries. Now the Banff working group, and I know we’re getting towards the end of our time, so I’m going to just make this very quick. The Banff group has been working very hard to try and replicate the success of prostate fusion biopsies to prove human biopsies.

00:40:38:10
Now they have come with donor biopsies, scoring sheets, which is basically, I think now many of the OPOs about adopting and many of the CompuMed OPOs are also adopting want a variation is basically the total number of Glomeruli the extent of any risk losses as well as the percentage can be calculated from these as well as the number of objects.

00:40:58:20
Now we need the number of options because it gives us an idea about how good these biopsies are, right? This is more of a, you know, is it an optimal biopsy? How good is the biopsy kind of question? The number of arteries would give you that, right. And you’d be able to compare the different biopsy results to different biopsies and figure out what is a good biopsy versus what is a suboptimal biopsy.

00:41:21:09
Now, other parameters that are being scored, you’ll talk about things like interstitial fibrosis, tubular atrophy, interstitial information, which we said is not an important parameter. It doesn’t correlate with graft function, but is important to put in context of the whole work, right? That work transplant things that are risky like a fit into fibrosis are high losses as well as the closest the number of glomeruli thrombosis.

00:41:46:05
So by the process I always comment on presence of other things like cumulative or signature or something that looks like a small tumor. I need to let you know if I see it. Things like focusing on the sclerosis. Now, the matter, of course, is 2010 has multiple fractures. They have done a beautiful study that is published out in the wreckage of transplantation in 2017.

00:42:09:11
And in addition to providing us with this, they gave us context. They told us how reproducible the results are right now. This study was done using only experienced and well-trained transplantation or kidney transplantation pathologists. Now, the things let’s talk about this graph on the left side. So basically here we’re comparing the intraclass correlation for different pathologists to biopsies.

00:42:36:22
There were read through frozen section and paraffin right. So paraffin tissue will always paraffin means it has gone through the regular processing, they’ve gotten rid of different artifacts. This is your classic way of doing pathology, which probably takes many, many hours for us to be able to treat. We do not have that luxury in the transplantation world, so we have to do the frozen section.

00:42:59:11
Now. What is relevant to us here is out of the bars in green, which are based on the section. You can see that we’re very good at getting a consistent count of glomeruli right between me and my other colleagues. Other colleagues. Right. We’re good at telling you the percentage of Glomeruli that are globally sclerosed as a percentage of course over the other column anyway but what are we bad at, we’re bad at arterial hyalinosis can be part of a scoring system which kind of gives us a good idea about complexity of kidney disease.

00:43:33:14
We’re also really bad at scoring tubular injury. Of course, we’re better at these things when we do it by paraffin, but even in paraffin tissue, we’re not extra in the concordant with each other right now. They didn’t just stop there. They also did something very unique to answer the question of what is better, which biopsy of the core labs.

00:43:59:01
Right. So and a core biopsy. It’s a few thing I can go from right to left and I know I’m not going to look at the same area more than once in a wedge biopsy. I might look at an area more than once. So counting and this is really reflective data is so much easier to do in a core biopsy.

00:44:17:02
And because we’re going on a straight line, usually from right to left or from top to bottom, and we’re not recounting the same glomeruli on core biopsy. The correlation between different pathologists is phenomenal. It is less of course, it’s still good, but it’s less on the wedge biopsy. Another thing we’re much better at correlating with each other when we score interstitial fibrosis on wedge biopsies versus core biopsies.

00:44:51:03
Right? So number of glomeruli. Like it’s always better to get a core biopsy. But keep in mind in which biopsy women get a larger number of glomeruli, which means things would even out because we’re giving you a percentage right. If you see the number 300 total glomeruli and about 20 then get the percentage right versus five out of 50.

00:45:15:08
Right. So you’ll always get the percentage. You’ll always put things in perspective using that percentage of globally sclerosed glomeruli percentage with the total number and now with interstitial fibrosis. Of course, if you biopsy these areas, then. All right, So I’m going to just be very quick here, but I’m going to say that, you know, the studies have shown that these biopsies in the hands of experienced kidney pathologists, not in regular overnight, midnight somewhere, 3:00 in the morning, bodies were not necessarily registered, certainly trained in kidney pathology is going to for three of two criteria, which is reproducibility, as well as prognostic value, not just the 12 month kidney function, but it can also discriminate between kidneys

00:46:02:24
that did well from those that are like now. There are different types of discordance. I don’t think we have enough time to go through them, but sometimes your results may from the right to the left kidney might be discordant. Maybe the left kidneys more damage done that I can not vice versa. But pay attention to this. You can’t biopsy the worst kidney from a different area that looks healthier.

00:46:24:01
See if that will change the biopsy before you decide to throw that in. Because sometimes you lose one kidney, it will be the other. But both kidneys are coming from the same patient and maybe we ought to kind of try and biopsy these kidneys just to see the pathologist kind of different. Maybe you’re able to give it to a patient who actually reducing.

00:46:43:08
Right. So I’m going to leave this out there. I’m going to start answering your questions because I think we’re running out of time. So, Laura, how do you how do we get to questions?

00:46:53:07
Laura Carroll
Thank you so, so much. I’ll go ahead and just remind everybody, you can start putting questions in the Q&A and we’ve got a few in there and we will definitely have Doctor El Hag on again. I just I actually quickly had a question for you. Didn’t you present at Banff recently and I think you’re in the most recent one.

00:47:12:12
I think you were a presenter of.

00:47:13:24
Dr. El Hag
Yeah, right.

00:47:15:04
Laura Carroll
Yeah. You’re always a little humble about it. So I just wanted to let everybody know, which is a really fascinating conference that you go to. So, so one of our first questions, Genevieve Springer, she says, What do you believe is the biggest barrier to better utilization question number?

00:47:34:02
Dr. El Hag
I think we have a lot of OPOs, I think, which is a good thing, by the way, because the US is a huge country, right? I think we utilize a lot more than our European counterparts and I think we were very good at it, but we’re not as efficient. I think efficiency needs to improve. We need to be able to utilize a lot more organs.

00:47:53:09
I think, one, we need to expand the donor and we need to convince as many people as possible to become organ donors, because then we can have the luxury of saying, Hey, this is it, he’s backing me. This is really badly wrong. We cannot use it too. I think practices are different from one transplant center to the next transplant center from one transplant zone or OPO to another from one owner’s region to another, I think is a lot.

00:48:22:04
It’s very hard to make practices uniform for so many reasons. Big transplantation centers, for example, can be more willing to take risk and accept water line organs, whereas because they can you know, they can. They can the numbers don’t look bad because they have a huge number of patients that they transplant. If a couple fail because they just took the risk and took a less than ideal organ, the numbers are not going to get worse.

00:48:49:14
But when you have a center that transplants, 20 to 35 of them didn’t do well, one year post-transplant, four opted into well, then their numbers much, much worse. Right. So there are centers that are willing to take the risk. They’re willing to expand the donor pool. They’re willing to take more HCV, they’re willing to try covered donors. They’re willing to do this while other centers maybe are not as willing to do these because, one, they want their reputation to be better.

00:49:17:23
They don’t want to be dinged by open UNOS for having less than ideal results because they may have accepted an organ that didn’t do well at the one year mark. So I think that’s a barrier that we can have further discussions on really how to draw these lines and kind of allow people to say, you know what, I think this is a marginal donor.

00:49:39:07
I want to take it. I think I have a patient that I can help out with this story. So that’s I think one thing. The other thing is, again, with donors being all around the place in Alaska and Wyoming, down in Cleveland, Pittsburgh, DC, LA, usually we rely a lot these hospitals to provide services for for that section kind of help us allocate these organs.

00:50:03:02
Now each different pathologists looks at it, a different clinician looks at it. It’s not centralized, meaning the discrepancy or I wouldn’t call it discrepancy, but the entered the observations are going to be descriptive or they’re going to be scored, meaning they’re not going to be translated, they’re not reproducible. One one clinician, one pathologists and a clinician will look at it and say, this is a horrible organ.

00:50:26:18
Then we’ll go somewhere else. And they say, this is this is a good look. And I think a recent example of this is liver and kidney. We got a local breed of about 60 or 70% statuses. Do you remember? Right. It was a highly misdiagnosis, which makes it a little better. Nobody would want transplant. This organ clinician called us.

00:50:47:07
We looked at it, said, no, this isn’t max 50% status now. And that correlated with the clinicians. The clinician said this organ doesn’t look bad. It’s just a different age group, extended criteria that wanted to make sure that there is no huge red flags. But we got to see, does it really correlate with what we’re seeing? So, yes, I can share the paper from Spain.

00:51:11:23
Let’s go back.

00:51:13:00
Laura Carroll
Here. Yeah, let’s let’s actually add this to this one. So. So this one’s from Nicholas Tanaka. This is a very clinical how do we manage arterial sclerosis? He says he feels it’s under red and frozen. Didn’t even looking at the frozen, he often reads more obit than the pathologists. What is moderate on your slide? Looks more severe to me based on the ratio of open lumen versus total.

00:51:39:15
Dr. El Hag
Remember, again, that’s a very good question. I do absolutely believe that. So please go back at some point and give them that. The reference to that. There’s a number of papers that were kind of, I think, cited in this, and I’ll give you the most recent ones. But again, just that question That’s very good question. I absolutely do agree that arterial vascular sclerosis or arterial sclerosis, as well as arterial section of the numerator, knows this is a worse problem here.

00:52:04:17
Right. But I do truly believe that they’re both and they’re present. Not everybody needs them. Not everybody’s going to give you the results. Correct. For something arteriosclerosis or accuracy causes. Again There are parameters I mean, here about and I’ll show you the paper, which kind of must go back which kind of kind of lays out exactly what these are and how that evaluated.

00:52:28:03
But remember, again, most we we evaluate on the worst artery and we talk about still intimate sclerosis, less than 25%, but between 26, 25% of lumen You have to remember that these arteries are not always cut flush, meaning they’re not cut perfectly. They’re always cut up an angle. It’s very hard to get analogy that was 100% the right way.

00:52:49:01
Right. Is just not going to happen because of how this tissue is and how the and adding it looks like and how solid it looks like. So we have to kind of compensate for that tangential section. Sometimes it’s what might look severe if you apply things without the knowledge that the angle affects the amount of arterial sclerosis, that can be a problem.

00:53:08:13
And that is actually one of the big difficulties in assessing arterial sclerosis. I hope that answers the question because what might be mild to me might be moderate to somebody else, might be more that somebody else might be liable to somebody. You know what I mean? There is a little bit of variability, but most of the time we’re very good at detecting severe disease as well as mild disease.

00:53:31:17
That moderate kind of has become a problem. But to me here in how this, for example, on this side is less but is more beside I know it wasn’t cut perfectly so for me, more 60% of the lumen is not involved by disease. So for me, this is one of.

00:53:49:01
Laura Carroll
I’m going to get one more quick question in. And again, everyone, if you have more questions, you can keep submitting them to us and also on the survey and we will do be having more of these with Dr.. I can’t thank you enough for your time on this. Dr. El Hag So one other really quick question is I believe you kind of answered this was how you believe the current ecosystem makes the job of transplant surgeons possibly harder than it needs to be?

00:54:17:10
Dr. El Hag
You know, I think there is a lot of demand on organs. There is a lot of attention to the number of organs. That is again, that is that emphasis on results that we have to deliver always and I think is some of those burdens are lessened on transplant centers that people may be more willing to maybe, you know, of course, with the consent of the patients, maybe a little bit riskier, of course, you know, address other issues that include logistics, transportation, differences from one setting to the other, as well as the availability of organs.

00:54:50:12
And that’s why I have been a huge proponent of donor cations, because that gives you guarantees you your time. You don’t have to go in with the hospital says you could go. And I think that has been a huge goal and that has been a big reason and a good reason to have donor candidates, for example. I think these are just some of the few challenges that they share.

00:55:11:03
I’m not a transplant surgeon, but I think these are some of the challenges that they, you know, speaking to them. These are some of the challenges that they have. Great.

00:55:22:03
Laura Carroll
Well, great. I wanted to be respectful of everyone’s time at this point. And there are some other questions and we’ll see what we can do to get you on again and get some of these answered. And Nicholas, maybe I saw you. Maybe we can have you get on a call with Dr.El Hag directly with you in your group.

00:55:37:18
Anyway, we thank you so much, everyone, for participating in this. Again, if you wouldn’t mind, take a little bit of the time to fill out the survey then. Not only do we just love this, that you took the time to do this, doctor, we love working with you, the coordinators. I get the opportunity to work with you. You’ve just you’ve really you and the peer group with the pathologists that we have is the bar on and what services we feel we can provide to the community and transplantation pathology.

00:56:07:17
So so thank you so much.

00:56:09:15
Dr. El Hag
Thank you, Lauren. Again, thank you so much for the help for you and for Steve, the team for going to help put this together. Happy to answer questions. Anytime anybody has them. You can put feed to share my email address with them. And thank you again for attending us.

00:56:22:14
Laura Carroll
Great. Thank you so much.

00:56:23:19
Dr. El Hag
To be here with you.