Welcome to this module of the MCCRC adult course, Complications of Solid Organ Transplantation. My name is Luke Kaplan. I am a surgical intensivist at the University of Pennsylvania and its affiliated VA Medical Center. These are my disclosures, none of which are financial in nature. You can decide based upon my editorial board commitments whether I have reasonably selected evidence throughout this particular presentation. As a part-time VHA employee, my views are independent, as are my statements. The government disavows all knowledge or endorsement of anything I have to say. These are our objectives. We'll talk about common complications of organ transplantation and then spend some time specifically looking at hepatic and renal transplantation. Some of the domains that will be important to explore will be issues around technical performance of the transplant, infection and medication-related issues, as well as the management of acute rejection in any form it happens to take. So organ diagnostic common complications are those that are relevant for those of us who work within transplant ICUs, either regularly or periodically, because you may also encounter pancreas or pulmonary or cardiac transplants. And these kinds of common complications are shared across all of those different kinds of solid organ transplants. So we think about what is common. It is infection, both early and late, and there are different kinds of organisms that are typically implicated in early versus late infections, and we'll delve into those more deeply. Graft failure may be acute in the operating room, which is quite unique, but most commonly it is not that, but it is early within the post-transplant period, as opposed to more chronic graft failure, which may be related to rejection, but also may be related to organ failure that is related to disease recurrence. There are other organs that may be acutely injured during the transplant process, and of course there is the unique entity of graft-versus-host disease. These are not uncommon, they are typically late, and two stand out. One is induced diabetes and the other is persistent hyperparathyroidism after renal transplantation. There is a plethora of pharmacologic issues to address, drug-drug interactions, toxicity from the immune suppressives, and of course, further out, the induction of de novo malignancy that is uniquely related to the immune suppressive agents. The recognition of those common complications has identified two broad areas where there is targeted work to help prevent complications. One is immune-related, which typically takes the form of critical sensitization to human antibodies, antibody-mediated rejection, and the development of anti-HLA antibodies, a process that is markedly improved with advanced screening techniques. Other common areas are primary organ disease that may recur in the transplanted organ, coronary disease, which is quite common, infection, and then de novo malignancy. Much of what happens with organs that have been transplanted has been related to abnormalities of the endothelium and what has been termed endotheliopathy. When you look at the underlying causes for endotheliopathy, they're different from the endotheliopathy that follows in the wake of injury. Here, there are endothelium antigen-specific antibodies that are either alloantibodies or induced autoantibodies, and the latter in particular is the subject of intense research to reduce the frequency with which you develop endothelial autoantibodies after a solid organ transplantation. This does parallel some work around brain injury to reduce the incidence of autoantibodies to your cerebral parenchyma and unique cells that live within the CNS. So this kind of work is not unique to solid organ transplantation. This is a look at cardiovascular disease following the wake of renal transplantation. If you look all the way on the left, this is any cardiovascular disease, and this is the percent of people who have that particular issue. It's over 40%. If you break it down in terms of what they have, clearly coronary disease and peripheral arterial disease and heart failure and atrial fibrillation dominate. This is part of the surveillance approach for those who have had prior solid organ transplantation. This is just one example from those that have had renal transplant. Some of the issues that we're dealing with are related to the particular kinds of immune suppressive agents. What you have before you here is a timeline of how we have achieved immune suppression. In the pre-1950s, there was a radiation, and you can see the development of different kinds of agents in a very long span where azathioprine and steroids were really the only immune suppressives. After the early 1980s, there's been an explosive growth of different kinds of agents, and you may see the agents that are common in your center listed to the right of your screen. Far and away for the two organs that we take care of most commonly, those with kidney and liver transplants, you can see tacrolimus and mycophenolate with steroids predominates for both of them. You will see there are a variety of regimens that don't always have steroids, and this is one of the approaches to reduce immune suppression as organs are more tolerated. This is not organ tolerance. That's a different process, but the amount of immune response to the non-native organ may in fact wane over time and not need as intense immune suppression. Each of the agents that you see are aligned with a particular pathway, and you can see agents in blocks you can see in green, tacrolimus and cyclosporine, and the particular pathway that each of them addresses. You'll see here moving counterclockwise antithymocyte, golybulin, glucocorticoids, a variety of antimetabolites, sirulimus and everolimus. So each of them have a unique pathway, and the blockade of those pathways leads to a variety of potential problems down the line with sustained use, which is of course the goal to survive your transplant. One of those is the induction of de novo malignancy, and you're looking here at standardized incidence ratios compared to the general populace. If you look at all of the people that have transplanted organs and all of the cancers, there are more than two and a half times more likely to develop a de novo malignancy. In particular, squamous cell cancer is much more common, and squamous cell cancer after renal transplantation is incredibly common in almost every other person. You can see there is a lesser incidence after hepatic transplantation. So there is either something about the immune suppressive regimen or the organ or the interface of the transplanted organ with the immune suppressive regimen that leads to skin-based malignancies, and therefore patients that are status post-solid organ transplant should also have routine dermalogic surveillance. One of the other complications is post-transplant lymphoproliferative disorders, or PTLD. It has a very variable incidence, 1 to 20 percent, but mortality is quite high. It is approximately 50 percent, either due to failure of the applied therapy to manage the lymphoproliferative disorder or related to complications of chemotherapy that you will see in all of our ICUs. There is a bimodal distribution within the first or second year versus late 5 to 10 year. Most of the early cases are related to EBV, and it can be up to 80 percent of those cases. There is a well-described EVP reactivation pathway that leads to PTLD, but there is also a not well-understood pathway for it in those that are EBV negative. Just because they do not test positive for any markers of EBV does not mean that they can't have PTLD. You'll see in this schematic healthy individuals, transplant recipients, and those that have PTLD by compartment, plasma and serum, plasma-based myeloid cells, and whole blood. You'll see that most of the healthy individuals have occasional reactivation of their latently infected B cell to have a free EBV of iron. Transplant recipients have this occur as a more likely event, and it can be recovered from plasma and serum as well as whole blood. But if they have PTLD, they have a huge pool of these latently infected B cells, many of whom undergo apoptosis, and therefore the release of not only active virions, but also the epithelial DNA is vastly increased and is certainly incorporated in the cells of those that have PTLD. This offers a screening opportunity, and here's a screening pathway. You can see high-risk EBV, if they have HLA mismatch, intestines greater than lung, greater than heart, so kidney is down on that list, as is liver, extremes of age, particular drugs that they've used, versus low transplant ones. You can see as you move down the pathway if there is the need for monitoring, which is monthly in high-risk versus a more truncated kind of approach in those that are low-risk. Positivity leads to workup, and the workup is there at the bottom, which is CT scan and PET scan to detect the presence of PTLD. We mentioned diabetes earlier, and what you're looking at here is the percent of patients that have new-onset diabetes after transplant, or NODAT, based upon agents, cyclosporine, sirolimus in the middle, and tacrolimus on the right of the screen. Patients are broken down over the course of about 15 years post-transplant into those that had preoperative diabetes, they're in black, or they did not have it in orange. You can see that if you look at the cyclosporine bar, the incidence is relatively low, it's around 10% at the onset, but by year 15, it's up over 20%, there's a doubling. If you have sirolimus as your immune suppressive, there's a much more rapid uptake in those that have diabetes, and then it tends to fall off. And tacrolimus has a more delayed peak, but then after it drops, it starts to increase again by year 10. So what this means is that you can target your screen to the particular kind of agent that is being used, but you should look for this in all of the patients because it can have a fairly rapid onset, especially based upon particular kinds of immune suppressive agents. So when you look at the odds ratio of comparing tacrolimus and sirolimus to cyclosporine, you'll see that if you look at all in the bottom, odds ratios are about 1.4 to 1.75. And if you look across each of the years, sirolimus doesn't seem to have its peak until year five, but tacrolimus really seems to be much more likely to induce diabetes throughout the entirety of its course. One of the other unusual complications is neurologic. This is posterior reversible encephalopathy syndrome, or PRESS. It happens in less than 0.5% of patients, but it does not have a particular time frame. It does present with an altered mental status, seizures, visual changes, and often severe hypertension. Headache as a component is rare and helps to differentiate it from hypertensive crisis. This is by MRI. In particular, the T2 flare occipital and parietal regions are well highlighted and outlined in those that have PRESS. And the primary therapy is to stop the immune suppressive agent, and if you need to continue after this resolves, changing the agent that is being used. These are typical PRESS MRI findings, and you can see that these are T2 flare images, and you can see hyperintensity in the areas that are impacted by PRESS. There are a couple of putative mechanisms. One is the hyperperfusion approach, and that's on the left of your screen, and the right is the endothelial injury approach. Either you have hyperperfusion that exceeds the limits of autoregulation, resulting in regional specific intracranial salt and water excess, and therefore you have edema. Or you have an induced endothelial injury and a decrease in the integrity of the blood brain barrier, but it all leads to vasogenic edema and the kinds of T2 flare images that you had just seen. When you think about infection, all of these particular sites, bloodstream, lungs, urine, the CNS, we often forget about that one, and the surgical site are all subject to infection and infectious complications after solid organ transplantation. I'll call particular attention to peripheral and central nervous system infections, and you can see they're broken into three blocks. There's a wide variety of diffuse CNS infections causing either meningitis, meningoencephalitis, or encephalitis, versus fewer that cause focal and even fewer that cause peripheral nervous system infection. Now, they're not here so that you memorize all these. It's more that it drives you to think about the plethora of nervous system manifestations of infection when you're considering infection in other sites. All of these help you formulate your initial post-transplant evaluation. This is often what we are called upon to do. And the early assessment of allograft function has a variety of elements and events that drive how you begin to think about that patient. Certainly, who was the donor? How far away were they? What is the physiologic condition of the recipient? And were there any unusual intraoperative events from hypo or hypertension, massive blood loss, or issues with the organ? Donor physiology is key in terms of organ-based perfusion. Did they have concomitant infections, which you now must also treat the recipient? Organ function used to be very strictly controlled where it had to be just perfect, and now we are much more permissive. And we've changed a lot about how we procure and preserve organs for movement between the site of procurement and the site of implantation. Intraoperative elements are important, including the technical ones. Did the graft begin to function right away or not? Was there a size mismatch? A large spore, body habitus liver may create intraabdominal hypertension. And what was the allergenic exposure with component therapy transfusion if it was needed? A number of our liver transplants need no transfusion at all, and then others are still in the 80 to 100 unit overall space. When you think about how you get organs, we are most commonly acquiring organs through brain death by neurologic criteria pathways. However, donation after cardiac death is increasing. There is some ethical controversy around all of that, which we won't delve into today, but I would encourage you to read about. There is live donation from living related and living unrelated donors as well. And then some of the controversy around DCD has to do with how the organs are preserved after the donation, after the cardiac death has been determined. So normothermic regional perfusion, either abdominal or thoracobdominal, has great controversy associated with that. The preservation of that organ for transport has typically occurred with flushing the organ with a cold preservative solution like the University of Wisconsin solutions. There are others. And then packaging that organ in ice and transporting it. Increasingly, organs are being continually perfused during their transport. So this was the very typical kind of approach, cold solution flush and ice transport. And the organs would arrive in a styrofoam bucket. Increasingly, this is a device that is used for kidney transport. The kidney gets continually perfused and it's maintained at a particular temperature. You can set the temperature that you wish it to be maintained at. And therefore, this may present an organ that has less need for post-donation recovery. And it may also abrogate some of the concerns about the transport time. This is a slightly more complex solution that is being used for liver transport. And you can see this perfused liver is in fact still making bile. You can see that in the bag right at the bottom in the middle. And that green effluent is in fact reasonable quality bile. It is viscous. How did your organ get to you? Your organ might get to you by drone. There are pathways being worked out. This is one of the organs that was flown by drone as a proof of concept at the University of Maryland. This is being extended to all kinds of other organs as well. It's not surprising since we're also moving things like blood around by drones between hospitals or out to the field. So you may have your organs arrive this way in particular if you have a helipad. If you're not quite familiar with normothoracic regional perfusion, one of the things that you should be acquainted with is that after the heart stops and death is declared, you can see in the left-hand panel, the clamps that clamp off all of the major branches that would get to the brain allow the institution of what is basically a bypass circuit so that all the organs get perfused and oxygenated and they have a very, very short period of ischemia. This means that the super rapid harvest approach, quote unquote, does not need to be undertaken. This can all be done with a little bit more leisure and meticulous approach because you're not under time pressure. You can have this just as a abdominal approach and you can see the cannulation, instead of being central, is through the groin. That's on the right-hand panel. But both of these have come under lots of scrutiny and there's lots of ethical debate, so feel free to read about those. What is coming is machine learning and augmented intelligence approaches to detection of complications, to help with clinical decision making, pharmacologic interfaces, and the evaluation of radiology in the post-organ transplant patient will benefit, or at least we're assuming that it's going to benefit from ML-AI approaches in terms of nudging clinicians to be concerned about particular kinds of events. This is not to suggest that there'll be autonomy, but with all of the medications that are being used and the fact that not all organ transplant patients get all their care at an organ transplant center, this may be a benefit for those who are taking care of such patients in a non-organ transplant setting, comfortable environment. With that, let's talk about kidney transplantation. And in particular, some technical complications. If you've not seen renal transplantation, this is one example. Note that the native kidneys remain in place and the transplanted kidney is attached to the iliacs for inflow and outflow, and the ureter is directly hooked into the bladder. This can occur on either side. So this is just a diagram that shows on the right side, but you can now recognize that there are three different anastomosis, one arterial, one venous, and then one that results in urinary drainage into the bladder. Each of these can have problems with either leak or stenosis. You can have kinking of any of them. And of course, the organ, in fact, can be compressed since it's sitting in a non-native space. All these technical complications are listed here. Everything from vascular to collecting system to peritransplant collection, in particular, hematoma and urinoma are much more common. Lymphocele occurs less frequently, but is well described. And of course, you can have an organ that doesn't work particularly well for a variety of reasons. How do you surveil this for bleeding? Examine the patient. You'll be able to feel a mass if they are bleeding into that space. Ultrasound is particularly helpful. It doesn't need to be a formal radiology ultrasound, bedside evaluation looking at peritransplant hematoma and looking for it and tracking it can be done by an intensivist. Leak also has the same kinds of things. What is the exam like? Is there anything draining from the wound that looks like urine? Ultrasound is far preferred over CT in terms of reduction in radiation exposure. And it is, of course, repeatable. And then the very standard approach looking at organ-based function. Infectious complications are plethora. Donor-derived infection is not particularly common, but renal transplantation has perfectly fine outcomes if the donor is infected and has received between 24 and 48 hours of directed antibiotic therapy with clinical improvement. Post-transplantation based upon immune suppression and the abrogation of host defense generally leads to seven to 10 days of culture-directed antibiotics as well. CMV and EBV are common and ubiquitous and therefore transmission from donor to recipient is expected and therefore there's no universal prophylaxis that is practiced. Cardiovascular and pulmonary events are common. You've seen cardiovascular disease in about 80% of patients. Atrial fibrillation is really common. Fatality related to cardiovascular disease occurs in up to 30% of renal transplant recipients while the graft still has perfectly appropriate function. Post-op pulmonary edema is uncommon by comparison and is uniquely tied to diastolic dysfunction in the setting of acute kidney injury. So not the most common events, but worthwhile considering. Why do people come to your ICU after they've had a successful renal transplant? It's about five to 10% of patients. Generally for either invasive mechanical ventilation, renal replacement therapy, or the need for mean arterial pressure management using a vasopressor. You can see the admission etiologies on the right. And I'll call your attention in particular to altered mental status that occurs in up to one in five. Practical aspects of treating critically ill renal transplant recipients can be put into five buckets, if you will. One is rapid ICU admission as opposed to management on the floor. Routine cardiac performance evaluation by bedside POCUS. A careful evaluation for infection or pulmonary or other immune suppression agent toxicity. And one particular pulmonary issue is to decide whether or not they're likely to have pneumocystis gervici pneumonia and whether they would benefit from a bronchoalveolar lavage for either secretion management or to obtain a particular culture. Other kinds of things are relatively routine, and this is all part of your standard ICU admission pathway other than assessing duplex graph function, looking at flow and collections. You can break down post-renal transplant infections into three buckets. Less than one month. You can see the bacteria that are listed there are fairly common. Viruses are not unexpected. Fungal infection is less common, is typically candida. And then there are a variety of parasitic infections that span everything from malaria to panosoma cruzii. And one to six months, you may end up with bacterial infections that can be broken into those that have prophylaxis versus those that aren't taking prophylaxis. Viral infections look as you would expect them to, but now fungi start to have more unusual organisms, aspergillus, cryptococcus, mucora. And those who have not taken their prophylaxis, this is the group that is at risk for pneumocystis. Parasitic infections are increasingly common during months one to six, and they have toxoplasma, strongyloides, trypanosomes, and leishmaniasis. More than six months is very common to have UTIs and pneumonias. Viral infections, including reactivation events, are more common. And cryptococcus and rhodococcus and aspergillus head the list of fungal infections. There are acute and long-term infections that can be considered. You can even break down these infections to zero to 30 days, a month to a year, and then more than a year. And it doesn't matter which way you break them down, but I will call your attention to the more than a year. And the opportunistic infections that you can see there are both important to treat, but you have to ask why they're occurring then. And this drives a search for things like PTLD. Community-acquired infections are common after a year, and they get whatever else has, and we would add to this list, COVID. Since, well, it's not at the height that we had during the start of the pandemic, it does seem to be persistent. And we can also add to that respiratory syncytial virus, since that seems to be increasingly common as well. Hospital readmission occurs in almost half of patients, and principally related to the genitourinary system, which is not a surprise if you have an organ that's not yours. Infection and endocrine issues are much less common. If you require readmission, you are more likely to lose your allograft than those who don't need it. And of course, this also means you have an accelerated mortality risk. We'll call specific attention to the BK virus nephropathy. It is a latent virus. It is typically related to receiving immune suppression, which allows for viral reactivation. And in year one, it is well tied to the occurrence of ureteral stenosis. And therefore, one must regularly screen for this, and here's where ultrasound is particularly helpful. And the treatment for BK virus nephropathy, which can lead to graft loss, is, of course, a reduction in the immune suppression regimen. How do those that are having graft dysfunction present? Proteinuria, oliguria, an abnormal creatinine, and in particular, on exam, they often have pain over the graft. And so the evaluation is just what you would think. Ultrasound follows in the wake of the physical exam. You can have radionuclide imaging, but often this requires a graft biopsy. This is all a bit of an emergency to preserve graft functions that you can understand why this is happening and how best to treat it. Early dysfunction, acute rejection, drug-drug interactions or toxicity, BK virus nephropathy, inflow or outflow thrombosis, or problems with the urine outflow from the kidney or its connection to the bladder. Late issues are transplant glomerulopathy, glomerulonephritis, BK virus nephropathy, so you can have it both early and late, and renal artery stenosis, which is a particular kind of endothelial abnormality that results from intimal hyperplasia. And therefore, some of those stenotic arteries are being managed with drug-coated balloon angioplasty or drug-coated stents to reduce the likelihood that the intima regrows. Hyperacute rejection, which occurs in the OR, is rare based upon how well we type people. There are those who get a new kidney and have persistent hyperparathyroidism. You can see that there are a variety of risk factors, and I'm not going to go through all of them, but the effects are important, and so important bone mineralization effects, fractures, vascular calcification. This may be uniquely tied to cardiovascular disease, but more importantly, it's tied to allograft dysfunction and graft loss. So the screening for PTH concentration in those that start out high or have high calcium levels is important so that you can figure out whether or not this patient is going to be at risk for all of these untoward events, and to drive therapy to reduce it. Acute rejection after renal transplantation is important. You will see acute organ transplantation in the emergency department, on the acute care unit in the ICU. Hyperacute is really uncommon. That occurs in the operating room, but cellular and antibody-mediated rejection, cellular is now really called T-cell-mediated, are fairly evenly split for the rest. Hyperacute rejection stems from preformed antibody to the donor, and so this is generally a screening failure. The graft turns blue, it acutely swells. There is no salvage for it. It is, in fact, explanted right after implantation. The rate at which we are dealing with acute rejection has progressively fallen, and you can see here on this particular graph that shows the percent of those with acute rejection and the induction of different immune-suppressive agents. And so now acute rejection occurs in less than 10% of patients. How you diagnose it. This is a guideline that was articulated at a expert consensus conference in Banff in 2017, and you can see there are a variety of categories in terms of increasing intensity of acute T-cell or cell-mediated rejection. You can see the criteria on the right. And then there are also criteria for antibody-mediated rejection, which is also very much reliant on a biopsy to identify. There are a wide variety of antibody-mediated rejection mechanisms of injury. Recognize that what you have is the interaction of antibodies with cell surface antigens. There are complement components that are activated, and this leads to a capillaritis, all related to the initial interaction of antibodies with cell surface antigens. So in many ways, this is a lot like the endothelial antibodies that we talked about earlier for the generation of cardiovascular disease, but now you have it in an organ-specific fashion. Acute rejection treatment. There is, of course, an algorithm for this, and therefore, if you start with a graft that isn't working appropriately, there are things to rule out, infection, drug toxicity, abnormal cardiac performance, and, of course, structural perigraft things like fluid collections, obstruction, a new hematoma. So you should, if you don't have those, you look for new donor-specific antibodies, that's DSA, and you get a biopsy. If the biopsy is not safe or it can't be done, initial therapy with steroids is then broken down to those who have their acute kidney injury resolved versus those who don't, and further broken down by whether there are new donor-specific antigens. If the biopsy is able to be obtained and they have T-cell rejection, there are approaches that are driven by the category. There are, for 1A and 1B, it's steroid-based, 1B adds antithymosite globulin, and the rest of them just have antithymosite globulin. If they have antibody-mediated rejection, plasma exchange, IVIG, and rituximab are the mainstays of therapy. If there's mixed rejection, then you also include the T-cell component rescue approaches. So while I'd like this to be much more clean than what it is, there is still some uncertainty around it because not everyone can be rapidly biopsied. All of the therapeutics that are applied, and you can see them here, whether it's rituximab or IVIG or plasma exchange, they all have some interface either with major histocompatibility antigens or complement and the membrane attack complex. So the stabilizing the organ reduces each of the driving forces for triggering these events. Regulatory T-cells are a key in terms of suppressing immune responses, mostly by these five things. They generate adenosine, which works in an anti-metabolite sort of way, depletes IL-2, they can induce apoptosis, they can block antigen-presenting cells, and they can elaborate inhibitory cytokines. So regulatory T-cell therapy is on the horizon as another approach for this. Let's switch gears and talk about hepatic transplantation. The pathways to liver transplantation, which include pre-transplant failure, really can be broken down into three post-transplant courses. Those that have a very high meld-as-an-out patient or those that have concomitant hepatocellular carcinoma generally have a fairly straightforward course. Those who have intraoperative complications may have a much more prolonged course. And then those with inpatient complications have a much less salutary course. And therefore, we can think about those that undergo hepatic transplantation as three somewhat distinct groups based upon how they have responded to their new organ. Major postoperative priorities are to evaluate synthetic function. And you can see that here, which is why most of the transplant services are uninclined to either address the INR or the platelet count with exogenous therapeutics, using these as indicators of the adequacy of synthetic function. We do trend lactate and acid-base balances and indicators of the adequacy of synthetic function in the patient. We do trend lactate and acid-base balances an indicator of hepatic health, because your liver typically metabolizes about 4,500 millimoles of lactate in a day. And a pre-transplant liver generally metabolizes less than 1,500. So if your lactate is going up when it should be going down, that's an indication of a lack of graft performance. Of course, also, your liver is uniquely related to your glycemic control, which gets complicated by the addition of steroids, regardless of the taper. So glucose is trended, but it's not necessarily the best indicator of synthetic function. Ultrasonography evaluates hepatic artery and portal vein inflow, as well as hepatic vein outflow. And you're looking at intravascular volume with the goal of maintaining a low hepatic venous pressure, so that you have good trans-organ flow, and you don't create organ edeme on the basis of a high post-hepatic pressure. This means that it's also helpful to keep your intrathoracic pressure low. And the ultrasound will also help you assess for both hemorrhage and the generation of new ascites. Technical complications may be numerous. And so what you're looking at here on panel A is the diseased liver that is separated from the suprapatic and infrapatic cava, the portal vein, the hepatic artery, as well as the common bile duct. The new organ is sewn back into place, so this is orthotopic. It replaces the organ in exactly the same way, as opposed to heterotopic, which is how the kidney is placed in. It does not replace the native kidney. It's in a new location. Each of these anastomoses is subject to stenosis or leak. Those that have blood in them are subject to thrombosis. And of course, hemorrhage may displace the organ and create stress across those anastomoses. You may not, in fact, have transplanted a whole liver. Living donor hepatic transplantation takes a portion of the liver. And sometimes, even if it's a deceased donor liver, the liver will be split if it's going to be used for, let's say, pediatric transplantation. So you may only have a portion of the liver that's being put in. This, of course, abrogates size mismatch differences. But still maintains all the anastomoses. So when you look at technical complications, you can see that they are vascular. Listed on the left, there's peritransplant collections, of which biliary peritransplant collections appear to dominate. And there's a bunch of miscellaneous ones that we'll talk more about in a moment. One of the things that is important is ischemic cholangiopathy. Because the bile ducts, as opposed to the rest of the liver, is also subject to untoward effects from ischemia. And so that when you look at the method of organ acquisition and preservation, you are comparing normothermic regional perfusion to surgical peritransplantation. Regional perfusion to super rapid recovery. So when you look at ischemic cholangiopathy, IC, it appears, at least in this multicenter study recently published, to be abrogated entirely with NRP. Anastomotic stricture is less, but it doesn't impact other biliary complications. But ischemic cholangiopathy is one of the important causes of post-transplant grafted liver failure. Survival outcomes from that same multicenter study, you're looking at years, up to four years after transplant. And there appears to be a selective advantage with normothermic regional perfusion as opposed to super rapid recovery. And therefore, when you are looking at patients who have come back with complications after their liver transplant, we often don't think about the method of organ acquisition and preservation prior to implantation. And this study suggests that we should. Hepatic artery thrombosis is the most common complication in post-orthotopic liver transplantation. Two to 12%. It's up to about 20% in children. And mortality is highly variable based upon recognition and timing of repair. This is an early complication occurring within the first few months. And the more severe your hepatic disease happens to be, the more complicated the operation happens to be. Perhaps the greater the likelihood that it will occur, but the earlier it does occur, it has a greater impact. Remember that the bile ducts are exclusively supplied by the hepatic artery, which has about a third of the blood flow, but most of the oxygenation. And therefore, thrombosis may induce biliary ischemia and necrosis. Diagnosis principally by duplex ultrasonography. And this is a routine surveillance, at least in our center. Bile leak, up to 10%. It would occur more commonly when we were using T-tubes to decompress the common bile duct. Most of the anastomoses now are made without T-tube. So this has decreased. Leak can occur from either the anastomosis or the cystic duct stump. More commonly, the anastomosis and diagnosis is either by MRCP or technetium hydoscan, which looks at excretion into the bile stream, and less commonly by cholangiogram or ERCP. What triggers an investigation? An increase above 1.5 times more than the baseline of bilirubin, INR, or transaminases. Generally, post-transplant transaminases peak by 48 hours and then steadily decrease. And if the transaminases don't and they keep going up, for some, this is an indication for repeat transplantation if there is not a correctable lesion. Two prime causes of primary non-function versus hepatic artery thrombosis, and certainly thrombosis may be able to be salvaged with a thrombectomy and hepatic artery reconstruction and anticoagulation. How do we monitor hepatic function? It depends upon the day. This is a standard approach. It's by no means the only approach, and you can see that the great frequency during days one to three is very common, looking principally at synthetic function, acid-base balance, and the stability of blood-based elements. When you get out more than six months, some stability is indicated by a sampling that is typically every other month. What causes hepatic allograft dysfunction? Less than one month. It's vascular, biliary leak restriction or infection, one to 12 months, rejection, viral recurrence or reactivation, fewer vascular events, and an increased prevalence of CMV, in particular, after that first month. More than a year of rejection, either acute or chronic, and de novo disease that includes hepatocellular carcinoma, HCV, and injury from alcohol or other toxins. So how do you evaluate changes in LFTs that may be accompanied by fever and or graft pain? So you've now heard this with each of the grafts. Ultrasound, CT, or MR can all be used. If it's normal, there's a pathway for biopsy and an MRCP, and you can see with different kinds of abnormalities, abnormal ultrasound, dilatation of biliary ducts or collections that are identified de novo or mass, they all have a particular pathway that moves from less invasive to more invasive, as well as having some surveillance options in there. Infectious complications, common. Transplant to one month, donor-derived infections, really common, surgical site infection, iatrogenesis imperfecta with CLABSI or CAUTI, hospital-acquired pneumonia, and increasingly C. difficile. One to six months, opportunistic infections are much more common, cryptococcus and the Sinemono-Zurovesi are at the top of that list. Reactivation of other viral infections is common, and chronic infection begins to be known. More than six months, note, and this is the same for renal transplantation, community-acquired pathogens again reemerge, generally with reductions in the intensity of immune-suppressive regimens. But you get unusual things like Strep pneumo or Legionella, Listeria, Aspergillus, and of course, reactivation of EBV. Nearly 90% of liver transplant recipients will have some kind of pulmonary complication that is rapidly occurring after their transplant. If they have it, it increases the risk to have a longer ventilator, an isolent to stay, it increases their risk of mortality. Pleural effusion is associated with these things. It occurs principally on the right side in up to half of patients. Adelectosis is really common because they get compressive adelectosis. Fluid overload that is often related to transfusion associated circulatory overload has a very broad prevalence, but this depends upon the complexity of the intraoperative events and whether or not they have post-operative hemorrhage. Right diaphragm dysfunction is really common, and therefore, these patients do much better having a reduction in extravascular lung water so that their compliance is enhanced. And some will end up with a right-sided pneumonia that presents after post-op day four in up to one in five. And therefore, very careful attention to pulmonary function is particularly important in the immediate peritransplant period. Pneumonia after liver transplant, 60% of these are related to gram-negative rods, gram-positive organisms, and about 40% CMV is much less common. Acute fungal infection is very rare, and when you look at the kinds of organisms, multidrug-resistant organisms are rising in frequency in part related to the ecology of the hospital environment and the kinds of antibiotics and the duration for which they are being used. This is a particular focus of transplant-associated antibiotic stewardship programs to try and reduce overall antibiotic use and decrease multidrug-resistant organism related infection. Acute rejection. It's a little bit different for the liver than the kidney. In many ways, the liver is immune privileged. T-cell mediated rejection occurs in up to two-thirds of recipients, but interestingly enough, and unlike the kidney, it seems to not have any impact on the ultimate fate of the graft nor the patient. And antibiotic-mediated rejection is exceedingly rare. T-cell-mediated rejection after liver transplantation has a direct pathway that's in the top box, an indirect pathway, as well as a semi-direct pathway. And note that there is an interface between the lymph node and the liver, and in the bottom panel, you can see major histocompatibility, major histocompatibility complex-related events from T-cells that are CD8 positive and others that are CD4 positive. So this is all T-cell-driven. How do you treat this? Wu-Hu corticoids is incredibly effective, and most T-cell-mediated rejection occurs early, weeks one to six, much less common later on. One of the interesting therapies to help prevent T-cell-mediated rejection is low-dose aspirin. And what you're looking at in this particular study, you're looking at cumulative survival in panels A, B, C, and D, and you're looking at time in months. In regards of how you measure this, those that are on low-dose aspirin, 81 milligrams are in red, those that did not get aspirin in black, and their outcomes are all more favorable up to 60 months after transplantation. So when you look at the plot to the right, all kinds of different factors from whether they were an individual that received a graft after DCD, regardless of whether the MELD was high, the only therapy that is strongly associated with the reduction in T-cell-mediated rejection is aspirin after transplant. T-cell-mediated rejection may also be impacted by machine perfusion, so this is a visual abstract. It's a systematic review. There's a bunch of studies that were included. And so you're comparing some kind of machine perfusion to static cold storage, and all of the indices were better with machine perfusion. So therefore, not only does it appear that the method of organ acquisition and then transport ahead of implantation matter with regard to overall survival ischemic cholangiopathy, but it also seems to be related to T-cell-mediated rejection. Antibody-mediated rejection post-liver transplant, really uncommon. It's thought to be related to these kinds of factors, and you can see them there. It is characterized by diffuse C4D deposition in the endothelium. So you need biopsy to help identify this, but it's singularly rare. There are mechanisms, of course, for this, all of which you can see, again, related to the activation of complement and the formation of a membrane attack complex. And whether it's a neutrophil or macrophage or a natural killer cell, it results in endothelial injury and cell death through activation of the FC receptor. Treatment of antibody-mediated rejection, we're not sure. We are borrowing from what you do for other organs. And so first line here is tacrolimus and steroids. Second line, plasma exchange and IVIG. And if that doesn't work, anti-CD20 or proteasome inhibitors, but there is not good data. There's some weak data, but at the end, most will consider retransplantation because we're not really sure how best to address antibody-mediated rejection. What happens if you need to be readmitted after your liver transplant? You're looking at graft A for 30 days and graft B for 90 days. And you're looking at, in red, those who needed to be readmitted and blue, those who did not. You can see that decreases in survival are common with early readmission, but it doesn't seem to matter with later readmission. Most of these are infection-related more than technical, and the technical ones occur with an equal frequency to altered mentation, and all those occurred much more frequently than associated acute kidney injury. So in summary, I will leave you with these points. Regardless of which organ you look at, there are infectious and non-infectious etiologies, and that provides a very broad framework that can be adjudicated by time. The immediate complications that are technical occur more commonly with those who receive a liver transplant rather than a kidney transplant, unsurprisingly, since it is more complex. And then you do need to be concerned about rejection, infection, and medication interactions all in the context of obtaining a routine laboratory profile while you consider whether any of the events are related to the method by which the organ was acquired and preserved and transported prior to implantation. With that, I will thank you for your time and your attention, and if this was live, I'd be happy to take any questions. Thank you.

solid organ transplants

renal complications

hepatic complications

anastomotic issues

graft rejection

immunosuppressive regimens

post-transplant infections

organ transport innovations

machine learning in transplants