D. Weppler

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Intestinal and multivisceral transplantation

Intestinal transplantation has been established as a treatment option for patients that suffer from intestinal failure with complications from total parenteral nutrition. It is still rapidly evolving and just reached a landmark of 1,000 cases worldwide. Intestinal allografts can be transplanted as isolated, combined with the liver or as a part of a multivisceral allograft. Tacrolimus-based immunosuppression regimens have been used universally with improved outcomes. Clinical outcome in intestinal transplantation has improved significantly over time, impacted by refinement of surgical technique and novel immunosuppression. However rejection, infection, and technical complications still remain the most difficult barrier to improve patient and graft survival.

Comparison of tacrolimus with microemulsion cyclosporine as primary immunosuppression in hepatitis C patients after liver transplantation

BACKGROUND Immunosuppression in patients with hepatitis C virus (HCV) following orthotopic liver transplantation can lead to significant increases in serum viral loads. Our aim was to analyze the effect of a randomized study of two immunosuppressive agents (tacrolimus vs. microemulsion cyclosporine) on the outcome of HCV patients following orthotopic liver transplantation. METHODS From December 1995 to September 1996, 50 adult patients transplanted for HCV cirrhosis were randomly assigned to receive tacrolimus (Prograf) (group 1, 25 patients) or microemulsion cyclosporine (Neoral) (group 2, 24 patients). All patients received alpha-interferon after transplantation, and the overall steroid doses were no different between the groups. Serum RNA levels were measured by signal amplification of Chiron. Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens. RESULTS There were more episodes of rejection in the Neoral group, but there were no differences in bacterial and viral infections, nor in the rate of HCV recurrence between the two groups. There were seven deaths in group 1 and eight in group 2. Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68% and 67 and 64%, respectively. CONCLUSIONS (a) Both immunosuppression regimens had similar HCV recurrence rates; (b) there were no differences in bacterial or opportunistic infections; and (c) patient and graft survival was similar between the two groups.

Efficacy of lamivudine in controlling hepatitis B virus recurrence after liver transplantation

BACKGROUND Indication of liver transplantation for patients infected with hepatitis B virus (HBV) remains controversial because of the high incidence of posttransplant HBV recurrence and aggressive involvement of the allograft. In this article, we provide evidence that the introduction of lamivudine may favorably alter the prognosis of these patients. METHODS Lamivudine was used in 40 HBV-infected adult patients suffering from chronic end-stage liver disease who underwent liver transplantation. The drug was used in the following settings: failure of prolonged passive immunoprophylaxis, elective conversion from immunoprophylaxis, de novo posttransplant HBV infection, and primary treatment with lamivudine which started before and continued after transplantation. Twenty patients (50%) had viral replication at the time lamivudine was started. Posttransplant and antiviral treatment follow-ups were 8-64 months (median follow-up: 27.5 months) and 9-39 months (median follow-up: 19 months), respectively. RESULTS The patient and graft survival rates were 97.5% (39/40). Thirty-three patients (82.5%) have remained free of viral recurrence. In the seven re-infected patients, the manifestations of HBV involvement of the allograft have been mild. There have been no side effects related to lamivudine, and the treatment is substantially less costly than with other anti-HBV agents. CONCLUSIONS Compared with historic series utilizing other modalities of treatment, the use of lamivudine has, so far, yielded superior results. This drug may be an important acquisition for antiviral prophylaxis in HBV-infected liver recipients. Because of the risk of viral mutations, however, efforts should proceed to achieve more efficacious methods for prevention and control of HBV recurrence.

Use of liver grafts from donors positive for antihepatitis B-core antibody (anti-HBc) in the era of prophylaxis with hepatitis-B immunoglobulin and lamivudine.

Background. The increasing demand for transplantation has resulted in a trend toward using virologically compromised donors. We reviewed our experience with liver grafts from hepatitis-B surface antigen (HBsAg)(−), antibody to core antigen (anti-HBc)(+) donors. Methods. Sixty-two liver transplants using HBsAg(−), anti-HBc(+) donors were studied. The decision to use prophylaxis was based on the presence or absence of donor and recipient risk factors for posttransplant hepatitis-B virus (HBV) transmission or reinfection. If the donor or recipient showed positive HBVDNA, hepatitis-B immunoglobulin (HBIg) and lamivudine were used. If both donor and recipient HBVDNA were negative, a choice between lamivudine and no prophylaxis was made on the basis of presence or absence of HBsAg and antibody to the surface antigen (anti-HBs) in the recipient. Results. No death or graft loss could be ascribed to HBV. Mild HBV infection occurred in two patients who were not taking the recommended prophylaxis. Among the other 60 patients, 1 showed positive e antigen (HBeAg) early after transplantation, and 2 (1 with recurrent cancer, 1 with HIV infection) showed HBsAg(+). None of the three patients had any other evidence of HBV infection. Forty-seven patients underwent liver biopsies. Changes consistent with hepatitis were observed in 26, and 24 had HCV infection; immunostains for HBV antigens were negative in all cases, and 7 showed positive HBVDNA. Conclusions. A selective protocol based on donor and recipient risk factors for post-liver transplant HBV infection can prevent hepatitis-B infection and avoid unnecessary administration of antiviral prophylaxis in recipients of HBsAg(−), anti-HBc(+) liver allografts.

Ten-year experience in porto-caval hemitransposition for liver transplantation in the presence of portal vein thrombosis

Porto‐caval hemitransposition (PCH) in liver transplantation allows revascularization of the liver when the porto‐mesenteric axis is thrombosed. We, here, review our experience over an 11‐year period. A total of 23 patients underwent liver transplantation using PCH. Immunosuppression was based on tacrolimus, with sirolimus used in case of renal insufficiency. Most common diagnoses were hepatitis C, Laennecs, Budd‐Chiari and cryptogenic cirrhosis. Six patients needed splenectomy prior to transplant, 5 during transplant, 1 post‐transplant, 11 had no splenectomy. Overall survival was 60% at 1 year and 38% at 3 years, with 10 of 23 patients currently alive and the longest survivor at 9.3 years. Most common cause of death was sepsis/multisystem organ failure, followed by pulmonary embolism. A total of 7/23 patients experienced post‐operative gastrointestinal bleeding episodes, 6/23 patients developed thrombosis of the vena cava (median 162 days post‐op). Post‐operative ascites was noted in almost all patients. Renal dysfunction was commonly seen even after the first month post‐transplant. PCH offers a feasible option for liver transplantation in those patients with complex thrombosis of the mesenteric and portal circulation.

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.

The Pathology of full-thickness cadaver skin transplant for large abdominal defects: a proposed grading system for skin allograft acute rejection.

Closure of large abdominal defects after extensive abdominal surgery is a major technical surgical problem. Failure to close the abdomen leaves the patient at risk for grave complications. Full-thickness abdominal wall skin transplantation appears to solve this problem. This is the first time that detailed histopathologic features of skin abdominal wall transplantation from cadaver donors are described. Five adults and four children underwent 10 transplants because of large abdominal wall defects. Twenty-two posttransplantation skin specimens were evaluated during a mean follow-up of 23.5 weeks, and the findings were compared with the clinical appearance of the skin. Rejection was manifested as a maculopapular rash. The histologic features were categorized as perivascular infiltrates, epidermal changes, and stromal changes. A grading system is proposed based on the number of cases encountered: No rejection, grade 0 (n = 9): No perivascular infiltrates. Indeterminate for rejection, grade 1 (n = 2): Up to 10% of vessels show infiltrates of small lymphocytes. No eosinophils, large lymphocytes, spongiosis, epidermal, or stromal inflammation are seen. Mild rejection, grade 2 (n = 5): 11% to 50% of vessels are infiltrated by small lymphocytes. Eosinophils and mild spongiosis may or may not be present. No epidermal infiltrates, stromal infiltrates, or large lymphocytes are seen. Moderate rejection, grade 3 (n = 4): Greater than 50% of vessels show lymphocytic infiltrates that may be accompanied by epidermal and stromal inflammation. Spongiosis is absent or mild. Endothelial plumping, eosinophils, and large lymphocytes may be seen. Severe rejection, grade 4 (n = 2): Greater than 50% of vessels show infiltrates, but different from moderate rejection, there is dyskeratosis and the epidermis shows heavier lymphocytic infiltrates and moderate to severe spongiosis. The stroma shows infiltrates extending into the base of the epidermis. Endothelial plumping, eosinophils, and large lymphocytes are present. The mean number of weeks after transplantation for the development of clearcut rejection (grades 2–4) was 8.36. Among the 9 nonrejection cases, 4 specimens from 3 patients had thrombosis of the vessels feeding the graft. A grading system serves to better assess skin allograft rejection.

MicroRNA Signature of Intestinal Acute Cellular Rejection in Formalin-Fixed Paraffin-Embedded Mucosal Biopsies

Despite continuous improvement of immunosuppression, small bowel transplantation (SBT) is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need to uncover novel insights that will lead to strategies to achieve better control of ACR. We hypothesized that particular miRNAs provide critical regulation of the intragraft immune response. The aim of our study was to identify miRNAs involved in intestinal ACR. We examined 26 small intestinal mucosal biopsies (AR/NR group; 15/11) obtained from recipients after SBT or multivisceral transplantation. We investigated the expression of 384 mature human miRNAs and 280 mRNAs associated with immune, inflammation and apoptosis processes. We identified differentially expressed 28 miRNAs and 58 mRNAs that characterized intestinal ACR. We found a strong positive correlation between the intragraft expression levels of three miRNAs (miR‐142‐3p, miR‐886‐3p and miR‐132) and 17 mRNAs including CTLA4 and GZMB. We visualized these miRNAs within cells expressing CD3 and CD14 proteins in explanted intestinal allografts with severe ACR. Our data suggested that miRNAs have a critical role in the activation of infiltrating cells during intestinal ACR. These differences in miRNA expression patterns can be used to identify novel biomarkers and therapeutic targets for immunosuppressive agents.