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ABSITE Review: Transplant Surgery
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ABSITE Review: Transplant Surgery
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Segment:0 .
DR. KNIERY: Welcome back to Behind the Knife's ABSITE review. Today we have a completely new episode for you, transplant surgery. And we also will shortly be releasing a completely new thoracic surgery episode. This is our thanks to you guys for supporting us and making our book the number one study guide on Amazon. So thank you guys for that. And we hope you enjoy these two new episodes. I want to leave you with one final quote on discipline from Abraham Lincoln.
DR. KNIERY: "Discipline is choosing between what you want now and what you want most." I think it's very applicable to our ABSITE studying, hang in there, guys, it's almost over and best of luck, dominate the ABSITE.
DR. KNIERY: So I'm here with Jason and Meghana. And Jason is going to take us through transplant. So take it away, Jason.
DR. BINGHAM: All right, let's get right into it. So let's just go through some basics of transplant. Meghana, so we talked about warm ischemia time and cold ischemia time. What do we mean by that? And why does it matter? [Dr. Kashyap] So warm ischemia time is two periods. It's prior to organ removal from the body when it's normothermic, and it's also the period after the cold preservation before reperfusion.
DR. BINGHAM: Cold ischemia time is that period from the time of cooling the organ to removal from the cold preservation solution. Most importantly though, is that reperfusion time, so after cold ischemia, when the organ is revascularized, the majority of injury occurs during this time and it's this ischemia-reperfusion injury.
DR. BINGHAM: Exactly. Yeah. So it's important to know that distinction between the warm and cold, but I think really the question is going to be when does that ischemia-reperfusion injury happen? And that's after cold ischemia time when the organ revascularized. All right, so Meghana, we're going to stick with you on this one. So there's some different options for cold preservation of organs, and there's some different preservation solutions.
DR. BINGHAM: What are the different intracellular preservation solutions? And how do they work? [Dr. Kashyap] So there's three solutions that are named and out there, one is called Euro-Collins, one is called histidine-tryptophan-ketoglutarate or HTK, and then the one that we hear about the most is the University of Wisconsin solution. These all provide electrolytes that reduce cellular swelling during preservation time.
DR. BINGHAM: And notably the University of Wisconsin solution due to what it's composed of, allows extended preservation of both the liver and pancreas.
DR. BINGHAM: Great. Yeah. So yeah, I don't see this showing up too much on the ABSITE, the different preservation solutions, but it's good to have a general idea of how they work. And then, there's also simple cold storage, which is more straightforward and less expensive. And then there's some different products out there for pulsatile machines, which have been shown to lower the incidence of delayed graft function for kidneys.
DR. BINGHAM: But just have a general idea of how organs are preserved. So moving on, Kevin. Drained organ procurements, aberrant anatomy is often encountered. What are some of the most common aberrant anatomy that we need to know when talking about transplant? Start with kidney.
DR. KNIERY: Yeah. So this is important both for transplant and kind of other specialties, such as vascular, when performing procedures on these organs. So for the kidney, you'll always want to look for multiple renal arteries. You have to check that CT scan because that can change how you reconstruct things and make the procedure more complicated. There's like, I think it's close to 10% of kidneys will have multiple renal arteries.
DR. KNIERY: Sometimes the lower pole of the right renal artery will pass in front of the IVC rather than behind it. And then the other thing you have to look out for is a retroaortic left renal vein. And this is especially important in vascular for when you're clamping the aorta, you can cause massive bleeding from a retroaortic left renal vein by clamping the aorta and not recognizing that the renal vein is behind the aorta rather than anterior, where it normally lies.
DR. BINGHAM: Perfect. And I think the question that's going to show up is "What's the most common--?" And for kidney, it's multiple arteries. But absolutely, there's this other important variants that you need to know about. Okay. Now, how about liver?
DR. KNIERY: For the liver the most common is the aberrant right hepatic artery rising from the SMA. So rather than coming off the celiac, as a branch of the celiac, your right hepatic comes off the SMA, and this is important both in transplant and also in just doing a common bile duct exploration, et cetera, beause you can damage that right hepatic artery, if it's not visualized appropriately.
DR. BINGHAM: Or even a cholecystectomy. It's important for even just your standard cholecystectomy. And that's a question that shows up a lot, it's "What's the most common anatomic variant there?" And it's the aberrant right hepatic artery. And where does it originate from? The SMA. Okay, let's keep going, how about aberrant anatomy of the pancreas?
DR. KNIERY: Yeah, for the pancreas, it has multiple different embryologic things that can happen. It can be an annular pancreas, you can have a preduodenal portal vein rather than the portal vein being behind the duodenum. And then you can have a duplication of the portal vein, and actually sometimes there's an absence of portal vein.
DR. BINGHAM: Okay. So now we're going to talk about some different types of donors. So, we know there's living donors, there's brain dead donors, and then there's circulatory determination of death donors. And we'll talk a little bit more about what that means in a little bit. But let's start with just some living donors. So Meghana, contraindications to organ donation for living donors.
DR. BINGHAM: What are some absolute contraindications? [Dr. Kashyap] So absolute contraindications are HIV and hepatitis infection. Although if the recipient is positive, it is not a contraindication. Cirrhosis, active systemic infection with positive blood cultures, and then melanoma, even if it's indolent for many years, because this can end up showing up in organs and they can have mets that you don't know about.
DR. BINGHAM: Yeah, good, I agree with you, I think that HIV historically has been an absolute contraindication, but more recently, especially for renal transplants, being an HIV positive donor to an HIV positive recipient has become more common. Now how about some potential contraindications? [Dr. Kashyap] So potentially if the donor has a UTI, if they have urosepsis, it's a contraindication, but if they just have a plain simple UTI, they can still be a donor.
DR. BINGHAM: If they have low grade visceral malignancies, it's a case by case basis, whether or not they can be a donor. They also can still be a donor if they have a low grade brain tumor, such as a glioblastoma. And finally, if they have a history of abdominal surgery for a benign disease, they can still be a donor.
DR. BINGHAM: Great. Kevin, so staying with living donors, so living donor hepatectomy. So, indications for transplant are the same as deceased donor transplant, but what are some contraindications for a living donor for liver?
DR. KNIERY: So these patients generally have to be very healthy in order to give up half of their liver or however much it is, so they can't have advanced cardiopulmonary disease, they can't have any primary liver pathology, they can't have any communicable infections, or active or recent cancer histories. And then there is of course, a lot of anatomic restraints that has to be ideal situation because it's such a high risk surgery, donating your liver.
DR. KNIERY: So if there's multiple hepatic arteries, if there's aberrant biliary anatomy, or insufficient residual liver volume, all of these can be potential contraindications.
DR. BINGHAM: Okay, great. And along the lines of that anatomy for a living donor, what are some possible living donor grafts? What segments do they procure?
DR. KNIERY: So they can use the right lobe of the liver, which is segments 5 through 7. They can use the left lobe of the liver, which is 2 through 4, or sometimes they can just go with the left lateral, which is generally 2 and 3.
DR. BINGHAM: Yeah. I mean, so you mentioned that-- Perfect, that was great. But you mentioned that these donors have to be relatively healthy. What are some potential complications for the donor?
DR. KNIERY: So they can get infections, they can have bile leaks, incisional hernias. If they have a small residual liver volume, it can lead to liver failure, which is one of the most dreaded obviously. And then there's any kind of vascular complications, whether it's thrombus in the IVC. And then, unfortunately some of these patients die. Multiorgan failure and death are risks of being a living donor.
DR. BINGHAM: Exactly, so the complications are real and can be incredibly morbid. That's why you need a pretty healthy donor and they need to know what they're signing up for. How about follow-up for donors?
DR. KNIERY: So generally daily labs for three to four days, and they'll get a post-op hepatic duplex. And then if there's a concern for a leak, they may end up getting a HIDA scan, but otherwise kind of routine outpatient follow-up, once they're discharged.
DR. BINGHAM: Great. So Meghana we're going to move on to living donor nephrectomies, living donor kidney donors. So when we're talking about a living donor versus a deceased donor kidney transplant, what are the respective outcomes for those? [Dr. Kashyap] So this is something where they do-- I've seen questions on this, where living donors actually have improved outcomes. So the recipient outcomes in both patient and graft survival are better with a living donor kidney.
DR. BINGHAM: They also spend less time on the waiting list. And you can also, because of that less time on the waiting list, they can possibly have a preemptive transplant and avoid dialysis altogether.
DR. BINGHAM: Yeah, exactly. And I agree with you 100%. That's a very testable question. And I've seen that showing up several times. So we talked a little bit about general contraindications. What about some of the contraindications for a living donor nephrectomy? [Dr. Kashyap] So for nephrectomies, if they have active or an incompletely treated malignancy, if they have an active infection, especially for kidneys, if they have diabetes or uncontrolled hypertension, these would be absolute contraindications.
DR. BINGHAM: There's also some relative contraindications. So if they have a chronic illness or a poor functional status, they wouldn't be able to handle having a single kidney. If they have impaired renal function obviously, recurrent kidney stones, if they have controlled hypertension, that's debatable, and then if they have a history of treated malignancy, obviously if they're ABO or HLA incompatible, and then another relative contra-indication is pregnancy.
DR. BINGHAM: Okay, great. And how do you follow these patients, the donors? How do you follow the donor patients postoperatively? [Dr. Kashyap] So they actually need a little more follow-up than the liver. So they get blood pressure, BMI, creatinine, glomerular filtration rate, urine albumin, all checked at discharge or six weeks post-op, and again at six months again at one year, and then finally at two years follow-up.
DR. BINGHAM: Perfect. And how do you counsel these patients what are some potential post-op complications to donating a kidney? [Dr. Kashyap] So commonly for them GI issues, getting constipation, there can be some bleeding complications or respiratory distress, and then the standard complications that are related to surgery and anesthesia.
DR. BINGHAM: Great. Okay. So that's a quick run through of living donors. So let's move on to that next category, which is donation after brain death. First off, Kevin, this is something you might run into when you're on, let's say, your trauma rotation, but what are the diagnostic criteria for brain death? How do you pronounce somebody brain dead?
DR. KNIERY: Okay. So the diagnostic criteria for brain death. So you need clinical or neuroimaging evidence of a CNS or central nervous system catastrophe. The biggest thing is you have to exclude complicating medical conditions. They can't have any drug intoxication, they have to be normothermic with a blood pressure systolic over a hundred. On a neuro exam, you'd have an absent motor response, an absent pupillary light reflex, no corneal reflex.
DR. KNIERY: You have to check the ocular vestibular reflex, known as doll eye, a jaw jerk test, they can't have a gag, cough with tracheal suctioning, or the sucking and rooting reflexes. And they have to be apneic.
DR. BINGHAM: Yeah, so they do talk about the apneic test. So yeah, absence of all, basically, your brainstem reflexes and then a positive apneic test. So let's say now you have somebody who's brain dead, and you're trying to get them to transplants. That can oftentimes be very difficult because these patients a lot of times are very physiologically unstable. Meghana, what are the common physiologic disturbances seen in brain dead individuals that need to be aggressively managed as you're trying to bridge them to transplant?
DR. BINGHAM: [Dr. Kashyap] So they obviously need to maintain their tissue perfusion so that their organs are retrievable and usable. They can get hypernatremia, so correcting that hypernatremia is important. If they develop diabetes insipidus, that needs to be treated. Of course, maintaining their oxygenation and ventilation, if you need to provide inotropic support, that may be necessary.
DR. BINGHAM: And then preventing hypothermia, which is all again, to maintain the organs until retrieval.
DR. BINGHAM: Yeah, I mean, you think the patient's brain dead but it actually becomes very labor intensive just to keep them in a physiologic homeostasis to where they'll be eligible to donate, and getting them to that transplant can be very difficult. Okay, so we talked about our living donor. We talked about our donation after brain death. Now we're going to move on to that third category called the donation after circulatory determination of death.
DR. BINGHAM: So Kevin, what are the criteria for donation after circulatory determination of death?
DR. KNIERY: Yes, this is a little more complicated. These are patients that have no hope of full recovery, many times a massive stroke, cardiac arrest, multiple trauma, and the decision is made to withdraw life support. And so they're expected to expire within 60 minutes of withdrawing this life support. Procurement can start two minutes after the patient is dead, but if the patient doesn't expire after the removal of that support within 60 minutes, they're no longer an organ donor.
DR. BINGHAM: Okay. Well, how about outcomes? What do you know about outcomes after donation after brain death versus the donation after circulatory determination of death?
DR. KNIERY: Yeah, interestingly for kidneys, donors after circulatory death have equivalent outcomes to brain death donors, but for livers, they've shown that donors after circulatory death have a higher incidence of biliary complications.
DR. BINGHAM: Great. Okay, Meghana, so now we're ready to go forward to transplants. So what's important in the workup of the donor and the recipients for transplant? [Dr. Kashyap] So they get an extensive workup in order to make sure that they match and to prevent rejection. So the first thing is performing the crossmatch, which is looking for pre-formed antibodies against the new organ.
DR. BINGHAM: This is done by mixing the serum of the recipient with donor lymphocytes. If that's positive, they are at risk for hyperacute rejection, which we'll talk about later. And then if their crossmatch is okay, I guess, Jason, throw it back to you, how would you test for HLA mismatch?
DR. BINGHAM: Okay, so for HLA mismatch you need a panel of reactive antibody performed against recipients antibodies for HLA, and you get the PRA. So if the PRA is greater than 50%, that's a contraindication to transplant. So PRA greater than 50%, contraindication to transplant. Things that can increase this are transfusions, pregnancy, previous transplants, autoimmune diseases, and currently plasmapheresis is being investigated as a way to treat sensitized individuals prior to transplant.
DR. KNIERY: And I think this topic that we're discussing right here is a guaranteed question. And specifically I've seen on question banks and the tests, "How do you perform a crossmatch?" And so it's really important to know that you mix the serum of the recipient with the donor lymphocytes. And I think that's a very common question.
DR. BINGHAM: Yeah. That shows up pretty often, as well as the different types of rejection. Those are very testable things, so be sure you have those down. Those are easy points to miss. So okay, let's move on to liver transplantation. So when we talk about liver transplantation, we spent a lot of time talking about MELD score. So Kevin, what are the components of a MELD score? And what's the minimum score you need to be considered for liver transplantation?
DR. KNIERY: So its components are INR, bilirubin and creatinine. 15 is the minimum score. And then you refer to a hepatologist to get them kind of on the transplant list once they hit a MELD of around 10.
DR. BINGHAM: Right, so 15 is the number, a very important number that qualifies you for transplant, that's been shown at that number, your survival is better with transplant. So there are some exceptions, however, that will just automatically give you a score of 22. And Meghana, what is that exception? [Dr. Kashyap] So the exceptions that give you an automatic score of 22 are hepatocellular carcinoma within the Milan criteria, hilar cholangiocarcinoma, hepatic artery thrombosis, and hepatopulmonary syndrome.
DR. BINGHAM: Okay, you mentioned the Milan criteria. What is that exactly? What's the Milan criteria? [Dr. Kashyap] So that's where people with hepatocellular carcinoma, if they have one lesion between two to five centimeters, two to three lesions that are less than three centimeters or no vascular invasion, they meet the criteria to get a hepatic transplant. And so they get their score of 22.
DR. BINGHAM: Okay. I'm just going to repeat all this, to go over this all real quick again, because this is all highly testable things. So MELD score, made up of the PT/INR, bilirubin, creatinine. 15 is that number, that's the cutoff for transplantation, although there are some exceptions. So hepatocellular carcinoma with Milan criteria, hilar cholangiocarcinoma, hepatic artery thrombosis, and hepatopulmonary syndrome. With the Milan criteria being one lesion between two and five, two to three lesions less than three and no vascular invasion.
DR. BINGHAM: Perfect. Contraindications to liver transplantation, Kevin.
DR. KNIERY: So, this is a big surgery they're going to undergo, so they have to be somewhat stable. So if they have insufficient cardiopulmonary stability, if they have active sepsis, if they have an uncontrolled extrahepatic malignancy, if they're still abusing substances such as alcohol, if they have a lack of social support or a recent intracranial hemorrhage.
DR. BINGHAM: What about hepatitis?
DR. KNIERY: So hepatitis is not a contraindication. Generally hep C is known to reinfect the new liver allograft but with new medications that can be controlled. And then hep B, you can give the hepatitis B immunoglobulin and lamivudine to prevent reinfection.
DR. BINGHAM: Okay. So let's talk about complications after liver transplantation. So what are some complications that require going back to the operating room?
DR. KNIERY: So going back to the operating room, if it's a primary non-function, the risks for this is a patient who has a kind of fatty liver or macro steatosis is a risk factor for this.
DR. BINGHAM: Okay, that's very nice. I've seen that question, just to stop you real quick, I've seen that question happen a lot. So what is a predictor or risk factor for primary non-function and the answer is macro steatosis. That shows up pretty commonly. Sorry to interrupt, but go ahead, other complications requiring take back to the operating room after liver transplant.
DR. KNIERY: So the post-op hemorrhage is an obvious complication, hepatic artery stenosis can generally be treated with a stent, but can potentially need a revision of the anastomosis. And then one of the most dreaded complications is the hepatic artery thrombosis.
DR. BINGHAM: And what do you do for that?
DR. KNIERY: So if it's early hepatic artery thrombosis, you can fix it, if it's identified early. But many times these patients need to be emergently retransplanted.
DR. BINGHAM: Okay. And what about if it's late?
DR. KNIERY: If it's late, generally they'll kind of show up with biliary strictures and abscesses due to the lack of blood flow. And so then you can potentially attempt endovascular management of this versus potential retransplant. [Dr. Kashyap] And that's one where I've seen--
DR. BINGHAM: Okay, so--
DR. BINGHAM: [Dr. Kashyap] Sorry, I've seen multiple questions about a patient presenting after hepatic transplant with an abscess and they want you to draw that connection between hepatic artery thrombosis and abscess formation.
DR. BINGHAM: Absolutely, absolutely. Okay. There's a few more other complications out there, Kevin?
DR. KNIERY: Yeah, so you can have portal vein stenosis or thrombosis. This will generally present early, if it does present early, it'll present with abdominal pain, late, these patients may have upper GI bleed, ascites, that's another effect of this portal vein thrombosis. The treatment for this if it's early, you should do a thrombectomy and revise the anastomosis.
DR. BINGHAM: Okay.
DR. KNIERY: And then, okay. So you can have an IVC stenosis or thrombosis from reimplanting liver on that, and that can lead to edema, ascites, renal insufficiency. The treatment for this generally is if it's far enough out from surgery, potentially thrombolytics, anticoagulation and potentially an IVC stent, and then you can have early allograft dysfunction in these liver transplants.
DR. BINGHAM: Okay. Yeah, so those are all the complications that may require return to the operating room. And then there is still some more complications that can generally be managed non-operatively. Kevin, we're going to stick with you. What are we talking about with those?
DR. KNIERY: So the bile leak is the most common complication, and generally this can be managed with placing a percutaneous drain and stent open with an ERCP.
DR. BINGHAM: Okay.
DR. KNIERY: And then cholangitis
DR. KNIERY: is a kind of subsequent complication and these you can treat with antibiotics.
DR. BINGHAM: Yeah, and as Meghana said, the way these typically show up in a Board or a testing scenario, is they'll give you the complication or they'll give you how the patient's presenting. And they'll ask you what the underlying complication is. Generally, what they're going for is either the hepatic artery thrombosis, the early versus late, as Meghana has said, the patients shows up with abscess, so they're asking you what's going on.
DR. BINGHAM: Another common one is that bile leak or stricture. So a lot of these questions just have to do with they give you a patient that's post-transplant and they're having a problem, and they're asking you what the underlying physiology is. Okay. So let's move on out of liver transplant and we'll move on to renal transplant. So Meghana, with renal transplants, how are these, technically, how are they done?
DR. BINGHAM: [Dr. Kashyap] So these are most commonly done through a retroperitoneal approach, where you attach the donor kidney to the iliac vessels of the recipient.
DR. BINGHAM: Yeah, so you're putting them in the pelvis, you're reattaching them to the iliac vessels. How about some technical nuances, some technical complications that can occur? What are the most common? [Dr. Kashyap] So, I kind was thinking parallel to the liver. You can get renal artery and vein thromboses. So these you would want to diagnose by an ultrasound immediately when you have suspicion. And sometimes you may see proteinuria, which would be an indication of a renal vein thrombosis.
DR. BINGHAM: And then you want to treat this with a PTA and stent.
DR. BINGHAM: Okay. [Dr. Kashyap] You can also get ureteral stenosis and leak from that anastomosis. And urine leak is actually the most common complication after kidney transplant. And the treatment for this is a percutaneous drain and ureteral stenting. And then there's one other complication, which is a lymphocele. Which usually presents as external compression of the ureter.
DR. BINGHAM: This most commonly occurs three weeks after transplant showing up with decreased urine output, hydronephrosis and fluid collection due to that external compression. And this can also be treated with percutaneous drainage, but sometimes that fails and you need to create a peritoneal window to allow drainage.
DR. BINGHAM: Great, okay. You touched on this a little bit, but common complications in the post-op period after a renal transplant? [Dr. Kashyap] So you can see oliguria due to acute tubular necrosis. There may be excessive diuresis due to urea and glucose. And then some patients may develop diabetes due to the immunosuppressive medications that are used for the renal transplant.
DR. BINGHAM: So Kevin, the way I see this show up a lot of times on the ABSITE and the Boards is they'll give you a patient that's post-op from a real transplant and they're not making urine. And a lot of times they'll ask you, "What's the best next step for evaluation?" So what do you think? Somebody who's in an early post-op period, not making urine from renal transplant? What do you want to do?
DR. KNIERY: This is a STAT ultrasound. This can tell you both, if the artery is open, if the vein is open or if there's some sort of leak or a hydronephrosis presenting.
DR. BINGHAM: Yeah, so yeah. Renal ultrasound gives you a lot of information. So again, you can evaluate that renal artery or vein for thrombosis, you can look for urinoma, or you can look for lymphocele, that's maybe causing some compression. So generally that's what they're looking for with that next best step. Okay. So we've covered liver, we've covered kidney, we're going to cover one that you may not have as much familiarity with or see as much, at least I didn't in residency, and that's the pancreas transplant.
DR. BINGHAM: So Meghana, who is a candidate for pancreas transplantation? [Dr. Kashyap] So most commonly the people who get pancreas transplantation are those with diabetes with renal failure.
DR. BINGHAM: Okay. Diabetes with renal failure, perfect. There's three different kinds of pancreas transplants, what's are those, Meghana? [Dr. Kashyap] So you can do a pancreas transplant alone, you can do a pancreas transplant after kidney transplant, or you can do the simultaneous kidney and pancreas.
DR. BINGHAM: Right. Exactly. Kevin, you're a vascular surgeon, what are the arteries and veins you need for a pancreas transplant?
DR. KNIERY: So you need the donor celiac artery, and you also need the SMA for the arterial supply to implant into the patient. And you also need the donor portal vein for drainage.
DR. BINGHAM: Perfect, so you need a donor celiac, SMA and portal vein. What are the different operative methods, Kevin?
DR. KNIERY: So they have a couple different ways of implanting these. They can do enteric drained where the pancreas is anastomosed to bowel where the pancreas is anastomosed to bowel and that is how you get the pancreatic enzymes. Or you can do bladder drained, where they plug the pancreas directly into the bladder. And then you can also do a venous drained or portal drainage.
DR. BINGHAM: Well, what's the most common?
DR. KNIERY: Systemic drainage is the most common, but the portal vein drainage has not shown any advantage.
DR. BINGHAM: Yeah, so most common, systemic venous drainage is what happens here with these pancreas transplants. Okay, Kevin, you mentioned enteric versus bladder drains. What's the most common there? And what's the advantage of that?
DR. KNIERY: So most anastomose to the small bowel versus the bladder, the advantage of draining to the bladder is the ability to monitor the amylase in the urine. But this has long-term complications of strictures and leaks.
DR. BINGHAM: Perfect. Okay. Meghana, talk about what are the different comorbidities associated with the diabetes that can be ameliorated after a pancreas transplantation? [Dr. Kashyap] So a lot of comorbidities with diabetes and renal failure, so retinopathy, it may not be reversed or improve, but it'll at least stabilize after pancreas transplant.
DR. BINGHAM: The neuropathy will stabilize and can even improve, pancreas transplant also protects kidney transplants from recurrent diabetic nephropathy so it's renal protective, and patients consistently have a benefit in quality of life. The one thing that is not going to get better is the vascular disease, which continues to progress.
DR. BINGHAM: Okay, great. Complications, Meghana? [Dr. Kashyap] So you can get allograft venous thrombosis, which is very difficult to treat and then rejection, and in pancreas transplant rejection, you'll see increased glucose or amylase, fever, leukocytosis, and it tends to be hard to diagnose if the patient does not have a simultaneous kidney transplant.
DR. BINGHAM: Okay. And is there a mortality benefit for pancreas transplants or is it purely the quality of life? [Dr. Kashyap] So the benefit in mortality is when they also have a kidney transplant, because the benefit is actually from the kidney transplant.
DR. BINGHAM: Yep, yep, so the benefit of mortality is from the kidney transplant. Again, just to rehash those comorbidities, so, it'll stabilize retinopathy, it'll stabilize your neuropathy, potentially improve your neuropathy. The real advantage here though is that it protects the kidney transplant from recurrent diabetic nephropathy. And again, your vascular disease is going to progress.
DR. BINGHAM: Okay, so we've covered liver, we've covered kidney, we've covered pancreas. Now let's go on to talk about immunosuppression. And of all transplant this is probably the most highly tested and highest yield. So Meghana, when we talk about rejection, what cell lines are responsible for each type of rejection? What's the treatment?
DR. BINGHAM: Let's start with hyperacute, so hyperacute rejection. Tell us a little bit about that. [Dr. Kashyap] This is something I have to review every year for ABSITE. I spend a lot of time on it. So hyperacute rejection occurs within minutes to hours, and this is due to that ABO mismatch. So it's the pre-formed antibodies against the donor lymphocytes, which is also a type II hypersensitivity reaction.
DR. BINGHAM: Exactly. So let's say this happens, what do you see intraoperatively? Let's say, if we're doing a kidney transplant and they have a hyperacute rejection. How's that going to present in the OR? [Dr. Kashyap] So you would see the organ immediately becoming muddled, it'll turn purple, become soft. And then in the kidney transplant, it would demonstrate decreased urine output.
DR. BINGHAM: And what do you do? What's the treatment? [Dr. Kashyap] You have to retransplant them, unfortunately.
DR. BINGHAM: Yeah. Unfortunately, retransplantation. So again, these are very high yield, very highly testable. Hyperacute, minutes to hours, it's from an ABO mismatch. Again, it's pre-formed antibodies from lymphocytes and it's a type II hypersensitivity reaction. It presents intraoperatively muddled, purple organ, need to retransplant. Okay. Kevin, acute rejection. How does that present?
DR. KNIERY: So acute rejection, this occurs a little more delayed. This is weeks to about one month out from surgery. And this is from cytotoxic helper T cells.
DR. BINGHAM: Okay. How about in the kidney? How does acute rejection present?
DR. KNIERY: So generally, the creatinine will rise, approximately one month after the transplant, but your ultrasound will show a normal duplex. It'll have normal inflow and outflow and no lymphocele, but you'll end up getting a biopsy of the kidney and that'll show tubulitis, and these patients will generally have decreased urine output.
DR. BINGHAM: Okay. And the patients will also kind of note some tenderness from the graft side, they may have some fevers, and generalized feelings of just feeling unwell and malaise. And you'll see again, as you kind of mentioned elevated serum creatinine and leukocytosis can also be seen. Okay. How about acute rejection with a liver? Tell me a little bit about that.
DR. KNIERY: So once again, this is T cell mediated and these T cells are attacking the blood vessels in the liver. So these patients will present with the same kind of fever. They may have jaundice, they may have decreased bile output. And then with your lab, you're going to see leukocytosis, you're going to see eosinophilia, increased LFTs and total bilirubin along with increased PT or INR. And then on the path for this, once you get your liver biopsy, you'll show portal triad lymphocytosis, and then endotheliitis and then bile duct injury.
DR. BINGHAM: Okay. And how do you treat these patients?
DR. KNIERY: So both for kidneys and livers, acute rejection, which is weeks to month after, you're going to increase immunosuppression. Generally, kind of steroids.
DR. BINGHAM: Okay. Again, so acute rejection weeks to month, it's T cell mediated, we went over a little bit of what you could see in a kidney and a liver. The treatment is increased immunosuppression with the addition of steroids. Okay. Meghana, so chronic rejection? How does that present and what is that mediated by? [Dr. Kashyap] Chronic rejection occurs months to years post-transplantation.
DR. BINGHAM: This is mediated by both the B and T cells. And this eventually leads to graft failure. It is a type IV hypersensitivity reaction.
DR. BINGHAM: Great. So months to years, B and T cell, graft failure, type IV hypersensitivity reaction. What do we see with these various organ? So how does it present after a liver transplant? [Dr. Kashyap] So this is a common question too, where the patient has disappearing, vanishing bile ducts. You can also see an increase in their alk phos and portal fibrosis.
DR. BINGHAM: Yeah, exactly, those disappearing bile ducts. Okay. How about lung? There's a very kind of a-- I'm not going to say pathognomonic, but at least, in the test taking it is. How does this present after lung transplants, especially on Board exams? [Dr. Kashyap] Yeah, so the words to remember bronchiolitis obliterans.
DR. BINGHAM: Yeah, exactly. Bronchiolitis obliterans after lung transplant, chronic rejection. Treatment? [Dr. Kashyap] So again, you would increase their immunosuppression, but because this has been chronic, they will eventually need a retransplantation.
DR. BINGHAM: Okay. And then there's something called chronic allograft vasculopathy. Kevin, again, this is a vascular thing, so we're going back to you, tell us about that.
DR. KNIERY: So this would be a chronic rejection of the blood vessels resulting in fibrosis. Most commonly, it is seen in cardiac transplant patients and the treatment for this is steroids and eventually retransplant.
DR. BINGHAM: So let's talk about our natural killer cells. So how do these work? They identify cells by expression of what? [Dr. Kashyap] So natural killer cells. They use the major histocompatibility complexes. So MHC class I, it's present on all of the nucleated cells and the binding of the CD8 T cell receptors and the binding of the CD8 T cell receptors to MHC class I triggers the APC to undergo death via cell apoptosis.
DR. BINGHAM: So this is why natural killer cells are associated with cell death.
DR. BINGHAM: Perfect. So CD8 T cells receptor to the MHC class I and death via apoptosis, I've seen that actually, "What is the mechanism of death after this interaction?" It's apoptosis. So natural killer cells are actually inhibited by MHC class I, so if a cell does not express that, it will be destroyed by the natural killer cells. So this is your innate immunity. So Kevin, we're talking about MHC class I, what are the three MHC class I expressions?
DR. KNIERY: So you have HLA-A, HLA-B and HLA-C.
DR. BINGHAM: What's an easy way of remembering that?
DR. KNIERY: So one letter for MHC class I versus two letters for class II.
DR. BINGHAM: Okay. So keep going with that, so MHC class II, what are these? Where are they located?
DR. KNIERY: So these are the antigen presenting cells. This complex presents antigens to the helper T cells that express the CD4 receptor. So binding of the CD4 receptor to the MHC II complexes, primes the naive helper T cells and polarizes a cell to become either a memory T cell or an effector T cell.
DR. BINGHAM: Great. Another way I kind of remember that interaction is when you multiply those numbers, it should add up to eight. So MHC class II with CD4, two times four is eight, MHC class I with CD8, one times eight equals eight. Maybe that helps you, maybe that doesn't, but it helps me. So antigen presenting cells, what do they do? And where do they come from?
DR. KNIERY: So these bring phagocytized material to the thymus and lymphocytes to assist in cell-mediated immunity.
DR. BINGHAM: Okay. So we talked about MHC class I being HLA-A, B and C. What is MHC class II? What are those HLAs?
DR. KNIERY: So it's HLA-DP, DQ and DR.
DR. BINGHAM: Okay. So the question may say something like, "Which of these MHC class II molecules--?" and you'll see the two letter HLA, and these are the most important for matching a donor and recipient. Okay. Moving on into immunosuppressive drugs. Again another very high yield topic that everybody always has to review prior to the ABSITE. So what are the three classes of drugs to prevent rejection, Meghana?
DR. BINGHAM: [Dr. Kashyap] The three classes are the induction agents, the antiproliferatives and then the calcineurin inhibitors. the antiproliferatives and then the calcineurin inhibitors.
DR. BINGHAM: Okay. So tell us a little bit first off about those induction medications, when are they used, and what are the more common induction medications? [Dr. Kashyap] So the induction agents are used immediately postoperatively to prime the patient. In some of the induction regimens, they actually also deplete T cells, and the medications for that are monoclonal antibodies that bind to the IL-2 receptor of the T cells to impair their proliferation, so that is, and pardon my pronunciation, daclizumab and basiliximab.
DR. BINGHAM: So those are the T cell depleting induction agents. So those are the T cell depleting induction agents. And then in addition, patients are typically given steroids for induction and remember that steroids inhibit IL-1, IL-6 and macrophages. Steroids are also used throughout transplantation, both induction maintenance and for rejection, as we described.
DR. BINGHAM: And then the other one used is anti-thymocyte globulin. You may have heard this as thymoglobulin, which is a rabbit polyclonal antibody against the T cell antigens or the ATGAM or Atgam, which is an equine polyclonal antibody. And these are against T cell CD2, CD3 and CD4. So thymoglobulin is used as an induction agent, and it can also be used for acute rejection.
DR. BINGHAM: Excellent. So yeah, those are your induction agents, so you have your monoclonal antibodies, which you pronounce beautifully, I'm not going to even try to repeat those. I have trouble with those. Your steroids, and then your anti-thymocyte globulin. Again, we're talking a new class of induction agents. Kevin, so the next class is antiproliferative. What are our antiproliferative drugs?
DR. BINGHAM: How do they work? What are the side effects? Go.
DR. KNIERY: So mycophenolate and azathioprine are the main antiproliferative medications. So for mycophenolate also known as MMF or CellCept, it inhibits de novo purine synthesis, which inhibits growth of T cells. There can be many side effects of this. The main one with mycophenolate is GI intolerance, and then you can have myelosuppression and then you can also have CMV infections. But this is a good maintenance therapy.
DR. KNIERY: And then for azathioprine the mechanism is also, it's a purine antagonist and that's how it works.
DR. BINGHAM: Yeah. So anti-proliferative, the CellCept or mycophenolate inhibits de novo purine synthesis, and then azathioprine is purine antagonist, as Kevin mentions. Side effect, most common is a GI intolerance. Okay. Meghana, moving back to that third class, those calcineurin inhibitors. What are our different calcineurin inhibitors and how do they work?
DR. BINGHAM: [Dr. Kashyap] I feel like I see these questions most commonly for the immunosuppressives. So there is cyclosporine, tacrolimus and sirolimus. Cyclosporine binds to the cyclophilin protein, that then goes and inhibits calcineurin, which causes a decrease in IL-2 and IL-4. This is also used as a maintenance immunosuppressive, but the big thing is the adverse reactions. It causes nephrotoxicity, hepatotoxicity, you get tremors, seizures, and you can even get hemolytic uremic syndrome.
DR. BINGHAM: And then importantly, this is metabolized in the hepatic system and excreted in the bile.
DR. BINGHAM: Yeah. So Kevin, cyclosporine, hepatic metabolism, biliary excretion, how does this show up on the test?
DR. KNIERY: So generally this would be a kidney transplant patient who presents an acute renal failure after getting a common bile duct exploration with a T-tube. And so their cyclosporine is being drained through the T-tube into their bag, their T-tube bag. And so they're not getting their immunosuppression.
DR. BINGHAM: Exactly. And that's exactly how this shows up. It's a classic question. And they'll give you somebody who had a kidney transplant previously, and now they've had a T-tube placed. They won't even tell you what immunosuppressive they're on. They'll either ask you what's going on or they'll ask you what medication were they on? And so it's cyclosporine and it's because of that hepatic metabolism and the biliary excretion.
DR. BINGHAM: Okay. Sorry, Meghana, I interrupted you. So that's cyclosporine, a calcineurin inhibitor. You mentioned a couple of other ones in there. How do they work? [Dr. Kashyap] So tacrolimus or FK506 or Prograf, this binds the FK binding protein, which then again goes to inhibit the calcineurin protein. And again, inhibits IL-2, IL-4 and interferon gamma. The side effects of this drug is nephrotoxicity, GI symptoms, you can get mood changes or diabetes.
DR. BINGHAM: And then sirolimus or rapamycin, it binds the FK binding protein, which then goes and inhibits mTOR, which blocks IL-2. Importantly with this, it's not nephrotoxic as versus cyclosporine and tacrolimus, but the side effect of this drug is interstitial lung disease.
DR. BINGHAM: Perfect, okay. So those are your calcineurin inhibitors. So let's move on to infectious complications after transplant. Kevin, what are the most common infections?
DR. KNIERY: So CMV, the BK virus and then PCP, or pneumocystis carinii pneumonia.
DR. BINGHAM: Okay. Respectively, how do those three different things present?
DR. KNIERY: So CMV, the patients can have flu like symptoms, they can have hepatitis, nephritis, lymphadenitis, leukopenia, and they may also have pneumonitis and GI symptoms, such as gastritis, colitis, esophagitis or bleeding peptic ulcers.
DR. BINGHAM: Okay.
DR. KNIERY: And then for the BK seen after renal transplant, they can present with ureteral stenosis and obstruction, and they can also have tubulointerstitial nephritis, and a rise in their serum creatinine. And then for the PCP pneumonia, they have hypoxia, dyspnea and coughing. The chest X-ray usually is normal, but CT will show diffuse interstitial infiltrates and nodular infiltrates.
DR. BINGHAM: So how do we prevent these? What are typical prophylaxis regimens given for these different pathogens? given for these different pathogens?
DR. KNIERY: So for PCP, they're on Bactrim daily for four to six months post-transplant, or lifelong in some circumstances. For CMV, if they underwent a T cell depletion during induction, they're going to be on six months of an antiviral. If no T cell depletion, they can be on just three months of an antiviral. And then to prevent mucocutaneous candida, sometimes they're on oral clotrimazole or nystatin b.i.d..
DR. BINGHAM: Perfect. Okay. So those are your typical prophylaxis that you give post-transplant to prevent some of those common post-transplant infections. So let's talk about some long-term-- So we're going to stay with the theme of postoperative long-term complications. So Meghana, we touched on this earlier actually, but first step in evaluating post-operative kidney and liver dysfunction, what are you looking for with each of them?
DR. BINGHAM: So what's the first step? We mentioned it before. You have somebody whose kidneys aren't working or the liver is not working, post-op from a transplant. [Dr. Kashyap] Yeah, so you want to get that ultrasound, always remember to get the ultrasound as your first step, because in the kidney, like Kevin had mentioned, you can identify the arterial and venous flow, you can identify any fluid collections, like a lymphocele or a urine leak, and hydronephrosis of the kidney.
DR. BINGHAM: Similarly in the liver, you can assess the portal venous flow, the hepatic arterial flow, hepatic venous flow, the patency of the IVC and look for any intraductal biliary dilation.
DR. BINGHAM: Great. Yeah, exactly. So ultrasound is extremely useful in post kidney and post liver transplants, to kind of sort out what exactly is going on. Okay, Kevin, how about delayed graft function? How does this present after kidney, liver, and pancreas transplant? Delayed graft function in these different organs, how does it present?
DR. KNIERY: Yeah, for the kidney they'll generally present with oliguria or requirement for dialysis within the first week after transplant. And then for the liver, you'll see AST and ALT increasing, generally greater than 1,500 within 72 hours after the transplant. And then for primary non-function, in the first 24 hours where the biliary is greater than 10, and the bile output decreases to less than 20 cc's per 12 hours, or they've increased INR PTT.
DR. KNIERY: And then after 96 hours, they can actually get altered mental status, even further increase in the LFT, renal failure, respiratory failure.
DR. BINGHAM: And those patients are all headed towards what?
DR. KNIERY: Retransplant.
DR. BINGHAM: Yeah, those patients are all headed toward retransplant, okay. Pancreas?
DR. KNIERY: For pancreas, they're going to have high insulin requirements within the first week after transplant.
DR. BINGHAM: Okay. Meghana, what's the best test to follow in a liver transplant patient to determine the synthetic function of the liver long-term? [Dr. Kashyap] That's going to be your PT or INR. It's the most helpful for liver function. LFTs is a misnomer, so these liver function tests don't actually - so AST, ALT they don't actually test the synthetic function of the liver. So it's more of a marker of inflammation or cell death.
DR. BINGHAM: Exactly. So yeah, your liver function tests are not actually your liver function tests. For your function you want to go to your INR or PT. Your PTT and albumin are also helpful. And, you know, bilirubin has too many extrinsic factors to really rely upon as a determinant of liver function, so INR, PT, maybe PTT, maybe albumin to test that synthetic function of your liver. Kevin, what is post-transplant lymphoproliferative disorder, or PTLD?
DR. KNIERY: So this is related to the Epstein-Barr virus. These patients can present with a small bowel obstruction or mass or adenopathy. And the risk factors for this are some of the immunosuppression that they're on. So if they're on a cytolytic drugs, such as thymoglobulin, this puts them at higher risk for these Epstein-Barr virus-related problems. You treat this with further immunossupp-- I'm sorry... You treat this with withdrawal of immunosuppression.
DR. KNIERY: And maybe switching them over to something like rituximab and they may need chemo XRT, if it is an aggressive form.
DR. BINGHAM: Perfect. Okay. So that's our general overview of a transplant. Let's move on. We'll finish up with our, as always, with our quick hits. So Kevin, number one malignancy following any transplant? Common question.
DR. KNIERY: Squamous cell skin cancer.
DR. BINGHAM: Yeah, following any transplant, number one malignancy is squamous cell skin cancer. Meghana, most common cause of mortality after kidney transplant? [Dr. Kashyap] It's MI.
DR. BINGHAM: Yeah, MI. Mortality after kidney transplant, most common. Kevin, most common reason for indication for liver transplants in adults?
DR. KNIERY: Hepatitis C.
DR. BINGHAM: Great. Meghana, who has power of attorney of a brain dead patient who has no designated POA, but has a girlfriend, sister and mother at the hospital, all waiting to make decisions. [Dr. Kashyap] So the power of attorney in that situation is going to be the mother. So the order of this is the spouse, but in this situation there was no spouse, an adult child, also not presented in this situation, next up would be either parent, and then finally is an adult sibling.
DR. BINGHAM: Yeah. And it's important to note that always allow the procurement agency to make contact to have these discussions. I've seen this question, as irritating as it is, this question does show up on the Boards. So you kind of do have to know that hierarchy and that's exactly how they'll give it. You have a number of different people, you have a girlfriend, you have a cousin, you have a sister, you have an adult child there, who's able to make that decision.
DR. BINGHAM: And I've even seen the question like who should have that initial conversation? The physician, the nurse, the procurement agency? So those are simple questions to miss, so to speak. Make sure you know that stuff. Again, so that's transplants, it's a small proportion of the ABSITE, it's about 2%. But generally the questions are pretty straightforward. And if you have a general understanding of some of this transplant, particularly the drugs, the side effects, and the post-op complications, the side effects, and the post-op complications, you'll be able to pick up those extra 2% and that'll be the difference between your 80th percentile and your 98th percentile.
DR. BINGHAM: So it's a small proportion, but important. So I hope everybody's studying is going well. So good luck and dominate the ABSITE.