John F. Thompson

100 Multivisceral Transplants at a Single Center

Objective:The objective of this study was to summarize the evolution of multivisceral transplantation over a decade of experience and evaluate its current status. Summary Background Data:Multivisceral transplantation can be valuable for the treatment of patients with massive abdominal catastrophes. Its major limitations have been technical and rejection of the intestinal graft. Methods:This study consisted of an outcome analysis of 98 consecutive patients who received multivisceral transplantation at our institution. This represents the largest single center experience to date. Results:The most common diseases in our population before transplant were intestinal gastroschisis and intestinal dysmotility syndromes in children, and mesenteric thrombosis and trauma in adults. Kaplan Meier estimated patient and graft survivals for all cases were 65% and 63% at 1 year, 49% and 47% at 3 years, and 49% and 47% at 5 years. Factors that adversely influenced patient survival included transplant before 1998 (P = 0.01), being hospitalized at the time of transplant (P = 0.05), and being a child who received Campath-1H induction (P = 0.03). Among 37 patients who had none of these 3 factors (15 adults and 22 children), estimated 1- and 3-year survivals were 89% and 71%, respectively. Patients transplanted since 2001 had significantly less moderate and severe rejections (31.6% vs 67.6%, P = 0.0005) with almost half of these patients never developing rejection. Conclusions:Multivisceral transplantation is now an effective treatment of patients with complex abdominal pathology. The incidences of serious acute rejection and patient survival have improved in the most recent experience. Our results show that the multivisceral graft seems to facilitate engraftment of transplanted organs and raises the possibility that there is a degree of immunologic protection afforded by this procedure.

Intestinal and Multivisceral Transplantation in Children

Objective:To describe a single-center experience of pediatric intestinal transplantation (Itx) and to provide an overview of the children who underwent this procedure along with their outcomes. Summary Background Data:Pediatric Itx presents multiple challenges because of the very young ages at which patients require transplantation and their higher susceptibility to infectious complications. Methods:We have performed 141 Itx in 123 children with a median age of 1.37 years. Primary grafts included isolated intestine (n = 28), liver and intestine (n = 27), multivisceral (n = 61), and multivisceral without the liver (n = 7). Two protocol modifications were introduced in 1998: daclizumab induction and frequent rejection surveillance. In 2001, indications for multivisceral transplantation were expanded, and induction with Campath-1H was introduced. Results:Actuarial patient survival at 1 and 3 years for group 1 (January 1994 to December 1997, n = 25), group 2 (January 1998 to March 2001, n = 29), group 3a (April 2001 to present, daclizumab, n = 51), and group 3b (April 2001 to present, Campath-1H, n = 18) was 44%/32%, 52%/38%, 83%/60%, and 44%/44%, respectively (P = 0.0003 in favor of group 3a). Severe rejection implied a dismal prognosis (65% mortality at 6 months). Observed incidence of severe rejection in groups 1, 2, 3a, and 3b was 32%, 24%, 14%, and 11%, respectively. In multivariable analysis, use of a multivisceral (with or without liver) transplant (P = 0.002), induction with daclizumab (P = 0.005), patient at home prior to transplant (P = 0.007), and age at transplant ≥1 year (P = 0.02) favorably influenced patient survival. Multivisceral transplant was protective with respect to the mortality rate due to rejection, while an older age at transplant was associated with both a lower incidence rate of developing respiratory infection and lower risk of mortality following the respiratory infection. Survivors are off parenteral nutrition and have demonstrated significant growth catch-up. Conclusions:Itx in children still is a high-risk procedure but has now become a viable option for children who otherwise have no hope for survival. Control of respiratory infection is of particular importance in the younger children.

A controlled trial of cyclosporine in renal transplantation with conversion to azathioprine and prednisolone after three months.

Thirty-five patients given an HLA-DR-incompatible cadaver kidney that was diuresing immediately after transplantation were randomly allocated to treatment with cyclosporine alone for 3 months followed by conversion to azathioprine and prednisolone (AP), or to conventional treatment with AP. Although many patients had to be converted to AP before 90 days because of rejection requiring more than two treatment courses of high-dose i.v. methylprednisolone, 16 of 21 grafts were functioning at 3 months, and 12 of 14 grafts in the control group were functioning. However 3 further grafts were lost from chronic rejection in the control group, and none were lost from chronic rejection in the cyclosporine group. All but one patient on cyclosporine had depressed renal function, and in all these patients function improved on conversion to AP. This depression of renal function is attributed both to cyclosporine nephrotoxicity and to a low-grade rejection reaction, the latter suggesting that the addition of steroids to cyclosporine might be beneficial in some patients. The strategy of a three-month course of cyclosporine followed by conversion to AP provides satisfactory immunosuppression, and it may be of value if long-term side effects of cyclosporine emerge with further experience.

An Analysis of the Association between Serum Citrulline and Acute Rejection among 26 Recipients of Intestinal Transplant

Small preliminary studies suggest that serum citrulline levels may act as a marker for acute cellular rejection in small intestinal transplant recipients. The results comparing serum citrulline concentrations with biopsy‐based grades of rejection are summarized here for an expanded group of 26 isolated intestinal and multivisceral transplant recipients. Other factors considered included patient and donor age and sex, ischemia time, serum creatinine, and type of transplant. Straight‐line fits reasonably described how each patients citrulline levels changed over time. Among 21 patients who demonstrated increasing citrulline levels over time, the estimated median time‐to‐achieve normal citrulline (≥30 μmol/L) was 79 days post‐transplant. Using stepwise linear regression, two characteristics were associated with a significantly higher maximum grade of rejection after 14 d post‐transplant: longer time‐to‐achieve normal citrulline (using ranks, p < 0.00001) and the patient not receiving a multivisceral transplant (p = 0.0005). Only the latter characteristic was significantly associated with maximum grade of rejection during the first 14 d post‐transplant (p = 0.01). Clearly, time‐to‐normalization of citrulline was delayed by the incidence of rejection, and in some cases with moderate‐to‐severe rejection, normalization of citrulline levels never occurred. We plan to further examine the use of citrulline as a marker for rejection in larger prospective studies.

Analysis of Acute Cellular Rejection Episodes in Recipients of Primary Intestinal Transplantation: A Single Center, 11‐Year Experience

Intestinal transplantation has evolved over the years with major improvements in patient and graft survival. Acute cellular rejection of the intestine, however, still remains one of the most challenging aspects of postoperative management. We analyzed retrospectively collected data from 209 recipients of primary intestinal grafts at our institution over the past 11 years. A total of 290 episodes of biopsy‐proven rejection requiring clinical treatment were analyzed. Rejection episodes doubled in length, on average, with each increasing grade (mild, moderate, severe). We observed increased incidence of overall rejection and particularly severe rejection in recipients of isolated intestinal and liver‐intestine grafts in comparison with multivisceral grafts. Two rejection history variables had a significant negative impact on graft survival: the occurrence of a severe rejection episode and a rejection episode lasting ≥21 days. The lower incidence rate of severe rejection in recipients of multivisceral grafts might be due to a combination of increased donor lymphatic tissue and larger load of donor‐derived immune competent cells present in the graft. The development of more effective monitoring and treatment protocols to prevent the occurrence of severe and/or lengthy rejection episodes is of critical importance for intestinal graft survival.

MULTIVISCERAL TRANSPLANTATION FOR MEGACYSTIS MICROCOLON INTESTINAL HYPOPERISTALSIS SYNDROME

BACKGROUND Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare autosomal recessive disorder causing a functional neonatal bowel obstruction. Its etiopathogenesis is not fully understood. The prognosis is poor in the majority of cases; most patients die before the age of 6 months. In this report, we describe our experience with three patients with MMIHS in whom multivisceral transplantation was performed. METHODS Three patients with MMIHS underwent multivisceral transplantation. All patients were females with a history of long-term total parenteral nutrition (TPN) with TPN-related cholestatic liver disease. RESULTS Patient 1 died 17 months after transplantation because of aspiration after revision of her feeding gastrostomy. At the time of death, the graft was functioning and the patient was completely off TPN. Patient 2 is alive 17 months after transplant. She is a fully functional, active 2-year-old and has also recently begun oral feeding after intensive rehabilitation. Patient 3 died on day 44 of multisystem failure. CONCLUSIONS This is the first report in the literature of multivisceral transplantation for MMIHS. Although one of the three patients died 44 days after surgery from multiorgan system failure, the other two patients had long-term survival after transplant and both grew well on enteral feeding alone. One patient died 17 months from a non-transplant-related complication, while the other is living at home off of TPN, with almost complete dietary rehabilitation 17 months after transplant. Our case reports suggest that multivisceral transplantation is a valuable therapeutic option for patients affected by MMIHS with TPN-induced liver failure.

Zoom endoscopic monitoring of small bowel allograft rejection

BackgroundThe small bowel has been successfully transplanted in patients with irreversible intestinal failure. This report aims to describe endoscopic monitoring of small bowel rejection.MethodsA magnification endoscope (zoom endoscope) was used in this study. In the first part of the study (October 1998 to March 2000, 271 endoscopy sessions), the specific endoscopic findings that correlated with rejection were determined. An analysis then was performed on data from the second period (March 2001 to November 2002, 499 sessions) to evaluate the zoom endoscope’s accuracy in monitoring rejection.ResultsSpecific endoscopic findings of rejection found in the first period included background erythema, villous congestion, blunted villous tip, and shortened villous height. When the rejection was successfully treated, endoscopic appearance returned to normal. On the basis of these findings, five endoscopic criteria (villous shortening, villous blunting, background erythema, villous congestion, and mucosal friability) were used to score endoscopic sessions in the second period. Endoscopic diagnosis of rejection was compared with histology. Adult patients showed a sensitivity of 45%, a specificity of 98%, a positive predictive value of 82%, and a negative predictive value of 88%. In pediatric patients, these values were, respectively, 61%, 84%, 57%, and 86%. On 59 distinct occasions (30 in period 1 and 29 in period 2) in which the results were endoscopy negative yet biopsy positive (mild) for rejection, we elected not to treat these rejections on the basis of clinical evaluation, and 58 (98%) resolved without further therapy.ConclusionsWith the use of magnification, endoscopy is a useful tool for monitoring acute rejection in the small bowel allograft.

Tacrolimus and diarrhea: Pathogenesis of altered metabolism

Isolated from Streptomyces tsukubaensis, tacrolimus is a macrolide lactone that has been used extensively for immunosuppressive therapy in pediatric transplant recipients (1, 2). It is the backbone of immunosuppressive therapy for pediatric solid organ and bone marrow transplant in many centers, including ours. In this month’s issue of Pediatric Transplantation, Frühwirth et al. describe three cases of solid organ transplanted children who suffered increased morbidity caused by a raised trough blood level of tacrolimus in association with rotaviral gastroenteritis (3). A similar observation has been made in two liver transplant infants who exhibited a three-fold rise in the trough levels of tacrolimus and required a reduction in the dose of tacrolimus for less than 1 week during acute diarrheal illness with rotavirus (4). Chronic diarrhea of non-rotaviral etiology has also been shown to be associated with a similar phenomenon in a pediatric renal transplant patient (5). This patient required a three-fold reduction in the dose of tacrolimus during 6 weeks of chronic diarrheal illness and returned to her usual tacrolimus dose when the diarrhea stopped. In patients with intestinal transplant, a sudden rise in the level of tacrolimus has been observed with episodes of rejection (N. Mittal, T. Kato, A. Tzakis, unpubl. obs.). Possible explanations for the rise in blood levels of tacrolimus include hemoconcentration, fasting, increased absorption as a result of increased intestinal permeability, or reduced hepatic metabolism caused by reduced hepatic blood flow or hepatic dysfunction (3–5). Despite the extensive use of tacrolimus for almost a decade, until recently little was known about the important role that the intestine plays in its metabolism (6). Factors involved in oral drug bioavailability – gastric emptying, pH, interaction with food, absorption parameters of the drug (dissolution, lipophilicity, particle size, active uptake by mucosa), and hepatic extraction as ‘first-pass metabolism’ – have traditionally been important considerations. The contributions of intestinal metabolism and Pglycoprotein (P-gp) to the observed changes in the bioavailability of tacrolimus have recently been investigated and these may play dominant roles (6–10).

Sirolimus in pediatric gastrointestinal transplantation : The use of sirolimus for pediatric transplant patients with tacrolimus-related cardiomyopathy

Abstract: Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin®). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post‐transplant. One patient died of post‐transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post‐transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post‐transplant and maintained a whole‐blood trough level of 15–20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.

Portosystemic shunting in children during the era of endoscopic therapy : Improved postoperative growth parameters

BACKGROUND Surgical portosystemic shunting has been performed less frequently in recent years. In this retrospective study, recent outcomes of portosystemic shunting in children are described, to evaluate its role in the era of endoscopic therapy. METHODS Retrospective chart review of children who underwent surgical portosystemic shunt procedures between October 1994 and October 1997. RESULTS Twelve children (age range, 1-16 years) underwent shunting procedures. The causes of portal hypertension were extrahepatic portal vein thrombosis (n = 6), congenital hepatic fibrosis (n = 2), hepatic cirrhosis (n = 2), and other (n = 2). None of the patients were immediate candidates for liver transplantation. Types of shunt included: distal splenorenal (n = 10), portocaval (n = 1), and other (n = 1). Median follow-up was 35 months (range, 24-48 months). All patients are currently alive and well with patent shunts. The mean hospital stay was 8 days. Three patients required readmission for further interventions because of shunt stenosis in two and small bowel obstruction in the other. Mild portosystemic encephalopathy was seen in one child with pre-existing neurobehavioral disturbance. Excluding a patient who underwent placement of a portosystemic shunt for a complication of liver transplantation, mean weight-for-age z score in nine prepubertal patients improved from -1.16 SD to +0.15 SD (P = 0.023), and mean height-for-age z score from -1.23 SD to 0.00 SD (P = 0.048) by 2 years after surgery. CONCLUSIONS Surgical portosystemic shunting is a safe and effective method for the management of portal hypertension in childhood. Patients show significant improvements in growth parameters after the procedure. Surgical portosystemic shunting should be actively considered in selected children with portal hypertension.