Hiro Furukawa

Clinical intestinal transplantation: new perspectives and immunologic considerations.

Background: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high-dose treatment has inhibited the widespread use of these procedures. We have examined our 1990–1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. n nStudy Design: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. n nResults: With a mean followup of 32 ± 26 months (range, 1–86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. n nConclusions: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol.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 and overview with intestinal transplantation.

Current status of intestinal transplantation in children

PURPOSEnA clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN).nnnMETHODSnFifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n=33), and multivisceral (MV) (n=8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n=14), volvulus (n=13), necrotizing enterocolitis (n=6), intestinal atresia (n=8), chronic intestinal pseudoobstruction (n=5), Hirschsprungs disease (n=4), microvillus inclusion disease (n=3), multiple polyposis (n=1), and trauma [n=1).nnnRESULTSnCurrently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n=18), intestinal allograft rejection (n=52), posttransplant lymphoproliferative disease (n=16), cytomegalovirus (n=16) and graft-versus-host disease (n=4). A combination of associated complications included intestinal perforation (n=4), biliary leak (n=3), bile duct stenosis (n=1), intestinal leak (n=6), dehiscence with evisceration (n=4), hepatic artery thrombosis (n=3), bleeding (n=9), portal vein stenosis (n=1), intraabdominal abscess (n=11), and chylous ascites (n=4). Graft loss occurred as a result of rejection (n=8), infection (n=12), technical complications (n=8), and complications of TPN after graft removal (n=3). There were four retransplants (SB, n=1; LSB n=3).nnnCONCLUSIONSnIntestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation.

Urgent revascularization of liver allografts after early hepatic artery thrombosis

Between April 1993 and May 1995, 17 adult orthotopic liver transplant recipients were found to have early hepatic artery thrombosis (HAT) after a median of 7 postoperative days (mean, 11). The HAT was diagnosed in all cases by duplex ultrasound. Thrombectomy was performed with urgent revascularization (UR), using an interposition arterial graft procured from the cadaveric liver donor, and arterial patency was verified with intraoperative angiography. In seven cases, intra-arterial urokinase was administered after the thrombectomy. Fifteen (88%) of the livers remained arterialized throughout the follow-up period (median, 15 months); the remaining two patients developed recurrent HAT after 6 and 8 months. Although there was a high rate of subsequent complications, 11 (65%) of the patients are alive without retransplantation, with a mean follow-up of 17 months. Despite having a patent hepatic artery, the remaining six patients (35%) died from infectious complications that usually were present before the UR. Thus, UR effectively restored arterial inflow in 88% of the patients with early HAT. The ultimate outcome was determined mainly by the presence of intra-abdominal complications at the time of UR. In conclusion, UR, rather than retransplantation, should be considered the prime treatment option for patients who develop early posttransplant HAT.

Quality of Life After Small Intestinal Transplantation and Among Home Parenteral Nutrition Patients

BACKGROUNDnThe purpose of the study was to quantify changes in the quality of life of small bowel recipients before and after transplantation and of home parenteral nutrition (HPN)-dependent patients before and after therapy. We examined quality of life across multiple areas of function including physical, social, and emotional indices.nnnMETHODSnThe Quality of Life Instrument in the form of a self-administered questionnaire was completed voluntarily by the recipients of small intestinal transplants and by a cohort of HPN-dependent patients.nnnRESULTSnSmall intestinal transplant recipients reported significant improvement in the quality of their life and function. They also rated their quality of life and function during the pretransplant, TPN-dependent period to be worse than before the development of chronic intestinal failure. Similarly, HPN recipients reported significant worsening across most areas of quality of life when they compared their premorbid period to the HPN-dependent state.nnnCONCLUSIONSnTPN dependence causes significant impairment in the quality of life in most areas of functioning. In contrast, small intestinal transplantation restores the quality of life among recipients with functioning grafts.

The use of clonidine for the treatment of high intestinal output following small bowel transplantation

Abstract The use of small bowel transplant (SBT) for short bowel syndrome poses unique and challenging problems posttransplantation. High intestinal output or diarrhea following SBT is extremely common and often requires intravenous (IV) fluid supplementation or even HPN intermittently. Various methods to control this output have been utilized, but frequently are not very successful.

Clinical intestinal transplantation

Background: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high-dose treatment has inhibited the widespread use of these procedures. We have examined our 1990–1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. n nStudy Design: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. n nResults: With a mean followup of 32 ± 26 months (range, 1–86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. n nConclusions: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol.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 and overview with intestinal transplantation.

Autologous lymphokine-activated killer cell therapy of lymphoproliferative disorders arising in organ transplant recipients

Abstract Cell lymphomas which often contain the Epstein-Barr virus (EBV) make up the preponderance of tumors that collectively have been termed posttransplant lymphoproliferative disorders (PTLD). The unusual susceptibility of PTLD to immune surveillance was first demonstrated in organ allograft recipients following reduction (or discontinuance) of immunosuppression 1 with its attendant risk of precipitating allograft rejection. Restoration of tumor surveillance has recently been accomplished in bone marrow transplant recipients with PTLD by infusing naive cytotoxic T lymphocytes (CTL) obtained from the original donors into the tumor-bearing recipients. In these cases the tumors are invariably of donor origin, and HLA-restricted effector cells directed against viral targets are thought to be the main mediators of tumor regression. 2,3 The unavailability of naive pretransplant recipient leukocytes has precluded direct application of this technology to the PTLDs which develop after organ transplantation and which are almost always of recipient origin. 4 However, we report herein an approach whereby the anti-PTLD activity of the recipients own cells can be intensified in vitro. Reinfusion of these cells has been associated with clinical tumor regression in several cases.

Intestinal and multivisceral transplantation

Intestinal transplantation for treatment of irreversible intestinal failure is the newest of the transplantation operations to be developed for clinical use. Because the bowel is more vulnerable to rejection than heart, lung, kidney, liver, or pancreas, practical clinical intestinal transplantation has been relatively slow to develop and is still in its infancy. Imaging studies play an important role in the initial evaluation of the residual native gastrointestinal tract for patients who are potential candidates for enteric implant. After transplantation, gastrointestinal contrast studies help monitor the recovery of gastrointestinal function and permit early detection of postoperative technical complications. CT, ultrasound, and angiography are useful for diagnosis and in some cases treatment of a variety of posttransplantation complications.

Psychiatric evaluations of small intestine transplantation patients

We are gaining experience in small intestine transplantation, however, the procedure is still experimental. Morbidity and mortality can be significant with frequent rehospitalizations. The indications for small intestine transplantation are varied though most patients have developed short gut syndrome requiring total parenteral nutrition (TPN) for nutritional support. Patients may present with a chronic illness (such as Crohns disease), chronic pain, and psychiatric comorbidity that may need to be addressed during the perioperative period. Faced with the complicated postoperative course, transplant recipients develop a range of endogenous and organic psychiatric disorders. Psychiatric treatment may be complicated by these factors in addition to the nutritional, biochemical, and metabolic abnormalities of a transplanted small intestine.

Influence of donor criteria on early outcome after intestinal transplantation.

From May 1990 to September 1995. a total of 72 patients received 77 intestinal grafts (27 isolated intestine, 36 liver and intestinal, and 14 multivisceral) at our center. Donors ranged from newborn to age 48 years. Fifty-one donors were male, and 26 were female. The most common causes of death were motor-vehicle accidents, cerebrovascular accidents. and gunshot wounds. Length of hospital stay for the donors was 1 to 21 days. Ten of 77 donors had cardiopulmonary resuscitation, and 18 were maintained on high vasopressor (either higher than 10 J.Lg/kg per minute of dopamine, norepinephrine and/or epinephrine) during the donor operation. A total of 2 to 4 L (50 to 100 mL/kg in children) of University of Wisconsin (UW) solution was used for in situ perfusion in the donor operation. Cold ischemia time (CIT) ranged from 2.8 to 17 hours, with a mean of 7.7 hours. Donor and recipient procedures are described elsewhere.2 Postoperative immunosuppression was with tacrolimus (FK 506), steroids, and in selected cases azathioprine (AZA). In an effort to predict the quality of early posttransplant graft function, donor variables such as age, sex, hospital stay, CPR. vasopressor. oxygenation (ratio of Po2/Fio2 ). sodium. creatinine. total bilirubin, AST, AL T, and CIT were studied. The donor variables were analyzed in regard to 3-month actual graft survival and grading of tissue damage of postperfusion intestinal specimens (2 to 4 hours after reperfusion) as well as posttransplant intestinal biopsy (within 7 days after transplantation). The grading of histology was by Park classification on a scale of I to 8. Multivariate stepwise (backward elimination method) logistic regression for survival and linear regression for intestinal histology were used for statistical analysis.