Laurens Ceulemans

New insights in intestinal ischemia-reperfusion injury: implications for intestinal transplantation.

Purpose of reviewIschemia–reperfusion injury is inevitable during intestinal transplantation and can negatively affect the transplant outcome. Here, an overview is provided of the recent advances in the pathophysiological mechanisms of intestinal ischemia–reperfusion injury and how this may impact graft survival. Recent findingsThe intestine hosts a wide range of microorganisms and its mucosa is heavily populated by immune cells. Intestinal ischemia–reperfusion results in the disruption of the epithelial lining, affecting also protective Paneth cells (antimicrobials) and goblet cells (mucus), and creates a more hostile intraluminal microenvironment. Consequently, both damage-associated molecular patterns as well as pathogen-associated molecular patterns are released from injured tissue and exogenous microorganisms, respectively. These ‘danger’ signals may synergistically activate the innate immune system. Exaggerated innate immune responses, involving neutrophils, mast cells, platelets, dendritic cells, as well as Toll-like receptors and complement proteins, may shape the adaptive T-cell response, thereby triggering the destructive alloimmune response toward the graft and resulting in transplant rejection. SummaryInnate immune activation as a consequence of ischemia–reperfusion injury may compromise engraftment of the intestine. More dedicated research is required to further establish this concept in man and to design more effective therapeutic strategies to better tolerize intestinal grafts.

Autophagy and the Kidney: Implications for Ischemia-Reperfusion Injury and Therapy

Autophagy, an evolutionary conserved intracellular lysosome-dependent catabolic process, is an important mechanism for cellular homeostasis and survival during pathologic stress conditions in the kidney, such as ischemia-reperfusion injury (IRI). However, stimulation of autophagy has been described to both improve and exacerbate IRI in the kidney. We summarize the current understanding of autophagy in renal IRI and discuss possible reasons for these contradictory findings. Furthermore, we hypothesize that autophagy plays a dual role in renal IRI, having both protective and detrimental properties, depending on the duration of the ischemic period and the phase of the IRI process. Finally, we discuss the influence of currently used diuretics and immunosuppressive drugs on autophagy, underscoring the need to clarify the puzzling role of autophagy in renal IRI.

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.

Belgian multicenter experience with intestinal transplantation.

Intestinal transplantation (ITx) has evolved from an experimental procedure toward a clinical reality but remains a challenging procedure. The aim of this survey was to analyze the multicenter Belgian ITx experience. From 1999 to 2014, 24 ITx in 23 patients were performed in Belgium, divided over five centers. Median recipient age was 38 years (8 months–57 years); male/female ratio was 13/10; six were children; and 17 adults. Intestinal failure was related to intestinal ischemia (n = 5), volvulus (n = 5), splanchnic thrombosis (n = 4), Crohn (n = 2), pseudo‐obstruction (n = 2), microvillus inclusion (n = 2), Churg‐Strauss (n = 1), necrotizing enterocolitis (n = 1), intestinal atresia (n = 1), and chronic rejection (n = 1). Graft type was isolated ITx (n = 9), combined liver‐ITx (n = 11) and multivisceralTx (n = 4). One was a living donor‐related transplantation and five patients received simultaneously a kidney graft. Early acute rejection occurred in 8; late acute rejection in 4; and chronic rejection in 2. Two patients developed a post‐transplant lymphoproliferative disease. Nine patients have died. Among 14 survivors at last follow‐up, 11 have been transplanted for more than 1 year. None of the latter has developed renal failure, and all were nutritionally independent with a Karnofsky score > 90%. One‐/five‐year patient and graft survivals were 71.1%, 62.8%, 58.7% and 53.1%, respectively. Based on this experience, ITx has come of age in Belgium as a lifesaving and potentially quality of life restoring therapy.

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.

Combined liver–thoracic transplantation: single-center experience with introduction of the ‘Liver-first’ principle

Combined liver/thoracic transplantation (cLiThTx) is a complex procedure for end‐stage/advanced liver and heart(H)/lung(Lu) disease. To avoid futile use of multiple organs in single recipients, results should be scrutinously analyzed. Single‐center cLiThTx (04/2000–12/2015) were reviewed for the following: demographics, indications, surgical technique, complications, rejection, and five‐year patient survival. Results are reported as median (range). Fourteen consecutive patients underwent cLiThTx: 3 cLiHTx, 10 cLiLuTx, and 1 cLiHLuTx. Recipient age was 42 years (17–63 years). Most frequent indications were cystic fibrosis (n = 5), hepatopulmonary fibrosis (n = 2), amyloidosis (n = 2), and epithelioid hemangio‐endothelioma (n = 2). Thoracic organs were transplanted first, except in three where LiTx preceded LuTx. In the latter, lungs were preserved by normothermic ex vivo lung perfusion. Stenting was performed for stenosis of bile duct (n = 4), hepatic artery (n = 2), and bronchus (n = 2). Abdominal interventions were required for bleeding (n = 3), evisceration (n = 1), and adhesiolysis (n = 1). One liver (cLiLuTx) was lost to hepatic artery thrombosis 3 months post‐transplant and successfully retransplanted. One patient (cLiHTx) died 4 months post‐transplant (myocardial infarction). Follow‐up was 4 years (2 months–16 years). One liver and 5 pulmonary rejections occurred, all mild and reversible. Two patients developed bronchiolitis obliterans, one is clinically well 16 years post‐transplant, and the other successfully retransplanted. Estimated 5‐year patient survival is 90%. CLiThTx is safe with excellent short‐/long‐term surgical and immunological results.

A weakly acidic solution containing deoxycholic acid induces esophageal epithelial apoptosis and impairs integrity in an in vivo perfusion rabbit model

Impaired esophageal mucosal integrity may be an important contributor in the pathophysiology of gastroesophageal reflux disease (GERD). Nevertheless, the effect of potentially harmful agents on epithelial integrity is mainly evaluated in vitro for a short period of time and the possible induction of epithelial apoptosis has been neglected. Our objective was to assess the effect of an acidic and weakly acidic solution containing deoxycholic acid (DCA) on the esophageal epithelium in an in vivo rabbit model of esophageal perfusion and to evaluate the role of the epithelial apoptosis. The esophagus of 55 anesthetized rabbits was perfused for 30 min with different solutions at pH 7.2, pH 5.0, pH 1.0, and pH 5.0 containing 200 and 500 μM DCA. Thereafter, animals were euthanized immediately or at 24 or 48 h after the perfusion. Transepithelial electrical resistance, epithelial dilated intercellular spaces, and apoptosis were assessed in Ussing chambers, by transmission electron microscopy, and by TUNEL staining, respectively. No macroscopic or major microscopic alterations were observed after the esophageal perfusions. The acidic and weakly acidic solution containing DCA induced similar long-lasting functional impairment of the epithelial integrity but different ultrastructural morphological changes. Only the solution containing DCA induced epithelial apoptosis in vivo and in vitro in rabbit and human tissue. In contrast to acid, a weakly acidic solution containing DCA induces epithelial apoptosis and a long-lasting impaired mucosal integrity. The presence of apoptotic cells in the esophageal epithelium may be used as a marker of impaired integrity and/or bile reflux exposure.

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.

Systematic literature review on self-reported quality of life in adult intestinal transplantation

Quality of life (QoL) gains importance in intestinal transplantation (ITx). This systematic review aimed to summarize all evidence on self-reported QoL in adult ITx. PubMed, EMBASE, CCTR, CINAHL, and PsycINFO were searched until October 2014. Structured data abstraction was performed and methodological quality was assessed using a standardized checklist. Nine eligible studies were identified addressing one or more study-aims: (i) QoL comparison pre- and post-ITx (n=4); (ii) QoL follow-up post-ITx (n=1); and (iii) QoL comparison between ITx and home parenteral nutrition (HPN) patients (n=6), healthy subjects (n=1), general population (n=1). Assessments indicated sub-optimal methodology throughout, e.g., retrospective (n=2) and cross-sectional (n=7) study designs, non-probabilistic sampling with inadequate matching of ITx subjects, non-standard terminology, lack of operational definitions and variety in assessment instruments. Still, despite these inconsistencies, this review produced three encouraging findings: (i) post-ITx QoL improved versus pre-ITx (anxiety, sleep, social support, leisure); (ii) post-ITx QoL improved with longer follow-up (anxiety, impulsiveness/control); and (iii) QoL between ITx and HPN patients was similar for most domains yet ITx patients excelled for energy, social functioning and travel ability. Although results are encouraging, QoL research in adult ITx is scarce and needs methodological improvement by implementing prospective multicenter studies, adequate QoL conceptualization and appropriate measurements.

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.