The Current State of Intestinal Transplantation

Clinical intestinal transplantation has continued to evolve over recent years, with recent developments in both the medical practice and the ability of medical centers to offer this life-saving therapy. Various changes both in the practice of intestinal transplantation as well as public recognition of advances in this field will have an impact on future developments. Factors contributing to improvements in intestinal transplant outcomes include advances in surgical technique, refinements in recipient selection criteria and organ allocation, recognition of previously unrecognized complications and their management, standardized grading of rejection and recognition of atypical features of rejection, and an improved understanding of certain aspects of intestinal transplant immunology. Factors that threaten the further development of the field include the failure of Centers for Medicare and Medicaid (CMS) to assign a specific reimbursement to the assigned diagnostic related group (DRG) for this transplant, the continued high cost of the procedure, and the lack of generally recognized and accepted criteria for timing of referral of patients. In addition, reimbursement criteria chosen by CMS for reimbursement currently stifle the development of new centers, from which a plurality of new ideas and innovations could be expected in the future (1). SURGICAL PROGRESS Most candidates for intestinal transplantation continue to be patients suffering either short-bowel syndrome, functional disorders of the intestine (both motility and mucosal), or benign tumors of the mesenteric root. The International Intestinal Transplant Registry, as of May 31 2003, lists 63% of both pediatric and adult patients receiving intestinal allografts as having a primary diagnosis of short-bowel syndrome. An additional 17% of adults suffer from tumors, and 8% of adults and 17% of children suffer primary disorders of intestinal motility (2). The small bowel is generally transplanted either as an isolated intestinal allograft (42%), part of a combined liver-small bowel allograft (44%), or as part of one of a variety of modifications of a multivisceral allograft (14%), which may include or exclude the liver (3–5). Although early results indicated the importance of including the liver as part of the allograft, more recent results indicate that the highest survival rates may be achieved with isolated intestinal allografts, with registry data approaching a significantly better 1-year patient survival with this transplant (P<0.07). One recent study sited 3-year survival rates for isolated intestine recipients of 88%, with 95.5% of survivors free of parenteral support (6). This survival rate is commensurate with survival rates published with parenteral nutrition in a generally less ill population (7,8). Survival rates have increased generally after intestinal transplantation, with current patient survival rates cited between 55% and 88% 3 years after transplantation, varying with which organs are transplanted and by center. Increasing numbers of patients are undergoing the isolated intestine procedure in instances where they previously might have been considered only for combined organ transplantation (9). For instance, patients with primary motility disorders of the small bowel and nonfunction of the stomach are increasingly considered for transplantation of the small intestine without other organs, sometimes in combination with a gastric emptying procedure (9,10). Alternatively, such patients may receive a modified multivisceral allograft consisting of stomach, pancreas, and small bowel drained through the native portal vein into the native liver (11). There is also mounting evidence of the reversibility of parenteral–nutrition-associated liver disease after successful transplantation, and this has contributed to the increased application of isolated intestinal transplantation as salvage therapy for the early failing liver (9). Although common wisdom previously dictated late referral of patients with established cirrhosis for multiorgan grafts (12), early referral of patients in whom the liver may be salvaged is increasing. Although large unresectable benign tumors of the intestinal mesentery were once considered only for palliation or transplantation, intestinal-transplant techniques have recently been applied to such tumors using bench surgery for atypical resections. Tzakis et al. (13) have reported removal of the entire jejunoileum with the mesenteric vessels and tumor followed by back-table resection of the tumor and reimplantation of a sufficient portion of the small bowel to provide nutritional autonomy. Since then, we and others have used this technique for some candidates initially referred for transplantation. Other technical advances have dealt with the difficult abdominal wall of multiply operated patients who suffered previous fistulas and massive tissue loss. A variety of techniques have developed in different centers, using small-for-size organ matching, reduction of allografts, reconstructive procedures to obtain coverage, and vascularized transplantation of the abdominal wall (14–17). Live-donor intestinal transplantation has been performed and a standard donor procurement technique published (18). However, this has been applied to a narrow segment of the population awaiting intestinal transplantation, primarily adolescent or young adults patients and identical twins (19). The larger problem of death on the waiting list has not been impacted by this technique because the majority of such patients are small babies who require both liver and intestinal transplants. The technical challenge of concomitant live-donor liver and small-bowel transplantation for this population is formidable and has prevented wide application. The liver graft would require bile duct anastomosis to transplanted intestine, and the small hepatic artery as well as diminutive distal mesenteric vessels in such partial bowel grafts make the likelihood of success with both organs low, and most centers have not focused on development of such techniques. In one small series of transplants performed with cut down liver and small-bowel segments from cadaver donors, only two of five patients survived (20). IMMUNOSUPPRESSIVE PROGRESS Accompanying improved patient selection and techniques, several novel immunosuppressive strategies for intestinal transplantation have been attempted recently. Although tacrolimus remains the gold-standard agent for all regimens, there is no consensus among centers regarding what adjunctive agents are most efficacious. Several approaches used by different teams can improve results, whereas each has associated complications. We demonstrated both significantly reduced rates of early rejection and severity of rejection when sirolimus was used in combination with tacrolimus and an interleukin-2 agent (21). This regimen led to high survival rates, particularly among recipients of isolated intestinal allografts (9). However, this regimen led to three instances of thrombotic microangiopathy among patients so treated, as has been reported more widely for recipients of other solid organs (22–24). Sudan et al. (25) reported similar improvements in rejection rates using only basiliximab with tacrolimus and steroids. Campath 1-H, a monoclonal depleting antibody against the CD52 receptor, has been used in intestinal transplantation recently, after Calne et al. (26,27) previously reported its effectiveness in kidney transplantation. In the largest reported series overall, patient survival was only 12 of 21 patients, with rejection still seen in 12 of 16 grafts. Two of these were vascular rejections. Immune modulation of the graft through low-dose irradiation (7.5 Gy) has been used at Pittsburgh with good early results, but few published follow-up results are available with patients treated with only this modality, and this practice has recently been abandoned in favor of induction therapy with very high-dose Thymoglobulin. Early results with this depleting antibody have led to high early survival rates (100% patient and 73% graft, with unknown follow-up time). However, the mean tacrolimus level during the first 30 days was over 20 ng/dL or full dose. Longer follow-up will be required to determine the impact of all these approaches on long-term graft and patient survival (28–30). Although these approaches are all of interest, none appears overwhelmingly superior to the alternative approaches of other centers. We recently successfully treated four patients with late ulcerating rejection refractory to treatment with Infliximab, the monoclonal antibody to tumor necrosis factor-alpha. One patient was refractory to treatment with Thymoglobulin, whereas the other three had relative contraindications to depleting antibody therapy (prior posttransplant liver disease or adenovirus infection). All patients presented with mucosal ulcerations similar to those seen in ulcerating inflammatory bowel disease, met standard histologic criteria for moderate or severe rejection, and fully resolved after Infliximab therapy. Two other late rejections were so treated in Germany and also resolved (31). These instances raise fascinating questions as to the nature of immune-mediated histologic changes seen in the transplanted intestine, suggesting that in at least some instances, they may parallel closely other inflammatory intestinal conditions unrelated to solid-organ transplantation. What appears clear is that early rejection rates can be controlled sufficiently using newer agents in combination with tacrolimus to allow high patient survival rates using a variety of different approaches by experienced teams in different settings. MEDICAL PROGRESS Recognition of new disease processes have also contributed to refinements in patient management after transplantation. One major problem after intestinal transplantation has been the development of secretory diarrhea, particularly in pediatric patients (32). This finding is associated with rejection and frequently mandates augmented immunosuppression. However, some cases remain of unclear etiology, and detailed basic investigation in the past implicated altered motility patterns, denervation with altered sympathetic tone, or other factors (33,34). Recent clinical investigation suggests that novel and specific pathogens not described after other solid-organ transplants may infect the transplanted intestinal allograft. Calcivirus, the class of virus that includes the Norwalk agent, was recently isolated by polymerase chain reaction (PCR) analysis from the mucosa of five pediatric patients suffering secretory diarrhea after intestinal transplantation (35). Symptoms were refractory to treatment for rejection but resolved with withdrawal of immunosuppression. This finding suggests other pathogens may exist and await identification in such circumstances. Analysis of intestinal transplant tissue by PCR has also been applied to the earlier diagnosis of adenoviral enteritis in pediatric recipients in Miami and appears superior to blood evaluations. Management of other infectious complications of intestinal transplantation has also improved. Although cytomegalovirus infection resulted in significant graft losses in the early intestinal transplant literature, this has been well controlled with a variety of prophylactic regimens. Most have used a combination of hyperimmune globulin (Cytogam TM) with intravenous ganciclovir in the peritransplant period, reporting between 15% and 25% incidence of disease (36–38). In addition, although posttransplant lymphoproliferative disease was reported to occur in approximately 10% of patients and result in death in 4.6% of recipients in 1996 (39), more recent reports indicate a decreased incidence of death and graft loss caused by this complication (40). The underlying reason for this improvement is unclear but probably relates to earlier diagnosis caused by both the strategy of preemptive monitoring of viral load, increased awareness of early disease, and better control of early rejection. Rituximab use has been reported with success in five cases in Miami (375 mg/m2), given for variable periods with some patients receiving infusions for up to 8 months, but with remission in all cases maintained at a median 8 months follow-up (41). Another step forward in the development of intestinal transplantation involves standardization of the grading of allograft rejection. Although animal studies have reported relatively standard grading of rejection in rodents, little literature or consensus have been reached regarding the grading of human intestinal allograft rejection. Schemata suggesting the efficacy of grading rejection according to certain histologic standards similar to those reached for other solid organs have been published recently (42). A workshop held in September 2003 at the International Symposium on Intestinal Transplantation led to the formulation of standardized criteria for the grading of acute cellular rejection that should be published shortly (Michael Ruiz MD, unpublished 2003). These will facilitate clear communication among programs and in the literature and our capacity to implement multicenter trials with rigid assessment of immunologic endpoints. Standardization of both the clinical diagnosis and histologic criteria for chronic rejection, sometimes referred to as chronic allograft enteropathy, remain a challenge. Recurrence of immune-mediated diseases of the intestine may be difficult to identify in the transplanted allograft, and distinguishing these from rejection is sometimes challenging. We have demonstrated granulomas in the allografts of two of six surviving recipients suffering from Crohn’s disease (unpublished observation), whereas Colangelo et al. recently reported no recurrence among 14 survivors (presented at the VIII annual International Intestinal Transplant Symposium, October 2003, Miami). Viral enteritides may also masquerade as rejection, and increased recognition and clarity of description will be critical to differentiate these processes, as noted above. PUBLIC POLICY CHALLENGES Although the outcomes of intestinal transplantation continue to improve, several challenges in public policy threaten the future development of this field. Although intestinal transplantation has been embraced superficially by the CMS, the process of certification that has occurred for this organ has been different than that of other solid organs in the past. Although CMS agreed to reimburse selected centers for performance of intestinal transplantation on October 4, 2000, no specific payment has yet been affixed for this DRG. Thus, although these procedures and their aftercare remain costly, no guarantee for minimal reimbursement levels exists. These procedures can still generally be considered to result in lost money for an institution on a per case basis. Nevertheless, restrictive volume criteria (10 transplants per year or nearly 10% of national volume) has been adopted as a requirement to qualify for reimbursement, despite a lack of specific evidence that annual volume impacts quality or outcomes. Third-party payers have adopted these criteria, directing most cases to only the few Medicare certified centers for transplantation. Thus, new centers or transplant physicians with particular interest in this field are stifled from participating because they will be required to provide this procedure almost exclusively as free care. Although high survival rates and the development of centers with particular interest and expertise in specific transplants in ostensibly the goal, this field is so young, with so few regional centers, that development of a plurality of intellectually novel approaches is necessary for future development. In addition, although the National Institutes of Health have demonstrated an interest in fostering the advancement of intestinal transplantation, this has fallen short of acceptance of the need for a consensus conference, and the NIH instead conducted a workshop in conjunction with the annual meeting of the American Society for Parenteral and Enteral Nutrition. Although this is a step forward, the workshop lacks the impact accorded a consensus conference, as occurred for liver transplantation in 1988. Slower progress toward adequate reimbursement, acceptance of these transplants for increasing indications over time, and slower acceptance by the medical community at large can be anticipated. This can be seen in the types of patients seen and patterns of referral of patients for intestinal transplants. Despite the progress made over the last several years and the excellent long-term survival achieved in the general population requiring parenteral nutrition, we still frequently encounter both pediatric and adult patients with intestinal failure who are not referred for transplantation and often not surgically salvaged to begin therapy on home parenteral nutrition. Such patients are commonly still placed on narcotic drips at the time of discovery of intestinal infarction and not offered counseling that transplantation is an option. Such patients also often self refer because of the lack of physician awareness and recognition that this therapy is no longer experimental. In my experience caring for over 300 such patients, more than one third were self referrals to the transplant center. Thus, although we have made surgical, medical, and immunosuppressive progress over recent years, we and our professional societies still have an obligation to increase public and professional awareness of this increasingly successful transplant and advocate for the adequate reimbursement that will facilitate its further maturation.