Intestinal transplantation: an update.

PURPOSE OF REVIEW: The role of intestinal transplant has expanded in recent years and is no longer only considered for patients with no other options remaining. 5 year survival in high-volume centres is over 80% for certain graft types. The aim of this review is to update the audience on the current state of intestinal transplant, with a focus on recent medical and surgical advances. RECENT FINDINGS: There has been a greater understanding of the interplay and balance of host and graft immune responses, which may facilitate individualized immunosuppression. Some centres are now performing 'no-stoma' transplants, with preliminary data showing no adverse effects from this strategy and other surgical advances have lessened the physiological insult of the transplant operation. Earlier referrals are encouraged by transplant centres, such that vascular access or liver disease has not progressed too much to increase the technical and physiological challenge of the procedure. SUMMARY: Clinicians should consider intestinal transplant as a viable option for patients with intestinal failure, benign unresectable abdominal tumours or acute abdominal catastrophes.

Use of Lt Systems in Large Class Lab Delivery.

The attainment of laboratory-based skills is essential for the development of all students who study the Life Sciences. When the COVID-19 pandemic hit and Universities worldwide closed campuses, there was great uncertainty around how long people would have to work from home, leading to a real risk that students could miss out on obtaining laboratory practice for one or perhaps 2 years. It, therefore, became critical that processes were put in place that would allow students the opportunity to gain insight into what the laboratory environment is like, and to also gain experience in data collection, interpretation, and analysis. The adoption of Lt systems (a cloud-based learning platform for the Life Sciences) to create laboratory-based teaching allowed for these issues to be addressed. Detailed planning, teamwork and production of online lab sessions allowed for the creation of bespoke lessons that replicated as best as possible the 'face-to-face' experience. This was achieved by taking aspects of pre-existing labs, filming new material and utilising interactive data analysis tools in order to create online Lt labs that gave students a feel of what it would be like to be in a laboratory on campus. Lt systems also doubled as a revision tool to enhance student learning and ultimately allowed intended learning outcomes to be successfully met. The labs were well received by students and the online material meant that they could access content at a time convenient to them. This 'online anytime' possibility was crucial for such a large class (n = 378) who were working from home in many different countries worldwide during a pandemic. Going forward, the online lessons built during the pandemic can be integrated with future face-to-face sessions to create a more enhanced learning experience for the student.

DEVELOPMENT OF A MOBILITY ASSESSMENT SCORE FOR EVALUATION OF THE EFFECTS OF ORAL HYALURONIC ACID ON CLINICAL LAMENESS IN ASIAN SMALL-CLAWED OTTERS (AONYX CINEREA) AND AFRICAN SPOT-NECKED OTTERS (HYDRICTIS MACULICOLIS) UNDER HUMAN CARE.

Oral hyaluronic acid has been shown to reduce inflammation and pain in humans with osteoarthritis. Eight Asian small-clawed otters (Aonyx cinerea) and two African spot-necked otters (Hydrictis maculicolis) with varying degrees of osteoarthritic changes identified on radiographs were selected for a randomized, double-blinded, placebo-controlled clinical trial. Animal husbandry staff completed otter mobility assessment (OMA) questionnaires for each animal prior to study commencement and following either oral hyaluronic acid at a loading dose of 4 mg/kg PO SID for 10 d followed by a maintenance dose of 2 mg/kg PO SID for 20 d, or placebo for 30 d. Four veterinarians with experience assessing otters watched randomized videos of otter gaits and assigned a clinical lameness score. Two additional evaluators watched the videos: an experienced veterinarian in small animal practice and a final-year veterinary student. All evaluators for OMA and clinical lameness score were blinded to treatment group. Radiographs performed prior to, and following, the study were assessed by a board-certified radiologist (Dennison). The OMA questionnaire had high reliability coefficients and correlated strongly with clinical gait scores and radiographic assessment. Although hyaluronic acid appears to be safe for use in otters at the dose described, there was no observed significant effect of hyaluronic acid on clinical lameness scores, OMA scores, or radiographic assessment of the limbs. The development of the OMA questionnaire is a promising tool for evaluating lameness in managed-care otters and may be further validated in future studies investigating therapeutics or incorporated as a component of animal welfare assessment.

Transplant-associated thrombotic microangiopathy and immune haematological complications following intestine-containing organ transplantation: experience from over 100 consecutive cases.

Descriptions of passenger lymphocyte syndrome (PLS), immune cytopenias and transplant-associated thrombotic microangiopathy (TA-TMA) after intestine-containing transplants remain scarce. We describe our centre's experience of these complications from 2007 to 2019. Ninety-six patients received 103 transplants. PLS occurred in 9 (9%) patients (median 12 days post-transplant); all due to ABO antibodies. There were 31 minor ABO mismatch transplants. No patient required change in immunosuppression. Immune cytopenias (excluding PLS) occurred in six patients at an incidence of 1·7/100 patient years; three immune haemolysis, one immune thrombocytopenia, one acquired Glanzmann's and one immune neutropenia; 50% occurred with other cytopenias. All cases eventually responded to treatment, with a median of four treatments (range 1-8) and 5/6 were treated with rituximab. One patient with immune haemolysis required bortezomib. Complications were common in patients with immune cytopenias; 4/6 with infection needing intravenous antibiotics and 3/6 with venous thromboembolism. In 3/6 cases, a secondary cause for the immune cytopenia was evident. Switching from tacrolimus to ciclosporin was not necessary. There were five cases of transplant-associated thrombotic microangiopathy (TA-TMA; 1·5/100 patient years) requiring calcineurin inhibitor withdrawal; two cases associated with acute rejection. Two cases were managed with plasma exchange, one with plasma infusions and one with eculizumab. Further research in this patient group is required.

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.

Renal transplantation during the SARS-CoV-2 pandemic in the UK: Experience from a large-volume center.

There is uncertainty about the safety of kidney transplantation during the SARS-CoV-2 pandemic due to the risk of donor transmission, nosocomial infection and immunosuppression use. We describe organ donation and transplant practice in the UK and assess whether kidney transplantation conferred a substantial risk of harm. Data from the UK transplant registry were used to describe kidney donation and transplant activity in the UK, and a detailed analysis of short-term, single-center, patient results in two periods: during the pre-pandemic era from 30th December 2019 to 8th March 2020 ("Pre-COVID era") and the 9th March 2020 to 19th May 2020 ("COVID era"). Donor and recipient numbers fell by more than half in the COVID compared to the pre-COVID era in the UK, but there were more kidney transplants performed in our center (42 vs. 29 COVID vs. pre-COVID respectively). Overall outcomes, including re-operation, delayed graft function, primary non-function, acute rejection, length of stay and graft survival were similar between COVID and pre-COVID era. 6/71 patients became infected with SARS-CoV-2 but all were discharged without critical care requirement. Transplant outcomes have remained similar within the COVID period and no serious sequelae of SARS-CoV-2 infection were observed in the peri-transplant period.

Graft versus host disease after multivisceral transplantation: A UK center experience and update on management.

Graft versus host disease (GVHD) following transplantation of an intestine-containing graft occurs more frequently than with other solid organ transplants and is known to have a poor outcome. The presentation differs from other solid organ transplants, as the gastrointestinal tract is not involved following intestinal transplant. Diagnosis is based on clinical symptoms arising due to native tissue damage and the detection of donor T lymphocytes in circulating blood (T-cell chimerism). The ideal treatment strategy has not been defined, with advocates for both increased and decreased immunosuppression. We reviewed all cases of GVHD in an adult intestinal transplant center in the United Kingdom and report on management strategies of five cases and methods of detecting T-cell chimerism. The practice in our center has evolved with experience. The first two patients received an increase in immunosuppression, which was only successful in one case. Subsequently, reducing immunosuppression has been more effective. However, patients with bone marrow involvement have a poorer prognosis. We demonstrate successful treatment of GVHD after multivisceral transplant with a reduction in immunosuppression. This should be followed by vigilant graft surveillance and serial monitoring of the level of T-cell chimerism, with reintroduction of immunosuppression at the earliest sign of graft dysfunction.

A single-centre experience of Roux-en-Y enteric drainage for pancreas transplantation.

Exocrine drainage following pancreas transplantation can be achieved by drainage into the bladder or bowel, the latter typically by direct duodeno-jejunostomy; the use of Roux-en-Y enteric drainage is uncommon. We report a retrospective analysis of a single-centre experience of Roux-en-Y enteric drainage following pancreas transplantation. Over a 14-year period (2001-2015), 204 consecutive adult pancreas transplants were performed (96.6% simultaneous pancreas and kidney transplants), of which 26.0% were from donors after circulatory death (DCD). During a median follow-up of 67 months (range 13-183 months), 14 (6.9%) recipients experienced complications related to their enteric drainage. Complications during follow-up included early enteric anastomotic haemorrhage (five patients), non-anastomotic enteric bleeding (one patient), small bowel obstruction (four patients) and graft duodenal perforation (two within 6 weeks, five beyond 12 months). No recipient lost their graft as a direct result of complications related to enteric drainage. Patient and pancreas graft survival at 1 year was 99.0% and 94.0% and at 5 years 91.3% and 84.9%, respectively. We conclude that Roux-en-Y enteric drainage following pancreas transplantation is a safe and effective procedure and facilitates graft salvage in the event of graft duodenal perforation.

Renal Autotransplantation for Uncontrolled Hypertension in Nonatherosclerotic Renal Artery Stenosis-2 Case Reports and a Brief Review of the Literature.

Fibromuscular dysplasia is the most common cause of renovascular hypertension in young adults under 40 years old. It is potentially amenable to renal artery angioplasty, which frequently normalizes blood pressure. However, limited options exist if angioplasty is not technically possible, or restenosis occurs. Here, we describe 2 patients who presented with hypertension secondary to renal artery stenosis. In the first case, a young adult with hypertension secondary to renal artery stenosis (fibromuscular dysplasia), developed restenosis 11 weeks after an initially successful renal artery angioplasty. In the second case, a patient with neurofibromatosis type 1 was diagnosed with hypertension secondary to renal artery stenosis. Angioplasty was not possible due to multiple branch occlusions. Both individuals went on to have successful renal autotransplantations, which ultimately cured their hypertension. In this article, we review the background, indications, and blood pressure outcomes in relation to renal autotransplantation in nonatherosclerotic renal artery stenosis.

Treatment of Complex Desmoid Tumors in Familial Adenomatous Polyposis Syndrome by Intestinal Transplantation.

Background: Desmoid tumors are fibroblastic lesions which often have an unpredictable and variable clinical course. In the context of familial adenomatous polyposis (FAP), these frequently occur intra-abdominally, especially in the small-bowel mesentery resulting in sepsis, fistulation, and invasion of the abdominal wall and retroperitoneum. In selected cases where other modalities have failed, the most radical option is to perform a total enterectomy and intestinal transplantation (ITx). In this study, we present our center's experience of ITx for desmoid in patients with FAP. Methods: We performed a retrospective review of our prospectively collected database between 2007 and 2022. All patients undergoing ITx for FAP-related desmoid were included. Results: Between October 2007 and September 2023, 144 ITx were performed on 130 patients at our center. Of these, 15 patients (9%) were for desmoid associated with FAP (7 modified multivisceral transplants, 6 isolated ITx, and 2 liver-containing grafts). The median follow-up was 57 mo (8-119); 5-y patient survival was 82%, all with functioning grafts without local desmoid recurrence. These patients presented us with several complex surgical issues, such as loss of abdominal domain, retroperitoneal/abdominal wall involvement, ileoanal pouch-related issues, and the need for foregut resection because of adenomatous disease. Conclusions: ITx is a viable treatment in selected patients with FAP and extensive desmoid disease. The decision to refer for ITx can be challenging, particularly the timing and sequence of treatment (simultaneous versus sequential exenteration). Delays can result in additional disease burden, such as secondary liver disease or invasion of adjacent structures.

A metagenomic prospective cohort study on gut microbiome composition and clinical infection in small bowel transplantation.

Two-thirds of small-bowel transplantation (SBT) recipients develop bacteremia, with the majority of infections occurring within 3 months post-transplant. Sepsis-related mortality occurs in 31% of patients and is commonly caused by bacteria of gut origin, which are thought to translocate across the implanted organ. Serial post-transplant surveillance endoscopies provide an opportunity to study whether the composition of the ileal and colonic microbiota can predict the emergence as well as the pathogen of subsequent clinical infections in the SBT patient population. Five participants serially underwent aspiration of ileal and colonic bowel effluents at transplantation and during follow-up endoscopy either until death or for up to 3 months post-SBT. We performed whole-metagenome sequencing (WMS) of 40 bowel effluent samples and compared the results with clinical infection episodes. Microbiome composition was concordant between participants and timepoint-matched ileal and colonic samples. Four out of five (4/5) participants had clinically significant infections thought to be of gut origin. Bacterial translocation from the gut was observed in 3/5 patients with bacterial infectious etiologies. In all three cases, the pathogens had demonstrably colonized the gut between 1-10 days prior to invasive clinical infection. Recipients with better outcomes received donor grafts with higher alpha diversity. There was an increase in the number of antimicrobial resistance genes associated with longer hospital stay for all participants. This metagenomic study provides preliminary evidence to support the pathogen translocation hypothesis of gut-origin sepsis in the SBT cohort. Ileal and colonic microbiome compositions were concordant; therefore, fecal metagenomic analysis could be a useful surveillance tool for impeding infection with specific gut-residing pathogens.

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.

Alemtuzumab (Campath-1H): a systematic review in organ transplantation.

Alemtuzumab (Campath-1H) is a powerful antilymphocyte antibody that produces profound and long-lasting lymphopenia. It is being used with increasing frequency for induction in organ transplantation, with the aim of allowing steroid-free and/or calcineurin-free/sparing maintenance immunosuppressive protocols. Despite a considerable experience with this agent, mostly in kidney transplantation, there are only two relatively small randomized controlled trials available, and therefore the level of evidence for its role in transplantation is limited. Nevertheless, it does appear that the incidence of acute rejection is low after induction with alemtuzumab, perhaps if used with a calcineurin inhibitor, and that steroid-free and calcineurin-sparing protocols are possible. Although there is a profound and long-lasting T cell lymphopenia after administration of alemtuzumab, there is no apparent increase in infection, posttransplantation lymphoproliferative disease, or other side effects, other than perhaps autoimmune disease. Whether alemtuzumab is more effective than Thymoglobulin or anti-interleukin 2 receptor antibodies cannot be answered at this time. However from a cost aspect, the use of alemtuzumab for induction compares more than favorably with other lymphocyte-depleting agents. Alemtuzumab is an attractive agent for induction in organ transplantation, but there is a need for more and larger randomized trials with long-term follow-up before its true role can be established, particularly with respect to safety.

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.

Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review.

BACKGROUND: Mycophenolate mofetil (MMF) has increasingly replaced azathioprine (AZA) as the antimetabolite of choice in immunosuppressive protocols. Initial trials comparing MMF with AZA in patients receiving cyclosporine A sandimmune showed a clinical benefit in reducing the incidence of acute rejections. It has been questioned whether this benefit remains significant when using newer formulations of cyclosporine A (neoral) and tacrolimus. METHODS: Literature searches were performed using the Transplant Library, Cochrane library, Medline, and Embase for all randomized controlled trials directly comparing MMF with AZA in renal transplant recipients. Trials were assessed for quality using the Jadad scoring system. Trials were pooled using meta-analysis software. Confidence intervals were set at 95%. RESULTS: Nineteen relevant studies were identified, including a total of 3143 patients. MMF significantly reduces the risk of acute rejection when used in combination with any calcineurin inhibitor (relative risk 0.62, 0.55-0.87, P<0.00001). The hazard for graft loss, including death with a functioning graft, is also significantly reduced in patients treated with MMF (hazard ratio 0.76, 0.59-0.98, P=0.037). There is no significant difference in patient survival or renal transplant function between groups. Risk of adverse events, including cytomegalovirus infection, anemia, leukopenia or rates of malignancy, does not differ significantly. A greater risk of diarrhea is seen in MMF-treated patients. CONCLUSIONS: We have shown that MMF used with a calcineurin inhibitor does indeed confer a clinical benefit over AZA by reducing the risk of acute rejection and also possibly reducing graft loss. This effect is independent of whether MMF is used in combination with sandimmune, neoral or tacrolimus.

Constraints on torsion from bounds on lorentz violation.

Exceptional sensitivity to space-time torsion can be achieved by searching for its couplings to fermions. Recent experimental searches for Lorentz violation are exploited to extract new constraints involving 19 of the 24 independent torsion components down to levels of order 10(-31) GeV.

Torsion of the gallbladder: a case report.

INTRODUCTION: Torsion of the gallbladder is a rare condition that most commonly affects the elderly. Pre-operative diagnosis is the exception rather than the rule. Any delay in treatment can be fatal as the gallbladder may rupture, leading to biliary peritonitis. CASE PRESENTATION: We present the case of an 80-year-old woman who was admitted with right upper quadrant pain initially thought to be secondary to acute cholecystitis. Subsequent ultrasound and computed tomography scans of the abdomen revealed signs suggestive of acute cholecystitis but neither modality detected any gallstones. As the patient's symptoms failed to resolve on conservative management, she was taken to theatre for an open cholecystectomy. Intra-operatively, the gallbladder had undergone complete torsion and appeared gangrenous. A routine cholecystectomy followed and she recovered from the operation without incident. CONCLUSION: It is rare to diagnose torsion of the gallbladder pre-operatively despite advances in diagnostic imaging. However, this differential diagnosis should be borne in mind particularly in the elderly patient, without proven gallstones, who fails to improve on conservative management. An emergency cholecystectomy is indicated in the event of diagnosing torsion of the gallbladder to avert the potentially lethal sequelae of biliary peritonitis.