Causes of late mortality in pediatric liver transplant recipients.

OBJECTIVE: This study was undertaken to review the incidence and causes of death in children who have survived long-term (more than 1 year) after liver transplantation (LT). SUMMARY BACKGROUND DATA: No studies of the causes of late mortality in pediatric LT recipients are currently available in the literature. METHODS: The study group consists of 212 pediatric patients who survived more than 1 year after LT. Twenty-three of these patients subsequently died (mean follow-up = 5.3 yr). Hospital records, office charts, and autopsy records were reviewed retrospectively to identify the causes of death. The patients who died were further evaluated by age, gender, length of survival, primary diagnosis, immunosuppression, and retransplantation. RESULTS: The most common cause of death was graft failure, followed closely by infection. In patients dying from graft failure, eight of the nine patients underwent retransplantation and no child survived more than three liver transplants. Overwhelming infections occurred suddenly in eight children who had been previously healthy. Noncompliance was the third most common cause of death, primarily in older children. One child died from a posttransplant lymphoproliferative disorder (PTLD). Actuarial survival at 10 years is 83.7% (based on 100% survival at 1 year). There was no difference in survival based on primary disease. Retransplantation was far more prevalent in the nonsurvivors (47.8%) compared with survivors (13.7%) (p < 0.05). There were no significant differences in survival based on age, gender, or immunosuppression. CONCLUSIONS: Late mortality in children continues to be directly related to complications of LT and immunosuppression, even after the first year of transplantation. This is in contrast to adult liver transplant recipients, where approximately 50% of late deaths were related to LT and the remainder were because of unrelated illnesses.     

Results of split liver transplantation in children

OBJECTIVE: To analyze the outcome of 80 consecutive pediatric split liver transplants performed at the authors' center between 1994 and 2000. SUMMARY BACKGROUND DATA: Split liver transplantation has become an accepted method of increasing the number of available grafts for pediatric liver transplant recipients. METHODS: The age of the patients at the time of transplantation ranged from 5 days to 16 years (median 3 years). Sixteen transplants were performed for acute liver failure and 64 for chronic liver failure. The ex situ splitting technique was used for all but four grafts. Fourteen livers were split for two pediatric recipients. Posttransplant follow-up ranged from 6 to 84 months (median 42 months). RESULTS: Overall patient survival at 6 months follow-up was 96.2%. Graft survival at six months was 93.7%. The Kaplan-Meier patient survival rates at 1 and 3 years were 93.5% and 88.1%, and the graft survival rates were 89.7% and 86.1%, respectively. Four patients required retransplantation. In the acute group (n = 16), the patient survival rates were 93.7% at 1 year and 76.4% at 3 years; there were three deaths due to posttransplant lymphoproliferative disease (PTLD), sepsis, and chronic rejection. In the chronic group (n = 64), the 1- and 3-year patient survival rates were 93.6% and 90.9%, respectively. There were six deaths in this group. Four patients died in the first year after the transplant due to intracranial bleeding, cerebral tumor recurrence, PTLD, and chronic rejection. There were two deaths at 3 years, one due to progressive renal failure secondary to cyclosporin toxicity and the other due to sepsis, portal hypertension, and recurrent bleeding. Vascular complications occurred in six (7.5%) patients and biliary complications in seven (8.7%). CONCLUSIONS: These results, which represent the experience of a single institution over the last 6 years, indicate that ex situ split liver transplantation can be performed in children with good overall outcome and acceptable morbidity.     

The absence of chronic rejection in pediatric primary liver transplant patients who are maintained on tacrolimus-based immunosuppression: a long-term analysis

BACKGROUND: Although the outcome of liver transplantation has improved significantly during the past two decades, graft loss caused by chronic rejection after liver transplantation still occurs in 2% to 20% of recipients. The overall incidence of chronic rejection is also reported to be low in adult recipients, and risk factors have been identified. Chronic rejection is associated with the inability to maintain baseline immunosuppression. Additionally, the diagnoses of primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, hepatitis B virus, and hepatitis C virus, common indications for liver transplantation in adults, are associated with a higher incidence of chronic rejection. Fortunately, these diagnoses are rarely seen in children. Little is known about chronic rejection in long-term pediatric liver transplant survivors. The purpose of this longitudinal study was to examine the incidence of biopsy-proven chronic rejection in long-term survivors of primary pediatric liver transplantation under tacrolimus-based immunosuppression. METHODS: From October 1989 to December 1992, 166 children (boys=95, girls=71; mean age=5.0+/-2.9 years) received a primary liver transplant. These patients were followed until March 2000 with a mean follow-up of 9+/-0.8 (range, 7.4-10.4) years. All liver biopsy specimens and explanted grafts were evaluated for evidence of chronic rejection using the International Banff Criteria. RESULTS: The mortality rate during the follow-up period was 15% (n=25). Retransplantation was required in 11% (n=18) of recipients. Actuarial patient and graft survival rates at 10 years were 84.9% and 80.1%, respectively. There were 535 liver biopsy samples available for evaluation, including the 18 explanted allografts. Biopsy specimens of three other functioning allografts showed evidence of chronic rejection. Immunosuppression had been discontinued or drastically reduced in these recipients because of life-threatening infections, noncompliance, or both. On restoring baseline immunosuppression, all three children had normalized liver function and the allografts were maintained; the liver transplant patients who are alive currently have normal liver functions. CONCLUSION: The findings of this study suggest that chronic rejection does not occur in pediatric liver transplant recipients receiving tacrolimus-based immunosuppression, provided baseline immunosuppression is maintained.     

Posttransplant lymphoproliferative disorders in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0+/-22.5 months after transplantation, 25.0+/-24.7 months in adults and 14.4+/-18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor --> seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.     

Pediatric liver transplantation. A single center experience spanning 20 years

BACKGROUND: Survival after liver transplantation has improved significantly over the last decade with pediatric recipients faring better than adults. The 20-year experience of pediatric liver transplantation at Children's Hospital of Pittsburgh is reported in terms of patient survival; graft survival in relation to age, gender, and immunosuppressive protocols; causes of death; and indications for retransplantation. METHOD: From March 1981 to April 1998, 808 children received liver transplants at Children's Hospital of Pittsburgh. All patients were followed until March 2001, with a mean follow-up of 12.2+/-3.9 years (median=12.6; range=2.9-20). There were 405 female (50.2%) and 403 male (49.8%) pediatric recipients. Mean age at transplant was 5.3+/-4.9 years (mean=3.3; range 0.04-17.95), with 285 children (25.3%) being less than 2 years of age at transplant. Cyclosporine (CsA)-based immunosuppression was used before November 1989 in 482 children (50.7%), and the subsequent 326 recipients (40.3%) were treated with tacrolimus-based immunosuppression. Actuarial survival was calculated using the Kaplan-Meier statistical method. Differences in survival were calculated by log-rank analysis. RESULTS: Overall patient survival at 1, 5, 10, 15, and 20 years was 77.1%, 72.6%, 69.4%, 65.8%, and 64.4%, respectively. There was no difference in survival for male or female patients at any time point. At up to 10 years posttransplant, the survival for children greater than 2 years of age (79.5%, 75.7%, and 71.6% at 1, 5, and 10 years, respectively) was slightly higher than those at less than 2 years of age (72.6%, 66.9%, and 65.3% at 1, 5, and 10 years, respectively). However, at 15 and 20 years posttransplant, survival rates were similar (>2 years=67.3% and 65.8%; <2 years=64.1% and 64.1%). A significant difference in survival was seen in CsA-based immunosuppression (71.2%, 68.1%, 65.4%, and 61%) versus tacrolimus-based immunosuppression (85.8%, 84.7%, 83.3%, and 82.9%) at 1, 3, 5, and 10 years, respectively (P=0.0001). The maximum difference in survival was noted in the first 3 months between CsA and tacrolimus; thus, indicating there may have been other factors (nonimmunological factors) involved in terms of donor and recipient selection and technical issues. The mean annual death rate beyond 2 years posttransplant was 0.47%, with the mean annual death rate for patients who received tacrolimus-based immunosuppression being significantly lower than those who received CsA-based immunosuppression (0.14% vs. 0.8%; P=0.001). The most common etiologies of graft loss were hepatic artery thrombosis (33.4%), acute or chronic rejection (26.6%), and primary nonfunction (16.7%). Of note, retransplantation for graft loss because of acute or chronic rejection occurred only in those patients who received CsA-based immuno-suppression. CONCLUSION: The overall 20-year actuarial survival for pediatric liver transplantation is 64%. Survival has increased by 20% in the last 12 years with tacrolimus-based immunosuppression. Although this improvement may be the result of several factors, retransplantation as a result of acute or chronic rejection has been completely eliminated in patients treated with tacrolimus.     

Pediatric renal transplantation under tacrolimus-based immunosuppression

BACKGROUND: Tacrolimus has been used as a primary immunosuppressive agent in adult and pediatric renal transplant recipients, with reasonable outcomes. Methods. Between December 14, 1989 and December 31, 1996, 82 pediatric renal transplantations alone were performed under tacrolimus-based immunosuppression without induction anti-lymphocyte antibody therapy. Patients undergoing concomitant or prior liver and/or intestinal transplantation were not included in the analysis. The mean recipient age was 10.6+/-5.2 years (range: 0.7-17.9). Eighteen (22%) cases were repeat transplantations, and 6 (7%) were in patients with panel-reactive antibody levels over 40%. Thirty-four (41%) cases were with living donors, and 48 (59%) were with cadaveric donors. The mean donor age was 27.3+/-14.6 years (range: 0.7-50), and the mean cold ischemia time in the cadaveric cases was 26.5+/-8.8 hr. The mean number of HLA matches and mismatches was 2.8+/-1.2 and 2.9+/-1.3; there were five (6%) O-Ag mismatches. The mean follow-up was 4.0+/-0.2 years. RESULTS: The 1- and 4-year actuarial patient survival was 99% and 94%. The 1- and 4-year actuarial graft survival was 98% and 84%. The mean serum creatinine was 1.1+/-0.5 mg/dl, and the corresponding calculated creatinine clearance was 88+/-25 ml/min/1.73 m2. A total of 66% of successfully transplanted patients were withdrawn from prednisone. In children who were withdrawn from steroids, the mean standard deviation height scores (Z-score) at the time of transplantation and at 1 and 4 years were -2.3+/-2.0, -1.7+/-1.0, and +0.36+/-1.5. Eighty-six percent of successfully transplanted patients were not taking anti-hypertensive medications. The incidence of acute rejection was 44%; between December 1989 and December 1993, it was 63%, and between January 1994 and December 1996, it was 23% (P=0.0003). The incidence of steroid-resistant rejection was 5%. The incidence of delayed graft function was 5%, and 2% of patients required dialysis within 1 week of transplantation. The incidence of cytomegalovirus was 13%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 12%. The incidence of early Epstein-Barr virus-related posttransplant lymphoproliferative disorder (PTLD) was 9%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 4%. All of the early PTLD cases were treated successfully with temporary cessation of immunosuppression and institution of antiviral therapy, without patient or graft loss. CONCLUSIONS: These data demonstrate the short- and medium-term efficacy of tacrolimus-based immunosuppression in pediatric renal transplant recipients, with reasonable patient and graft survival, routine achievement of steroid and anti-hypertensive medication withdrawal, gratifying increases in growth, and, with further experience, a decreasing incidence of both rejection and PTLD.     

Basiliximab induction in adult liver transplant recipients with 93% rejection-free patient and graft survival at 24 months

Induction with the use of interleukin-2 receptor monoclonal antibodies may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLTx). We describe our experience with the use of basiliximab induction therapy in adult OLTx recipients on tacrolimus-based immunosuppression. Forty-six consecutive deceased donor primary OLTx were analyzed. All patients received standard doses of basiliximab, tacrolimus, and steroids. Mycophenolate mofetil was also used as indicated. The mean follow-up period was 17.9 months. Forty-three patients remained rejection-free during follow-up. The actuarial patient and graft survival rate at 2 years was 93%. The rate of histology-proven hepatitis C virus (HCV) recurrence was 24%, with two progressing to severe cholestatic recurrent HCV. None of the study patients developed (cytomegalovirus (CMV) infection or posttransplant lymphoproliferative disease (PTLD). Results were compared to a historical group of 46 OLTx recipients on tacrolimus-based immunosuppression without basiliximab induction. The historical group had a rejection rate of 34% with lower patient and graft survival rates of 71.74% and 69.5%, respectively, at 24 months as well as a higher histological HCV recurrence rate of 77% (17/22), with three patients progressing to graft failure within 2 years. CMV infection and disease developed in 4.5% of the patients. Although PTLD was not observed, three recipients with hepatocellular carcinoma (HCC) developed and died of metastatic HCC. Induction with basiliximab in combination with tacrolimus-based immunosuppressive regimen reduces the incidence of rejection and improves rejection-free survival rate after OLTx without increasing the incidence of CMV, PTLD, or HCV recurrence.     

Late Graft Loss or Death in Pediatric Liver Transplantation: An Analysis of the SPLIT Database

Late graft loss (LGL) and late mortality (LM) following liver transplantation (LT) in children were analyzed from the studies of pediatric liver transplantation (SPLIT) database. Univariate and multivariate associations between pre- and postoperative factors and LGL and LM in 872 patients alive with their primary allografts 1 year after LT were reviewed. Thirty-four patients subsequently died (LM) and 35 patients underwent re-LT (LGL). Patients who survive the first posttransplant year had 5-year patient and graft survival rates of 94.2% and 89.2%, respectively. Graft loss after the first year was caused by rejection in 49% of the cases with sequelae of technical complications accounting for an additional 20% of LGL. LT for tumor, steroid resistant rejection, reoperation in the first 30 days and >5 admissions during the first posttransplant year were independently associated with LGL in multivariate analysis. Malignancy, infection, multiple system organ failure and posttransplant lymphoproliferative disease accounted for 61.8% of all late deaths after LT. LT performed for FHF and tumor were associated with LM. Patients who are at or below the mean for weight at the time of transplant were also at an increased risk of dying. Frequent readmission was also found to be associated with LM.     

Posttransplantation lymphoproliferative disorder in pediatric liver transplantation

INTRODUCTION: The aim of this study was to evaluate the clinical features of risk factors for posttransplantation lymphoproliferative disorder (PTLD) in pediatric liver transplantation. MATERIALS AND METHODS: Between June 1996 and June 2002, among 41 pediatric patients who underwent liver transplantation, 7 died in the postoperative period. Thirty-five patients, including 1 patient who died of PTLD, were reviewed. Based on the serology results, patients were divided into a high-risk group (EBV-naive recipients of EBV-positive grafts) and a low-risk group (patients other than those in the high-risk group). RESULTS: Five of 41 patients (12.2%) developed PTLD. All of them belonged to the high-risk group. The incidence of PTLD in the high-risk group was 31.3% (5 of 16). The mean duration between operation and diagnosis for PTLD was 9.8 months. Primary EBV infection developed at a median of 6 months after transplantation. Three of 5 patients developed rejection before the diagnosis of PTLD. One patient was diagnosed with laryngeal and gastrointestinal PTLD, whereas the other 4 had gastrointestinal PTLD. They experienced the following symptoms and signs: anemia (100%), hypoalbuminemia (100%), fever (80%), diarrhea (80%), gastrointestinal bleeding (80%), and anorexia (60%). CONCLUSION: The common features of PTLD development were as follows: (1) EBV-positive donors placed into EBV-naive recipients, (2) primary EBV infection approximately 6 months after transplantation, (3) young age, 1 year old at operation, and (4) requirement for intensive posttransplantation immunosuppression.     

Risk Factors for Posttransplant Lymphoproliferative Disorder in Pediatric Liver Transplant Recipients With Cytomegalovirus Antigenemia

Epstein-Barr virus (EBV) infections, associated with posttransplant lymphoproliferative disorder (PTLD) are known to develop in cytomegalovirus (CMV)-infected transplant recipients due to the indirect effects of CMV. This study evaluated risk factors for PTLD among pediatric liver transplant recipients with CMV infections. We reviewed the medical records of 119 patients ≤18 years old who underwent liver transplantation between September 1996 and April 2009. Sixty-six subjects (55.5%) displayed CMV antigenemia during the study period; 15 (12.6%) developed PTLD. Of these, 10 developed PTLD after CMV antigenemia. The other patients (n = 5) were excluded due to negative CMV antigenemia. The incidence of PTLD influenced by CMV infection was not significantly different from the incidence of PTLD without underlying CMV (P = .258). There were no differences in age, gender, antiviral prophylaxis, type of liver transplantation, or acute rejection episodes in the incidence of between patients with versus without PTLD. EBV but not CMV high-risk groups were a predictor for the development of PTLD (P = .035). CMV syndrome, tissue-invasive CMV disease, and CMV peak titer were not associated with an increased risk of PTLD. The primary risk factor for PTLD was EBV high-risk patients (donor positive/recipient negative). CMV disease was not associated with PTLD in pediatric liver transplant recipients with CMV infections.     

Posttransplant diabetes mellitus in liver transplant recipients

CONTEXT: Approximately 20% of liver transplant recipients develop posttransplant diabetes mellitus. Hepatitis C, a leading indication for liver transplantation, has been identified as a risk factor for posttransplant diabetes mellitus and is an observation that is not well described. OBJECTIVE: To evaluate the incidence of posttransplant diabetes mellitus and risk factors associated with this condition. DESIGN: A retrospective chart review. SETTING: A large urban transplant center. PATIENTS: One hundred fifteen liver transplant recipients who received a transplant between January 1, 1998, and August 31, 2001. RESULTS: The rate of posttransplant diabetes mellitus, calculated at 3-month intervals in the first year after liver transplantation, ranged from 19.4% to 24.6%, which is similar to the averages reported in most published studies. The cumulative rate of posttransplant diabetes mellitus, which includes all patients who developed this condition during the time studied, was 31.3%. Clinical and demographic factors, including immunosuppression regimens, were similar between patients with and without posttransplant diabetes mellitus. Two risk factors for posttransplant diabetes mellitus were identified: hepatitis C, which was the leading indication for transplantation in this group (54.8%), and cytomegalovirus infection during the first year after transplantation. Other clinical and demographic variables, such as gender, age, ethnicity, rejection episodes, body mass index, and immunosuppression, were not identified as risk factors for posttransplant diabetes mellitus in liver transplant recipients.     

Analysis of risk factors for the development of posttransplant lymphoprolipherative disorder among 119 children who received primary intestinal transplants at a single center

Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication after pediatric transplantation. We analyzed all potential risk factors to assess patient and graft outcomes of 119 children who received intestinal transplantations. MATERIALS AND METHODS: Between August 1994 and March 2005, 119 patients underwent cadaveric intestinal transplantation. Their median age at transplant was 1.4 years (range: 0.6-17), median weight was 9.5 kg (range: 4.7-67), and 57% were boys. The median follow-up among 49 ongoing survivors was 41 months (range: 4-121). All PTLD cases were biopsy proven. In the past 5 years, treatment included antiviral therapy, immunosuppression withdrawal, and use of rituximab. RESULTS: The incidence of PTLD was 11.8% (14/119). No patient experienced graft failure secondary to PTLD, while two patients died from PTLD (14.2%). The PTLD group was divided into an early onset group (<4 months, 6 of 14; 42.8%) and a late onset group (>2 years, 8 of 14; 57.2%). No patient experienced PTLD between 4 months and 2 years after transplantation. The use of OKT3 was the only significant risk factor for the development of PTLD. No factor was specifically associated with the early versus late development of PTLD. CONCLUSIONS: The only factor associated with a significantly higher risk of PTLD was the use of OKT3 to treat a rejection episode. Finally, since the the introduction of anti-CD20 antibodies as part of the treatment protocol for PTLD, the risk of death due to PTLD appears to have become manageably low.     

Early posttransplant lymphoproliferative disease in pediatric liver transplant recipients

Among 23 pediatric patients who underwent orthotopic liver transplant (OLT), we report two (11 and 26 months old) with posttransplant lymphoproliferative disease (PTLD) that occurred in the early posttransplantation period. They were Epstein-Barr Virus (EBV)-negative and received graft from EBV-positive donors. The surveillance for EBV viremia using serial EBV polymerase chain reaction determinations in the peripheral blood was positive at 10 and 90 days after OLT concomitant with symptoms of primary infection, both patients were treated with gancyclovir. The patients should progression to a Burkitt's and a non-Hodgkin's lymphoma that appeared 3 months posttransplantation. They were treated by withdrawal of immunosuppression and six courses of cyclophosphamide as well as anti-CD20 monoclonal antibody (Rituximab) every 21 days. One patient experienced acute graft rejection, which resolved with steroids and low doses of tacrolimus, she is free of disease at 24 months after the end of treatment. The other patient relapsed with a cerebral lymphoma, receiving aggressive chemotherapy, but died due to sepsis. In conclusion, PTLD occurred among in 2/23 patients who underwent OLT and appeared in the first quarter post OLT. The risk factors associated with early PTLD were primary EBV infection after OLT, young age, and EBV-negative recipient receiving a transplant from an EBV-positive donor. Antiviral treatment alone was inefficient; withdrawal of immunosuppression and courses of Rituximab and cyclophosphamide were well tolerated and controlled PTLD. The risk of graft rejection was increased by withdrawal of immunosuppression. One patient died.     

Post-Transplant Lymphoproliferative Disorders Following Liver Transplantation: Incidence, Risk Factors and Survival

This study investigates retrospectively the incidence, risk factors and mortality of post-transplant lymphoproliferative disorders (PTLD) in adult orthotopic liver transplant (OLT) recipients. Among 1206 OLT recipients at a single institution, 37 developed a PTLD. The incidence of PTLD was highest during the first 18 months and relatively constant thereafter with cumulative incidence of 1.1% at 18 months and 4.7% at 15 years. The risk of PTLD was approximately 10% to 15% of the risk of death without PTLD. During the first 4 years following OLT, PTLD were predominantly related to EBV, while afterward most PTLD were EBV negative. Significant risk factors for PTLD in OLT recipients were transplantation for acute fulminant hepatitis during the first 18 months following OLT (HR = 2.6, p = 0.007), and rejection therapy with high-dose steroids (HR = 4.5, p = 0.049) and OKT3 (HR = 3.9, p = 0.016) during the previous year. Therapy with high-dose steroids or OKT3 (HR = 3.6, p = 0.0071) were also significant risk factors for PTLD-associated mortality. OLT recipients remain at risk for PTLD years after transplantation. The strong association of PTLD with rejection therapy and the worse post-PTLD prognosis among recipients of rejection therapy indicate the need to balance the risk of immunosuppression against the risk of PTLD following rejection treatment.     

Quantitative Epstein-Barr virus viral load monitoring in pediatric liver transplantation

The aim of this study was to determine whether the implementation of the quantitative Epstein-Barr virus polymerase chain reaction (qEBV-PCR) test in 2003 decreased the incidence of posttransplant lymphoproliferative disease (PTLD) and PTLD-related mortality. Of the 128 children who underwent liver transplantation between January 1994 and May 2007, 110 (85.9%) survived. Patients were divided into pre (1994 to 2002; n = 86) and post (2003 to 2007; n = 42) EBV-PCR groups. There were no between-group differences in mean age, percentage of patients <12 months old, or seronegative for EBV. The incidence rates of primary EBV infection in the pre- and post-EBV-PCR groups were 14.0% and 33.3%, respectively (P < .05). In contrast, the pre- and post-EBV-PCR groups showed similar incidences of symptomatic EBV infection (31.3% vs 35.7%; P = .625) and PTLD (10.5% vs 9.5%; P = .869), but different survival rates (80.2% vs 97.6%; P < .001). Five of nine PTLD patients in the pre-EBV-PCR group died of PTLD, but there was no PTLD-related mortality in the post-EBV-PCR group, indicating that PTLD-related mortality decreased after qEBV-PCR monitoring. These findings suggested that frequent EBV viral load monitoring and subsequent modulation of immunosuppression can reduce PTLD and PTLD-related mortality among pediatric liver transplant patients.     

Alemtuzumab Pre-Conditioning With Tacrolimus Monotherapy in Pediatric Renal Transplantation

We employed antibody pre-conditioning with alemtuzumab and posttransplant immunosuppression with low-dose tacrolimus monotherapy in 26 consecutive pediatric kidney transplant recipients between January 2004 and December 2005. Mean recipient age was 10.7 +/- 5.8 years, 7.7% were undergoing retransplantation, and 3.8% were sensitized, with a PRA >20%. Mean donor age was 32.8 +/- 9.2 years. Living donors were utilized in 65% of the transplants. Mean cold ischemia time was 27.6 +/- 6.4 h. The mean number of HLA mismatches was 3.3 +/- 1.3. Mean follow-up was 25 +/- 8 months. One and 2 year patient survival was 100% and 96%. One and 2 year graft survival was 96% and 88%. Mean serum creatinine was 1.1 +/- 0.6 mg/dL, and calculated creatinine clearance was 82.3 +/- 29.4 mL/min/1.73 m(2). The incidence of pre-weaning acute rejection was 11.5%; the incidence of delayed graft function was 7.7%. Eighteen (69%) of the children were tapered to spaced tacrolimus monotherapy, 10.5 +/- 2.2 months after transplantation. The incidence of CMV, PTLD and BK virus was 0%; the incidence of posttransplant diabetes was 7.7%. Although more follow-up is clearly needed, antibody pre-conditioning with alemtuzumab and tacrolimus monotherapy may be a safe and effective regimen in pediatric renal transplantation.     

Long-term patient survival in a pediatric renal transplantation program

In adult renal transplant recipients, reports have shown continuing mortality beyond 5 years after transplantation with the majority of deaths due to myocardial infarctions, malignancies, and liver failure. Little information is available on the long-term survival of children following renal transplantation. Children with end-stage renal disease have fewer systemic complications than adults and should have better long-term survival. Furthermore, analysis of mortality in the pediatric population should be more informative of the risks of renal transplantation, separate from underlying pretransplant diseases and the inherent complications of aging. We analyzed, therefore, the long-term mortality of renal transplant recipients in a single pediatric center. A total of 299 renal transplants were performed in 251 patients from 1971 through 1990. No patient was excluded from the evaluation. Over all, actuarial survival was 91% at 1 year, 83% at 10 years, and 81% at 15 years. Patient's age at transplantation, donor source, and number of previous allografts were not correlated with patient survival. There were 35 deaths with 51% attributable to infections. The majority of deaths (71%) occurred within the first 6 months after renal transplantation during the period of greatest immunosuppression. Mortality within the first 12 months following renal transplantation was higher during the period 1971-1974 when compared to subsequent years. These data demonstrate that in a pediatric renal transplant center, long-term patient survival is excellent. Most deaths occur within the first 6 months following renal transplantation and are caused by infections. As expected, long-term survival in children is better than reports in adult renal transplant recipients and may more accurately reflect true renal-transplant-related mortality.     

Posttransplant Lymphoproliferative Disorder Following Pancreas Transplantation

The incidence, risk factors and impact on patient and graft survival were evaluated for posttransplant lymphoproliferative disorder (PTLD) among 212 pancreas transplant recipients. Thirteen (6.1%) developed PTLD during 71 ± 27 months follow-up. Cumulative incidences of PTLD at 1, 3, 5 and 10 years posttransplant were 4.2%, 5.3%, 6.0% and 7.0%, respectively. Incidence of PTLD was lower for recipients of simultaneous pancreas kidney compared to pancreas after kidney transplant or pancreas transplant alone, though not significantly so. Recipient Epstein–Barr virus (EBV) seronegativity and number of doses of depleting antibody therapy administered at transplant were associated with increased risk of PTLD, while recipient age, gender, transplant type, cytomegalovirus mismatch maintenance immunosuppression type and treated acute rejection were not. All 13 cases underwent immunosuppression reduction, and 10 received anti-CD20 monoclonal antibody. During follow-up, 10/13 (77%) responded to treatment with complete remission, while 3 (23%) died as a result of PTLD. Patient and graft survivals did not differ for recipients with and without PTLD. The strong association of PTLD with EBV-seronegativity requires considering this risk factor when evaluating and monitoring pancreas transplant recipients. With reduction of immunosuppression and anti-CD20 therapy, survival for pancreas transplant recipients with PTLD was substantially better than previously reported.     

Postransplant lymphoproliferative disorder localized near the allograft in renal transplantation

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD), a complication of immunosuppression, develops in approximately 1% of renal allograft recipients. Typically, PTLD is a proliferation of B-cells associated with Epstein-Barr virus (EBV) infection; it is said to be most often a systemic disease. Involvement occasionally is localized near the allograft. METHODS: This is a retrospective analysis of all cases of PTLD in recipients of 1474 renal transplants performed at University of Alabama at Birmingham between 1993 and 1997. RESULTS: Of 14 patients developing PTLD, 10 had disease localized near the allograft. The mean interval from transplantation to diagnosis was 221 +/- 70 days. All patients presented with renal dysfunction; an ultrasound examination revealed a hilar mass, with hydronephrosis in five and stenosis of renal vessels in eight. No patient had lymphadenopathy, according to computerized tomographic or magnetic resonance imaging findings. After reduction of immunosuppressive therapy, seven required a nephrectomy because of rejection, progressive dysfunction, or mass enlargement. Tissue recovered in four patients was consistent with PTLD; the tumors in the remaining three patients were unresectable and regressed. One patient died 1 month after a nephrectomy, and another died 4 years after surgery; neither had evidence of PTLD when they died. Three patients retain functional grafts without clinical or radiographical evidence of progression. All patients with disseminated disease died. CONCLUSIONS: In a large cohort of renal allograft recipients, PTLD affected 1%. Disease localized near the allograft was the most common variant. For most patients with localized disease, the outcome was graft loss, and the mortality was low. Localized PTLD should be considered in the differential diagnosis of allograft dysfunction in the 1st posttransplant year.     

Anthracycline-based chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation

BACKGROUND: Recommended first-line treatment for posttransplant lymphoproliferative disorder (PTLD) is reduction in immunosuppressive therapy, irrespective of histopathological type. Second-line treatment with chemotherapy is generally reserved for tumors that fail to respond to reduced immunosuppression. In view of the similarities between monomorphic PTLD and non-Hodgkin's lymphoma in the general population, our policy is to treat monomorphic PTLD with anthracycline-based chemotherapy as first-line treatment. METHODS: A retrospective single-center analysis of 18 adults who developed PTLD following liver or kidney transplantation was undertaken, with particular emphasis on tumor histology, treatment received, and clinical outcome. RESULTS: Of the 18 patients with PTLD, 13 had high-grade malignant lymphoma on diagnostic biopsy and received anthracycline-based chemotherapy and reduction in immunosuppression as first-line therapy. Nine (69%) of the 13 patients achieved complete remission and eight (62%) remained in complete remission five years after diagnosis. There was no graft loss from rejection or drug toxicity. Four (22%) patients had polymorphic PTLD on diagnostic biopsy (of which two were re-classified as monomorphic) and one had a low-grade malignant lymphoma. All five patients were treated by reduction in immunosuppression without chemotherapy and were in complete remission at a median of two years after diagnosis. Overall, complete remission was seen in 14 out of 18 patients (78%) at one year following diagnosis. CONCLUSION: The use of anthracycline-based chemotherapy and reduction of immunosuppression as first-line treatment in adults with monomorphic PTLD is well tolerated and achieves sustained complete remission in around 70% of patients with a low risk of graft loss.