Risk Factors Associated with PTLD Related Mortality in Adult Multivisceral Transplant Recipients - A Single Centre Cohort Study.

Background: PTLD is a heterogeneous group of lymphoproliferative diseases which can add significant mortality following multivisceral transplantation (MVTx). Our study aimed to identify potential risk factors of mortality in adult MVTx recipients who developed PTLD. Methods: All adult recipients of intestinal-containing grafts transplanted in our institution between 2013 and 2022, and who developed PTLD, were included in the study. Results: PTLD-associated mortality was 28.6% (6/21). Increased relative risk of mortality was associated with Stage 3 ECOG performance score (p=0.005; HR 34.77; 95%CI 2.94-410.91), if the recipients had a splenectomy (p=0.036; HR 14.36; 95%CI 1.19-172.89), or required retransplantation (p=0.039; HR 11.23; 95% CI 1.13-112.12). There was a significant trend for increased risk of PTLD mortality with higher peak EBV load (p=0.008), longer time from MVTx to PTLD diagnosis (p=0.008), and higher donor age (p 0.001). Peak LDH before treatment commencement was significantly higher in the mortality group vs the survival group (520.3 +- 422.8 IU/L vs 321.8 +- 154.4 IU/L; HR 1.00, 95%CI 1.00 to 1.01, p=0.019). Peak viral load prior to treatment initiation (Cycle Threshold (CT) cutoff = 32) correlated with the relative risk of death in MVTx patients who developed PTLD [29.4 (3.5) CTs in survivors compared to 23.0 (4.0) CTs in the mortality group]. Conclusions: This is the first study to identify risk factors for PTLD-associated mortality in an adult MVTx recipient cohort. Validation in larger multicentre studies and subsequent risk stratification according to these risk factors may contribute to better survival in this group of patients.

Clinical Utility of 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) in Multivisceral Transplant Patients.

Multivisceral transplant (MVTx) refers to a composite graft from a cadaveric donor, which often includes the liver, the pancreaticoduodenal complex, and small intestine transplanted en bloc. It remains rare and is performed in specialist centres. Post-transplant complications are reported at a higher rate in multivisceral transplants because of the high levels of immunosuppression used to prevent rejection of the highly immunogenic intestine. In this study, we analyzed the clinical utility of 28 18F-FDG PET/CT scans in 20 multivisceral transplant recipients in whom previous non-functional imaging was deemed clinically inconclusive. The results were compared with histopathological and clinical follow-up data. In our study, the accuracy of 18F-FDG PET/CT was determined as 66.7%, where a final diagnosis was confirmed clinically or via pathology. Of the 28 scans, 24 scans (85.7%) directly affected patient management, of which 9 were related to starting of new treatments and 6 resulted in an ongoing treatment or planned surgery being stopped. This study demonstrates that 18F-FDG PET/CT is a promising technique in identifying life-threatening pathologies in this complex group of patients. It would appear that 18F-FDG PET/CT has a good level of accuracy, including for those MVTx patients suffering from infection, post-transplant lymphoproliferative disease, and malignancy.

Bilateral lower extremity gait and function after unilateral total ankle arthroplasty: a case report.

BACKGROUND: End-stage ankle osteoarthritis is one of the leading causes of chronic disability in North America. The main purpose of this case report was to describe the functional recovery of a person following total ankle arthroplasty (TAA) surgery using the INFINITY™ system for end stage osteoarthritis of the left ankle. CASE DESCRIPTION: We report a case of a 55-year-old male who had attempted conservative management for end stage ankle osteoarthritis in his left ankle but ultimately elected to undergo TAA using The INFINITY™ Total Ankle System. He not only had significant left ankle pain limiting his daily function, but also had developed severe right knee pain. We performed gait analysis both before and 6 months after his TAA surgery to examine the sagittal and frontal-plane motions of bilateral ankle, knee, and hip joints during gait. OUTCOMES: At 6 months post-surgery, the patient demonstrated a 44-point improvement in his Foot and Ankle Outcome questionnaire scores as well as an increase in both left knee and left ankle motion in the sagittal and frontal planes. Kinematic deviations in the left ankle, hip, and knee joints during gait also reduced post-surgery. Despite improvement in his left ankle and overall function, the participant's right knee pain and altered kinematics of the right limb during gait worsened after surgery. DISCUSSION: Interventions, either before or after ankle surgery, should consider bilateral lower extremities simultaneously in order to optimize patient care and minimize future secondary complications for individuals with unilateral ankle osteoarthritis.

Liver Transplantation Outcomes From Controlled Circulatory Death Donors: SCS vs in situ NRP vs ex situ NMP.

OBJECTIVE: To compare the outcomes of livers donated after circulatory death (DCD) and undergoing either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion (NMP) with livers undergoing static cold storage (SCS). SUMMARY OF BACKGROUND DATA: DCD livers are associated with increased risk of primary nonfunction, poor function, and nonanastomotic strictures (NAS), leading to underutilization. METHODS: A single center, retrospective analysis of prospectively collected data on 233 DCD liver transplants performed using SCS, NRP, or NMP between January 2013 and October 2020. RESULTS: Ninety-seven SCS, 69 NRP, and 67 NMP DCD liver transplants were performed, with 6-month and 3-year transplant survival (graft survival non-censored for death) rates of 87%, 94%, 90%, and 76%, 90%, and 76%, respectively. NRP livers had a lower 6-month risk-adjusted Cox proportional hazard for transplant failure compared to SCS (hazard ratio 0.30, 95% Confidence Interval 0.08-1.05, P = 0.06). NRP and NMP livers had a risk-adjusted estimated reduction in the mean model for early allograft function score of 1.52 (P < 0.0001) and 1.19 (P < 0.001) respectively compared to SCS. Acute kidney injury was more common with SCS (55% vs 39% NRP vs 40% NMP; P = 0.08), with a lower risk-adjusted peak-to-baseline creatinine ratio in the NRP (P = 0.02). No NRP liver had clinically significant NAS in contrast to SCS (14%) and NMP (11%, P = 0.009), with lower risk-adjusted odds of overall NAS development compared to SCS (odds ratio = 0.2, 95%CI 0.06-0.72, P = 0.01). CONCLUSION: NRP and NMP were associated with better early liver function compared to SCS, whereas NRP was associated with superior preservation of the biliary system.

Decline in renal function following intestinal transplant: is the die cast at 3 months?

INTRODUCTION: This study reports the incidence of chronic kidney disease (CKD) after intestinal transplant (IT) at a single, adult center in the United Kingdom. METHODS: A retrospective review of IT was undertaken. Methods of renal function assessment pre-transplant were compared. Post-transplant renal function and renal sparing strategies were analyzed. RESULTS: There was a 30% variation (p < .001) in estimated glomerular filtration rate (eGFR) and normalized GFR at assessment. In the first 3 months post-transplant, there was a 40% decline in eGFR which was irreversible. Liver inclusion was not protective with similar eGFR at 3 months (60 ml/min/1.73 m2 ) compared with IT (55 ml/min/1.73 m2 ). The rate of decline in the first 2 months was less in multivisceral transplant (MVT; 21%) than IT (52%) suggesting surgical magnitude did not contribute. Thirty percentage of recipients had acute cellular rejection post-transplant; 58% of these were in the first 3 months with a higher proportion in MVT (64%) than IT (27%). Tacrolimus exposure did not correlate with decline in renal function over the first 3 months post-transplant. CONCLUSION: We demonstrated a 40% decline in renal function within 3 months post-IT which was irreversible despite renal sparing strategies. Early intervention should be considered in patients with an acute decline in this post-transplant period.

Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.

Long-term outcomes of liver transplant recipients followed up in non-transplant centres: Care closer to home.

INTRODUCTION: Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this 'hub-and-spoke' healthcare model. METHODS: A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa), was performed. RESULTS: The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or de novo cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008). CONCLUSION: Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home without compromising patient survival and long-term clinical outcomes.

Use of ex vivo normothermic machine perfusion after normothermic regional perfusion to salvage a poorly perfused DCD kidney.

Normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) have both been used in the procurement and conditioning of abdominal organs from donation after circulatory death donors with reported improved outcomes for the recipients. Here, we describe an unusual case of a kidney that underwent NMP after NRP. After 2 hours of abdominal NRP, the intra-abdominal organs were cold flushed in situ. The liver and right kidney were well flushed, but the left kidney was poorly flushed. Further attempts to clear the left kidney by flushing on the backtable were unsuccessful, and the kidney was thought to be unsuitable for transplant. The left kidney then underwent a 1-hour period of NMP using a red cell-based perfusate. During NMP, the kidney met previously described quality assurance criteria for transplant with good global perfusion and adequate renal blood flow and urine production. The kidney was transplanted into a suitable recipient who had slow early graft function but did not require dialysis posttransplant. The recipient was discharged 6 days posttransplant, and the serum creatinine level was 160 µmol/L (1.8 mg/dL) at 2 months posttransplant.

Direct Procurement of Donor Heart With Normothermic Regional Perfusion of Abdominal Organs.

PURPOSE: We wanted to evaluate if direct procurement of the heart is possible in combination with normothermic regional perfusion of abdominal organs in donors after circulatory death. DESCRIPTION: A donation after circulatory death pathway was used for a 41-year-old woman after an irreversible brain injury. After meeting criteria for the organ donation, the heart was retrieved and re-animated on ex situ perfusion system, and abdominal organs were perfused with normothermic regional perfusion. EVALUATION: All the donated organs and their recipients had excellent short-term outcome. CONCLUSIONS: We demonstrated a successful combination of direct procurement of the heart and normothermic regional perfusion of the abdominal organs.

Simultaneous Intestinal and Kidney Transplantation in Adults.

Aim of the study: Intestinal transplantation (IT) is a life-saving procedure for carefully selected patients with intestinal failure. We evaluated patients who had undergone simultaneous intestinal and kidney transplantation (SIKT) to determine whether UK guidelines for inclusion of a renal allograft (dialysis dependent or estimated glomerular filtration rate ((eGFR)) < 45 ml/min/1.73 m2) are justified. Methods: A single centre analysis was undertaken of adults undergoing IT at the Cambridge Transplant Centre between December 2007 and January 2016. A prospectively maintained database was used to identify SIKT recipients and determine outcomes. Results: Over this period, 63 intestinal transplants were performed. Seven (11.1%) recipients received a SIKT. Five were pre-dialysis (median eGFR 29 ml/min/1.73 m2, range 16-36 ml/min/1.73 m2). One recipient was on dialysis, and one needed bilateral nephrectomy at transplant. There were no primary kidney allograft failures and at three months, the median eGFR (55 ml/min/1.73 m2 range 39-124) was similar to recipients of IT alone (median eGFR 56 ml/min/1.73 m2 range 17-143 ml/min/1.73 m2). Two recipients required dialysis due to sepsis related kidney injury and died from multi-organ failure (20 and 63 months). Two died with a functioning renal transplant (10 and 15 months). The remaining three patients are alive at follow up (12-96 months) with an eGFR of 20-45 ml/min/1.73 m2. Conclusion: Patients with significant renal impairment (eGFR <45 ml/min/1.73 m2), and receiving dialysis may benefit from SIKT. Patient survival and renal function are broadly comparable to those undergoing IT alone. Further studies are required to justify allocation of a kidney to this complex high risk group.

Fatal breakthrough mucormycosis in a multivisceral transplant patient receiving micafungin: Case report and literature review.

Introduction: Antifungal agents are routinely used in the post-transplant setting for both prophylaxis and treatment of presumed and proven fungal infections. Micafungin is an echinocandin-class antifungal with broad antifungal cover and favorable side effect profile but, notably, it has no activity against molds of the order Mucorales. Presentation of case: A 47-year-old woman underwent multivisceral transplantation for intestinal failure-associated liver disease. She had a prolonged post-operative recovery complicated by invasive candidiasis and developed an intolerance to liposomal amphotericin B. In view of her immunosuppression, she was commenced on micafungin as prophylaxis to prevent invasive fungal infection. However, she developed acute graft versus host disease with bone marrow failure complicated by disseminated mucormycosis which was only diagnosed post mortem. Discussion: Non-Aspergillus breakthrough mold infections with micafungin therapy are rare with only eight other cases having been described in the literature. Breakthrough infections have occurred within one week of starting micafungin. Diagnosis is problematic and requires a high degree of clinical suspicion and microscopic/histological examination of an involved site. The management of these aggressive infections involves extensive debridement and appropriate antifungal cover. Conclusion: A high level of suspicion of invasive fungal infection is required at all times in immunosuppressed patients, even those receiving antifungal prophylaxis. Early biopsy is required. Even with early recognition and aggressive treatment of these infections, prognosis is poor.

Urgent Multivisceral Transplantation for Widespread Splanchnic Ischemia.

BACKGROUND: Multivisceral transplantation (transplantation of the stomach, intestine, liver, and pancreas) is usually undertaken as a semi-elective procedure after thorough assessment in patients who have intestinal failure with cirrhosis, cirrhosis with portomesenteric venous thrombosis, or tumors such as desmoids involving the liver and mesentery. STUDY DESIGN: Data were collected prospectively from the time of referral and held in a central database. We used it to report the first cases of urgent multivisceral transplantation (MVT) in patients with widespread splanchnic ischemia (occlusion of the celiac axis and superior mesenteric artery) resulting in small bowel infarction and hepatic failure. RESULTS: Three women (ages 33, 48, and 50 years) were referred to our center with superior mesenteric artery and celiac axis occlusion. All other modes of treatment had been considered and/or attempted. After transfer to our institution, all patients were assessed, urgently listed, and underwent transplantation in 10, 7, and 5 days. Two patients are still alive after 2 years and 1 died at 8 months from multiorgan failure due to infections and graft vs host disease. CONCLUSIONS: Treatment options for patients presenting with widespread splanchnic ischemia with hepatic and intestinal failure/infarction were previously limited to salvage surgery and attempted revascularization. In situations in which these failed, the only previous option would have been palliation. In selected cases, we propose that urgent multivisceral transplantation should be considered as a life-saving treatment. This represents a previously unreported indication for MVT.

Subcutaneous administration of alemtuzumab in simultaneous pancreas-kidney transplantation.

Alemtuzumab (MabCampath, Campath-1H) is a potent lymphocyte-depleting monoclonal antibody increasingly used at induction in solid organ transplantation. Previously, it had been given by intravenous infusion; such administration is associated with a first-dose cytokine release syndrome characterized by fever and hypotension. Subcutaneous administration of alemtuzumab avoids this first-dose reaction while achieving a similar concentration to intravenous administration. The avoidance of infusion-associated hypotension is particularly important in pancreas transplantation where venous thrombosis is a major problem. We therefore treated 21 recipients of combined pancreas and kidney transplants with two 30-mg doses of alemtuzumab administered subcutaneously on days 0 and 1. No patient suffered a first-dose reaction. Lymphocyte depletion after subcutaneous alemtuzumab was profound and comparable to that seen in a group of renal transplant recipients who had received intravenous alemtuzumab. Subcutaneous alemtuzumab was associated with similar rates of acute rejection (14% at 1 year), patient survival (100%), and pancreas and kidney graft survival (95% and 100%, respectively) to those observed in centers using intravenous alemtuzumab in simultaneous pancreas kidney transplantation. There was no excess incidence of adverse events. We therefore recommend this route of administration to all transplant centers using alemtuzumab.

Evidence of macrophage receptors capable of direct recognition of xenogeneic epitopes without opsonization.

BACKGROUND: We have previously demonstrated that porcine livers perfused with human blood remove most of the erythrocytes from three units of human blood over the course of a 72-h extracorporeal perfusion. Red blood cell loss did not appear to involve classical complement pathway-mediated hemolysis, but instead resulted from porcine Kupffer cell phagocytosis. METHODS: We developed a method incorporating collagenase digestion and metrizamide separation to isolate and maintain porcine Kupffer cells in primary culture. An in vitro rosetting assay was used to assess the binding of human and porcine erythrocytes to porcine Kupffer cells. Immunohistochemistry was used to confirm the presence of porcine macrophages. The rosetting assay was quantified using 51Cr-labeling of erythrocytes to assay for both rosette formation and phagocytosis. RESULTS: Porcine Kupffer cells were successfully isolated and maintained in primary culture. The presence of porcine macrophages was confirmed using the monoclonal antibody 74-22-15A. Human, but not porcine, erythrocytes were bound in an in vitro rosetting assay as confirmed by immunohistochemistry, electron microscopy and 51Cr-quantitation. Porcine Kupffer cells bound human erythrocytes regardless of the presence of opsonizing antibody. Approximately 70% of the isolated porcine Kupffer cells demonstrated the capacity to bind non-opsonized human erythrocytes. Phagocytosis was not observed. CONCLUSIONS: Using primary porcine Kupffer cell cultures, we have demonstrated that a subpopulation of porcine macrophages has the ability to recognize specifically xenogeneic human erythrocyte epitopes without the need for prior opsonization. The possibility is discussed that lectin-mediated carbohydrate binding plays a role in the cellular and humoral recognition and rejection of xenografts.