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Clinical intestinal transplantation
Clinical Nutrition (1996) 15:45-52 © Pearson Professional Ltd 1996
REVIEW
Clinical intestinal transplantation H. FURUKAWA, J. REYES, K. ABU-ELMAGD and S. TODO Pittsburgh Transplantation Institute, University of Pittsburgh, 4C Falk Clinic, 3601 Fifth Avenue, Pittsburgh, PA 15213, USA (Reprint requests and correspondence to H. F.) ABSTRACT--The advent of tacrolimus allowed clinical intestinal transplantation to become a feasible procedure for patients with irreversible intestinal failure. Over last 5 years, 71 patients underwent intestinal transplantation. Forty-one recipients were children, and 30 recipients were adults. Twenty-five patients received an isolated intestinal graft, 34 patients received a combined liver-intestinal graft, and 12 received a multivisceral graft. The colon was included the intestinal graft in 29 patients. One-year, 2-year, and 4-year actuarial patient survival is 72%, 57%, and 45%, respectively. Our experience has shown that infectious, and immunological problems have caused significant morbidity and mortality. In this paper, we present our clinical experience ~ind overview with intestinal transplantation.
Introduction
survival was poor. Only 2 of 13 patients (15%) receiving isolated intestinal transplantation are currently alive with functioning grafts; only 2 of 11 patients (18%) receiving a combined liver intestinal or multivisceral graft are currently alive (15-20). Encouraged by new success with intestinal transplantation under cyclosporine, a clinical trial of tacrolimus (a new potent immunosuppressant for intestinal transplantation) was initiated at the University of Pittsburgh in May 1990. Tacrolimus, a macrolide isolated from Streptomyces tsukubanesis that is 10-100 times stronger than cyclosporine, was shown to be effective in clinical liver, kidney and heart transplantation, as well as experimental animal intestinal transplantation (21-24). Over the past 5 years, 71 patients have received intestinal grafts, either as isolated graft, combined with the liver, or as a part of a multiple abdominal viscera graft (25-28). In this paper, we present our clinical experience with these 71 intestinal transplantation recipients.
Before the introduction of cyclosporine, a total of eight intestinal transplantations were performed in humans, with the first two attempts occurring in Boston in 1964 (1-6). The longest patient survival was 76 days (6). Immunosuppressive strategies for these early attempts included azathioprine, steroids, anti-lymphocyte globulin (ALG), or thoracic duct drainage. All of these early attempts ended in patient death from technical failure, rejection, or sepsis. The development of total parenteral nutrition (TPN) in the late 1960s markedly improved survival for patients with short bowel syndrome, and decreased interest in intestinal transplantation. However, high morbidity and mortality due to TPN-induced liver failure or catheter-related complications renewed efforts at clinical intestinal transplantation. The success of organ transplantation under cyclosporinebased immunosuppression in the early 1980s prompted Cohen et al to perform the first intestinal transplantation using cyclosporine in 1985 (7); however, this patient survived for only 10 days. Contrary to the success of cyclosporine in liver, heart and kidney transplantation, the outcome after clinical intestinal transplantation under cyclosporine-based immunosuppression was poor (7-14). The first reports of prolonged survival after intestinal transplantation were by Starzl et al with multivisceral recipients in 1987 (multivisceral grafts consisted of the stomach, pancreas, liver, and intestine) and by Grant et al with a combined liver and intestine recipient in 1989 (15, 16). The early impression was that survival appeared to be better when the intestine was combined with the liver. The combined graft recipients tended to survive longer than isolated graft recipients. Five of the patients that received combined or multivisceral graft died more than 100 days after transplantation from posttransplant lymphoproliferative disease (n = 4) and tumor recurrence (n = 1). However, in the long term overall
Intestinal failure Irreversible intestinal failure is defined as the inability to maintain nutrition or positive fluid and electrolyte balance without special support owing to the loss of absorptive surface or function of the native small bowel. The types of intestinal failure can be classified into two categories: intestinal failure due to surgical or anatomical loss of intestine (short bowel syndrome), or failure due to functional abnormality. The primary causes of surgical intestinal failure in adults were abdominal trauma, Crohn's disease, surgical adhesions, Gardner's syndrome, desmoid tumor and occlusion of the superior mesenteric vessels. Primary causes of surgical intestinal failure in children were necrotizing enterocolitis, intestinal atresia, midgut volvulus and gastroschisis. 45
46 CLINICALINTESTINALTRANSPLANTATION
Significant absorptive, secretory, or motility disorders can cause functional intestinal failure. Impairment of absorptive and secretory capacity of the enterocyte is caused by microvillus inclusion disease, autoimmune enteropathy, radiation enteritis, extensive inflammatory bowel disease and massive intestinal polyposis. Motility disorders of the gastrointestinal tract are chronic pseudo-obstruction, which is manifested by defective gastrointestinal motility due to either hollow visceral myopathy or neuropathy, and total intestinal aganglionosis.
Intestinal adaptation Massive intestinal resection can result in short bowel syndrome, diarrhea, dehydration, electrolyte imbalance, malabsorption, and progressive malnutrition. The severity of these complications depends on the length, location, and absorptive function of the remaining bowel and its ability to compensate for the loss of absorptive area. Compensation occurs by the widening the villus circumference and the elongation of the villus height. Maximization of this compensatory process may take 1-2 years, during which TPN is frequently required (29). In 1972, Wilmore reviewed the outcome of 50 infants with short gut syndrome. All infants, with more than 38 cm of bowel, except one, were able to survive; however, survival was unlikely if there was less than 38 cm of bowel, without the ileocecal valve (30). Recent advancements in the treatment of short bowel syndrome with enteral and parenteral nutrition has allowed intestinal adaptation to occur after 5-17 months in infants with enteral lengths of 10-30 cm, in'espective to the existence of the ileocecal valve (31). Intestinal adaptation even occurred 15 months after resection in a 33-year-old patient with only 15 cm of remaining jejunum without the ileocecal valve (32). Generally, there is a high risk for permanent loss of intestinal absorptive function when more than 80% of the small bowel and the ileocecal valve are resected. Loss of intestinal absorptive function is less likely when the ileum is preserved. Resection of more than 100 cm of ileum usually results in significant malabsorption of vitamin B12, bile acids and dietary fat. Resection of the large bowel is also serious since the gastrointestinal tract loses the ability to absorb water and electrolytes, and short-chain fatty acids yielded from bacterial fermentation of malabsorbed carbohydrates (33).
life-threatening, complication, especially in infants. Cholestasis occurs in 30-40% of the patients undergoing long-term TPN management. Of 60 infants on long-term TPN in Grosfeld's series, 5 of 9 deaths (55%) were from liver failure (37). At our center, of the 202 patients evaluated, 34 died during or after evaluation for intestinal transplantation. Twenty-one (62%) of the mortalities were due to TPNinduced liver failure (38). Cholelithiasis (39), renal disease (40) and bone disease (41) have also been reported as common complications. Although patients often adjust to their treatment and underlying disease, HPN sometimes impairs social and leisure activities, affects sexual and interpersonal relationships and may cause psychological problems (42). Of the 1594 patients in the USA followed by the OASIS registry since 1984, patients with benign intestinal diseases required 2.6 hospitalizations per year for complications. Three-year patient survival ranged from 65% to 80% depending on the cause of disease. TPN-related complications accounted for 6.7% of the deaths. The annual cost for HPN was estimated at $75 000-$150 000 (35). Of 200 patients with intestinal failure registered in the UK and Ireland, 34 have died. Ten (29%) died from HPN-related complications, which were mainly manifested as catheter-related septicemia. HPN in UK costs £25 000 per patient per year (43).
Types of and indications for transplantation Irreversible intestinal failure is the primary indication for intestinal transplantation. The causes of intestinal failure for our 71 patients are summarized in Table 1. The three primary types of intestinal transplantation are isolated intesfinal, combined liver and intestinal, or multivisceral transplantation. The type of transplant performed depends upon the cause and severity of intestinal failure and the presence of extra-enteric organ dysfunction. Isolated intestinal transplantation is indicated for the patients who have irreversible intestinal failure, with no other organ dysfunction. This procedure is performed in carefully selected patients who have poor venous access, frequent line sepsis, uncontrollable diarrhea, or high stomal output. Combined liver and intestinal transplantation is indicated for patients who suffer from intestinal failure, and TPNrelated cholestatic liver failure. It is also the procedure of choice for patients with liver failure and concomitant Table 1
Cause of intestinal failure
Limitations of total parenteral nutrition (TPN) Children
TPN is the primary therapy for patients with irreversible intestinal failure. Home TPN (HPN) is "required by estimated 40 000 patients in the USA, of whom 15 000 patients are on HPN due to intestinal failure (34). Although HPN is life-sustaining therapy, patients suffer from medical and psycho-social complications, repeated hospitalizations and a significant financial burden. Frequent catheter-related complications and re-hospitalization occur in the majority of patients (35, 36). Hepatic dysfunction is a common, yet
Gastroschisis Necrotizing enterocolitis Intestinal atresia Pseudo-obstruction Hirchsprung's disease Microvillus inclusion disease Intestinal polyposis Volvulus
Adult Total 10 9 7 7 3 3 1 1 41
Vascular thrombosis Crohn's disease Desmoid tumor Trauma Intestinal adhesions Intestinal polyposis Budd Chiari Gastrinoma Pseudo-obstruction
Total 9 7 4 4 2 1 1 1 1 30
CLINICAL NUTRITION 47
thrombosis of the entire portomesenteric system. In these patients, enterectomy of the normally functioning native intestine is required. Simultaneous liver replacement, despite absence of the liver failure, may be indicated only in patients with vascular thrombosis due to congenital coagulation defects (protein C/S or antithrombin III deficiency). In some of these patients, multivisceral transplantation is inevitable because of insufficient vasculature of the remaining upper abdominal organs including the stomach, duodenum and pancreas. Multivisceral transplantation is indicated for patients with irreversible failure of more than two of the abdominal visceral organs including the intestine. Generally, the liver, pancreas, stomach, duodenum and intestine are transplanted. The liver can be omitted from multivisceral graft if the patient has a normal native liver. The common causes of multivisceral failure are extensive thrombosis of the splanchnic vessels, massive gastrointestinal polyposis and generalized chronic pseudoobstruction. Multivisceral transplantation can also be considered for patients with potentially curable abdominal malignancies that require upper abdominal evisceration. Intestinal transplantation is contraindicated for patients with significant cardiopulmonary insufficiency, history or presence of aggressive and incurable malignancy, persistent abdominal or systemic infection, and those with extensive atherosclerosis or severe autoimmune and immunodeficiency syndromes. Older (> 60 years) patients with an inactive lifestyle, and patients' who have failed alcohol or drug rehabilitation, should not be candidates.
Donor selection and management All grafts for intestinal transplantation were obtained from cadaveric donors. The general criteria for donor selection do not differ significantly from those for liver donors. Organs from young (< 45 years old) local donors that are hemodynamically stable are preferred. Since the intestine is very sensitive to ischemia, a donor on high dose of vasopressors, suffering from long periods of hypotension, cardiac arrest and/or cardiopulmonary resuscitation should be avoided. Donors with systemic infection and malignancy are also excluded. Donors should be smaller or of similar size to the recipient. Smaller donors are usually preferred because the peritoneal cavity of the recipient has usually shrunk due to multiple previous surgeries. Donor and recipient blood type (ABO) should be identical. HLA matching is not considered and has been universally poor. Cytomegalovirus (CMV) seropositive donors should be avoided for all intestinal recipients. We have shown that recipients who receive CMV seropositive grafts have significantly higher mortality than recipients receiving CMV seronegative grafts (44). This guideline should be strictly observed in isolated intestinal recipients, and observed whenever possible in combined and multivisceral graft recipients. Ideally, donors with positive lymphocytotoxic crossmatch should be avoided. This is not done, however, since waiting for the
crossmatch result may prolong cold ischemia and jeopardize the graft. All donors receive routine gut decontamination. Amphotericin B/mycostatin, aminoglycosides and polymyxin E, are administered through a nasogastric tube. Intravenous ampicillin and cefotaxime are given every 6-8 h before organ procurement, and at the time of organ procurement. The graft lymphoreticular tissue is not altered with antilymphocyte preparations or by other modalities. The University of Wisconsin (UW) solution is used for in-situ perfusion and simple cold storage of the graft. Grafts obtained from adult donors require 1-2 liters of in-situ UW perfusion, and grafts from pediatric donors require 50-100 ml/kg. When the colon is not included in the intestinal graft, no attempt is made to flush the lumen of the intestinal graft with UW or other cold solutions; however, when the colon is included, the intestinal lumen is flushed with 1-2 liters of chilled lactated Ringer's solution containing amphotericin B, aminoglycosides and polymyxin E.
Transplantation procedures A key factor in successful intestinal transplantation is the procurement of high quality intestinal grafts, with satisfactory anatomy. The three typical types of intestinal allografts are illustrated in Figure 1. The principles and details of the donor and recipient operations have been described elsewhere (25, 26, 45, 46). All recipients receive routine gut decontamination and intravenous antibiotics prophylaxis. Isolated intestine
The superior mesenteric artery of the graft is anastomosed to the anterior wall of the recipient infrarenal aorta. The venous outflow of the intestinal graft is usually directed into the recipient portal venous system; however, systemic venous outflow (through the recipient vena cava) is occasionally used. The proximal jejunum of the graft is anastomosed to either the jejunum or duodenum of the recipient. A temporary enterostomy is created with the terminal ileum to facilitate clinical, endoscopic and histologic monitoring of the graft. A distal side-to-end anastomosis of the ileum and colon is only performed in patients who still have their native rectosigmoid colon. A permanent terminal ileostomy or colostomy is performed in patients who have lost their native rectosigmoid colon. Combined intestine and liver
Combined liver and intestinal transplantation is performed using the 'piggyback' technique, and veno-veno bypass is not used (47). The common arterial conduit of the combined graft is anastomosed to the recipient infrarenal aorta. After reperfusion, the temporary portocaval shunt (created to decompress the recipient portal system) is converted to a portoportal shunt by re-anastomosing the end of recipient portal vein to the side of the graft portal vein (48). When the
48 CLINICAL INTESTINAL TRANSPLANTATION
PV
•'
SMA
Fig. 1 Three types of intestinal allografts: intestine alone (n = 25, right), intestine with liver (n = 34, left), and multivisceral (n = 12, middle). Colonic segments (shaded) were included in 29 patients scattered through the three cohorts. IVC: inferior vena cava; PV: portal vein; HA: hepatic artery; SMA: superior mesenteric artery; SMV: superior mesenteric vein; SA: splenic artery; LGA: left gastric artery.
recipient portal vein is too short or when the graft portal vein is too small, the portocaval shunt is left in place permanently. The biliary tract is anastomosed to the proximal end of the graft jejunum in end-to-side fashion, and the second portion of the proximal graft jejunum is used for the proximal intestinal anastomosis. Gastrointestinal tract is restored using the same technique described for the isolated intestinal graft.
Multivisceral As with the combined liver-intestine graft, vascular reconstruction requires both hepatic venous and graft arterial anastomoses. The graft suprahepatic cava is anastomosed to the recipient hepatic veins (piggyback). The arterial conduit is anastomosed to the recipient celiac or infrarenal aorta. Proximal reconstruction of the alimentary tract is established by anastomosing the distal esophagus or the remaining portion of the stomach of the recipient to the anterior gastric wall of the graft. Distal continuity of the intestinal tract is reestablished using the same method described for the isolated intestinal graft.
of 0.15 mg/kg/day. Enteral administration of tacrolimus is started 1-2 weeks after transplantation at a dose of 0.3 rag/ kg/day in two divided doses. Intravenous tacrolimus doses are slowly tapered over several days as oral therapy is initiated. Tacrolimus whole blood trough levels are monitored daily. Target trough levels for intestinal transplant recipients are between 20 and 30 ng/ml. Tacrolimus is augmented with methylprednisolone. Adults received a 1 g bolus of methylprednisolone intraoperatively, followed by a tapering dose of steroids for 5 days (200 mg to 40 rag), and maintained with a dose of 20 mg/day thereafter. The doses were scaled down for children. Prostagiandin E1 was started intraoperatively at a dose of 0.2-0.6 mcg/kg/h and continued for 7-14 days. Low-dose azathioprine (1-2 mg/kg/day) was used in selected cases. Treatment of acute graft rejection was based upon the severity rejection, as determined by clinical impression and histological diagnosis. Treatment of rejection was accomplished by increasing the tacrolimus dose, giving a steroid bolus or taper, or by giving a course of OKT3 (49).
Prophylaxis of infection
Postoperative management Immunosuppression Tacrolimus, the primary immunosuppressive agent, is given as a continuous intravenous infusion initially at a dose
Selective decontamination, consisting a combination of amphotericin B/nystatin, tobramycirggentamicin and Polymyxin E, is given by mouth or nasogastric/enterostomy, four times a day for 3-4 weeks after transplantation. Decontamination is re-instituted during episodes of severe rejec-
CLINICAL NUTRITION 49
tion and in patients with apparent bacterial overgrowth. Standard intravenous antibiotic prophylaxis, with cefotaxime and ampicillin, is administered for 5-7 days after transplantation and resumed, if needed, based upon the results of blood and body fluid cultures. To obtain evidence of microbial translocation in patients with an active systemic infection, quantitative stool cultures and blood cultures are periodically done to monitor changes in intestinal flora. Ganciclovir and CMV immunoglobulin (Cytogam) are used for CMV prophylaxis, and co-triimoxazole (sulfamethoxazoletrimethoprim) is used for pneumocystis carinii prophylaxis.
acute rejection of the intestinal allograft. Severe episodes of rejection may also present as graft ileus, intestinal bleeding, septic shock, and/or adult respiratory distress. Endoscopieally, rejection usually causes the intestinal mucosa to appear ischemic or dusky with focal ulcerations and causes reduced or even complete loss of peristalsis. Grafts with severe rejection showed either nodular mucosa or diffuse ulceration with bleeding. Histological criteria for the diagnosis of acute intestinal allograft rejection include mononuclear cell infiltrate, villous blunting and cryptitis. Complete sloughing of the intestinal mucosa with crypt destruction was seen in patients with severe rejection.
Nutrition TPN is continued during the early postoperative course. After confirming the integrity of the gastrointestinal anastomoses and the partial recovery of gut motility using the appropriate gastrointestinal contrast studies, enteral feeding, through a jejunostomy tube, is started. Enteral feeding is given continuously, and the volume is gradually increased. Parenteral nutrition is tapered gradually as enteral feeds are advanced, and eventually discontinued. In children, Pediatric Vivonex (Sandoz, Minneapolis, MN) is used for enteral feeding for the first 4-6 weeks since it contains a large amount of glutamine, which is an essential nutrient for the intestine. After intestinal absorption improves, the formula is switched to Peptamin Junior (Clintec Nutrition Co., Deerfield, IL). Adult patients receive Peptamin (Clintec Nutrition Co., Deerfield, IL) for enteral feeding. Both Peptamin Junior and Peptamin are isotonic elemental diets that contain peptide-based protein, medium-chain triglycerides, and glutamine. Enteral feedings are gradually decreased as oral intake is increased. Weaning of the enteral nutritional support is usually accomplished by decreasing the daily duration of tube feeding. Opiates, loperamide and pectin are used for patients who have high stomal output or diarrhea.
Graft monitoring Diagnosis of intestinal graft rejection is based primarily upon clinical findings, endoscopic observations and histopathologic examination of endoscopic-guided mucosal biopsies. Surveillance graft endoscopy, with multiple random mucosal biopsies, is performed when clinically indicated, and at least once per week for the first 3 months, monthly for the next 3 mouths and every 3-6 months thereafter. Access to the ileum for endoscope-guided mucosal biopsies is usually achieved through the distal ileoscopy or by colono-ileoscopy. The jejunal biopsies are taken by regular upper gastrointestinal endoscopy. Since it has been shown that the ileum is more susceptible to rejection than the jejunum, ileal biopsies are needed to diagnose graft rejection.
Acute rejection Clinical symptoms of fever, abdominal pain, increased stomal output, watery diarrhea and vomiting usually suggest
Chronic rejection Chronic rejection of the intestinal aUograft usually presents as intractable diarrhea, abdominal pain, intermittent episodes of sepsis, progressive weight loss and intermittent intestinal bleeding. Periodic endoscopic examinations show pseudomembrane formation, thickened mucosal folds and chronic ulcers in a tubular intestine. Radiological studies show dilated intestinal loops, thickened intestinal wall, and effaced mucosal folds. Serial intestinal mucosal biopsies show apoptosis of crypt cells with a sparse inflammatory cell infiltrate. Angiographic studies sometimes demonstrate segmental narrowing of the mesenteric arterial arcade, which may dictate graft enterectomy. Full thickness histopathologic examination of grafts resected due to chronic rejection has shown mucosal ulceration with intramural abscesses, and obliterative arteriopathy. Graft enterectomy and subsequent retransplantation may be the only option to treat chronic rejection.
Graft versus host disease ( GVHD) Skin rash is the major manifestation of GVHD in intestinal transplantation recipients. The recipient's native gastrointestinal tract and liver are also possibly affected by GVHD. Biopsies of regions suspected for GVHD are necessary to confirm the diagnosis. Two methods are needed to confirm GVHD of the skin. Histologically, GVHD causes apopotosis of the epithelial cells. Immunologically, GVHD is diagnosed by the existence of donor lymphocytes in the epithelium, which is shown by either immunohistological stain for donor specific HLA antigen and/or in-situ hybridization using the Y-chromosome specific probe (if the donor was male and the recipient was female).
Graft function Biochemical batteries of hepatic and pancreatic enzymes are used to monitor the status of the liver and pancreas. Radiological contrast studies of the transplanted and native gastrointestinal tract are performed to study gastric emptying, intestinal transit, and changes in mucosal pattern. Serum concentrations of albumin, vitamins, minerals and trace elements are measured frequently to evaluate graft function. Absorption is assessed using D-xylose and oral tacrolimus
50 CLINICAL INTESTINAL TRANSPLANTATION
kinetic studies (after discontinuation of intravenous tacrolimus doses). Anthropometric measurement are obtained periodically to assess changes in weight and muscle mass. Current results
From May 1990 to June 1995, 71 patients underwent intestinal transplantation. Forty-one recipients were children, with a mean age of 4.5 + 4.7 years, and 30 recipients were adults, with a mean age of 34.1 _+ 10.2 years. Twenty-five patients received an isolated intestinal graft, 34 patients received a combined liver-intestinal graft, and 12 received a multivisceral graft. The colon was included the intestinal graft in 29 patients.
Survival Figure 2 shows the Kaplan-Meier actuarial patient and graft survival. Thirty-seven recipients (52%) are currently alive 3-62 months after intestinal transplantation. One-year, 2-year, and 4-year actuarial patient survival is 72%, 57%, and 45%, respectively. The main causes of death were pneumonia (n = 5), rejection (n = 5), post-transplant lymphoproliferative disorder (n = 4), sepsis (n = 3), technical (n = 3) and hepatitis C (n = 2). One year, 2-year and 4-year actuarial primary graft survival is 62%, 48%, and 37%, respectively. Four recipients required graft removal; two had intestinal rejection because of reduction of the immunosuppression due to diffuse demyelination i~ the brain, or intractable CMV infection, and the other two recipients had overwhelming rejection (n = 1) and pneumonia immediately after transplant (n = 1). Retransplantation was performed in five recipients. Three isolated intestinal graft recipients lost their grafts due to rejection and were retransplanted, two received isolated intestinal retransplantation and the other received multivisceral retransplantation. Two combined liver-intestinal recipients lost their grafts due to rejection and PTLD, and were retransplanted; one received liver and intestinal retransplantation, and the other received multivisceral retransplantation. 100' 908070"
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Immunologic complications (50) Acute rejection is a persistent problem in intestinal transplantation. Overall, 92% of the 71 patients experienced an average of 3.7 episodes of intestinal rejection. Rejection occurred in more than 50% of the patients 3 months after transplantation. In composite grafts that included the liver, the incidence of hepatic allograft rejection (43%) was much less than the incidence of intestinal graft rejection. Chronic rejection was diagnosed in two resected isolated intestinal grafts, and was also seen in both organs of one combined liver-intestinal graft recipient. GVHD has rarely been seen in our series. One pediatric combined liver-intestinal recipient was unequivocally diagnosed with acute GVHD before her death. One adult multiviseeral patient developed chronic GVHD several years after transplantation. Three isolated graft recipients (2 children and 1 adult) had skin rashes, suggestive of GVHD, after graft enterectomy and discontinuation of immunosuppression. The skin rashes of these three patients spontaneously resolved.
Infectious complications Most of the intestinal recipients have had infectious complications after transplantation, with a median of four episodes per patient. The incidence of bacterial, viral and fungal infection was 81%, 76%, and 62% respectively. While line, wound and intra-abdominal infections were the most common type of bacterial infection, candida esophagitis was the most frequent type of fungal infection (51). CMV has been the most problematic infectious complication for the adult patients. Twenty-four (34%) patients developed CMV disease, of which 15 (50%) were adults and 9 (22%) were children. While no CMV disease was seen in CMV seronegative patients receiving CMV seronegative grafts, significant CMV disease (55%) was seen in patients receiving CMV seropositive grafts. Cytomegalovirus disease was mainly confined to the intestinal graft, but CMV hepatitis, gastritis, and retinitis were also seen. Even when CMV disease was treated with ganciclovir or foscarnet, disease recurrence rate was high in the patients that received CMV seropositive isolated intestinal grafts (44). While CMV presented few problems in the children, Epstein Barr virus (EBV)-related lymphoproliferative disease caused significant difficulties. Of the 15 recipients (21%) that developed EBV-related post-transplant lymphoproliferative disease (PTLD), 12 were children. PTLD was treated by decreasing or discontinuing immunosuppression, acyclovir/ganciclovir, alpha or gamma interferon, hyperimmunoglobulin and/or chemotherapy. Seven of 15 patients died and 2 patients lost their grafts (52).
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--*-- Graft (n=76) 0
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1 2 3 4 Time After Transplantation (years)
Actuarial patient and primary graft survival of the 71 recipients.
Preoperatively, 68 patients had been on TPN for 1-180 months and most had experienced more than one episode of TPN-related complications. TPN-related liver failure was seen in 39 patients (55%). These patients had a median total bilirubin of 18.1 mg/dl, which ranged from 2.1 to 58.2 mg/dl.
CLINICAL NUTRITION 51 P o s t - o p e r a t i v e l y , T P N w a s r e s u m e d 2 4 - 4 8 h after t r a n s p l a n t a t i o n , a n d t h e n d i s c o n t i n u e d 2 - 3 0 w e e k s after t r a n s p l a n t a t i o n w h e n a d e q u a t e nutritional a b s o r p t i o n was a c h i e v e d f r o m t u b e f e e d i n g s a n d oral intake. T a c r o l i m u s k i n e t i c s a n d D - x y l o s e a b s o r p t i o n tests r e v e a l e d t h a t i n t e s t i n a l a b s o r p t i o n i m p r o v e s s i g n i f i c a n t l y 1 m o n t h after t r a n s p l a n t a t i o n (53). Serum albumin and vitamin levels of the patients were w i t h i n n o r m a l r a n g e s after t r a n s p l a n t a t i o n . D e l a y e d gastric e m p t y i n g w a s d e t e c t e d w i t h b a r i u m s t u d y ( 6 0 % ) or s c i n t i g r a p h i c t e c h n i q u e ( 3 8 % ) i n early posto p e r a t i v e period, b u t i m p r o v e d s i g n i f i c a n t l y 3 - 6 m o n t h s after t r a n s p l a n t a t i o n . T h e m e d i a n s m a l l b o w e l transit t i m e w a s 2 h, r a n g i n g f r o m 0.2 to 17.8 h. N o c o r r e l a t i o n w a s found between transit time and time after transplantation (54, 55). O f t h e 37 c u r r e n t s u r v i v o r s , 31 ( 8 4 % ) p a t i e n t s are free o f T P N a n d e n j o y i n g a n u n r e s t r i c t e d oral diet. T w o o f 37 surv i v o r s r e q u i r e partial n u t r i t i o n a l s u p p l e m e n t a t i o n w i t h T P N , a n d f o u r o f 37 s u r v i v o r s are o n T P N after g r a f t e n t e r e c t o m y .
Future of intestinal transplantation F o r the last t h r e e d e c a d e s t h e i n t e s t i n e h a s b e e n c o n s i d e r e d a ' f o r b i d d e n o r g a n ' for t r a n s p l a n t a t i o n b e c a u s e o f p o o r c l i n i c a l results. T h e i n t r o d u c t i o n o f t a c r o l i m u s h a s a l l o w e d c l i n i c a l i n t e s t i n a l t r a n s p l a n t a t i o n to b e c o m e a f e a s i b l e p r o c e d u r e f o r p a t i e n t s w i t h i r r e v e r s i b l e i n t e s t i n a l failure; however, our experience has shown that infectious and immunological problems have caused significant mo~idity a n d m o r t a l i t y e v e n 1 - 3 y e a r s after t r a n s p l a n t a t i o n . T o o v e r come these obstacles we have initiated a new protocol employing simultaneous donor derived bone marrow infusion a n d i n t e s t i n a l t r a n s p l a n t a t i o n . T h e a i m o f this n e w s t r a t e g y is to a u g m e n t the c h i m e r i s m a n d e n h a n c e a c c e p t a n c e o f the i n t e s t i n a l graft. N i n e p a t i e n t s h a v e a l r e a d y r e c e i v e d s i m u l t a n e o u s b o n e m a r r o w a n d i n t e s t i n a l t r a n s p l a n t a t i o n , b u t it is t o o e a r l y to assess t h e results. O u r h o p e is t h a t this m e t h o d will o p e n a n e w h o r i z o n for i n t e s t i n a l t r a n s p l a n t a t i o n in future.
References 1. Alican F, Hardy J, Cayirli Met al. Intestinal transplantation: laboratory experience and report of a clinical case (in discussion). Am J Surg 1971; 121:150-9 2. Lillehei R, Idezuki Y K, Feemster Jet al. Transplantation of stomach, intestine, and pancreas: experimental and clinical observations. Surgery 1967, 62:721-41 3. Okumura M, Fujimura I, Ferrari A et al. Transplante de Intestino Delgado: apresenta~ao de um caso. Rev Hosp Clin Fac Med San Paulo 1969; 2D: 39-54 4. Olivier C L, Rettori R, Olivier C H, Baur O, Roux J. Homotransplantation orthotopique de l'intestin gr~le et des crlons droit et transverse.chez l'homme. J Chir (Paris) 1969; 98:323-30 5. Alican F, Hardy J, Cayirli Met al. Intestinal transplantation: laboratory experience and report of a clinical case. Am J Surg 1971; 121:150-9 6. Fortner J, Sichuk G, Litwin S, Beattie E. Immunological responses to an intestinal allograft with HL-A-identical donor-recipient. Transplantation 1972; 14:531-5 7. Cohen Z, Silver R, Wassef R et al. Small intestinal transplantation using cyclosporine. Transplantation 1986; 42:613-21
8. Tattersall C, Gebel H, Haklin M, Hartsell W, Williams J. Lymphocyte responsiveness after irradiation in canine and human intestinal allografts. Curr Surg 1989; 46:16-19 9. Revillion Y, Jan D, Goulet O, Ricour C. Small bowel transplantation in seven children: preservation technique. Transplant Proc 1991; 23:2350-1 10. Goulet O, Revillon Y, Brousse Net al. Successful small bowel transplantation in an infant. Transplantation 1992; 53:940-3 11. Hansman M L, Deltz E, Gundlach Met al. Small bowel transplantation in a child. Am J Clin Pathol 1989; 920:686-92 12. Deltz E, Schroeder P, Gebhart H et al. Successful clinical small bowel transplantation: report of a case. Clin Transplant 1989; 3:89-91 13. Grant D, Sommerauer J, Mimeanlt R et al. Treatment with continuous high-dose intravenous cyclosporine following clinical intestinal transplantation. Transplantation 1988; 48:151-3 14. Wallander J, Ewald U, Lackgen Get al. Extremely short bowel syndrome in neonates: an indication for small bowel transplantation. Transplant Proc 1992; 24:1230-5 15. Starzl T E, Rowe M, Todo Set al. Transplantation of multiple abdominal viscera. JAMA 1989; 261:1449-57 16. Grant D, Wall W, Mimeault R et al. Successful small bowel/liver transplantation. Lancet 1990; 335:181-4 17. Williams. Splanchnic transplantation an approach to the infant dependent on parenteral nutrition who develops irreversible liver disease. JAMA 1989; 261:1458-62 18. McAlister V. Successful small intestinal transplantation. Transplant Proc 1992; 24:1236-7 19. Margreiter R. Successful multivisceral transplantation. Transplant Proc 1992; 24:1226-7 20. D'Alessandro A M. Liver-intestinal transplantation: Transplant Proc 1992; 24:1228-9 21. Thompson A. FK506 - How much potential? Immunology Today 1989; 10:6-9 22. Starzl T E, Todo S, Fung Jet al. FK506 for human liver, kidney and pancreas transplantation. Lancet 1989; 2: 1000M 23. Murase N, Demetris A J, Matsuzaki T et al. Long survival in rats after multivisceral versus isolated small bowel allotransplantation under FK506. Surgery 1991; 110:87-98 24. Yoshimi F, Nakamura K, Zhu Yet al. Canine total orthotopic small bowel transplantation under FK506. Transplant Proc 1991; 23:3240-2 25. Todo S, Tzakis A G, Abu-Elmagd K et al. Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation 1992; 53:369-76 26. Todo S, Tzakis A G, Abu-Elmagd K et al. Intestinal transplantation in composite visceral grafts or alone. Ann Surg 1992; 216:223-34 27. Abu-Elmagd K, Todo S, Tzakis A et al. Three years clinical experience with intestinal transplantation. J Am Col Surg 1994; 179:385-400 28. Todo S, Reyes J, Furnkawa H et al. Outcome analysis of 71 clinical intestinal transplantation. Ann Surg 1995; 222:270-82 29. Dudrick S J, Latifi R, Fosnocht D E. Management of the short-bowel syndrome. Surg Clin North Am 1991; 71:625-43 30. Wilmore D W. Factors correlating with a successful outcome following extensive intestinal resection in newborn infants. J Pediatr 1972; 80:88-95 31. Kurchubasche A, Rowe M, Smith S D. Adaptation in short-bowel syndrome: reassessing old limits. J Pediatr Surg 1993; 28:1069-71 32. Blackburn G L, Jensen G L. Medical management of the difficult patient with short-bowel syndrome. Nutrition 1993; 9:536-9 33. Nordgaard I, Hansen B S, Mortensen P B. Colon as a digestive organ in patients with short bowel. Lancet 1994; 343:373-6 34. Howard L, Ament M, Fleming C R, Shike M, Steiger E. Current use and clinical outcome of home parenteral and enteral nutrition therapies in the United States. Gastroenterology 1995; 109:355-65 35. Howard L, Heaphey L, Fleming R, Lininger L, Steiger E. Four years of North American registry home parenteral nutrition outcome data and their implications for patient management. JPEN 1991; 15:384-93 36. Kurkchubasche A G, Smith S D, Rowe M I. Catheter sepsis in shortbowel syndrome. Arch Surg 1992; 127:21-5 37. Grosfeld J L, Rescoria F J, West K W. Short bowel syndrome in infancy and childhood. Am J Surg 1986; 151:41-6 38. Reyes J, Tzakis A, Nour B et al. Candidates for intestinal transplantation and possible indicators of outcome. Transplant Proc 1994; 26:1447-8 39. Pitt H A, King W, Mann L L. Increased risk of cholecystlithiasis with prolonged total parenteral nutrition. Am J Surg 1983; 145:106-12 40. Buchman A L, Moukarzel A, Ament Met al. Serious renal
52 CLINICALINTESTINALTRANSPLANTATION
41. 42. 43. 44. 45. 46.
47. 48.
impairment is associated with long-term parenteral nutrition. JPEN 1994; 17:438-44 Koo W W K. Parenteral nutrition-related bone disease. JPEN 1992; 16:386-94 Ladefoged K. Quality of life in patients on permanent home parenteral nutrition. JPEN 1981; 5:132-7 Mughal M, Irving M. Home parenteral nutrition in the United Kingdom and Ireland. Lancet 1986; 2:383-6 Furukawa H, Manez R, Kusne Set al. Cytomegalovirus disease in intestinal transplantation. Transplant th-oc 1995; 27:1357-8 Starzl T E, Todo S, Tzakis Aet al. The many faces of multivisceral transplantation. Surg Gynecol Obstet 1991; 172:335-44 Fumkawa H, Abu-Elmagd K, Reyes J. Technical aspects of intestinal transplantation. In: Braverman M H, Tawe R L, eds. Surgical Technology International 2. San Francisco: Surgical Technology International, 1993:165-70 Tzakis A, Todo S, Starzl T E. Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 1989; 210:649-52 Tzakis A, Todo S, Reyes Jet al. Piggyback orthotopic intestinal transplantation. Surg Gynecol Obstet 1993; 176:297-8
Submission date: 13 October 1995; Accepted: 18 December 1995
49. Abu-Elmagd K, Tzakis A, Todo Set al. Monitoring and treatment of intestinal allograft rejection humans. Transplant Proc 1993; 25: 1202 50. Abu-Elmagd K, Todo S, Tzakis Aet al. Rejection of human intestinal allografts: alone or in combination with the liver. Transplant Proc 1994; 26:1430-1 51. Kusne S, Manez R, Bonet H et al. Infectious complications after small bowel transplantation in adults. Transplant Proc 1994; 26:1682-3 52. Reyes J, Tzakis A, Bonet H et al. Lymphoproliferative disease after intestinal transplantation under primary FK 506 immunosuppression. Transplant Proc 1994; 26:1426-7 53. Kadry Z, Furukawa H, Abu-Elmagd K et al. Use of the D-xylose absorption test in monitoring intestinal allograft. Transplant Proc 1994; 26:1645 54. Campbell W L, Abu-Elmagd K, Federle M Pet al. Contrast examination of the small bowel in patients with small-bowel transplants: Finding in 16 patients. AJR 1993; 161: 969-74 55. Furukawa H, Brown M, Abu-Elmagd K et al. Abnormal gastric emptying after intestinal transplantation. Transplant Proc 1994; 26:1634
REVIEW
Clinical intestinal transplantation H. FURUKAWA, J. REYES, K. ABU-ELMAGD and S. TODO Pittsburgh Transplantation Institute, University of Pittsburgh, 4C Falk Clinic, 3601 Fifth Avenue, Pittsburgh, PA 15213, USA (Reprint requests and correspondence to H. F.) ABSTRACT--The advent of tacrolimus allowed clinical intestinal transplantation to become a feasible procedure for patients with irreversible intestinal failure. Over last 5 years, 71 patients underwent intestinal transplantation. Forty-one recipients were children, and 30 recipients were adults. Twenty-five patients received an isolated intestinal graft, 34 patients received a combined liver-intestinal graft, and 12 received a multivisceral graft. The colon was included the intestinal graft in 29 patients. One-year, 2-year, and 4-year actuarial patient survival is 72%, 57%, and 45%, respectively. Our experience has shown that infectious, and immunological problems have caused significant morbidity and mortality. In this paper, we present our clinical experience ~ind overview with intestinal transplantation.
Introduction
survival was poor. Only 2 of 13 patients (15%) receiving isolated intestinal transplantation are currently alive with functioning grafts; only 2 of 11 patients (18%) receiving a combined liver intestinal or multivisceral graft are currently alive (15-20). Encouraged by new success with intestinal transplantation under cyclosporine, a clinical trial of tacrolimus (a new potent immunosuppressant for intestinal transplantation) was initiated at the University of Pittsburgh in May 1990. Tacrolimus, a macrolide isolated from Streptomyces tsukubanesis that is 10-100 times stronger than cyclosporine, was shown to be effective in clinical liver, kidney and heart transplantation, as well as experimental animal intestinal transplantation (21-24). Over the past 5 years, 71 patients have received intestinal grafts, either as isolated graft, combined with the liver, or as a part of a multiple abdominal viscera graft (25-28). In this paper, we present our clinical experience with these 71 intestinal transplantation recipients.
Before the introduction of cyclosporine, a total of eight intestinal transplantations were performed in humans, with the first two attempts occurring in Boston in 1964 (1-6). The longest patient survival was 76 days (6). Immunosuppressive strategies for these early attempts included azathioprine, steroids, anti-lymphocyte globulin (ALG), or thoracic duct drainage. All of these early attempts ended in patient death from technical failure, rejection, or sepsis. The development of total parenteral nutrition (TPN) in the late 1960s markedly improved survival for patients with short bowel syndrome, and decreased interest in intestinal transplantation. However, high morbidity and mortality due to TPN-induced liver failure or catheter-related complications renewed efforts at clinical intestinal transplantation. The success of organ transplantation under cyclosporinebased immunosuppression in the early 1980s prompted Cohen et al to perform the first intestinal transplantation using cyclosporine in 1985 (7); however, this patient survived for only 10 days. Contrary to the success of cyclosporine in liver, heart and kidney transplantation, the outcome after clinical intestinal transplantation under cyclosporine-based immunosuppression was poor (7-14). The first reports of prolonged survival after intestinal transplantation were by Starzl et al with multivisceral recipients in 1987 (multivisceral grafts consisted of the stomach, pancreas, liver, and intestine) and by Grant et al with a combined liver and intestine recipient in 1989 (15, 16). The early impression was that survival appeared to be better when the intestine was combined with the liver. The combined graft recipients tended to survive longer than isolated graft recipients. Five of the patients that received combined or multivisceral graft died more than 100 days after transplantation from posttransplant lymphoproliferative disease (n = 4) and tumor recurrence (n = 1). However, in the long term overall
Intestinal failure Irreversible intestinal failure is defined as the inability to maintain nutrition or positive fluid and electrolyte balance without special support owing to the loss of absorptive surface or function of the native small bowel. The types of intestinal failure can be classified into two categories: intestinal failure due to surgical or anatomical loss of intestine (short bowel syndrome), or failure due to functional abnormality. The primary causes of surgical intestinal failure in adults were abdominal trauma, Crohn's disease, surgical adhesions, Gardner's syndrome, desmoid tumor and occlusion of the superior mesenteric vessels. Primary causes of surgical intestinal failure in children were necrotizing enterocolitis, intestinal atresia, midgut volvulus and gastroschisis. 45
46 CLINICALINTESTINALTRANSPLANTATION
Significant absorptive, secretory, or motility disorders can cause functional intestinal failure. Impairment of absorptive and secretory capacity of the enterocyte is caused by microvillus inclusion disease, autoimmune enteropathy, radiation enteritis, extensive inflammatory bowel disease and massive intestinal polyposis. Motility disorders of the gastrointestinal tract are chronic pseudo-obstruction, which is manifested by defective gastrointestinal motility due to either hollow visceral myopathy or neuropathy, and total intestinal aganglionosis.
Intestinal adaptation Massive intestinal resection can result in short bowel syndrome, diarrhea, dehydration, electrolyte imbalance, malabsorption, and progressive malnutrition. The severity of these complications depends on the length, location, and absorptive function of the remaining bowel and its ability to compensate for the loss of absorptive area. Compensation occurs by the widening the villus circumference and the elongation of the villus height. Maximization of this compensatory process may take 1-2 years, during which TPN is frequently required (29). In 1972, Wilmore reviewed the outcome of 50 infants with short gut syndrome. All infants, with more than 38 cm of bowel, except one, were able to survive; however, survival was unlikely if there was less than 38 cm of bowel, without the ileocecal valve (30). Recent advancements in the treatment of short bowel syndrome with enteral and parenteral nutrition has allowed intestinal adaptation to occur after 5-17 months in infants with enteral lengths of 10-30 cm, in'espective to the existence of the ileocecal valve (31). Intestinal adaptation even occurred 15 months after resection in a 33-year-old patient with only 15 cm of remaining jejunum without the ileocecal valve (32). Generally, there is a high risk for permanent loss of intestinal absorptive function when more than 80% of the small bowel and the ileocecal valve are resected. Loss of intestinal absorptive function is less likely when the ileum is preserved. Resection of more than 100 cm of ileum usually results in significant malabsorption of vitamin B12, bile acids and dietary fat. Resection of the large bowel is also serious since the gastrointestinal tract loses the ability to absorb water and electrolytes, and short-chain fatty acids yielded from bacterial fermentation of malabsorbed carbohydrates (33).
life-threatening, complication, especially in infants. Cholestasis occurs in 30-40% of the patients undergoing long-term TPN management. Of 60 infants on long-term TPN in Grosfeld's series, 5 of 9 deaths (55%) were from liver failure (37). At our center, of the 202 patients evaluated, 34 died during or after evaluation for intestinal transplantation. Twenty-one (62%) of the mortalities were due to TPNinduced liver failure (38). Cholelithiasis (39), renal disease (40) and bone disease (41) have also been reported as common complications. Although patients often adjust to their treatment and underlying disease, HPN sometimes impairs social and leisure activities, affects sexual and interpersonal relationships and may cause psychological problems (42). Of the 1594 patients in the USA followed by the OASIS registry since 1984, patients with benign intestinal diseases required 2.6 hospitalizations per year for complications. Three-year patient survival ranged from 65% to 80% depending on the cause of disease. TPN-related complications accounted for 6.7% of the deaths. The annual cost for HPN was estimated at $75 000-$150 000 (35). Of 200 patients with intestinal failure registered in the UK and Ireland, 34 have died. Ten (29%) died from HPN-related complications, which were mainly manifested as catheter-related septicemia. HPN in UK costs £25 000 per patient per year (43).
Types of and indications for transplantation Irreversible intestinal failure is the primary indication for intestinal transplantation. The causes of intestinal failure for our 71 patients are summarized in Table 1. The three primary types of intestinal transplantation are isolated intesfinal, combined liver and intestinal, or multivisceral transplantation. The type of transplant performed depends upon the cause and severity of intestinal failure and the presence of extra-enteric organ dysfunction. Isolated intestinal transplantation is indicated for the patients who have irreversible intestinal failure, with no other organ dysfunction. This procedure is performed in carefully selected patients who have poor venous access, frequent line sepsis, uncontrollable diarrhea, or high stomal output. Combined liver and intestinal transplantation is indicated for patients who suffer from intestinal failure, and TPNrelated cholestatic liver failure. It is also the procedure of choice for patients with liver failure and concomitant Table 1
Cause of intestinal failure
Limitations of total parenteral nutrition (TPN) Children
TPN is the primary therapy for patients with irreversible intestinal failure. Home TPN (HPN) is "required by estimated 40 000 patients in the USA, of whom 15 000 patients are on HPN due to intestinal failure (34). Although HPN is life-sustaining therapy, patients suffer from medical and psycho-social complications, repeated hospitalizations and a significant financial burden. Frequent catheter-related complications and re-hospitalization occur in the majority of patients (35, 36). Hepatic dysfunction is a common, yet
Gastroschisis Necrotizing enterocolitis Intestinal atresia Pseudo-obstruction Hirchsprung's disease Microvillus inclusion disease Intestinal polyposis Volvulus
Adult Total 10 9 7 7 3 3 1 1 41
Vascular thrombosis Crohn's disease Desmoid tumor Trauma Intestinal adhesions Intestinal polyposis Budd Chiari Gastrinoma Pseudo-obstruction
Total 9 7 4 4 2 1 1 1 1 30
CLINICAL NUTRITION 47
thrombosis of the entire portomesenteric system. In these patients, enterectomy of the normally functioning native intestine is required. Simultaneous liver replacement, despite absence of the liver failure, may be indicated only in patients with vascular thrombosis due to congenital coagulation defects (protein C/S or antithrombin III deficiency). In some of these patients, multivisceral transplantation is inevitable because of insufficient vasculature of the remaining upper abdominal organs including the stomach, duodenum and pancreas. Multivisceral transplantation is indicated for patients with irreversible failure of more than two of the abdominal visceral organs including the intestine. Generally, the liver, pancreas, stomach, duodenum and intestine are transplanted. The liver can be omitted from multivisceral graft if the patient has a normal native liver. The common causes of multivisceral failure are extensive thrombosis of the splanchnic vessels, massive gastrointestinal polyposis and generalized chronic pseudoobstruction. Multivisceral transplantation can also be considered for patients with potentially curable abdominal malignancies that require upper abdominal evisceration. Intestinal transplantation is contraindicated for patients with significant cardiopulmonary insufficiency, history or presence of aggressive and incurable malignancy, persistent abdominal or systemic infection, and those with extensive atherosclerosis or severe autoimmune and immunodeficiency syndromes. Older (> 60 years) patients with an inactive lifestyle, and patients' who have failed alcohol or drug rehabilitation, should not be candidates.
Donor selection and management All grafts for intestinal transplantation were obtained from cadaveric donors. The general criteria for donor selection do not differ significantly from those for liver donors. Organs from young (< 45 years old) local donors that are hemodynamically stable are preferred. Since the intestine is very sensitive to ischemia, a donor on high dose of vasopressors, suffering from long periods of hypotension, cardiac arrest and/or cardiopulmonary resuscitation should be avoided. Donors with systemic infection and malignancy are also excluded. Donors should be smaller or of similar size to the recipient. Smaller donors are usually preferred because the peritoneal cavity of the recipient has usually shrunk due to multiple previous surgeries. Donor and recipient blood type (ABO) should be identical. HLA matching is not considered and has been universally poor. Cytomegalovirus (CMV) seropositive donors should be avoided for all intestinal recipients. We have shown that recipients who receive CMV seropositive grafts have significantly higher mortality than recipients receiving CMV seronegative grafts (44). This guideline should be strictly observed in isolated intestinal recipients, and observed whenever possible in combined and multivisceral graft recipients. Ideally, donors with positive lymphocytotoxic crossmatch should be avoided. This is not done, however, since waiting for the
crossmatch result may prolong cold ischemia and jeopardize the graft. All donors receive routine gut decontamination. Amphotericin B/mycostatin, aminoglycosides and polymyxin E, are administered through a nasogastric tube. Intravenous ampicillin and cefotaxime are given every 6-8 h before organ procurement, and at the time of organ procurement. The graft lymphoreticular tissue is not altered with antilymphocyte preparations or by other modalities. The University of Wisconsin (UW) solution is used for in-situ perfusion and simple cold storage of the graft. Grafts obtained from adult donors require 1-2 liters of in-situ UW perfusion, and grafts from pediatric donors require 50-100 ml/kg. When the colon is not included in the intestinal graft, no attempt is made to flush the lumen of the intestinal graft with UW or other cold solutions; however, when the colon is included, the intestinal lumen is flushed with 1-2 liters of chilled lactated Ringer's solution containing amphotericin B, aminoglycosides and polymyxin E.
Transplantation procedures A key factor in successful intestinal transplantation is the procurement of high quality intestinal grafts, with satisfactory anatomy. The three typical types of intestinal allografts are illustrated in Figure 1. The principles and details of the donor and recipient operations have been described elsewhere (25, 26, 45, 46). All recipients receive routine gut decontamination and intravenous antibiotics prophylaxis. Isolated intestine
The superior mesenteric artery of the graft is anastomosed to the anterior wall of the recipient infrarenal aorta. The venous outflow of the intestinal graft is usually directed into the recipient portal venous system; however, systemic venous outflow (through the recipient vena cava) is occasionally used. The proximal jejunum of the graft is anastomosed to either the jejunum or duodenum of the recipient. A temporary enterostomy is created with the terminal ileum to facilitate clinical, endoscopic and histologic monitoring of the graft. A distal side-to-end anastomosis of the ileum and colon is only performed in patients who still have their native rectosigmoid colon. A permanent terminal ileostomy or colostomy is performed in patients who have lost their native rectosigmoid colon. Combined intestine and liver
Combined liver and intestinal transplantation is performed using the 'piggyback' technique, and veno-veno bypass is not used (47). The common arterial conduit of the combined graft is anastomosed to the recipient infrarenal aorta. After reperfusion, the temporary portocaval shunt (created to decompress the recipient portal system) is converted to a portoportal shunt by re-anastomosing the end of recipient portal vein to the side of the graft portal vein (48). When the
48 CLINICAL INTESTINAL TRANSPLANTATION
PV
•'
SMA
Fig. 1 Three types of intestinal allografts: intestine alone (n = 25, right), intestine with liver (n = 34, left), and multivisceral (n = 12, middle). Colonic segments (shaded) were included in 29 patients scattered through the three cohorts. IVC: inferior vena cava; PV: portal vein; HA: hepatic artery; SMA: superior mesenteric artery; SMV: superior mesenteric vein; SA: splenic artery; LGA: left gastric artery.
recipient portal vein is too short or when the graft portal vein is too small, the portocaval shunt is left in place permanently. The biliary tract is anastomosed to the proximal end of the graft jejunum in end-to-side fashion, and the second portion of the proximal graft jejunum is used for the proximal intestinal anastomosis. Gastrointestinal tract is restored using the same technique described for the isolated intestinal graft.
Multivisceral As with the combined liver-intestine graft, vascular reconstruction requires both hepatic venous and graft arterial anastomoses. The graft suprahepatic cava is anastomosed to the recipient hepatic veins (piggyback). The arterial conduit is anastomosed to the recipient celiac or infrarenal aorta. Proximal reconstruction of the alimentary tract is established by anastomosing the distal esophagus or the remaining portion of the stomach of the recipient to the anterior gastric wall of the graft. Distal continuity of the intestinal tract is reestablished using the same method described for the isolated intestinal graft.
of 0.15 mg/kg/day. Enteral administration of tacrolimus is started 1-2 weeks after transplantation at a dose of 0.3 rag/ kg/day in two divided doses. Intravenous tacrolimus doses are slowly tapered over several days as oral therapy is initiated. Tacrolimus whole blood trough levels are monitored daily. Target trough levels for intestinal transplant recipients are between 20 and 30 ng/ml. Tacrolimus is augmented with methylprednisolone. Adults received a 1 g bolus of methylprednisolone intraoperatively, followed by a tapering dose of steroids for 5 days (200 mg to 40 rag), and maintained with a dose of 20 mg/day thereafter. The doses were scaled down for children. Prostagiandin E1 was started intraoperatively at a dose of 0.2-0.6 mcg/kg/h and continued for 7-14 days. Low-dose azathioprine (1-2 mg/kg/day) was used in selected cases. Treatment of acute graft rejection was based upon the severity rejection, as determined by clinical impression and histological diagnosis. Treatment of rejection was accomplished by increasing the tacrolimus dose, giving a steroid bolus or taper, or by giving a course of OKT3 (49).
Prophylaxis of infection
Postoperative management Immunosuppression Tacrolimus, the primary immunosuppressive agent, is given as a continuous intravenous infusion initially at a dose
Selective decontamination, consisting a combination of amphotericin B/nystatin, tobramycirggentamicin and Polymyxin E, is given by mouth or nasogastric/enterostomy, four times a day for 3-4 weeks after transplantation. Decontamination is re-instituted during episodes of severe rejec-
CLINICAL NUTRITION 49
tion and in patients with apparent bacterial overgrowth. Standard intravenous antibiotic prophylaxis, with cefotaxime and ampicillin, is administered for 5-7 days after transplantation and resumed, if needed, based upon the results of blood and body fluid cultures. To obtain evidence of microbial translocation in patients with an active systemic infection, quantitative stool cultures and blood cultures are periodically done to monitor changes in intestinal flora. Ganciclovir and CMV immunoglobulin (Cytogam) are used for CMV prophylaxis, and co-triimoxazole (sulfamethoxazoletrimethoprim) is used for pneumocystis carinii prophylaxis.
acute rejection of the intestinal allograft. Severe episodes of rejection may also present as graft ileus, intestinal bleeding, septic shock, and/or adult respiratory distress. Endoscopieally, rejection usually causes the intestinal mucosa to appear ischemic or dusky with focal ulcerations and causes reduced or even complete loss of peristalsis. Grafts with severe rejection showed either nodular mucosa or diffuse ulceration with bleeding. Histological criteria for the diagnosis of acute intestinal allograft rejection include mononuclear cell infiltrate, villous blunting and cryptitis. Complete sloughing of the intestinal mucosa with crypt destruction was seen in patients with severe rejection.
Nutrition TPN is continued during the early postoperative course. After confirming the integrity of the gastrointestinal anastomoses and the partial recovery of gut motility using the appropriate gastrointestinal contrast studies, enteral feeding, through a jejunostomy tube, is started. Enteral feeding is given continuously, and the volume is gradually increased. Parenteral nutrition is tapered gradually as enteral feeds are advanced, and eventually discontinued. In children, Pediatric Vivonex (Sandoz, Minneapolis, MN) is used for enteral feeding for the first 4-6 weeks since it contains a large amount of glutamine, which is an essential nutrient for the intestine. After intestinal absorption improves, the formula is switched to Peptamin Junior (Clintec Nutrition Co., Deerfield, IL). Adult patients receive Peptamin (Clintec Nutrition Co., Deerfield, IL) for enteral feeding. Both Peptamin Junior and Peptamin are isotonic elemental diets that contain peptide-based protein, medium-chain triglycerides, and glutamine. Enteral feedings are gradually decreased as oral intake is increased. Weaning of the enteral nutritional support is usually accomplished by decreasing the daily duration of tube feeding. Opiates, loperamide and pectin are used for patients who have high stomal output or diarrhea.
Graft monitoring Diagnosis of intestinal graft rejection is based primarily upon clinical findings, endoscopic observations and histopathologic examination of endoscopic-guided mucosal biopsies. Surveillance graft endoscopy, with multiple random mucosal biopsies, is performed when clinically indicated, and at least once per week for the first 3 months, monthly for the next 3 mouths and every 3-6 months thereafter. Access to the ileum for endoscope-guided mucosal biopsies is usually achieved through the distal ileoscopy or by colono-ileoscopy. The jejunal biopsies are taken by regular upper gastrointestinal endoscopy. Since it has been shown that the ileum is more susceptible to rejection than the jejunum, ileal biopsies are needed to diagnose graft rejection.
Acute rejection Clinical symptoms of fever, abdominal pain, increased stomal output, watery diarrhea and vomiting usually suggest
Chronic rejection Chronic rejection of the intestinal aUograft usually presents as intractable diarrhea, abdominal pain, intermittent episodes of sepsis, progressive weight loss and intermittent intestinal bleeding. Periodic endoscopic examinations show pseudomembrane formation, thickened mucosal folds and chronic ulcers in a tubular intestine. Radiological studies show dilated intestinal loops, thickened intestinal wall, and effaced mucosal folds. Serial intestinal mucosal biopsies show apoptosis of crypt cells with a sparse inflammatory cell infiltrate. Angiographic studies sometimes demonstrate segmental narrowing of the mesenteric arterial arcade, which may dictate graft enterectomy. Full thickness histopathologic examination of grafts resected due to chronic rejection has shown mucosal ulceration with intramural abscesses, and obliterative arteriopathy. Graft enterectomy and subsequent retransplantation may be the only option to treat chronic rejection.
Graft versus host disease ( GVHD) Skin rash is the major manifestation of GVHD in intestinal transplantation recipients. The recipient's native gastrointestinal tract and liver are also possibly affected by GVHD. Biopsies of regions suspected for GVHD are necessary to confirm the diagnosis. Two methods are needed to confirm GVHD of the skin. Histologically, GVHD causes apopotosis of the epithelial cells. Immunologically, GVHD is diagnosed by the existence of donor lymphocytes in the epithelium, which is shown by either immunohistological stain for donor specific HLA antigen and/or in-situ hybridization using the Y-chromosome specific probe (if the donor was male and the recipient was female).
Graft function Biochemical batteries of hepatic and pancreatic enzymes are used to monitor the status of the liver and pancreas. Radiological contrast studies of the transplanted and native gastrointestinal tract are performed to study gastric emptying, intestinal transit, and changes in mucosal pattern. Serum concentrations of albumin, vitamins, minerals and trace elements are measured frequently to evaluate graft function. Absorption is assessed using D-xylose and oral tacrolimus
50 CLINICAL INTESTINAL TRANSPLANTATION
kinetic studies (after discontinuation of intravenous tacrolimus doses). Anthropometric measurement are obtained periodically to assess changes in weight and muscle mass. Current results
From May 1990 to June 1995, 71 patients underwent intestinal transplantation. Forty-one recipients were children, with a mean age of 4.5 + 4.7 years, and 30 recipients were adults, with a mean age of 34.1 _+ 10.2 years. Twenty-five patients received an isolated intestinal graft, 34 patients received a combined liver-intestinal graft, and 12 received a multivisceral graft. The colon was included the intestinal graft in 29 patients.
Survival Figure 2 shows the Kaplan-Meier actuarial patient and graft survival. Thirty-seven recipients (52%) are currently alive 3-62 months after intestinal transplantation. One-year, 2-year, and 4-year actuarial patient survival is 72%, 57%, and 45%, respectively. The main causes of death were pneumonia (n = 5), rejection (n = 5), post-transplant lymphoproliferative disorder (n = 4), sepsis (n = 3), technical (n = 3) and hepatitis C (n = 2). One year, 2-year and 4-year actuarial primary graft survival is 62%, 48%, and 37%, respectively. Four recipients required graft removal; two had intestinal rejection because of reduction of the immunosuppression due to diffuse demyelination i~ the brain, or intractable CMV infection, and the other two recipients had overwhelming rejection (n = 1) and pneumonia immediately after transplant (n = 1). Retransplantation was performed in five recipients. Three isolated intestinal graft recipients lost their grafts due to rejection and were retransplanted, two received isolated intestinal retransplantation and the other received multivisceral retransplantation. Two combined liver-intestinal recipients lost their grafts due to rejection and PTLD, and were retransplanted; one received liver and intestinal retransplantation, and the other received multivisceral retransplantation. 100' 908070"
o~
60-
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50
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40'
Immunologic complications (50) Acute rejection is a persistent problem in intestinal transplantation. Overall, 92% of the 71 patients experienced an average of 3.7 episodes of intestinal rejection. Rejection occurred in more than 50% of the patients 3 months after transplantation. In composite grafts that included the liver, the incidence of hepatic allograft rejection (43%) was much less than the incidence of intestinal graft rejection. Chronic rejection was diagnosed in two resected isolated intestinal grafts, and was also seen in both organs of one combined liver-intestinal graft recipient. GVHD has rarely been seen in our series. One pediatric combined liver-intestinal recipient was unequivocally diagnosed with acute GVHD before her death. One adult multiviseeral patient developed chronic GVHD several years after transplantation. Three isolated graft recipients (2 children and 1 adult) had skin rashes, suggestive of GVHD, after graft enterectomy and discontinuation of immunosuppression. The skin rashes of these three patients spontaneously resolved.
Infectious complications Most of the intestinal recipients have had infectious complications after transplantation, with a median of four episodes per patient. The incidence of bacterial, viral and fungal infection was 81%, 76%, and 62% respectively. While line, wound and intra-abdominal infections were the most common type of bacterial infection, candida esophagitis was the most frequent type of fungal infection (51). CMV has been the most problematic infectious complication for the adult patients. Twenty-four (34%) patients developed CMV disease, of which 15 (50%) were adults and 9 (22%) were children. While no CMV disease was seen in CMV seronegative patients receiving CMV seronegative grafts, significant CMV disease (55%) was seen in patients receiving CMV seropositive grafts. Cytomegalovirus disease was mainly confined to the intestinal graft, but CMV hepatitis, gastritis, and retinitis were also seen. Even when CMV disease was treated with ganciclovir or foscarnet, disease recurrence rate was high in the patients that received CMV seropositive isolated intestinal grafts (44). While CMV presented few problems in the children, Epstein Barr virus (EBV)-related lymphoproliferative disease caused significant difficulties. Of the 15 recipients (21%) that developed EBV-related post-transplant lymphoproliferative disease (PTLD), 12 were children. PTLD was treated by decreasing or discontinuing immunosuppression, acyclovir/ganciclovir, alpha or gamma interferon, hyperimmunoglobulin and/or chemotherapy. Seven of 15 patients died and 2 patients lost their grafts (52).
30'
Graftfunction
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Patient (n=71)
--*-- Graft (n=76) 0
,
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-
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1 2 3 4 Time After Transplantation (years)
Actuarial patient and primary graft survival of the 71 recipients.
Preoperatively, 68 patients had been on TPN for 1-180 months and most had experienced more than one episode of TPN-related complications. TPN-related liver failure was seen in 39 patients (55%). These patients had a median total bilirubin of 18.1 mg/dl, which ranged from 2.1 to 58.2 mg/dl.
CLINICAL NUTRITION 51 P o s t - o p e r a t i v e l y , T P N w a s r e s u m e d 2 4 - 4 8 h after t r a n s p l a n t a t i o n , a n d t h e n d i s c o n t i n u e d 2 - 3 0 w e e k s after t r a n s p l a n t a t i o n w h e n a d e q u a t e nutritional a b s o r p t i o n was a c h i e v e d f r o m t u b e f e e d i n g s a n d oral intake. T a c r o l i m u s k i n e t i c s a n d D - x y l o s e a b s o r p t i o n tests r e v e a l e d t h a t i n t e s t i n a l a b s o r p t i o n i m p r o v e s s i g n i f i c a n t l y 1 m o n t h after t r a n s p l a n t a t i o n (53). Serum albumin and vitamin levels of the patients were w i t h i n n o r m a l r a n g e s after t r a n s p l a n t a t i o n . D e l a y e d gastric e m p t y i n g w a s d e t e c t e d w i t h b a r i u m s t u d y ( 6 0 % ) or s c i n t i g r a p h i c t e c h n i q u e ( 3 8 % ) i n early posto p e r a t i v e period, b u t i m p r o v e d s i g n i f i c a n t l y 3 - 6 m o n t h s after t r a n s p l a n t a t i o n . T h e m e d i a n s m a l l b o w e l transit t i m e w a s 2 h, r a n g i n g f r o m 0.2 to 17.8 h. N o c o r r e l a t i o n w a s found between transit time and time after transplantation (54, 55). O f t h e 37 c u r r e n t s u r v i v o r s , 31 ( 8 4 % ) p a t i e n t s are free o f T P N a n d e n j o y i n g a n u n r e s t r i c t e d oral diet. T w o o f 37 surv i v o r s r e q u i r e partial n u t r i t i o n a l s u p p l e m e n t a t i o n w i t h T P N , a n d f o u r o f 37 s u r v i v o r s are o n T P N after g r a f t e n t e r e c t o m y .
Future of intestinal transplantation F o r the last t h r e e d e c a d e s t h e i n t e s t i n e h a s b e e n c o n s i d e r e d a ' f o r b i d d e n o r g a n ' for t r a n s p l a n t a t i o n b e c a u s e o f p o o r c l i n i c a l results. T h e i n t r o d u c t i o n o f t a c r o l i m u s h a s a l l o w e d c l i n i c a l i n t e s t i n a l t r a n s p l a n t a t i o n to b e c o m e a f e a s i b l e p r o c e d u r e f o r p a t i e n t s w i t h i r r e v e r s i b l e i n t e s t i n a l failure; however, our experience has shown that infectious and immunological problems have caused significant mo~idity a n d m o r t a l i t y e v e n 1 - 3 y e a r s after t r a n s p l a n t a t i o n . T o o v e r come these obstacles we have initiated a new protocol employing simultaneous donor derived bone marrow infusion a n d i n t e s t i n a l t r a n s p l a n t a t i o n . T h e a i m o f this n e w s t r a t e g y is to a u g m e n t the c h i m e r i s m a n d e n h a n c e a c c e p t a n c e o f the i n t e s t i n a l graft. N i n e p a t i e n t s h a v e a l r e a d y r e c e i v e d s i m u l t a n e o u s b o n e m a r r o w a n d i n t e s t i n a l t r a n s p l a n t a t i o n , b u t it is t o o e a r l y to assess t h e results. O u r h o p e is t h a t this m e t h o d will o p e n a n e w h o r i z o n for i n t e s t i n a l t r a n s p l a n t a t i o n in future.
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52 CLINICALINTESTINALTRANSPLANTATION
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Submission date: 13 October 1995; Accepted: 18 December 1995
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