Improved survival after LTx-associated acute GVHD with mAb therapy targeting IL2RAb and soluble TNFAb: Single-center experience and systematic review.

Acute graft-versus-host disease (GVHD) after liver transplant (LTx) is a rare complication with a high mortality rate. Recently, monoclonal antibody (mAb) treatment, specifically with anti-interleukin 2 receptor antibodies (IL2RAb) and anti-tumor necrosis factor-α antibodies (TNFAb), has gained increasing interest. However, evidence is mostly limited to case reports and the efficacy remains unclear. Here, we describe 5 patients with LTx-associated GVHD from our center and provide the results of our systematic literature review to evaluate the potential therapeutic benefit of IL2RAb/TNFAb treatment. Of the combined population of 155 patients (5 in our center and 150 through systematic search), 24 were given mAb (15.5%)-4 with TNFAb (2.6%) and 17 with IL2RAb (11%) ("mAb group")-and compared with patients who received other treatments (referred to as "no-mAb group"). Two-sided Fisher exact tests revealed a better survival when comparing treatment with mAb versus no-mAb (11/24 vs 27/131; P = .018), TNFAb versus no-mAb (3/4 vs 27/131; P = .034), and IL2RAb versus no-mAb (8/17 vs 27/131; P = .029). This systematic review suggests a beneficial effect of mAb treatment and a promising role for TNFAb and IL2RAb as a first-line strategy to treat LTx-associated acute GVHD.

Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation.

BACKGROUND: Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Preconditioning, reconditioning and postconditioning with argon and xenon protects against renal ischaemia-reperfusion injury in rodent models. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function in a porcine renal autotransplant model was tested. METHODS: Pigs (n = 6 per group) underwent left nephrectomy after 60 min of warm ischaemia (renal artery and vein clamping). The procured kidney was autotransplanted in a separate procedure after 18 h of cold storage, immediately after a right nephrectomy. Upon reperfusion, pigs were randomized to inhalation of control gas (70 per cent nitrogen and 30 per cent oxygen), argon (70 per cent and 30 per cent oxygen) or xenon (70 per cent and 30 per cent oxygen) for 2 h. The primary outcome parameter was peak plasma creatinine; secondary outcome parameters included further markers of graft function (creatinine course, urine output), graft injury (aspartate aminotransferase, heart-type fatty acid-binding protein, histology), apoptosis and autophagy (western blot, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining), inflammatory mediators and markers of cell survival/growth (mRNA and tissue protein quantification), and animal survival. Results are presented as median (i.q.r.). ANOVA and Kruskal-Wallis tests were used where indicated. RESULTS: Peak plasma creatinine levels were similar between the groups: control 20·8 (16·4-23·1) mg/dl, argon 21·4 (17·1-24·9) mg/dl and xenon 19·4 (17·5-21·0) mg/dl (P = 0·607). Xenon was associated with an increase in autophagy and proapoptotic markers. Creatinine course, urine output, injury markers, histology, survival and inflammatory mediators were not affected by the intervention. CONCLUSION: Postconditioning with argon or xenon did not improve kidney graft function in this experimental model. Surgical relevance Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Based on mainly small animal experiments, noble gases (argon and xenon) have been proposed to minimize this ischaemia-reperfusion injury and improve outcomes after transplantation. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function was tested in a porcine kidney autotransplantation model. The peak plasma creatinine concentration was similar in the control, argon and xenon groups. No other secondary outcome parameters, including animal survival, were affected by the intervention. Xenon was associated with an increase in autophagy and proapoptotic markers. Despite promising results in small animal models, postconditioning with argon or xenon in a translational model of kidney autotransplantation was not beneficial. Clinical trials would require better results.

The Leuven Immunomodulatory Protocol Promotes T-Regulatory Cells and Substantially Prolongs Survival After First Intestinal Transplantation.

Intestinal transplantation (ITx) remains challenged by frequent/severe rejections and immunosuppression-related complications (infections/malignancies/drug toxicity). We developed the Leuven Immunomodulatory Protocol (LIP) in the lab and translated it to the clinics. LIP consists of experimentally proven maneuvers, destined to promote T-regulatory (Tregs)-dependent graft-protective mechanisms: donor-specific blood transfusion (DSBT); avoiding high-dose steroids/calcineurin-inhibitors; and minimizing reperfusion injury and endotoxin translocation. LIP was tested in 13 consecutive ITx from deceased donors (2000-2014) (observational cohort study). Recipient age was 37 years (2.8-57 years). Five-year graft/patient survival was 92%. One patient died at 9 months due to aspergillosis, another at 12 years due to nonsteroidal anti-inflammatory drug-induced enteropathy. Early acute rejection (AR) developed in two (15%); late AR in three (23%); all were reversible. No chronic rejection (CR) occurred. No malignancies developed and estimated glomerular filtration rate remained stable post-Tx. At last follow-up (3.5 years [0.5-12.5 years]), no donor-specific antibodies were detected and 11 survivors were total parenteral nutrition free with a Karnofsky score >90% in 8 recipients (follow-up >1 years). A high frequency of circulating CD4+ CD45RA- Foxp3hi memory Tregs was found (1.8% [1.39-2.21]), comparable to tolerant kidney transplant (KTx) recipients and superior to stable immunosuppression (IS)-KTx, KTx with CR, and healthy volunteers. In this ITx cohort we show that DSBT in a low-inflammatory/pro-regulatory environment activates Tregs at levels similar to tolerant-KTx, without causing sensitization. LIP limits rejection under reduced IS and thereby prolongs long-term survival to an extent not previously attained after ITx.

Inflammation and the bone-vascular axis in end-stage renal disease.

UNLABELLED: Bone loss and vascular calcification coincide in patients with end-stage renal disease, similar as to what is observed in the general population. In the present bone biopsy study, we provide further evidence that (micro-)inflammation may represent a common soil for both diseases. INTRODUCTION: Vascular calcification is a common complication of end-stage renal disease (ESRD) and is predictive of subsequent cardiovascular disease and mortality. Mounting evidence linking bone disorders with vascular calcification has contributed to the development of the concept of the bone-vascular axis. Inflammation is involved in the pathogenesis of both disorders. The aim of the present study was to evaluate the relationship between aortic calcification, inflammation, and bone histomorphometry in patients with ESRD. METHODS: Parameters of inflammation and mineral metabolism were assessed in 81 ESRD patients (55 ± 13 year, 68 % male) referred for renal transplantation. Static bone histomorphometry parameters were determined on transiliac bone biopsies performed during the transplant procedure. Aortic calcification was quantified on lateral lumbar X-rays using the Kauppila method. RESULTS: Aortic calcification, low bone turnover, and low bone area were observed in 53, 37, and 21 % of patients respectively. Inflammatory markers were found to be independently associated with aortic calcification (hsIL-6) and low bone area (TNF-α). Low bone area associated with aortic calcification, independent of age, diabetes, and inflammation. CONCLUSIONS: Low bone area and inflammation associates with aortic calcification, independent of each other and traditional risk factors. Our data emphasize the role of (micro-)inflammation in the bone-vascular axis in CKD.

Preoperative arterial embolization facilitates multivisceral transplantation for portomesenteric thrombosis.

Multivisceral transplantation (MvTx) for diffuse venous portomesenteric thrombosis is a surgically and anesthesiologically challenging procedure, partly because of the risk of massive bleeding during visceral exenteration. Preoperative visceral artery embolization might reduce this risk. In three consecutive MvTx, the celiac trunk (CT) and superior mesenteric artery (SMA) were embolized immediately pretransplant. We analyzed demographics, serum D-lactate, pH, base excess, hemoglobin, blood pressure, transfused packed cell (PC) units, intervention time and outcome. Results are reported as median (range). All recipients were male (43, 22, 47 years old). Portomesenteric thrombosis followed antiphospholipid syndrome, neuroendocrine tumor and liver cirrhosis. A peritransplant D-lactate peak of 6.1 (5.1-7.6) mmol/L, lowest pH of 7.24 (7.18-7.36) and lowest base excess level of -9.5 (-7.6 to -11.5) were observed. Values normalized within 3 h posttransplant. Embolization and exenteration times were 80 (70-90) min and 140 (130-165) min, respectively, during which blood pressure remained stable, lowest hemoglobin was 6.1 (6.1-7.6) g/dL and three (2-4) PC were administered. All procedures were uneventful. Follow-up was 7 (4-9) months. The first patient died 4 months post-MvTx after an intracranial bleeding; the other patients are doing well. Our experience suggests that preoperative embolization of CT and SMA facilitates native organ resection in MvTx.

Combined or Serial Liver and Lung Transplantation for Epithelioid Hemangioendothelioma: A Case Series.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with variable biological and clinical behavior. There is increasing experience with liver transplantation (LiTx) for hepatic EHE, even in cases of extrahepatic disease localization. Until now, no cases of lung transplantation (LuTx) had been reported for pulmonary EHE. This report describes three cases of EHE with multifocal disease in patients who underwent either serial or combined LiTx and LuTx.

The effect of anastomosis time on outcome in recipients of kidneys donated after brain death: a cohort study.

Whether warm ischemia during the time to complete the vascular anastomoses determines renal allograft function has not been investigated systematically. We investigated the effect of anastomosis time on allograft outcome in 669 first, single kidney transplantations from brain-dead donors. Anastomosis time independently increased the risk of delayed graft function (odds ratio per minute [OR] 1.05, 95% confidence interval [CI] 1.02-1.07, p < 0.001) and independently impaired allograft function after transplantation (p = 0.009, mixed-models repeated-measures analysis). In a subgroup of transplant recipients, protocol-specified biopsies at 3 months (n = 186), 1 year (n = 189), and 2 years (n = 153) were blindly reviewed. Prolonged anastomosis time independently increased the risk of interstitial fibrosis and tubular atrophy on these protocol-specified biopsies posttransplant (p < 0.001, generalized linear models). In conclusion, prolonged anastomosis time is not only detrimental for renal allograft outcome immediately after transplantation, also longer-term allograft function and histology are affected by the duration of this warm ischemia.

Combined liver and lung transplantation with extended normothermic lung preservation in a patient with end-stage emphysema complicated by drug-induced acute liver failure.

Isolated lung transplantation (LuTx) and liver transplantation are established treatments for irreversible lung and liver failure. Combined liver and lung transplantation (cLiLuTx) is a less common, but approved therapy of combined organ failure, mostly applied in patients suffering from progressive cystic fibrosis and advanced liver disease. We report a patient who was listed for LuTx due to end-stage chronic obstructive pulmonary disease and who developed drug-induced acute hepatic failure. The only therapeutic option was hyper-urgent cLiLuTx. To correct the poor coagulation in order to reduce the per-operative risk of bleeding, the liver was transplanted first. In anticipation of the longer lung preservation time, cold flushed lungs were preserved on a portable lung perfusion device for ex vivo normothermic perfusion for 11 h 15 min, transplanted sequentially off-pump, and reperfused after a total ex vivo time of 13 h 32 min and 16 h for the first and second lung, respectively. Ten months later, the patient is doing well and no rejection occurred. Normothermic ex vivo lung perfusion may help to prolong preservation time, facilitating long-distance transport and combined organ transplantation.

Combined kidney and intestinal transplantation in patients with enteric hyperoxaluria secondary to short bowel syndrome.

Kidney transplantation is the treatment of choice for end-stage renal disease whereas indications for intestinal transplantation are currently restricted to patients with irreversible small bowel failure and severe complications of total parenteral nutrition (mostly shortage and infection of venous accesses, major electrolyte disturbances and liver failure). Enteric hyperoxaluria is secondary to certain intestinal diseases like intestinal resections, chronic inflammatory bowel disease and other malabsorption syndromes and can lead to end-stage renal disease requiring kidney transplantation. We report two patients suffering from renal failure due to enteric hyperoxaluria (secondary to extensive intestinal resection) in whom we elected to replace not only the kidney but also the intestine to prevent recurrence of hyperoxaluria in the transplanted kidney.

Sarcopenia in end-stage liver disease and after liver transplantation.

Sarcopenia occurs in 30-70% of patients with end-stage liver disease and is associated with inferior pre- and post-liver transplant outcomes such as prolonged intubation times, long intensive care and hospitalization times, heightened risk of post-transplant infection, reduced health-related quality of life, and increased rates of mortality. The pathogenesis of sarcopenia is multifactorial and involves biochemical disturbances such as hyperammonemia, low serum concentrations of branched-chain amino acids (BCAAs) and low serum levels of testosterone, as well as chronic inflammation, inadequate nutritional status, and physical inactivity. Prompt recognition and accurate assessment of sarcopenia are critical and require imaging, dynamometry, and physical performance testing for the assessment of its subcomponents: muscle mass, muscle strength, and muscle function, respectively. Liver transplantation mostly fails to reverse sarcopenia in sarcopenic patients. In fact, some patients develop de novo sarcopenia after undergoing liver transplantation. The recommended treatment of sarcopenia is multimodal and includes a combination of exercise therapy and complementary nutritional interventions. Additionally, new pharmacological agents (e.g. myostatin inhibitors, testosterone supplements, and ammonia-lowering therapy) are under investigation in preclinical studies. Here, we present a narrative review of the definition, assessment, and management of sarcopenia in patients with end-stage liver disease prior to and after liver transplantation.

Cost-effectiveness of hypothermic machine preservation versus static cold storage in renal transplantation.

Static cold storage (CS) is the most widely used organ preservation method for deceased donor kidney grafts but there is increasing evidence that hypothermic machine perfusion (MP) may result in better outcome after transplantation. We performed an economic evaluation of MP versus CS alongside a multicenter RCT investigating short- and long-term cost-effectiveness. Three hundred thirty-six consecutive kidney pairs were included, one of which was assigned to MP and one to CS. The economic evaluation combined the short-term results based on the empirical data from the study with a Markov model with a 10-year time horizon. Direct medical costs of hospital stay, dialysis treatment, and complications were included. Data regarding long-term survival, quality of life, and long-term costs were derived from literature. The short-term evaluation showed that MP reduced the risk of delayed graft function and graft failure at lower costs than CS. The Markov model revealed cost savings of $86,750 per life-year gained in favor of MP. The corresponding incremental cost-utility ratio was minus $496,223 per quality-adjusted life-year (QALY) gained. We conclude that life-years and QALYs can be gained while reducing costs at the same time, when kidneys are preserved by MP instead of CS.

An unusual case of rectal perforation after liver transplantation.

We present the case of a 50-year-old patient in whom an anastomotic biliary stricture after liver transplantation was treated endoscopically by sphincterotomy, dilatation and stenting using a plastic biliary stent. A distal migration of the stent caused a perforation of the rectum which was treated following stent extraction per anum -- conservatively with antibiotics and temporary bowel rest.

The prognostic value of renal resistance during hypothermic machine perfusion of deceased donor kidneys.

Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been prospectively validated. Prospectively collected RR values of 302 machine-perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1-year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 38.1 [1.56-934]; p = 0.026) [corrected] but the predictive value of RR was low, reflected by a c-statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1-year graft failure (hazard ratio 12.33 [1.11-136.85]; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand-alone quality assessment tool cannot be used to predict outcome with sufficient precision.

Testicular torsion after pediatric kidney transplantation.

Kidney transplantation has become the treatment of choice for children with end-stage renal disease and offers recipients an excellent quality of life. Following kidney transplantation several types of medical and surgical complications can arise. In this report, a testicular torsion occurring on the sixth day after pediatric kidney transplantation is described. It remains unclear whether this unusual complication should be regarded as coincidental or as a direct consequence of the transplantation.

Acute appendicitis after liver transplantation: a case report and review of the literature.

INTRODUCTION: Acute appendicitis is rarely seen after liver transplantation. CASE: We present a case of acute appendicitis 16 days after liver transplantation. CT-scan suggested this diagnosis, but there were also signs of biliary leakage. Surgical exploration only revealed an acute appendicitis and an appendectomy was performed. Histological examination confirmed the diagnosis. Postoperative course was uneventful. LITERATURE: Until now only 15 cases of acute appendicitis after liver transplantation have been reported. CT-scan is considered to be an accurate diagnostic tool. The duration of hospitalization after appendectomy seems to be longer in the immunosuppressed patient. CONCLUSION: Although acute appendicitis is not common after liver transplantation, quick diagnosis and treatment can prevent major complications.

Successful conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium (myfortic) in liver transplant patients with gastrointestinal side effects.

OBJECTIVE: Gastrointestinal discomfort is one of the main adverse events in patients treated with mycophenolic acid (MPA). The aim of this prospective study was to evaluate the effect of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in liver transplant patients with gastrointestinal side effects. MATERIALS AND METHODS: A single center, open-label, single arm, prospective study was undertaken in previous MMF-treated liver transplant patients who stopped MMF due to gastrointestinal side effects. Patients were rechallenged with the same dose of MMF which previously provoked the discomfort. Subsequently, patients with gastrointestinal complaints were switched from MMF (mean dose, 1325 mg [interquartile range (IQR), 750-2000 mg]) to equimolar doses of EC-MPS (mean dose, 858 mg [IQR, 525-1170 mg]). RESULTS: Twelve patients received a rechallenge and 10 patients experienced complaints again. These patients (4 males, all Caucasian) of ages 14 to 68 years (mean, 54.5 years) were included in the study. There was a decrease in Visual Analogue Scale (VAS) of upper and lower gastrointestinal discomfort/pain between baseline to month 3 from mean 3.9 to 1.75 and from mean 7.6 to 0.2. The number of stools decreased from a mean of 2.25 (IQR, 1.4-2.9) to 0.5 (IQR, 0.3-0.625)/d and mean maximal stool frequency from 3 (IQR, 2-3.5) to 0.9 (IQR, 0.5-1.25)/d. No patients developed rejection. There was no graft loss. No significant changes occurred in hematological or biochemical parameters. CONCLUSIONS: Our results suggested that converting patients with gastrointestinal complaints from MMF to equimolar doses of EC-MMF reduced gastrointestinal-related symptom burden and frequency of stools.

Hypothermic Liver Machine Perfusion With EKPS-1 Solution vs Aqix RS-I Solution: In Vivo Feasibility Study in a Pig Transplantation Model.

OBJECTIVE: Hypothermic machine perfusion (HMP) is superior to simple cold storage for kidney preservation. We previous observed in a porcine liver transplantation model increased tumor necrosis factor-alpha (TNF-alpha) production eventually leading to poor recipient survival after HMP using standard kidney perfusion solution (KPS-1) compared with simple cold storage. We compared two solutions for HMP preservation of the liver: enriched KPS-1 (EKPS-1) and Aqix RS-I. METHODS: Pig livers were obtained after cold flushing with histidine-tryptophan-ketoglutarate solution. Subsequently, the livers were subjected to dual-vessel perfusion with two preservation solutions: EKPS-1 (n = 6) and Aqix RS-I (n = 3). After HMP preservation and transplantation, graft and recipient survival, hepatocellular damage (aspartate aminotransferase concentration), TNF-alpha production, and endothelial cell damage (hyaluronic acid clearance) were recorded. RESULTS: No primary graft nonfunction was observed. Recipient survival at postoperative day 3 was similar in both groups (33%). Aspartate aminotransferase concentration measured in serum samples after reperfusion was similar in both groups. After reperfusion, TNF-alpha concentration was higher and hyaluronic acid clearance was lower in the EKPS-1 group vs the Aqix RS-I group at 60, 120, and 180 minutes (all P < .05). CONCLUSION: Hypothermic machine perfusion provided adequate longer term graft survival. After reperfusion, TNF-alpha production seems to be reduced, and endothelial cell dysfunction remains pronounced with Aqix RS-1 solution compared with EKPS-1 solution.

Pancreas transplantation: towards minimization of technical graft loss.

The objective of the study is to determine whether evolution in surgical techniques results in minimization of technical graft loss after simultaneous pancreas-kidney transplantation (SPKTx). Eighty consecutive patients with insulin-dependent diabetes mellitus and end-stage nephropathy, and who received SPKTx, were studied. Patient, pancreas and kidney survival at 5 years were 89, 84 and 84% respectively. The porto-systemic venous anastomosis laterally to the arterial vessels resulted in exclusion of technical graft loss due to venous thrombosis. The switch from exocrine bladder drainage to enteric drainage lowered significantly the posttransplant surgical morbidity. This series indicates that excellent short- and long-term survival can be obtained after SPKTx and this with a low perioperative surgical morbidity.

Evolution in allocation rules for renal, hepatic, pancreatic and intestinal grafts.

Organ transplantation is the victim of his own success. The results of transplantation are excellent and more patients are activated on the waiting list. The need for organs exceeds the supply. Which criteria are used to allocate available grafts to patients on the waiting list ? Organ allocation and finding the "best match" between donor and recipients, is the goal of Eurotransplant, the organ sharing organization for seven European countries (Austria, Croatia, Germany, Luxemburg, Slovenia, The Netherlands and Belgium). Last decade, the allocation system has switched from a "center-driven" (organ allocated to a center) to a "patient-driven" system (organ allocated to a particular patient). For the allocation of abdominal organs some general allocation rules are followed: blood group compatibility, priority for high urgencies. The allocation of kidneys is based on a point score system based on waiting time, HLA and donor location (to reduce the cold ischemia time). In addition to this standard allocation procedure, there are still specific procedures for pediatric recipients and for candidates > or = 65 year old. There is also an "acceptable" mismatch program for recipients at high immunological risk. The liver allocation system recently changed and is now based on the MELD score, a formula that calculates the probability of death within 3 months on the waiting list. For pancreas and intestine, the system is based on blood group, medical urgency, waiting time, donor region and weight (for intestine).

Liver transplantation from non-heart-beating donors: current status and future prospects in an experimental model.

The widening gap between supply and demand for liver transplantation has prompted many transplant centers to use donors after cardiac death or non-heart-beating donors. These livers--contrary to "classical" brain-dead donors--are exposed to an unavoidable period of warm ischemia, jeopardizing graft function post-transplantation. In a newly developed preclinical model of liver transplantation, we studied--in a biologically unmodified environment--the exact tolerance of the liver to warm ischemia. Following the evidence that liver transplantation from non-heart-beating donors is feasible and safe, provided that warm and cold ischemia are kept short, a clinical programme of liver transplantation from non-heart-beating donors was successfully initiated in our and other Belgian centers. Recently, we demonstrated that the tolerance of such livers to warm ischemia could be substantially improved when some of the previously identified mechanisms leading to graft non-function were tackled by a multi-factorial pharmacological strategy. Meanwhile, cold storage has proven to be insufficient to optimally preserve organs from non-heart-beating donors. As an alternative, machine perfusion preservation was found to consistently improve outcome in kidney transplantation from non-heart-beating donors. Similarly, machine perfusion preservation could improve the preservation of livers, allowing to predict viability prior to transplantation and to ameliorate tolerance to warm ischemia. At present, the definition and development of optimal machine perfusion settings are under investigation at our institution.