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R W Busuttil

Publications and source records attributed to R W Busuttil.

At least 73 records · Page 4Linked to original sources
PubMed1999

Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients.

BACKGROUND: Infection and rejection are two common complications after liver transplants. In a preliminary study, administration of granulocyte colony-stimulating factor (G-CSF) to liver transplant recipients was associated with a decrease in sepsis episodes, sepsis-related deaths, and rejection compared with a historical control group of patients. The purpose of this study was to evaluate further the efficacy of G-CSF in liver transplant patients in a randomized, placebo-controlled, double-blind, multicenter trial. METHODS: Adult patients with a United Network Organ Sharing classification of 1 or 2 were randomized to receive a placebo, 100 microg/day of G-CSF or 300 microg/day of G-CSF. The study drug was started preoperatively and then continued after the transplant for a maximum of 21 days. Patients were evaluated for microbiologically-documented infection, biopsy-proven rejection, number of treatments for rejection, length of stay in the intensive care unit and hospital, graft survival, death, and adverse events. RESULTS: During the first 30 days after the transplant, the median peak white blood cell count was 16.5x10(9)/L, 34.6x10(9)L, and 54.8x10(9)/L for the placebo, low-dose G-CSF, and high-dose G-CSF patients, respectively. The incidence of infection was 30% in G-CSF patients (34 of 114 patients) and 34% in placebo patients (20 of 58 patients). Except for more nosocomial pneumonias in the G-CSF patients (7 in 114 patients vs. 0 in 58 patients, P=0.056), the types of infections and causative organisms were also similar in both treatment groups. Although the number of treatments for clinically suspected or proven rejection was similar in the G-CSF and placebo patients, biopsy-proven rejection occurred more often in G-CSF patients (34 of 114 patients or 30%) than placebo patients (11 of 58 patients or 19%) (P=0.093). There were no cases of graft loss caused by rejection. G-CSF had no effect on length of stay in the intensive-care unit or hospital. There were 22 G-CSF patients (18%) and 10 placebo patients (15%) who died within 120 days after the transplant. No serious adverse events were attributed to G-CSF. CONCLUSION: Despite producing substantial increases in the white blood cell count after the transplant, G-CSF had no beneficial effects on infection, rejection, or survival in this study. Biopsy-proven rejection and nosocomial pneumonias were more common in patients treated with G-CSF compared with those taking the placebo. No serious adverse events were attributed to G-CSF.

Adolescent↗
PubMed1999

Liver transplantation in polysplenia syndrome: use of a living-related donor.

Congenital anatomic anomalies often present technical obstacles during liver transplants. Biliary atresia is the most common indication for liver transplants in children, and approximately 7-10% of these patients have congenital anomalies comprising the "polysplenia syndrome." The polysplenia syndrome, which often includes abdominal situs inversus, is of particular concern in liver transplants because these anatomic anomalies result in a more complex hepatectomy, alterations in the placement of the donor grafts, and the need for additional vascular reconstruction. Earlier reports have shown mixed results for these patients who have undergone orthotopic liver transplants, reporting a high rate of postoperative complications and poor survival. The use of living-related donor grafts has produced excellent results in the general pediatric population. This is the first report of the successful use of a living-related donor graft for an orthotopic liver transplant to treat end-stage liver disease secondary to biliary atresia in a child with polysplenia syndrome.

Biliary Atresia↗
PubMed1999

Intrathymic immunomodulation and the "infectious" tolerance pathway in allograft recipients.

BACKGROUND: We have previously shown that >75% of LEW cardiac allografts survive indefinitely in BUF rats pretreated at Day -21 intrathymically (IT) with donor alloantigen in conjunction with a single intravenous dose of ALS. Spleen cells can adoptively transfer the tolerant state to new cohorts of test recipients. This study was designed to analyze cellular and humoral events contributing to the "infectious" tolerance pathway in this model. METHODS: Spleen cells (25 x 10(6)) harvested from BUF recipients bearing long-term cardiac allografts were injected intravenously into lightly irradiated (450 R) secondary BUF rats, followed 24 h later by transplantation of LEW of ACl hearts. Cardiac allografts were then analyzed serially by reverse transcription polymerase chain reaction for Th1 and Th2 cytokine gene expression. Donor-specific IgM and IgG alloantibody responses in host serum were screened by flow cytometry. RESULTS: Transfer of regulatory spleen cells harvested between Days 80 and 140 from tolerant hosts induced tolerance to heart grafts in a donor-specific manner. In the early posttransplant period, selective sparing of Th2 cytokines was noted. Adoptively transferred hosts showed overall depression of IgM, but a vigorous IgG1 and IgG2a alloantibody response. CONCLUSION: IT + ALS-induced tolerance can be transferred in a donor-specific "infectious" manner to new cohorts of engrafted recipients. The development of tolerance is nontemporally bound, and associates with an early Th2-type immune deviation at the graft site. The elevated levels of T cell-dependent IgG1 and IgG2 may interfere with the antigen reactivity and alloresponsive effector functions, contributing to graft acceptance in the "infectious" tolerance pathway.

Animals↗
PubMed1999

Factors affecting growth after pediatric liver transplantation.

BACKGROUND: Poor linear growth after pediatric orthotopic liver transplantation (OLT) is a well-described phenomenon. We have undertaken a bivariate and multivariate analysis of multiple factors that might effect postOLT growth in all children who underwent transplantation at a single center, with survival > 1 year and adequate follow-up. METHODS: Standardized height score (Z score) and height deficit (centimeters below the 50th percentile) were computed for each patient over time. The variables assessed were (i) age at OLT, (ii) gender, (iii) pretransplantation diagnosis, (iv) Z score and height deficit at OLT, (v) tacrolimus versus cyclosporine as primary immunosuppressive therapy, (vi) retransplantation, (vii) graft disease, (viii) chronic illness, (ix) posttransplant lymphoproliferative disease, (x) intractable rejection, and (xi) prednisone withdrawal. RESULTS: A total of 236 children met the inclusion criteria, with a mean follow-up of 3.8+/-1.9 years. For the population as a whole, the baseline Z score was -1.72 (fourth percentile) with a significant improvement to - 1.37 (ninth percentile) at 2 years, but with no additional gain at 5 years (Z score -1.4). The baseline height deficit was -6.4 cm, with no improvement at 2 years (-6.52 cm), and was significantly worse at 5 years (-7.87 cm). In the bivariate analysis, the most important variables affecting growth were age at OLT, Z score at OLT, and diagnosis. In general, children <2 years with biliary atresia and those with the most growth delay at OLT showed the best posttransplantation growth. In the multivariate analysis, 18 factors were considered, of which 9 were significant. These were (i) Z score at baseline, (ii) follow-up time, (iii) age at OLT, (iv) diagnosis of tumor, (v) diagnosis of fulminant hepatic failure, (vi) retransplantation, (vii) graft disease, (viii) posttransplant lymphoproliferative disease, and (ix) stoppage of prednisone. Multivariate models using these nine variables accounted for 84% of the variation in standardized height. CONCLUSION: In general, children after OLT show some potential for catch-up growth but do not achieve normal height compared with their age and sex-matched peers. A multivariate analysis was necessary to investigate the interdependent effects of the many variables that can affect growth after OLT. The most important detrimental affects were older age at time of OLT, Z scores greater than -2.0 at OLT, fulminant hepatic failure, tumor, and postOLT complications causing graft dysfunction.

Adolescent↗
PubMed1999

A simple model to estimate survival after retransplantation of the liver.

To formulate a model predicting survival after liver retransplantation, we analyzed in detail the last 150 cases of hepatic retransplantation at UCLA. Cox proportional hazards regression analysis identified five variables that demonstrated independent simultaneous prognostic value in estimating patient survival after retransplantation: (1) age group (pediatric or adult), (2) recipient requiring preoperative mechanical ventilation, (3) donor organ cold ischemia > or =12 hr, (4) preoperative serum creatinine, and (5) preoperative serum total bilirubin. The Cox regression equation that predicts survival based on these covariates was simplified by assigning individual patients a risk classification based on a 5-point scoring system. We demonstrate that this system can be employed to identify a subgroup of patients in which the expected outcome is too poor to justify retransplantation. These findings may assist in the rational selection of patients suitable for retransplantation.

Adult↗
PubMed1999

Characterization of human xenoreactive antibodies in liver failure patients exposed to pig hepatocytes after bioartificial liver treatment: an ex vivo model of pig to human xenotransplantation.

BACKGROUND: There are limited experimental data on the nature of the humoral response elicited in humans against pig antigens. In this study, we have examined the xenoantibody (XAb) response in eight patients with acute liver failure exposed to pig hepatocytes after treatment with the bioartificial liver (BAL). METHODS: Patients' plasma samples obtained before and after BAL treatment were tested for IgM and IgG XAbs, IgG subclasses, and XAb cytotoxicity, using enzyme-linked immunosorbent assay and flow-cytometric assays. The characterization of pig aortic endothelial cell (PAEC) surface xenoantigens was analyzed by immunoprecipitation. RESULTS: We observed by day 10, a strong anti-pig IgG and IgM XAb response in patients undergoing two or more BAL treatments, with a significant increase in all the IgG subclasses; in contrast, XAb titers did not change if the patients received only one BAL treatment. The majority of the XAbs produced to porcine antigens were primarily specific for the alphaGal epitope. Both IgG and IgM XAbs were cytotoxic to PAECs, and the cytotoxic activity of IgG was associated with high levels of IgG1 and IgG3 subclasses, known to be efficient on complement activation. The characterization of porcine surface antigens demonstrated that IgM human XAbs, before and after BAL exposure, recognized xenoantigens on PAECs with similar molecular weights, suggesting that the same population of XAbs were present in the patients before and after exposure to pig antigens. CONCLUSIONS: Repetitive exposure of humans to porcine antigens after BAL treatment, results in a strong IgG and IgM XAb responses that are primarily directed against the alphaGal epitope. These XAbs are cytotoxic to PAECs and the IgG toxicity correlates with high IgG1 and IgG3 levels. Our data also suggest that no new XAb specificity emerges after porcine exposure.

Animals↗
PubMed1999

Split liver transplantation.

OBJECTIVE: This study reviews the indications, technical aspects, and experience with ex vivo and in situ split liver transplantation. BACKGROUND: The shortage of cadaveric donor livers is the most significant factor inhibiting further application of liver transplantation for patients with end-stage liver disease. Pediatric recipients, although they represent only 15% to 20% of the liver transplant registrants, suffer the greatest from the scarcity of size-matched cadaveric organs. Split liver transplantation provides an ideal means to expand the donor pool for both children and adults. METHODS: This review describes the evolution of split liver transplantation from reduced liver transplantation and living-related liver transplantation. The two types of split liver transplantation, ex vivo and in situ, are compared and contrasted, including the technique, selection of patients for each procedure, and the most current results. RESULTS: Ex vivo splitting of the liver is performed on the bench after removal from the cadaver. It is usually divided into two grafts: segments 2 and 3 for children, and segments 4 to 8 for adults. Since 1990, 349 ex vivo grafts have been reported. Until recently, graft and patient survival rates have been lower and postoperative complication rates higher in ex vivo split grafts than in whole organ cadaveric transplantation. Further, the use of ex vivo split grafts has been relegated to the elective adult patient because of the high incidence of graft dysfunction (right graft) when placed in an emergent patient. Reasons for the poor function of ex vivo splits except in elective patients have focused on graft damage due to prolonged cold ischemia times and rewarming during the long benching procedure. In situ liver splitting is accomplished in a manner identical to the living donor procurement. This technique for liver splitting results in the same graft types as in the ex vivo technique. However, graft and patient survival rates reported for in situ split livers have exceeded 85% and 90%, respectively, with a lower incidence of postoperative complications, including biliary and reoperation for bleeding. These improved results have also been observed in the urgent patient. CONCLUSION: Splitting of the cadaveric liver expands the donor pool of organs and may eliminate the need for living-related donation for children. Recent experience with the ex vivo technique, if applied to elective patients, results in patient and graft survival rates comparable to whole-organ transplantation, although postoperative complication rates are higher. In situ splitting provides two grafts of optimal quality that can be applied to the entire spectrum of transplant recipients: it is the method of choice for expanding the cadaver liver donor pool.

Adolescent↗
PubMed1999

Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience.

OBJECTIVE: To determine the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV). SUMMARY BACKGROUND DATA: HCV has become the leading cause of cirrhosis and hepatic failure leading to OLT. Recurrent HCV after OLT is associated with significant complications and may lead to graft loss that requires retransplantation (re-OLT). The authors studied the outcome of transplantation for HCV, the effect of primary immunotherapy, and causes of retransplantation. METHODS: The authors conducted a retrospective review of their experience during an 8-year period (1990-1997), during which 374 patients underwent transplants for HCV (298 [79.6%] received one OLT; 76 [20.4%] required re-OLT). Median follow-up was 2 years (range 0 to 8.3). Immunosuppression was based on cyclosporine in 190 patients and tacrolimus in 132 patients. In a third group of patients, therapy was switched from cyclosporine to tacrolimus or from tacrolimus to cyclosporine (cyclosporine/tacrolimus group). RESULTS: Overall, 1-, 2-, and 5-year actuarial patient survival rates were 86%, 82%, and 76%, respectively. The 2-year patient survival rate was 81 % in the cyclosporine group, 85% in the tacrolimus group, and 82% in the cyclosporine/tacrolimus group. In patients receiving one OLT, overall 1-, 2-, and 5-year patient survival rates were 85%, 81%, and 75%, respectively. The 2-year patient survival rate was 79% in the cyclosporine group, 84% in the tacrolimus group, and 80% in the cyclosporine/tacrolimus group. The overall graft survival rates were 70%, 65%, and 60% at 1, 2, and 5 years, respectively. The graft survival rate at 2 years was similar under cyclosporine (68.5%), tacrolimus (64%), or cyclosporine/tacrolimus (60%) therapy. Re-OLT was required in 42 (11.2%) patients for graft dysfunction in the initial 30 days after OLT. Other causes for re-OLT included hepatic artery thrombosis in 10 (2.6%), chronic rejection in 8 (2.1%), and recurrent HCV in 13 (3.4%) patients. The overall survival rates after re-OLT were 63% and 58% at 1 and 2 years. The 1-year survival rate after re-OLT was 61 % for graft dysfunction, 50% for chronic rejection, 60% for hepatic artery thrombosis, and 60% for recurrent HCV. At re-OLT, 85.3% of the patients were critically ill (United Network for Organ Sharing [UNOS] status 1); only 14.7% of the patients were UNOS status 2 and 3. In re-OLT for chronic rejection and recurrent HCV, the 1-year survival rate of UNOS 1 patients was 38.4%, compared with 87.5% for UNOS 2 and 3 patients. In patients requiring re-OLT, there was no difference in the 1-year patient survival rate after re-OLT when cyclosporine (60%), tacrolimus (63%), or cyclosporine/tacrolimus (56%) was used for primary therapy. With cyclosporine, three patients (1.5%) required re-OLT for chronic rejection versus one patient (0.7%) with tacrolimus. Re-OLT for recurrent HCV was required in four (3%) and seven (3.6%) patients with tacrolimus and cyclosporine therapy, respectively. CONCLUSIONS: Orthotopic liver transplantation for HCV is performed with excellent results. There are no distinct advantages to the use of cyclosporine versus tacrolimus immunosuppression when patient and graft survival are considered. Re-OLT is an important option in the treatment of recurrent HCV and should be performed early in the course of recurrent disease. Survival after re-OLT is not distinctively affected by cyclosporine or tacrolimus primary immunotherapy. The incidence of re-OLT for recurrent HCV or chronic rejection is low after either tacrolimus or cyclosporine therapy.

Adult↗
PubMed1999

Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury.

We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy-induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation.

Adenoviridae↗
PubMed1999

Th1 and Th2 cytokines in organ transplantation: paradigm lost?

Identification of CD4+ T helper lymphocyte subsets that exhibit distinct cytokine elaboration patterns has provided a valuable framework for understanding the heterogeneity of the immune response. Much progress has been made in recent years in defining the cellular and molecular mechanisms by which cytokines induce T cell differentiation. In transplantation models, the Th1 cytokine profile often associates with allograft rejection, while the Th2 profile favors the acquisition of tolerance. However, this paradigm may not be sufficient to explain the recently demonstrated in vivo effects of cytokine manipulation on allograft survival. Th2 cytokines may not be necessary for tolerance induction, while Th1 cytokines may even be beneficial in promoting allograft survival. However, such data should be interpreted in light of the diverse and often redundant effects displayed by cytokine networks in vivo. Understanding the complex interactions of cytokines in the alloimmune cascade therefore is critical for designing therapeutic strategies that abrogate allograft rejection and induce donor-specific tolerance, an elusive goal in organ transplantation.

Animals↗
PubMed1998

Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients.

BACKGROUND: We have previously reported a 10% incidence of posttransplant lymphoproliferative disease (PTLD) in pediatric patients receiving first liver grafts and primarily immunosuppressed with tacrolimus. To decrease the incidence of PTLD, we developed a protocol utilizing preemptive intravenous ganciclovir in high-risk recipients (i.e., donor (D)+, recipient (R)-), combined with serial monitoring of peripheral blood for Epstein Barr virus (EBV) by polymerase chain reaction (PCR). METHODS: Consecutive pediatric recipients of a first liver graft were immunosuppressed with oral tacrolimus (both induction and maintenance), and low-dose prednisone. EBV serologies were obtained at the time of orthotopic liver transplant in recipients and donors. Recipients were divided into groups: group 1, high-risk (D+R-), and group 2, low-risk (D+R+; D-R-; D-R+). In group 1 (high-risk), all patients received a minimum of 100 days of intravenous ganciclovir (6-10 mg/kg/day), while, in group 2 (low-risk), patients received intravenous ganciclovir during their initial hospitalization and then were converted to oral acyclovir (40 mg/kg/day) at discharge. Semiquantitative EBV-PCR determinations were made at 1-2-month intervals. In both groups, patients with an increasing viral copy number by EBV-PCR had tacrolimus levels decreased to 2-5 ng/ml. Tacrolimus was stopped, and intravenous ganciclovir reinstituted for PTLD. A positive EBV-PCR with symptoms, but negative histology, was defined as EBV disease; PTLD was defined as histologic evidence of polyclonal or monoclonal B cell proliferation. RESULTS: Forty children who had survived greater than 2 months were enrolled. There were 18 children in group 1 (high-risk; mean age of 14+/-15 months and mean follow-up time of 243+/-149 days) and 22 children in group 2 (low-risk; mean age of 64+/-65 months and follow-up time of 275+/-130 days). In group 1 (high-risk), there was no PTLD and one case of EBV disease (mononucleosis-like syndrome), which resolved. In group 2 (low-risk), there were two cases of PTLD; both resolved when tacrolimus was stopped. Both children were 8 months old at time of transplant. Neither received OKT3, and they had one and two episodes of steroid-sensitive rejection, respectively. One child had EBV disease (mild hepatitis), which resolved. CONCLUSIONS: Since instituting this protocol, the overall incidence of PTLD has fallen from 10% to 5% for children receiving primary tacrolimus therapy after OLT. No high-risk pediatric liver recipient treated preemptively with intravenous ganciclovir developed PTLD. Both children with PTLD were less than 1 year at OLT and considered low-risk. However, their positive EBV antibody titers may have been maternal in origin and not have offered long-term protection. Serial monitoring of EBV-PCR after pediatric OLT is recommended to decrease the risk of PTLD by allowing early detection of EBV infection, which is then managed by decreasing immunosuppression and continuing intravenous ganciclovir.

Antiviral Agents↗
PubMed1998

Liver transplantation in the first three months of life.

BACKGROUND: Pediatric liver transplant recipients have traditionally been grouped according to age. Age-based classification schemes are useful in identifying clinical problems in selected age groups and also for developing solutions to these problems. Although infants in the first 3 months of life have not traditionally been considered a distinct age group, several features of these infants may distinguish them from other pediatric liver transplant recipients. METHODS: The experience with liver transplantation in infants during the first 3 months of life in three large pediatric liver transplant programs (University of Chicago, Stanford University, and UCLA) was analyzed in order to characterize this group. RESULTS: A total of 23 liver transplants were performed at these three centers in children younger than 3 months of age. This group of patients comprised approximately 37% of the U.S. experience between 1988 and 1994 according to United Network for Organ Sharing statistics. Age distribution at the time of transplantation included the following: <1 month, 28%; 1-2 months, 35%; and 2-3 months, 36%. Median age at the time of transplantation was 37 days (range, 7-90 days), and mean age was 57+/-30 days. Mean weight at the time of transplantation was 3.8+/-1.0 kg. Etiology of liver disease included idiopathic hepatitis, 52%; iron storage disease, 17%; and other causes, 31%. Types of liver allografts used included cadaveric, 85% (reduced size, 60%, and full-size, 25%); living donor, 15%; ABO-identical, 65%; and ABO-compatible, 35%. Actuarial patient and graft survival rates were 60% and 60% at 1 year and 60% and 42% at 2 years, respectively. Median follow-up was 1.5 years. Rejection occurred in 42% of patients, with a median time to first rejection of 13 days. Of these patients, 28% required steroids only and 14% required OKT3. Three patients (14%) were retransplanted at a median time to retransplantation of 1.6 years. Vascular thrombosis occurred in three patients (14%). CONCLUSIONS: Liver transplantation performed in infants younger than 3 months of age (1) provides acceptable short- and long-term patient and graft survival, (2) is associated with significant rates of rejection, and (3) is not associated with excessive rates of vascular thrombosis. The etiology of end-stage liver disease occurring in the first 3 months of life is distinct from that in other pediatric liver transplant recipient age groups. These infants should be referred promptly for liver transplantation as reasonable survival can be expected.

Antilymphocyte Serum↗
PubMed1998

De novo hepatitis C in children after liver transplantation.

BACKGROUND: We describe the incidence, results of interferon therapy, and outcome of hepatitis C virus (HCV) hepatitis occurring de novo after pediatric orthotopic liver transplantation (OLT). METHODS AND RESULTS: Of children undergoing OLT between 1984 and September 1996, 321 children survived for more than 1 year. Of these, 13 (4.0%) developed previously undiagnosed HCV disease, as suggested by HCV antibody testing and HCV polymerase chain reaction and confirmed by liver biopsy. Of the 117 children who received transplants before HCV screening of blood products or donors, 10.2% developed de novo HCV disease. The mean age at diagnosis of HCV hepatitis was 13.2+/-5.0 years, and the mean time to diagnosis after OLT was 8.1 years (range, 4-11 years). The mean alanine aminotransferase (ALT) level at diagnosis was 108 IU/ml, and the liver biopsy specimen showed chronic active or chronic persistent hepatitis in 11 children, cirrhosis in 1 child, and nonspecific changes in 1 child. Twelve children were treated with interferon-2alpha; children who weighed > or =20 kg received 3 x 10(6) units every other day, and those who weighed <20 kg received 1.5 x 10(6) units every other day. Four patients developed rapidly progressive liver failure while receiving interferon therapy and required urgent re-transplantation. Three of the four children again developed histologic evidence of recurrent HCV 4-6 months after the second OLT, and all three subsequently died of HCV-induced liver failure. One patient remains alive and well with no evidence of HCV recurrence and a negative HCV RNA. Of the remaining eight children treated with interferon, only two have had a sustained response (normal ALT) and one is now HCV RNA negative. HCV RNA levels did not correlate with outcome or disease severity. HCV antibody levels were unreliable, with two patients having negative HCV antibody but a positive HCV RNA at diagnosis. Six patients were able to be genotyped: four were la and two were 1b. CONCLUSION: Overall mortality for de novo HCV hepatitis was 23%. Seventy-five percent of children who received a second transplant for HCV hepatitis had early histologic recurrence that led to liver failure and death. Interferon therapy resulted in a sustained improvement in ALT in only 15% of children. The time to onset and progression of clinical disease both in the original graft and the retransplant graft were accelerated compared with nonimmunosuppressed individuals.

Adolescent↗
PubMed1998

Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management.

BACKGROUND: Although jejunoileal bypass results in end-stage liver disease in up to 100% of patients, little is known about outcome after liver transplantation. METHODS: The clinical courses of six patients who underwent liver transplantation at UCLA for decompensated cirrhosis owing to a jejunoileal bypass were reviewed. Liver function, allograft pathology, renal function, and nutritional status were assessed. RESULTS: Of the four patients with an intact jejunoileal bypass, two of the three who were biopsied had recurrent steatotic liver disease. The two patients whose jejunoileal bypass was reversed at the time of liver transplantation had lower alkaline phosphatase, lower creatinine, higher albumin, and higher cholesterol, and were more obese than their counterparts with intact bypasses. CONCLUSIONS: Patients undergoing liver transplantation for jejunoileal bypass-associated liver disease should, if possible, have their bypass reversed at the time of transplantation; otherwise, they must be followed closely and be biopsied routinely. Recurrent liver disease should prompt reversal of the jejunoileal bypass.

Adult↗
PubMed1998

Red cell aplasia in children on tacrolimus after liver transplantation.

Hematological toxicity of tacrolimus has been rarely reported. We report two pediatric recipients of liver transplantation with anemia. They were treated with tacrolimus for 8 and 47 months, respectively, before developing pure red cell aplasia (PRCA) confirmed by bone marrow biopsy. The children recovered quickly on withdrawal of tacrolimus. The clinical profile of these children is compared with the only other patient reported in the literature with PRCA due to tacrolimus. All three patients had similar hematological findings. However, the mechanism of the tacrolimus-induced PRCA in these children appears to be different from that reported in the adult patient.

Adult↗
PubMed1998

Effects of pravastatin on chronic rejection of rat cardiac allografts.

BACKGROUND: Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, inhibits coronary transplant vasculopathy in the clinical setting. To further delineate the immune modulatory effect of this agent, it was tested in a rat cardiac transplant model of chronic rejection. METHODS: Rat heterotopic abdominal cardiac transplants were performed using a Lewis to Fischer 344 combination. Fischer 344 recipients received a brief course of cyclosporine to decrease the incidence of acute rejection. Experimental groups were treated with either high-dose (10 mg/kg) or low-dose (5 mg/kg) pravastatin for 120 days, while a control group did not receive pravastatin. The effect of pravastatin on chronic rejection of cardiac allografts was analyzed by histology, and the expression of laminin, fibronectin, macrophages, and T cells was assessed by immunohistochemistry. RESULTS: Coronary transplant vasculopathy was inhibited in both groups of pravastatin-treated animals, as compared with controls. Immunohistochemistry revealed that control animals had degraded laminin and fibronectin which paralleled the degree of tissue necrosis. In contrast, pravastatin-treated animals had modest amounts of extracellular matrix proteins retained within intermyocytes and endothelium, a pattern seen in native cardiac tissue. The pravastatin-treated groups also had fewer graft-infiltrating macrophages, specifically within the arterial intima and perivascular areas. CONCLUSIONS: Progressive chronic vascular rejection, a leading cause of allograft failure, can be inhibited by pravastatin in a well-defined rat cardiac transplant model. Pravastatin appears to inhibit the synthesis and subsequent degradation of extracellular matrix proteins and block the infiltration of macrophages to the graft, which emphasizes that this inflammatory cell plays a major role in the pathogenesis of transplant chronic rejection.

Animals↗
PubMed1998

Fas ligand gene transfer to renal allografts in rats: effects on allograft survival.

BACKGROUND: Fas ligand (FasL) induces apoptosis of cells bearing its receptor Fas, and has been shown to be important in T-cell development and regulation and in immune privilege. We hypothesized that FasL expression by renal allografts might provide protection from rejection. METHODS: The murine FasL cDNA was cloned into a replication-defective adenovirus (AdV-FasL). Protein expression was confirmed by immunostaining of AdV-FasL-transduced HeLa cells. Allogeneic kidney transplants were performed between WF (RT1u) donors and Lewis (RT1) recipients. Donor kidneys were perfused in situ with saline alone (control), or 9 x 10(9) plaque-forming units of AdV-FasL. One native kidney was removed at the time of transplant and the other at 6 or 7 days. Uremic death was the endpoint, and deaths within 7 days of transplant were excluded. Transduced allografts were stained for FasL expression using a monoclonal antibody and tested for FasL mRNA production by reverse transcriptase-polymerase chain reaction and Northern blotting. RESULTS: Immunostaining of AdV-FasL-transduced allografts demonstrated efficient gene transfer lasting approximately 2 weeks, and FasL mRNA production in the AdV-FasL-transduced allografts was confirmed by Northern blotting and reverse transcriptase-polymerase chain reaction. Mean survival of animals with AdV-FasL-transduced renal allografts was 27.8 days vs. 11.6 days in control animals (P < 0.05). CONCLUSIONS: (1) Adenoviral vectors can successfully transduce rat kidneys with the FasL cDNA. (2) FasL gene transfer prolongs rat renal allograft survival.

Adenoviridae↗