Organ transplantation for intestinal failure
Iyer, Kishore R
Total parenteral nutrition (TPN) provides life-saving treatment for the patient with irreversible intestinal failure caused by short bowel syndrome and a variety of functional causes. Although TPN prolongs life in these patients, it is frequently complicated in the long term by life-threatening central venous catheter-related infections and cholestatic liver disease that may progress to cirrhosis. For this select subset of patients who have failed TPN, intestinal transplantation (Tx) provides an alternative approach that is rapidly emerging as the standard of care. Although intestinal Tx remains a procedure in evolution, refinements in surgical technique and immunosuppression, combined with a better understanding of postoperative care, have led to improved results.
HISTORY
Carrell1 laid the vascular basis for intestinal Tx nearly 100 years ago.2 Lillehei et al at the University of Minnesota carried out intestinal Tx studies in dogs,2 but clinical success remained elusive for the next 30 years.3-5 Limited success from an intestinal graft was first reported by Starzl et al6 in 1987, when 1 of 2 children who received a multivisceral graft survived for 192 days. Williams et al7 reported a similar outcome in the same year in 1 of 2 children; death in both instances occurred from lymphoproliferative disease and sepsis. In 1988, Grant8 reported what was to be the first truly successful liver-small bowel Tx in a 41-year-old patient, who was discharged from the hospital 8 months after Tx on an unrestricted oral diet and continued to do well for about 4 years. Immunosuppression was with cyclosporine, prednisone, and azathioprine with antibody induction using OKT3. Between 1987 and 1995, Goulet et al9 reported on 9 intestinal transplants performed in 7 children, with cyclosporine-based immunosuppression; 1 patient remained alive >6 years after Tx. These seminal cases paved the way for reports of improved results from a handful of centers. 10-16
INDICATIONS AND REFERRAL
With the recent determination by the Healthcare Financing Administration (HCFA) that intestinal Tx was no longer deemed to be an experimental procedure, there has been considerable interest from caregivers and patients regarding the indications for intestinal Tx. Quigley17 observed in 1996 that, for the well– adapted patient who is stable on home TPN, small intestinal Tx could not rival the established role of TPN. The basis for this observation stems from the home TPN registry data obtained by Howard et al,18 suggesting that for long-term patients on home TPN, land 4-year survival rates were of the order of 94% and 80%, respectively. Thus, unlike liver Tx, intestinal Tx has to be considered in the context of the fact that it must be applied to a select group of patients, for the majority of whom, a widely available and effective therapy, ie, TPN, is readily available. For intestinal Tx to become first-line therapy for the patient with refractory intestinal failure, the results of Tx have to be better than from long-term TPN. Thus, the indications for intestinal Tx can be simply stated as the following:
1. presence of irreversible intestinal failure, and
2. presence or onset of life-threatening complications of TPN.
The latter are chiefly in the form of onset of liver disease or central venous catheter-related complications such as recurrent or life-threatening sepsis and loss of venous access sites. Although there is general agreement that liver disease in the setting of short bowel syndrome and TPN dependence is a clear indication for intestinal Tx, indications related to central venous catheters are more contentious. Debate centers on two issues-the determination by HCFA, accepted by the major transplant centers, that a single episode of life-threatening or fungal sepsis in the appropriate setting may constitute an indication for Tx and that loss of major central venous access sites is an indication for intestinal Tx. Development of metastatic infectious foci, such as infective endocarditis or recurring severe septic episodes resulting in multiorgan system failure in the individual patient, constitute much clearer indications for intestinal Tx. Although it would be simplistic to suggest that the parties to this debate are simply seeing different patient populations with the very much sicker patients coming to transplant, it would seem that some patients are referred too late to transplant centers; certainly, based on our own experience at Omaha, we now regard inability to ensure secure central venous access for 6 months after a transplant procedure as a relative contraindication to intestinal Tx. The American Society of Transplantation has set forth fairly clear guidelines for pediatric intestinal Tx in a position paper, and they have suggested that in infancy, referral for intestinal transplant is appropriate when 2 of the 4 available standard access sites, the right and left subclavian veins and internal jugular veins have been lost to thrombosis. 19 In the older child, and by extension, the adult patient, referral for intestinal Tx would be appropriate when 3 of the 6 available standard access sites, the right and left internal jugular, right and left subclavian, and right and left femoral veins, have been lost to thrombosis. Into this decision-making must also be factored the inevitable wait for an appropriate donor organ, which, depending on size and blood type, can sometimes be greater than a year.
CONTRAINDICATIONS TO INTESTINAL TX
Although the contraindications to Tx of the intestine are similar to those for other solid organs (malignancy, severe systemic disease, etc), the considerable morbidity and mortality after this procedure place a larger onus on ensuring that transplantation is carried out with the hope of a good quality of life in the long term. Thus, patients with multiple severe congenital anomalies or severe neurologic disability are not appropriate candidates for Tx. Multisystem autoimmune diseases and severe immune deficiencies also represent contraindications to intestinal Tx.
RECIPIENT EVALUATION AND SELECTION
Recipient evaluation must be carried out by a multidisciplinary team, paying special attention to the following items:
1. irreversibility of intestinal failure,
2. presence of liver disease and potential for reversibility,
3. state of vascular access,
4. psychosocial issues, and
5. potential contraindications to Tx.
The importance of a careful evaluation cannot be overemphasized. In Omaha, this has led to alternative therapies in some cases and even allowed us to wean some patients off TPN. We have diagnosed missed intestinal anomalies in 3 children referred for intestinal transplantation within the last year; 1 patient had a duodenal web and 2 had complete distal small bowel atresias. Indications for potential intestinal Tx in the 3 patients were recurrent catheter infections in the first and advanced liver disease in the 2 patients with distal atresias. One patient with a distal atresia and endstage liver disease died after surgical repair of the atresia from pneumonitis secondary to respiratory syncytial virus (RSV). The remaining 2 patients are currently alive and off TPN with normal liver function (including the third child who had cirrhosis and portal hypertension at the time of repair of her atresia and concurrent intestinal lengthening).
CHOICE OF ALLOGRAFT
Once a decision is made to list a patient for Tx, a careful evaluation allows for a rational choice of allograft. Central to this decision is the recognition that the results of isolated intestinal Tx seem to be superior to that obtained from Tx with the larger composite grafts.13,14,20-22 It is also our experience that mild-tomoderate degrees of liver dysfunction with portal and even bridging fibrosis on a liver biopsy are not contraindications to Tx with an isolated small bowel graft, as opposed to a combined liver-intestine allograft.21,23 More advanced degrees of liver dysfunction and the presence of cirrhosis or clinical stigmata of significant portal hypertension mandate a combined liver-small bowel allograft., Of considerable interest is the idea that in carefully selected patients with TPN-associated end-stage liver disease, an isolated liver transplant may allow for intestinal adaptation to occur with eventual nutritional autonomy from TPN.24 Our initial enthusiasm for this concept has been sustained with accumulating experience, and we have performed transplants on >15 children with isolated liver allografts in the setting of short bowel syndrome and TPN– associated liver disease. It must be recognized that this subset of patients undergoing isolated liver transplantation represents a very high-risk group, demanding a team experienced in transplantation and in the management of short bowel syndrome.
DONOR AND RECIPIENT OPERATIONS
The donor and recipient operations have been described in considerable detail elsewhere.25-27 Cadaveric donors should be
The technique of liver-small bowel transplantation developed at the University of Nebraska Medical Center avoids all hilar dissection.27 Stomach and colon are excluded from all grafts. IV antithymocyte globulin (ATGAM; Upjohn, Kalamazoo, MI) and OKT3 (OrthoMacneil, Rariton, NJ) are administered before flushing cold University of Wisconsin solution through an infrarenal aortic cannula; venous outflow is vented as usual by transecting the cava above the diaphragm. The duodenum just beyond pylorus and the terminal ileum are transected between double rows of staples. A long segment of thoracic aorta is procured in continuity with the celiac axis and the SMA. On the back table, the celiac axis is dissected to the level of the splenic artery, which is ligated and divided. The donor aorta inferior to the origin of the SMA is oversewn. The pancreas is transected just to the right of the portal vein and its cut edge oversewn, allowing the bile duct to be preserved intact (Fig. 1).
After a standard recipient hepatectomy, arterial inflow to the combined liver-small bowel graft is accomplished through anastomosis between the donor thoracic aorta and the recipient supraceliac aorta, and venous outflow is through a standard caval anastomosis with a piggyback technique if size disparity between the donor and recipient cava requires it. A recipient porto-caval or porto-portal shunt allows for decompression of native remnant viscera. Intestinal continuity is restored in all cases with a loop ileostomy to allow access for endoscopy and graft biopsy (Fig. 2).
The isolated intestinal graft receives arterial inflow through anastomosis between the donor SMA and the infrarenal aorta. Portal venous drainage of the graft is accomplished by anastomosis between the donor portal vein and the recipient superior mesenteric vein at the inferior border of the pancreas or between the donor portal vein and the cava. The latter is favored in the presence of liver dysfunction, taking due care to ensure that the venous anastomosis is superior to the arterial anastomosis in all cases.
POSTOPERATIVE MANAGEMENT
Immunosuppression
Immunosuppression for intestinal transplantation is based on tacrolimus (FK 506, Prograf, Fujisawa, Deerfield, IL) and corticosteroids. The Pittsburgh group favors IV FK 506, started intraoperatively at a dose of 0.15 mg/kg per day and converted to an oral dose when patients can tolerate oral intake.30 The tacrolimus dose is adjusted to a target trough level of 15 to 30 ng/mL. Corticosteroids are started as methylprednisolone at a dose of 20 mg/kg and rapidly tapered over the next 5 to 7 days to a dose of 2 mg/kg per day. The patient is maintained on an oral prednisone dose of 0.3 mg/kg per day. The Pittsburgh group has also employed induction therapy with cyclophosphamide and subsequently switched to either mycophenolate mofetil or azathioprine. We do not use any antilymphocyte induction therapy and administer tacrolimus intragastrically from the outset. Our initial results with the use of basiliximab, an antiinterleukin 2 antibody, suggest that there may be a role for their use as induction agents in intestinal Tx (vide infra).
Diagnosis of Rejection
In recipients of intestinal transplants, it is our practice to carry out protocol surveillance intestinal biopsies at day 7, followed by weekly biopsies until week 6, and then as indicated. Indications for biopsies are often nonspecific and include unexplained fever, change in stoma output or appearance, and gastrointestinal bleeding. It would seem that the gross appearance of the mucosa does not correlate with histologic appearances.31 Although there is a lack of clear endoscopic criteria for diagnosis of rejection, endoscopy with biopsy remains the gold standard for diagnosis of rejection in intestinal allografts. Acute rejection of an intestinal allograft is characterized by a varying combination of crypt injury, mononuclear mucosal infiltrate, and an increase in crypt cell apoptosis.32 Although crypt cell apoptosis is not a specific or absolute finding, it represents a distinctive feature of acute cellular rejection even when other changes are minimal.33
Prevention of Infection
The exact role of luminal decontamination as practiced by some groups is unclear. We administer broadspectrum IV antibiotics and antifungals for 5 to 7 days and tailor specific therapy to the clinical situation. As protection against Epstein-Barr virus-driven lymphoproliferative disease, all patients receive IV immunoglobulin infusions monthly and daily oral acyclovir for 1 year after transplant. Prophylaxis against Pneumocystis carinii is employed using trimethoprim-sulfamethoxazole twice weekly.
Nutrition Management
We commence elemental jejunostomy feeds on about postoperative day 7, gradually advancing them based on enteral tolerance. Stoma losses of 40 to 50 mL/kg per day are deemed acceptable. Stool losses are often high in fluid and sodium content-careful attention must be placed on IV replacement of losses. Additionally, secretory diarrhea frequently develops in the presence of intercurrent infection or rejection.13
RESULTS
Patient and Graft Survival
The 1-year patient- and graft-survival figures since 1995 are 69% and 55%, respectively, for intestine alone; 66% and 63%, respectively, for small bowel-liver grafts; and 63% each for multivisceral grafts.10 Despite the apparent immunologic advantage conferred by simultaneous liver grafting at the time of small bowel transplantation, isolated intestinal Tx seems to provide better patient survival and graft function at all follow-up times.13,20,22,30 An important observation was the finding that programs that had performed at least 10 intestinal Tx had better patient and graft survival than programs that had performed
Retransplantation
The experience with retransplantation, particularly after liver-small bowel Tx, has been singularly disappointing. Out of 6 small bowel recipients who underwent retransplantation at Pittsburgh, only 1 patient who received a liver-small bowel graft is alive with a functioning graft at 428 days.34 Two children are receiving TPN, and the remaining 3 died. Of 3 patients who were retransplanted after primary liver-small bowel Tx, only 1 is alive with a functioning graft beyond a year.34 The experience at Omaha has been similarly disappointing; only 4 of 16 children who have undergone retransplantation, having initially received isolated bowel allografts, remain alive in the medium term.
Nutritional Status
Figures from the Intestinal Transplant registry suggest that of 126 survivors of intestinal Tx, 95 (77%) were weaned from TPN, 17 (14%) required partial PN, 4 (3%) were receiving TPN with their graft intact, and 8 (6%) were receiving TPN after removal of their graft.10 In our experience, median time to weaning TPN was just over a month. Vitamins and trace elements, particularly zinc and selenium, frequently need supplementation. The data on growth in children after intestinal Tx is limited-our own data indicate that children are markedly growth-retarded at the time of Tx.35 Even at 2 years after successful intestinal Tx, growth continues at the same rate with no evidence of catch-up in survivors. Our preliminary follow-up data suggest that 10 of 13 children who retain functional grafts at 5 years after intestinal Tx are beginning to show evidence of catch-up growth.36
Quality of Life
Studies on quality of life after intestinal transplantation have been few and largely confined to small studies on adult patients.37 These suggest a quality very similar to patients receiving long-term home TPN, and a trend toward improvement in this quality over time as anxiety over allograft function decreases.37 In our experience, pediatric intestinal transplant recipients report a quality of life that is similar to normal school children, and overall, is better than children with other chronic diseases (Sudan et al, unpublished data, 2002). Interestingly, the parents of intestinal transplant recipients report significant limitations, primarily in the domain of physical well-being of their children compared with normal school children. The reasons for this apparent discrepancy between the children’s perceptions and that of their parents acting as proxy is unclear and merits further study.
Complications
Rejection. Registry figures for the incidence of acute rejection after intestinal transplantation remain high-79% for intestine transplant alone, 71% for liver and intestine, and 56% for multivisceral transplants.10 Immunosuppression was based on tacrolimus in 78% and cyclosporine in 19%.10 Registry data support other observations that simultaneous liver grafting may reduce the risk of intestinal graft rejection.8,10,38 This apparent immunologic advantage does not seem to translate into a survival advantage, with isolated intestinal grafts performing better at all follow-up times.30 Our early experience with the use of basiliximab, an antiinterleukin 2 antibody, in the last 24 consecutive intestinal transplants, suggests a marked reduction in the incidence of acute rejection and in the severity of the rejection episodes. There was a predictable decrease in the incidence of infectious complications, particularly fungal and viral infections.
Infection. Infectious complications are frequent after intestinal Tx, and they are the major source of morbidity and mortality after the procedure. Bacterial infections are almost ubiquitous, occurring in >90% of cases after Tx; bacteremias are frequently related to intraperitoneal, central venous catheter-related, or pulmonary sepsis. Fungal infections occur in about 25% of cases. Registry data for cytomegalovirus (CMV) disease was 24% for isolated intestinal grafts, 18% for liver-intestinal grafts, and 40% for multivisceral grafts.10 The risk factors for CMV infections include transplantation from CMV-positive donors to CMV– negative recipients, increased tacrolimus levels, and increased numbers of corticosteroid boluses to treat acute rejection episodes. 39,40
Adenovirus was isolated in 44 of 117 patients after intestinal Tx (Iyer et al, unpublished data, 2002); the exact significance remains unclear because of the natural prevalence of the virus in the pediatric population. The bowel was the primary site in the majority; isolation of the virus was occasionally associated with nonspecific enteritis that was usually self-limiting and did not seem to need specific treatment. Three of 4 patients in whom the virus was isolated from broncho-alveolar lavage died from severe pneumonitis, which in the absence of other isolates was deemed to be adenoviral in etiology. All 4 were treated with reduced immunosuppression, and 1 patient who eventually died additionally received IV ribavirin. The 3 deaths were attributed to disseminated adenoviral infection with pneumonitis.
Graft versus host disease. The incidence of graft versus host disease would be expected to be high in an allograft with a large lymphocyte mass such as the gut. Our own experience indicates that the complication is rare; Reyes et al30 reported an incidence of 7%. Histopathological criteria for diagnosis include keratinocyte necrosis in biopsies of skin lesions, epithelial apoptosis of native gastrointestinal tract, or necrosis of oral mucosa. Immunohistochemical demonstration of donor cell infiltration into the lesions is required for confirmation.
Surgical complications. Surgical complications in the form of anastomotic leaks and intestinal perforations occur frequently; the latter are sometimes precipitated by endoscopic biopsies. Another significant source of morbidity and mortality seems to be sudden ischemic necrosis of the graft in the setting of a nonspecific diarrheal illness with attendant dehydration and hypovolemia. This catastrophic complication is frequently heralded by the appearance of pneumatosis intestinalis and sepsis. It is unclear if the process represents “necrotizing enterocolitis” in the graft as has been described,41 or in late cases, may simply be a consequence of failed autoregulation of splanchnic blood flow in a vulnerable graft that is undergoing unrecognized chronic rejection.
FUTURE PROSPECTS
More than a decade after the first reports of success in humans, intestinal Tx remains a therapy in evolution. Major advances have been made in the technical aspects and immunosuppressive management of these patients, which is reflected in much improved outcomes in the last 5 years compared with the first 5 years.10,12,13,15,20,30,34,35,42,43 Despite the improved results under tacrolimus-based immunosuppression, there is a clear need for more specific immunosuppressive agents that will reduce theincidence of acute, and perhaps more importantly, chronic rejection, without increasing the infectious complications to even more unacceptable levels. Our own preliminary experience with the use of basiliximab is very encouraging and holds such hope. Equally, the use of donor bone marrow augmentation in recipients where the intestine allograft was preconditioned by ex vivo irradiation has shown promising early results.34 Additional experience with this technique is awaited to confirm whether the risk of graft versus host disease will be minimized by prior irradiation of the graft as demonstrated in rats by Murase et al.44 An additional concern is the unknown long-term effects of even low-dose irradiation on the intestinal graft. The Pittsburgh experience suggests an apparently much higher incidence of chronic rejection seen in isolated small bowel transplants as opposed to the liver-small bowel transplants.34 Our own experience did not mirror this disparity.45 Irrespective of any differences in susceptibility of grafts to chronic rejection, it is clear that late graft loss because of chronic rejection is a frustrating issue that needs to be addressed with newer and novel immunosuppressive strategies.
The choice of appropriate allograft will continue to have an important bearing on outcome while remaining an issue for debate.22 We have maintained a philosophy that “less may be better” in the context of transplantation for intestinal failure. Our group has shown that improved results are obtainable with isolated intestinal transplantation even in the face of moderate degrees of liver dysfunction 21; it would seem that a functioning intestinal allograft is capable of reversing mild-to-moderate degrees of TPN-associated liver dysfunction in the absence of significant portal hypertension or established cirrhosis. Likewise, in select patients who have a history of some enteral tolerance with loss of enteral tolerance coinciding with development of liver disease, an isolated liver allograft may be capable of salvaging the short bowel from permanent “failure.”24
Finally, the role of living-related intestinal transplantation needs to be better defined. Although the technical feasibility of the procedure has been clearly established, we believe that recipient outcomes will need to show continued improvement before the procedure can be applied more liberally.46,47 Perhaps, with the advent of currently emerging immunosuppressive strategies, the results of intestinal Tx may soon improve sufficiently to replace TPN as the standard of care for the patient with irreversible intestinal failure, even in the absence of complications of TPN. That may also be the appropriate time to consider wider use of living-related intestinal Tx.
Copyright American Society for Parenteral and Enteral Nutrition Sep/Oct 2002
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