Naveen K Mittal

Transplantation of the abdominal wall

BACKGROUND Closure of the abdomen in patients undergoing intestinal transplantation can be extremely difficult, if not impossible. We describe our initial experience with abdominal wall allotransplantation to facilitate abdominal closure. METHODS We undertook nine cadaveric abdominal wall composite allograft transplants in eight patients. The grafts blood supply was based on the inferior epigastric vessels left in continuity with the donor femoral and iliac vessels. Skin biopsies were undertaken randomly and when rejection was suspected. Vessel patency was monitored by doppler ultrasound. FINDINGS Six patients have survived, five of whom have intact, viable abdominal wall grafts. Two patients have had a clinically mild episode of acute rejection of the skin of the abdominal wall that resolved with corticosteroid therapy. No clinically apparent graft-versus-host disease has been noted. INTERPRETATION Transplantation of an abdominal wall composite allograft can facilitate reconstruction and closure of the abdominal compartment in intestinal transplant recipients with complex abdominal wall defects.

Ninety-five cases of intestinal transplantation at the University of Miami.

Intestinal failure requiring total parenteral nutrition (TPN) is associated with significant morbidity and mortality. Intestinal transplantation can be a lifesaving option for patients with intestinal failure who develop serious TPN-related complications. The aim of this study was to evaluate survival, surgical technique, and patient care in patients treated with intestinal transplantation. We reviewed data collected from 95 consecutive intestinal transplants performed between December 1994 and November 2000 at the University of Miami. Fifty-four of the patients undergoing intestinal transplantation were children and 41 were adults. The series includes 49 male and 46 female patients. The causes of intestinal failure included mesenteric venous thrombosis (n = 12), necrotizing enterocolitis (n = 11), gastroschisis (n = 11), midgut volvulus (n = 9), desmoid tumor (n = 8), intestinal atresia (n = 6), trauma (n = 5), Hirschsprung’s disease (n = 5), Crohn’s disease (n = 5), intestinal pseudoobstruction (n = 4), and others (n = 19). The procedures performed included 27 isolated intestine transplants, 28 combined liver and intestine transplants, and 40 multivisceral transplants. Since 1998, we have been using daclizumab (Zenepax) for induction of immunosuppression and zoom videoendoscopy for graft surveillance. We began to use intense cytomegalovirus prophylaxis and systemic drainage of the portal vein. The 1-year patient survival rates for isolated intestinal, liver and intestinal, and multivisceral transplantations were 75%, 40%, and 48%, respectively. Since 1998, the 1-year patient and graft survival rates for isolated intestinal transplants have been 84% and 72%, respectively. The causes of death were as follows: sepsis after rejection (n = 14), respiratory failure (n = 8), sepsis (n = 6), multiple organ failure (n = 4), arterial graft infection (n = 3), aspergillosis (n = 2), post-transplantation lymphoproliferative disease (n = 2), intracranial hemorrhage (n = 2), and fungemia, chronic rejection, graft vs. host disease, necrotizing enterocolitis, pancreatitis, pulmonary embolism, and viral encephalitis (n = 1 case of each). Intestinal transplantation can be a lifesaving alternative for patients with intestinal failure. The prognosis after intestinal transplantation is better when it is performed before the onset of liver failure. Rejection monitoring with zoom videoendoscopy and new immunosuppressive therapy with sirolimus, daclizumab, and campath-1H have contributed to the improvement in patient survival.

Preliminary experience with campath 1H (C1H) in intestinal and liver transplantation

Background. The aim of this research was to study the efficacy of campath 1H in combination with low-dose tacrolimus immunosuppression for intestinal, multivisceral, and liver transplantation. Methods. Campath 1H (0.3 mg/kg) was administered in four doses: Preoperatively, at the completion of the transplant, and on postoperative days 3 and 7. Tacrolimus levels were maintained between 5 to 10 ng/dL. Suspected or mild rejections were treated with steroids. Moderate or severe rejections were treated with OKT3. Patients. We studied three groups of patients: adult recipients of intestinal or multivisceral transplants, high-risk pediatric recipients of small-bowel or multivisceral grafts, and adult liver-transplant recipients. Results. Twenty-one adult intestinal recipients received 24 grafts. With follow-up of 2.4 to 16 months, 14 patients are alive and 14 grafts are functioning. Eleven high-risk pediatric intestinal recipients received 12 grafts. There were four mortalities in this group, and after a follow up of 1 to 8.5 months, four patients have not experienced a rejection episode. Five adult liver recipients received five grafts. With a follow-up of 3 to 6.2 months, all five patients are alive. There were no rejection episodes in this group, and none of them required steroid therapy. Conclusions. This immunosuppressive regimen allows for the avoidance of maintenance adjuvant-steroid treatment in the majority of our patients. Our preliminary data show a trend toward a reduction of the incidence and the severity of rejection episodes, although we need to follow-up larger numbers of patients to confirm these results.

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.

Adenovirus infection in pediatric liver and intestinal transplant recipients: Utility of DNA detection by PCR

To evaluate the incidence of adenovirus (AdV) infection in pediatric liver and intestinal transplant recipients, the records of patients with possible AdV infection were reviewed for demographic data, symptomatology, methods of diagnosis, treatment and outcome. To evaluate the impact of polymerase chain reaction (PCR) amplification and identification of AdV DNA as a diagnostic test, the incidence and outcome of AdV before and after the introduction of PCR were compared. Adenovirus infection was identified in 4.1% of liver recipients and 20.8% of intestinal transplant recipients. The overall incidence of AdV did not increase over time, even following the introduction of PCR for virus detection. The higher incidence of AdV in the pediatric intestinal transplant recipients may be attributed to the frequent application of PCR methodology to intestinal biopsy material. Detection of AdV by PCR was associated with reduced mortality compared with detection by culture, either because of earlier detection of invasive disease or because PCR detects the presence of latent as well as active AdV.

Mucosal Vascular Alterations in Isolated Small-Bowel Allografts: Relationship to Humoral Sensitization

Acute vascular rejection (AVR) in human small‐bowel transplantation is an inadequately characterized entity whose frequency and severity is not well understood. As compared to severe AVR, changes identifying early, mild or evolving AVR are not known. We created a scoring system to evaluate subtle mucosal vascular changes and examined 188 biopsies from 21 patients obtained in the first 3 months post transplant. A majority of patients had a transient rise in vascular injury, often within 30 days of transplant. Small‐vessel congestion and erythrocyte extravasation were the most common alterations. The vascular injury score was not related to acute cellular rejection, HLA type or HLA antigen disparities. However, the patients with the vascular changes had significantly higher peak panel reactive antibodies (PRA) and a higher incidence of positive T‐cell and B‐cell crossmatch. Finally, graft survival was significantly lower in the patients demonstrating the early vascular lesions. These data suggest that the vascular injury is partially associated with humoral presensitization of the recipient and may be a form of acute vascular rejection. Since these vascular changes are frequent, we advocate early post‐transplant monitoring to identify and manage potentially high‐risk patients.

Bacterial infections after intestine and multivisceral transplantation

BACKGROUND The frequency of bacterial infections (BI) in intestinal transplant (IT) patients is high with sepsis being the leading cause of death after this procedure. We herein report our experience with major BI to ascertain the incidence, microbiological and clinical factors, risk factors and outcome. MATERIALS AND METHODS 124 patients (72 children and 52 adults) received 135 grafts: namely, 39 isolated intestine, 33 liver-intestine and 63 multivisceral. Only major BI were considered, namely, those associated with serious morbidity/mortality requiring specific therapy. Patient data were retrieved from computerized databases, flow-charts, and medical records. RESULTS 92.7% patients showed BI. There were 327 episodes, representing 2.6 episodes/patient (2.8/patients with infection): 193 episodes of bacteremia (1.7/patient with BI) including 29.5% due to catheter related sepsis, 16.5% from abdominal source, 5.7% from respiratory origin and 4.1% from the wound. The organ locations includes 46 respiratory infections, 33 intraabdominal abscesses or infected fluid collections, 8 diffuse peritonitis, 34 wound infections and other miscellaneous sites: empyema, soft tissue infections, cholangitis em leader etc. Median time of infection was nine days after surgery (mean 22+/-3 days), with 67.7% patients having at least one BI before the end of the first month. Infection was present in 76.2% of the 63 deceased patients. An infectious episode during month 1, a clinically manifest abdominal infection and a positive intraabdominal culture had negative impacts on patient survival. CONCLUSIONS BI are common and early complications after IT. The high rate of bacteremia, line sepsis and abdominal and respiratory infections reflect the recipients condition, with chronic deterioration superimposed with the effects of prolonged abdominal visceral surgery.

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).

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.