Anti-TNF-alpha therapy for acute rejection in intestinal transplantation

INTRODUCTION: We present our experience with infliximab rescue therapy for steroid- and OKT3-resistant rejection after intestinal transplantation (ITx). METHODS: Twelve ITx and one multivisceral transplant recipients were immunosuppressed with tacrolimus, rapamycin, daclizumab, steroids (n = 10) or tacrolimus, campath, and steroids (n = 3). RESULTS: In two patients, severe acute rejection did not resolve despite steroid bolus therapy plus 5 to 10 days of OKT3 treatment. Signs of moderate rejection persisted in the distal portions of the grafts. Treatment with infliximab, a chimeric anti-TNF-alpha antibody (four infusions of 3 mg/kg body weight), induced a complete remission of histological and clinical signs of rejection. Two further patients with steroid-resistant rejection received two courses of infliximab (3 mg/kg body weight) as antirejection therapy. All rejection episodes resolved completely. CONCLUSIONS: Infliximab effectively treats steroid and OKT3 resistant acute rejection episodes of intestinal transplantations.     

Bacteremia after intestinal transplantation in children correlates temporally with rejection or gastrointestinal lymphoproliferative disease

BACKGROUND: Bacteremia occurs frequently after intestinal transplantation (ITx) in children. During our initial experience with this procedure, we noted that bacteremic episodes tended to occur simultaneously with the presence of rejection and/or gastrointestinal (GI) posttransplant lymphoproliferative disease (PTLD). AIM: To document the association of bacteremia with rejection and GI PTLD in pediatric ITx recipients. METHODS: Retrospective analysis of all medical records from 62 children who underwent ITx between July 1990 and January 1998 at Children's Hospital of Pittsburgh. A bacteremic episode was defined as two positive blood cultures from different sites at the same time or from the same site at different times. Rejection and PTLD were defined using previously published criteria. RESULTS: A total of 39/62 ITx recipients had 133 blood stream infections (2.1 episodes/patient) including 121 episodes of bacteremia and 12 of fungemia. Enteric organisms were the most frequently recovered pathogens (Gram negative rods, n=76; enterococci, n=36). Enteric organisms were recovered as a single organism (n=57), with another enteric bacteria (n=23), or with coagulase negative staphylococci (CONS) (n=24). CONS were recovered as a single organism on 21 occasions. An obvious source of bacteremia was not found for 115/121 episodes. Endoscopy was performed for 107 of the 115 bacteremia episodes; an abnormal histology was identified in 74 revealing rejection (n=36), GI PTLD (n=21), or both (n=17). When endoscopy showed GI pathology, enteric organisms alone or in combination with CONS were recovered on 63/107 occasions, although CONS were recovered alone only 11 times. CONCLUSIONS: Bacteremia accompanies GI rejection and intestinal PTLD in ITx recipients. Endoscopy should be performed to inspect the allograft when bacteremia occurs without an obvious source in these patients. This is especially true for patients with bacteremia due to enteric organisms.     

Italian experience in adult clinical intestinal and multivisceral transplantation: 6 years later

PATIENTS AND METHODS: Between December 2000 and November 2006, 28 isolated intestinal transplants and nine multivisceral transplants (five with liver) from cadaveric donors have been performed for short gut syndrome (n = 15), chronic intestinal pseudo-obstruction (n = 10), Gardner's syndrome (n = 9), radiation enteritis (n = 1), intestinal atresia (n = 1), and massive intestinal angiomatosis (n = 1). Indications for transplantations were: loss of venous access, recurrent sepsis due to central line infection, and/or major electrolyte and fluid imbalance. Liver dysfunction was present in 19 cases. All patients were adults of median age at transplant of 34.7 years and mean weight 59.6 kg. All recipients were on total parenteral nutrition for a mean time of 38.8 months. Mean donor/recipient body weight ratio was 1.1. RESULTS: The mean follow-up was 892 +/- 699 days. Twenty-five patients were alive (67.5%) with 3-year patient survivals of 70% for isolated intestinal transplantations and 41% for the multivisceral transplantations (P = .01). The mortality rate was 32.5% with losses due to sepsis (63%) or rejection. Our 3-year graft survival rates were 70% for isolated intestinal transplantations and 41% for multivisceral transplantations (P = .02); graftectomy rate was 16%. These were 88% of grafts working properly with patients on regular diet with no need for parenteral nutrition. DISCUSSION AND CONCLUSIONS: Induction therapy has reduced the doses of postoperative immunosuppressive agents, especially in the first period, lowering the risk of renal failure and sepsis, mucosal surveillance protocol for early detection of rejection dramatically reduced the number of severe acute chronic rejections.     

Characterization of T cell immunophenotypes in intestinal transplantation: A pilot study

Immunophenotyping of peripheral blood mononuclear cells has been shown to be a useful, non-invasive method of predicting acute cellular rejection (ACR) following intestinal transplantation (ITx). Our objectives were to characterize differences in the T cell immunophenotype of ITx recipients in peripheral blood samples (1) collected late versus early after ITx and (1) associated with episodes of ACR and infectious enteritis. An IRB-approved, cross-sectional study of ITx recipients was performed. Peripheral blood samples were collected during normal visits and episodes of allograft dysfunction. A total of 38 patients were included in the analysis: 31 ITx recipients (87% liver-inclusive allografts) and 7 intestinal failure control patients. Of the ITx patients, 26 patients were pediatric patients (<21 years). A total of 70 samples were analyzed from ITx recipients, including 51 during normal visits and 19 during episodes of allograft dysfunction (median of 2 samples per patient; range of 1–6 samples per patient). In the late (n = 32) versus early post-ITx (n = 19) normal samples, there was a significantly higher percentage of central memory CD4 T cells (p = .001). In the ACR (n = 5) versus infectious enteritis (n = 14) samples, there was a higher percentage of CD8 T cells expressing HLA-DR (p = .002), CD57 (p < .001), and KLRG1 (p < .001) and a higher percentage of CD4 T cells expressing CD57 (p = .03). Additional studies are needed with larger cohorts to validate these changes in the T cell immunophenotype. Further elucidating T cell immunophenotypes in ITx will lead to a better understanding of immune mechanisms of allograft dysfunction, identification of potential biomarkers in ITx, and optimized selection of immunosuppressive therapies.     

Improved outcome after intestinal transplantation at a single institution over 12 years

PURPOSE: To evaluate the outcomes of patients undergoing intestinal transplantation (IT). METHODS: Retrospective review was undertaken using existing medical records and database. RESULTS: Between November 1991 and May 2003, 114 patients were referred for consideration for IT, of which 33 patients received 37 intestinal allografts. All patients had intestinal failure and all patients had significant complications from total parenteral nutrition (TPN). TPN was the predominant cause of liver failure (63%). Combined liver intestinal grafts were used in the majority of patients. Overall 1- and 3-year patient survival is 77% and 52% with patients transplanted since 1999 having a 1- and 3-year survival of 94% and 73%, respectively. The most common cause of death was sepsis. No graft or patient was lost to cytomegalovirus or Epstein-Barr virus disease. Twenty-seven percent of allografts were lost to rejection. Long-term TPN independence is 82% for grafts more than 30 days after IT. Statistical analysis revealed several important factors impacting outcome. CONCLUSIONS: Successful IT defined as prolonged patient and graft survival and TPN independence can be readily achieved in select patients with IF and complications related to TPN therapy. Outcomes have improved with experience gained and control of viral infections and rejection.     

Outcome analysis of 71 clinical intestinal transplantations.

OBJECTIVE: The aim of the study was to determine risk factors associated with graft failure and mortality after transplantation of the intestine alone or as part of an organ complex. SUMMARY BACKGROUND DATA: Even with modern immunosuppressive therapies, clinical intestinal transplantation remains a difficult and unreliable procedure. Causes for this and solutions are needed. METHODS: Between May 1990 and February 1995, 71 intestinal transplantations were performed in 66 patients using tacrolimus and low-dose steroids. The first 63 patients, all but one treated 1 to 5 years ago, received either isolated grafts (n = 22), liver and intestinal grafts (n = 30), or multivisceral grafts (n = 11). Three more recipients of allografts who recently underwent surgery and one undergoing retransplantation were given unaltered donor bone marrow cells perioperatively as a biologic adjuvant. RESULTS: Of the first 63 recipients, 32 are alive: 28 have functioning primary grafts and 4 have resumed total parenteral nutrition after graft enterectomy. Thirty-five primary grafts were lost to technical and management errors (n = 10), rejection (n = 6), and infection (n = 19). Regression analysis revealed that duration of surgery, positive donor cytomegalovirus (CMV) serology, inclusion of graft colon, OKT3 use, steroid recycle, and high tacrolimus blood levels contributed to graft loss. All four intestine and bone marrow recipients are alive for 2-3 months without evidence of graft-versus-host disease. CONCLUSION: To improve outcome after intestinal transplantation with previous management protocols, it will be necessary to avoid predictably difficult patients, CMV seropositive donors, and inclusion of the graft colon. Bone marrow transplantation may further improve outcome by ameliorating the biologic barriers of rejection and infection and allowing less restrictive selection criteria.     

Association of emergence of HLA antibody and acute rejection in intestinal transplant recipients: a possible evidence of acute humoral sensitization

Development of HLA antibody has been associated with chronic allograft failure in kidney recipients. We tested HLA antibody in posttransplant sera of intestinal recipients: 126 sera from 28 pediatric recipients were tested for HLA antibody by flow PRA (f-PRA). Median age was 1.1 years (0.44-17). Graft types included isolated intestine (n = 6), liver and intestine (n = 3), modified multivisceral (n = 3), and multivisceral grafts (n = 16). Greater than 10% of either class I (CI) or class II (CII) f-PRA was considered positive, and >30% strongly positive. Five of 28 patients had positive f-PRA in multiple samples; the remaining 23 had either no positive or only one positive sample. Three patients had strongly positive f-PRA. Patients with multiple positive samples were recipients of two modified multivisceral and three multivisceral grafts. Only one of these patients had a positive PRA pretransplant. Cytotoxic cross-match at transplant was negative for all. The three with strongly positive f-PRA showed significant episodes of rejection around the time of positive samples. One of them who persistently had f-PRA value >80% (from day 13-113) died of refractory rejection. The other two had f-PRA of 76% and 53% during the early postoperative course with associated episodes of rejection. F-PRA value decreased with rejection therapy. Only one of the 23 patients (4%) with negative f-PRA had an episode of rejection around the time of sample collection. Development of HLA antibody after intestinal transplantation seems to have significant association with acute rejection episodes.     

Ninety-five cases of intestinal transplantation at the university of Miami

Intestinal failure requiring total parenteral nutrition (TPN) is associated with significant morbidity and mortality. Intestinal transplantation can be a lifesaving option for patients with intestinal failure who develop serious TPN-related complications. The aim of this study was to evaluate survival, surgical technique, and patient care in patients treated with intestinal transplantation. We reviewed data collected from 95 consecutive intestinal transplants performed between December 1994 and November 2000 at the University of Miami. Fifty-four of the patients undergoing intestinal transplantation were children and 41 were adults. The series includes 49 male and 46 female patients. The causes of intestinal failure included mesenteric venous thrombosis (n = 12), necrotizing enterocolitis (n = 11), gastroschisis (n = 11), midgut volvulus (n = 9), desmoid tumor (n = 8), intestinal atresia (n = 6), trauma (n = 5), Hirschsprung’s disease (n = 5), Crohn’s disease (n = 5), intestinal pseudoobstruction (n = 4), and others (n = 19). The procedures performed included 27 isolated intestine transplants, 28 combined liver and intestine transplants, and 40 multivisceral transplants. Since 1998, we have been using daclizumab (Zenepax) for induction of immunosuppression and zoom videoendoscopy for graft surveillance. We began to use intense cytomegalovirus prophylaxis and systemic drainage of the portal vein. The 1-year patient survival rates for isolated intestinal, liver and intestinal, and multivisceral transplantations were 75%, 40%, and 48%, respectively. Since 1998, the 1-year patient and graft survival rates for isolated intestinal transplants have been 84% and 72%, respectively. The causes of death were as follows: sepsis after rejection (n = 14), respiratory failure (n = 8), sepsis (n = 6), multiple organ failure (n = 4), arterial graft infection (n = 3), aspergillosis (n = 2), post-transplantation lymphoproliferative disease (n = 2), intracranial hemorrhage (n = 2), and fungemia, chronic rejection, graft vs. host disease, necrotizing enterocolitis, pancreatitis, pulmonary embolism, and viral encephalitis (n = 1 case of each). Intestinal transplantation can be a lifesaving alternative for patients with intestinal failure. The prognosis after intestinal transplantation is better when it is performed before the onset of liver failure. Rejection monitoring with zoom videoendoscopy and new immunosuppressive therapy with sirolimus, daclizumab, and campath-1H have contributed to the improvement in patient survival. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (oral presentation).     

Outcome after intestinal transplantation: results from one center's 9-year experience; discussion 1031-2

HYPOTHESIS: Outcomes after intestinal transplantation have improved during the past decade with refinements in surgical techniques as well as advances in immunosuppression and antimicrobial therapy. DESIGN: Retrospective analysis. SETTING: Tertiary care medical center, August 1991 through December 2000. PATIENTS: Adult (5) and pediatric (12) patients with intestinal failure. All developed complications from long-term total parenteral nutrition therapy. Median age was 8.6 years and median weight was 22 kg. INTERVENTIONS: Primary intestinal transplantation with (n = 14) or without (n = 3) the liver. MAIN OUTCOME MEASURES: Patient and graft survival, viral infections, rejection, and nutritional autonomy. RESULTS: Twenty-one intestinal grafts were transplanted into the 17 recipients. All donors were cadaveric and were matched by ABO blood group and size. Patient survival at 1 and 3 years was 63% and 55%, respectively. Death-censored graft survival at 1 and 3 years was 73% and 55%, respectively. There were 1.5 acute cellular rejection episodes per graft and 3 grafts were lost to rejection. Incidences of infection with the Epstein-Barr virus and cytomegalovirus were negligible with aggressive prophylaxis and preemptive therapy. Nutritional autonomy was achieved in 69% of grafts surviving more than 30 days after intestinal transplantation. CONCLUSIONS: Intestinal transplantation is now the standard of therapy for patients with intestinal failure and complications resulting from total parenteral nutrition. Outcomes have markedly improved since initiation of the program. Aggressive immunosuppression as well as prophylaxis and preemptive antiviral therapy have led to low incidences of acute cellular rejection, Epstein-Barr virus, and cytomegalovirus. Finally, nutritional autonomy can be achieved after successful intestinal transplantation.     

Italian guidelines for intestinal transplantation: potential candidates among the adult patients managed by a medical referral center for chronic intestinal failure

In 2002, the Italian guidelines for eligibility of patients for intestinal transplantation (ITx) were defined as: life-threatening complications of home parenteral nutrition (HPN), lack of venous access for HPN, locally invasive tumors of the abdomen, Chronic intestinal failure (CIF) with a high risk of mortality, primary disease-related poor quality of life (QoL) despite optimal HPN. Our aim was to identify potential candidates for ITx according to these national guidelines among patients managed by a medical referral center for CIF. Records of patients who received HPN were reviewed. CIF was considered reversible or irreversible (energy by HPN <50% or >50% basal energy expenditure). Patients with irreversible CIF were considered eligible for ITx in the absence of a contraindication, as are used for solid organs Tx. From 1986 to 2003 among 64 patients who met the entry criteria 23 showed reversible and 41 irreversible, CIF. Twenty-one patients with irreversible CIF had an indication for ITx, but eight had also contraindications; thus 13 were eligible, including intestinal pseudo-obstruction (n = 6), mesenteric ischemia (n = 3), Crohn's (n = 2), radiation enteritis (n = 1), and desmoid (n = 1). Indications for ITx included HPN liver failure (n = 2), lack of venous access (n = 2), CIF with high risk of mortality (n = 3), very poor QoL (n = 6 including 5 with pseudo-obstruction). According to the Italian guidelines for ITx, 31% of patients with irreversible CIF managed by a medical referral center were eligible for ITx. Primary disease-related poor QoL was the indication in half of them. Studies on the QoL after ITx are required to allow patients to make an educated decision.     

Infectious enteritis after intestinal transplantation: incidence, timing, and outcome

BACKGROUND: The study reviews the incidence, timing, and outcome of infectious enteritis (IE) after intestinal transplantation (ITx). METHODS: A retrospective review of all patients who underwent ITx at a single institution between 1991 and 2003 was undertaken using database and medical records. Standard statistical analyses were performed. RESULTS: Of 33 ITx recipients, 13 (39%) developed 20 culture- or biopsy-proven episodes of IE. Recipient demographics included the following: 10 males, median age 34 (10-585) months, 11 liver + intestine grafts, and two isolated intestine grafts. Infections were diagnosed a median of 76 days (32-1,800 days) after ITx. There were 14 viral (one cytomegalovirus, eight rotavirus, four adenovirus, one Epstein-Barr virus), three bacterial (Clostridium difficile), and three protozoal (one Giardia lamblia, two Cryptosporidium) infections. The bacterial infections tended to present earlier than the viral infections, and the most frequent presenting symptom was diarrhea. Complete resolution was achieved in 17 (94%) incidences with the appropriate antimicrobial or conservative therapy. It was interesting that there were seven rejection episodes documented by biopsy at the approximate time of diagnosis of IE. There were two graft losses: one because of adenoviral enteritis and one because of rejection after rotavirus enteritis. Three-year patient survival is 74% with no deaths directly attributable to IE. CONCLUSIONS: IE can occur in 39% of recipients after ITx. Viral agents are the cause in two thirds of the cases. With supportive care and appropriate treatment, resolution is possible in the majority of cases. Differentiating rejection and infection on histopathology can be difficult and relies on cultures and immunostaining.     

Intestinal and multivisceral transplantation after abdominal trauma

SUMMARY: BACKGROUND Some trauma victims who survive acute illness develop lingering, debilitating syndromes that are incompatible with any semblance of normalcy. Intestinal failure, in particular, exacts a high price in terms of quality of life. Total parenteral nutrition (TPN) has served these patients well, but complications limit its long-term therapeutic effect. Consequently, transplantation is emerging as a life-saving therapy for some patients with the short gut syndrome.METHODS We reviewed eight adult and two pediatric recipients of intestinal and multivisceral transplants after severe abdominal trauma. Background demographics, type of abdominal trauma, transplant procedure, postoperative complications, and survival rates were appraised. This group was also compared with 47 nontrauma recipients of intestinal transplants performed during the same period.RESULTS Four patients (40%) died postoperatively (postoperative days 7, 53, 87, and 91) as a result of multiple organ failure after graft pancreatitis (n = 1), viral encephalitis (n = 1), and sepsis after severe rejection (n = 2). Six patients (60%) are alive (postoperative days 52-1,783). All are off TPN. The 4-year patient survival was 58%, with no significant difference between trauma and nontrauma patients.CONCLUSION Intestinal and multivisceral transplantation are viable options for the treatment of irreversible intestinal failure associated with severe trauma. Surviving patients are TPN independent and have a satisfactory quality of life.     

Intestinal transplantation for total intestinal aganglionosis: a series of 12 consecutive children

Background

Management of patients with total intestinal aganglionosis (TIA) is a medical challenge because of their dependency on parenteral nutrition (PN). Intestinal transplantation (ITx) represents the only alternative treatment for patients with irreversible intestinal failure for achieving intestinal autonomy.

Methods

Among 66 patients who underwent ITx in our center, 12 had TIA. They received either isolated ITx (n = 4) or liver-ITx (LITx, n = 8) after 10 to 144 months of total PN. All grafts included the right colon.

Results

After a median follow-up of 57 months, the survival rate was 62.5% in the LITx group and 100% in the ITx patients. The graft survival rate was 62.5% in the LITx group and 75% in the ITx group. All the surviving patients were fully weaned from total PN, after a median of 57 days. Pull through of the colon allograft was carried out in all patients. Fecal continence is normal in all but one of the surviving children.

Conclusion

These results suggest that ITx with colon grafting should be the preferred therapeutic option in TIA. Early referral to a transplantation center after diagnosis of TIA is critical to prevent PN-related cirrhosis and thereby to permit ITx, which is associated with a good survival rate.     

Twenty-five consecutive isolated intestinal transplants in adult patients: a five-yr clinical experience

PATIENTS AND METHODS: Between December 2000 and December 2005, 25 isolated intestinal transplants from cadaveric donors have been performed for short gut syndrome (short bowel syndrome, 52%), chronic intestinal pseudo-obstruction (24%), Gardner syndrome (16%), radiation enteritis (4%) and massive intestinal angiomatosis (4%). Indications for transplantation were: loss of venous access, recurrent sepsis due to central line infection, major electrolyte and fluid imbalance. Liver dysfunction was present in 13 cases. All patients were adult; median age was 36.3 yr and mean weight at transplantation 61.6 kg. All recipients were on life-threatening parenteral nutrition for a mean time of 23.7 months. Mean donor/recipient body weight ratio was 1.08. Rejection monitoring was accomplished by graft ileoendoscopies and intestinal biopsies through the temporary ileostomy. Our immunosuppressive regimen was based on induction therapy with three different protocols: daclizumab for induction, tacrolimus and steroids as maintenance therapy; alemtuzumab for induction and low-dose tacrolimus as maintenance; thymoglobulin for induction and maintenance based on low-dose tacrolimus. Closure of the abdomen at the end of transplantation represented a technical problem with several options performed: graft reduction, only skin closure, prothesic meshes, abdominal closure in two steps, cutaneous flaps and abdominal wall transplant in one case. RESULTS: The mean hospital stay was 37 days. The mean follow-up 27 months. Twenty patients are alive (80%) with two- and five-yr patient survival rate of 80% and 66%; mortality rate was 20% due to sepsis in all cases. Our two- and five-yr graft survival rate is 76% and 64%, graftectomy rate was 16%. Sixteen grafts are working properly, with no need of parenteral nutrition. We diagnosed 35 mild acute cellular rejection (ACRs), seven moderate ACRs and three severe ACRs (two needed graftectomy). We experienced two episodes of chronic rejection biopsy-proven. Rapamicine was added in case of renal failure or biopsy-proven intestinal rejection. Graft-vs.-host disease was not seen in our series while post-transplant lymphoproliferative disease in two cases. After discharge, the most common indication for medical support was dehydration. The abdominal wall transplant did not experience any rejection. DISCUSSION AND CONCLUSIONS: Induction therapy has reduced the amount of postoperative immunosuppressive agents, especially in the first period, lowering the risk of renal failure and sepsis and the mucosal surveillance protocol for early detection of rejection dramatically reduced the number of severe ACR.     

Incidence of graft rejection in small bowel transplanted pigs after immunosuppression withdrawal

As intestinal grafts require heavy immunosuppression, there are no reports of immunosuppression withdrawal after clinical small bowel transplantation. In this large-animal study, we investigated the occurrence of graft rejection in intestinal-transplanted pigs after withdrawal. Large-White unrelated piglets were transplanted and divided in three groups: group 1 (n = 5), intestinal transplantation (ITx) with no immunosuppression; group 2 (n = 7), Itx and 60 days of treatment with tacrolimus and mycophenolate mofetil; group 3 (n = 5), Itx and donor bone marrow infusion (DBMi) and 60 days of treatment with tacrolimus and mycophenolate mofetil. Follow-up time after withdrawal was 120 days. Group 1 pigs died of graft acute cellular rejection (ACR) after a median of 11 days. In group 2, two pigs died of ACR-related infection and another two of ACR within 90 days. The remaining three animals (43%) were sacrificed at day 180, and their grafts showed no signs of ACR. In group 3, two pigs died of ACR-related infection and one of graft versus host disease within 80 days; at day 180 the two surviving animals showed signs of chronic rejection in the allograft. This study demonstrates that total withdrawal after ITx is followed by sudden and lethal ACR (or ACR-related infection) in more than 50% of the recipients. When a tolerance-inducing strategy as DBMi is applied, lethal graft versus host disease may also occur. In group 3, the intestinal allograft, to which the recipients were partially tolerant, developed chronic rejection that was probably associated with a decline with time of donor-leukocytes chimerism, as recently demonstrated in rats.     

Long-term outcome of immunosuppression withdrawal after liver transplantation

Eighteen liver transplant recipients were followed up for 10 years after a trial of immunosuppression withdrawal. Three groups were identified according to the early outcome of complete (group A, n = 5), partial (group B, n = 9), and unsuccessful (group C, n = 4) withdrawal of immunosuppression. The indications for liver transplantation (LT) (August 1983-December 1988) were as follows: primary biliary cirrhosis (n = 3), primary sclerosing cholangitis (n = 3), Budd-Chiari syndrome (n = 3), acute liver failure (n = 3), hepatitis C virus (HCV) cirrhosis (n = 1), HCV and autoimmune hepatitis (n = 1), HCV and alcohol-related cirrhosis (n = 1), HCV and hepatocellular carcinoma (HCC) (n = 1), cystic fibrosis (n = 1), and liver metastases from testicular teratoma (n = 1). Immunosuppression was based on cyclosporine. All patients experienced 1 or more complications of prolonged immunosuppression (median, 7 years; range, 5-11). Thirteen patients (72%) are alive at a median interval of 17 years (range, 16-21) after LT. Of the 5 patients in group A, 2 currently have normal graft function with no rejection episodes, and 3 have restarted immunosuppression following late low-grade acute rejection (n = 1), retransplantation for chronic rejection (n = 1), and kidney transplantation (n = 1). Of the 9 patients in group B, 5 died. The deaths were due to ruptured arterial pseudoaneurysm following retransplantation, HCC recurrence, cardiac failure, renal failure, and posttransplant lymphoma at 5, 7, 7, 14, and 17 years after LT, respectively. All 4 patients in group C are alive on a full immunosuppressive regimen. Long-term follow-up of 18 LT recipients withdrawn from immunosuppression has shown that at a median of 17 years 10% of patients remain off all immunosuppression.     

Myeloid‐derived suppressor cells increase and inhibit donor‐reactive T cell responses to graft intestinal epithelium in intestinal transplant patients

Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid‐derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33⁺CD11b⁺ lineage(CD3/CD56/CD19)^?HLA‐DR^?/low cells with 3 subsets, CD14^?CD15^? (e‐MDSCs), CD14⁺CD15^? (M‐MDSCs), and CD14^?CD15⁺ (PMN‐MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa. Total MDSC numbers increased in PBMCs after ITx; among MDSC subsets, M‐MDSC numbers were maintained at a high level after 2 months post ITx. The MDSC numbers decreased in ITx recipients with ACR. MDSC numbers were positively correlated with serum interleukin (IL)‐6 levels and the glucocorticoid administration index. IL‐6 and methylprednisolone enhanced the differentiation of bone marrow cells to MDSCs in vitro. M‐MDSCs and e‐MDSCs expressed CCR1, ‐2, and ‐3; e‐MDSCs and PMN‐MDSCs expressed CXCR2; and intestinal grafts expressed the corresponding chemokine ligands after ITx. Of note, the percentage of MDSCs among intestinal mucosal CD45⁺ cells increased after ITx. A novel in vitro assay demonstrated that MDSCs suppressed donor‐reactive T cell–mediated destruction of donor intestinal epithelial organoids. Taken together, our results suggest that MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa in ITx, and may regulate ACR.     

Analysis of patients with longitudinal intestinal lengthening procedure referred for intestinal transplantation

BACKGROUND/PURPOSE: Longitudinal intestinal lengthening procedures (LILP) in patients with short gut syndrome (SGS) enhances small intestinal peristalsis and decreases bacterial overgrowth without reducing absorptive surface. Therefore, patients theoretically may be easily weaned off TPN. The aim of this study was to evaluate the impact of failed LILP in SGS patients referred for intestinal transplantation. METHODS: Twenty-seven (11%) of 230 children with SGS and total parenteral nutrition (TPN) dependency evaluated for intestinal transplantation at our institution had undergone LILP. This was performed at a mean age of 1.7 years (range, 1 day to 14.7 years); the mean age at the time of evaluation was 3.3 years (range, 0.4 to 17 years). Two patients underwent LILP immediately after birth. The principle diagnoses producing SGS were gastroschisis (n = 8), intestinal atresia (n = 11), neonatal volvulus (n = 7) and necrotizing enterocolitis (n = 1). Before LILP, the mean length of intestine was 32 cm (range, 8 to 70 cm). Fifteen (56%) patients had jaundice at the time of evaluation. RESULTS: All but one child were considered candidates for intestinal transplantation. The mean intestinal length achieved after LILP was 48 cm (range, 16 to 100). The mean follow-up from the date of LILP was 876 days (range, 109 to 4,109 days). After LILP, only 9 (33%) patients increased their caloric intake through the enteral route by > or =50%, and only 1 patient could be weaned off TPN. In the patients with liver dysfunction at the time of LILP, none recovered. Most of the patients had multiple episodes of sepsis after LILP. Fourteen (52%) of 27 patients underwent intestinal transplantation, 7 combined with a liver allograft because of TPN-induced end-stage liver disease. Six of the transplanted patients are alive and TPN free. Of the remaining 13 (48%) nontransplanted patients, 9 patients died. The main cause of death was TPN-induced liver failure. Three patients are on partial TPN, and only 1 patient was weaned off TPN. The presence of an ileocecal valve did not impact on outcome. Surprisingly, patients with > or =50% of colon at the time of LILP had poorer survival than those with less. Twelve (44%) of 27 patients had surgical complications, and in both patients with LILP performed in the neonatal period it failed immediately with acute complications. There were no differences in patient survival rate for patients with SGS without LILP (n = 203) and those with LILP (n = 27). CONCLUSION: Based on patients with unsuccessful LILP referred for intestinal transplantation, we believe this procedure should be avoided in the neonatal period, in those patients with liver dysfunction, and when intestinal length is <50 cm.     

Isolated intestinal transplants vs. liver-intestinal transplants in adult patients in the United States: 22 yr of OPTN data

We examined the outcomes of adult intestinal transplants (ITx); isolated ITx vs. liver-intestinal transplants (L-ITx) were compared using the UNOS database (1987-2009). Of 759 ITx transplants in 687 patients, 463 (61%) were isolated and 296 (39%) were L-ITx. Patient survival for primary isolated ITx at one, three, and five yr was 84%, 66.7%, and 54.2%; and primary L-ITx was, 67%, 53.3%, and 46% (p = 0.0005). Primary isolated ITx graft survival at one, three, and five yr was 80.7%, 57.6%, 42.8%; primary L-ITx was 64.1%, 51%, 44.1% (p = 0.0003 at one, three yr, Wilcoxon test). For retransplants (n = 72), patient and graft survival for isolated ITx (n = 41) at five yr was 40% in era 1 (1987-2000) and 16% in era 2 (p = 0.47); for retransplanted L-ITx (n = 31), it improved from 14% to 64% in era 2 (p = 0.01). Cox regression: creatinine >1.3 mg/dL and pre-transplant hospitalization were negative predictors for outcome of both; bilirubin >1.3 mg/dL was a negative predictor for isolated ITx and donor age >40 yr for L-ITx. Isolated ITx should be considered prior to liver disease for adults with intestinal failure; L-ITx is preferable for retransplantation.     

Factors influencing outcome after intestinal transplantation in children

We evaluated 131 patients (6 months-14 years) who experienced 21 deaths before listing, 11 continuing on the waiting list, 38 well on home parenteral nutrition, 6 off parenteral nutrition and 59 transplanted (20 girls) aged 2.5 to 15 years, (18 >7 years). They received cadaveric isolated intestine (ITx, n = 31) or liver-small bowel (LITx, n = 32), including right colon (n = 43; 23 LITx) for short bowel (n = 19), enteropathy (n = 20), Hirschsprung (n = 14), or pseudo-obstruction (n = 6). Treatment included tacrolimus, steroids, azathioprine, or interleukin-2 blockers. After 6 months to 10.5 years, the patient and graft survivals were 75% and 54%. Sixteen patients (10 LITx) died within 3 months from surgery (n = 3), bacterial (n = 5) or fungal (n = 6) sepsis, or posttransplant lymphoproliferative disorder (n = 2). Rejection occurred in 27 patients, including 10 steroid-resistant episodes requiring antilymphoglobulins. The grafts were removed due to uncontrolled rejection in seven ITx recipients. Surgical complications were observed in 38 recipients (25 LSBTx) within 2 months, including bacterial (n = 22) or fungal (n = 11) sepsis, cytomegalovirus disease (n = 12), adenovirus (n = 11), or posttransplant lymphoproliferative disorder (n = 12). Forty-two children (19 LSBTx) are alive. Weaning from parenteral nutrition was achieved after 42 days (median). Factors related to death or graft loss were pre-Tx surgery (P < .01), pseudo-obstruction (P < .01), age over 7 years (P < .03), fungal sepsis (P < .03), steroid resistant rejection (P < .05), hospitalized versus home patient (P < .01), and retransplantation (P < .05). Colon transplant did not affect the outcome. Interleukin-2 blockers improved isolated ITx (P < .05). Early referral and close monitoring of intestinal failure and related disorders are mandatory to achieve successful ITx.