L Martin

Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges.

Objective:To assess the evolution of visceral transplantation in the milieu of surgical technical modifications, new immunosuppressive protocols, and other management strategies. Summary Background Data:With the clinical feasibility of intestinal and multivisceral transplantation in 1990, multifaceted innovative tactics were required to improve outcome and increase procedural practicality. Methods:Divided into 3 eras, 453 patients received 500 visceral transplants. The primary used immunosuppression was tacrolimus-steroid-only during Era I (5/90–5/94), adjunct induction with multiple drug therapy during Era II (1/95–6/01), and recipient pretreatment with tacrolimus monotherapy during Era III (7/01–11/08). During Era II/III, donor bone marrow was given (n = 79), intestine was ex vivo irradiated (n = 44), and Epstein-Barr-Virus (EBV)/cytomegalovirus (CMV) loads were monitored. Results:Actuarial patient survival was 85% at 1-year, 61% at 5-years, 42% at 10-years, and 35% at 15-years with respective graft survival of 80%, 50%, 33%, and 29%. With a 10% retransplantation rate, second/third graft survival was 69% at 1-year and 47% at 5-years. The best outcome was with intestine-liver allografts. Era III rabbit antithymocyte globulin or alemtuzumab pretreatment-based strategy was associated with significant (P < 0.0001) improvement in outcome with 1- and 5-year patient survival of 92% and 70%. Conclusion:Survival has greatly improved over time as management strategies evolved. The current results clearly justify elevating the procedure level to that of other abdominal organs with the privilege to permanently reside in a respected place in the surgical armamentarium. Meanwhile, innovative tactics are still required to conquer long-term hazards of chronic rejection of liver-free allografts and infection of multivisceral recipients.

Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation.

Objective:To assess long-term survival, graft function, and health-related quality of life (QOL) after visceral transplantation. Background:Despite continual improvement in early survival, the long-term therapeutic efficacy of visceral transplantation has yet to be defined. Methods:A prospective cross-sectional study was performed on 227 visceral allograft recipients who survived beyond the 5-year milestone. Clinical data were used to assess outcome including graft function and long-term survival predictors. The socioeconomic milestones and QOL measures were assessed by clinical evaluation, professional consultation, and validated QOL inventory. Results:Of 376 recipients, 227 survived beyond 5 years, with conditional survival of 75% at 10 years and 61% at 15 years. With a mean follow-up of 10 ± 4 years, 177 (92 adults, 85 children) are alive, with 118 (67%) recipients 18 years or older. Nonfunctional social support and noninclusion of the liver in the visceral allograft are the most significant survival risk factors. Nutritional autonomy was achievable in 160 (90%) survivors, with current serum albumin level of 3.7 ± 0.5 gm/dL and body mass index of 25 ± 6 kg/m2. Despite coexistence or development of neuropsychiatric disorders, most survivors were reintegrated to society with self-sustained socioeconomic status. In parallel, most of the psychological, emotional, and social QOL measures significantly (P < 0.05) improved after transplantation. Current morbidities with potential impact on global health included dysmotility (59%), hypertension (37%), osteoporosis (22%), and diabetes (11%), with significantly (P < 0.05) higher incidence among adult recipients. Conclusions:With new tactics to further improve long-term survival including social support measures, visceral transplantation has achieved excellent nutritional autonomy and good QOL.

Preformed and de novo donor specific antibodies in visceral transplantation: long-term outcome with special reference to the liver.

Despite improvement in early outcome, rejection particularly chronic allograft enteropathy continues to be a major barrier to long‐term visceral engraftment. The potential role of donor specific antibodies (DSA) was examined in 194 primary adult recipients. All underwent complement‐dependent lymphocytotoxic crossmatch (CDC‐XM) with pre‐ and posttransplant solid phase HLA–DSA assay in 156 (80%). Grafts were ABO‐identical with random HLA‐match. Liver was included in 71 (37%) allografts. Immunosuppression was tacrolimus‐based with antilymphocyte recipient pretreatment in 150 (77%). CDC‐XM was positive in 55 (28%). HLA–DSA was detectable before transplant in 49 (31%) recipients with 19 continuing to have circulating antibodies. Another 19 (18%) developed de novo DSA. Ninety percent of patients with preformed DSA harbored HLA Class‐I whereas 74% of recipients with de novo antibodies had Class‐II. Gender, age, ABO blood‐type, cold ischemia, splenectomy and allograft type were significant DSA predictors. Preformed DSA significantly (p < 0.05) increased risk of acute rejection. Persistent and de novo HLA–DSA significantly (p < 0.001) increased risk of chronic rejection and associated graft loss. Inclusion of the liver was a significant predictor of better outcome (p = 0.004, HR = 0.347) with significant clearance of preformed antibodies (p = 0.04, OR = 56) and lower induction of de novo DSA (p = 0.07, OR = 24). Innovative multifaceted anti‐DSA strategies are required to further improve long‐term survival particularly of liver‐free allografts.

Graft Versus Host Disease in Intestinal Transplantation

Our aim was to analyze the clinical course and outcome of patients with graft vs. host disease (GVHD) after intestinal transplantation (ITx). All patients receiving ITx between May, 1990 and December, 2003 were retrospectively reviewed for evidence of GVHD. Two hundred and fifty patients underwent ITx during the study period. Graft vs. host disease was suspected clinically in 23 patients on the clinical basis of presentation such as skin rash, ulceration of oral mucosa, diarrhea, lymphadenopathy, or native liver dysfunction. Fourteen (eight children and six adults) patients (5.6% of total patient population) had GVHD confirmed by histopathological criteria including keratinocyte necrosis (n = 9), epithelial apoptosis of the native gastrointestinal tract (n = 4), and epithelial cell necrosis of oral mucosa (n = 1). Donor‐cell tissue infiltration or extensive peripheral blood donor‐cell chimerism was documented on seven occasions. The majority of cases of GVHD resolved with steroid administration and optimization of tacrolimus immunosuppression.

Lymphoproliferative disorders and de novo malignancies in intestinal and multivisceral recipients: improved outcomes with new outlooks.

Background. Early experience with intestinal and multivisceral transplantation was plagued with high risk of rejection and posttransplant lymphoproliferative disorders (PTLD). To improve outcome, innovative management and immunosuppressant strategies were sequentially evolved. Methods. With initiation of the program in 1990, serial monitoring of Epstein-Barr-Viral load was introduced in 1994 with adoption of preemptive antiviral therapy. In 1995, cyclophosphamide or daclizumab induction was added to the tacrolimus-steroid-based multiple drug immunosuppressions. Such a conventional approach was replaced in 2001 with a novel immunosuppressive protocol consisting of recipient pretreatment with a single dose of rabbit antithymocyte globulin or alemtuzumab and posttransplant tacrolimus monotherapy. Results. With a total of 395 consecutive primary recipients, de novo malignancy(s) developed in 61 (15%) patients, with PTLD in 52 (13%), and nonlymphoid cancer (NLC) in 13 (3.2%). Malignancy was donor driven in 3 (4.6%) recipients and associated with graft-versus-host disease in 7 (11.4%). Children were at a significantly higher risk (P<0.001) of PTLD, and adults were more vulnerable (P=0.01) to NLC. With multivariate analyses, type of immunosuppression, recipient age, splenectomy, and treatment of rejection were significant PTLD risk factors. Conclusions. Despite pretransplant lymphoid depletion, preemptive antiviral therapy and minimization of posttransplant immunosuppression significantly reduced PTLD morbidity (P=0.0001) and mortality (P=0.001) with no impact on NLC. Patient survival was also improved (P=0.0001) with 91% at 1 year and 75% at 5 years.

Chronic rejection of small bowel grafts: pediatric and adult study of risk factors and morphologic progression.

One hundred and seventy-two patients underwent small bowel transplantation at Childrens Hospital of Pittsburgh and University of Pittsburgh Medical Center between May 1990 and August 2001. Thirty-four patients had complete or partial resection of their primary graft and in 15, histologic features of chronic rejection were present in the resected small bowel. This is a descriptive and correlative study of the demographic, perioperative, and histologic features associated with progression to intestinal graft failure. Variable features associated with an increased risk of chronic rejection included acute rejection within the 1st month, increased number and higher grade of acute rejection episodes, isolated small bowel grafts rather than small bowel–liver grafts, older recipient age, non-Caucasian race, and Caucasian to non-Caucasian transplant. The mucosal biopsies showed predictive changes many months before the grafts were excised. The mucosal biopsy diagnosis of chronic vascular rejection can be difficult because the affected vessels, the distal branches of the mesenteric arteries, and the larger arteries of the subserosa and submucosa are not routinely sampled. The possibility of underlying arteriopathy, however, can be inferred in some instances from the presence of secondary mucosal changes in the small bowel biopsies though the “early” changes lack specificity. It is the progression of biopsy findings over time that is predictive of outcome. It is important to recognize the persistence of “late” mucosal changes of chronic rejection so that patients are not subjected to increased immune suppression when it is unlikely to be of significant benefit.

Long-term outcomes and predictors in pediatric liver retransplantation.

Historically, 9–29% of pediatric liver transplant recipients have required retransplantation. Although outcomes have improved over the last decade, currently published patient and graft survival remain lower after retransplant than after primary transplant. Data from liver retransplantation recipients at our institution between 1991 and 2013 were retrospectively reviewed. Kaplan–Meier estimates were used to depict patient and graft survival. Predictors of survival were analyzed using a series of Cox proportional hazards models. Predictors were analyzed separately for patients who had “early” (≤30 days after primary transplant) and “late” retransplants. Eighty‐four patients underwent retransplant at a median time of 241 days. Sixty percent had late retransplants. At one, five, and 10 yr, actuarial patient and graft survival were 73%/71%, 66%/63%, and 58%/53%, respectively. Since 2002, patient and graft survival improved to 86%/86% at one yr and 93%/87% at five yr. While operative complications were a common cause of death after earlier retransplants, since 2002, infection has been the only cause of death. Significant morbidities at five‐yr follow‐up include renal dysfunction (15%), diabetes (13%), hypertension (26%), chronic rejection (7%), and PTLD (2%). Current survival after pediatric liver retransplantation has improved significantly, but long‐term immunosuppressant morbidity remains an opportunity for improvement.