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T E Starzl

Publications and source records attributed to T E Starzl.

At least 19 recordsLinked to original sources
PubMed2002

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.

Adolescent↗
PubMed2001

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report.

BACKGROUND: Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined. METHODS: An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day. RESULTS: Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8+/-9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF. CONCLUSION: This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF.

Adult↗
PubMed2001

Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence.

BACKGROUND: Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. METHODS: Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. RESULTS: In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were overrepresented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. CONCLUSIONS: Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease.

Adult↗
PubMed2001

Mucosal damage and recovery of the intestine after prolonged preservation and transplantation in dogs.

BACKGROUND: Although much is known about the mucosal damage that occurs after intestinal warm ischemia and reperfusion and its recovery, little is known about the effect of cold preservation and transplantation on the mucosa. We studied the electrophysiological, biochemical, and histological changes of the intestinal mucosa after preservation for 24 hr and subsequent transplantation. METHODS: The small intestines from adult mongrel dogs were harvested. The intestines were orthotopically autotransplanted immediately (control group) or after preservation for 24 hr (preservation group). Jejunal and ileal tissues were taken before harvesting, at the end of preservation, 1 hr after reperfusion, and on postoperative days 3, 7, 14, and 28. The Ussing chamber method was used to study the electrophysiologic changes. Tissue maltase, diamine oxidase, and ornithine decarboxylase were measured. A histological analysis was also performed. RESULTS: Control group grafts showed no evident deterioration in electrophysiology, biochemistry, or morphology. In contrast, preservation group grafts exhibited electrophysiological and biochemical degradation, complete denudation of the villi, and crypt injury (especially in the ileum) after reperfusion. Electrophysiologic function and the mucosa biochemical marker recovered within 3 days in the jejunum and within 7-14 days in the ileum; however, histological recovery of mucosal injury required 28 days in the jejunum and more than 28 days in the ileum. CONCLUSIONS: Our study showed that despite severe destruction of mucosal integrity by prolonged preservation and transplantation, the intestinal mucosa has an enormous regenerative capacity. Our study also showed that regeneration was more pronounced in the jejunum than in the ileum.

Animals↗
PubMed2001

Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs.

Early chronic liver allograft rejection (CR) is characterized by distinctive cytological changes in biliary epithelial cells (BECs) that resemble cellular senescence, in vitro, and precede bile duct loss. If patients suffering from early CR are treated aggressively, the clinical and histopathological manifestations of CR can be completely reversed and bile duct loss can be prevented. We first tested whether the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR, and whether treatment reversed the expression. The percentage of p21+ BECs and the number of p21+ BECs per portal tract is significantly increased in early CR (26 +/- 17% and 3.6 +/- 3.1) compared to BECs in normal liver allograft biopsies or those with nonspecific changes (1 +/- 1% and 0.1 +/- 0.3; P: < 0.0001 and P: < 0.02), chronic hepatitis C (2 +/- 3% and 0.7 +/- 1; P: < 0.0001 and P: < 0.04) or obstructive cholangiopathy (7 +/- 7% and 0.7 +/- 0.6; P: < 0.006 and P: = 0.04). Successful treatment of early CR is associated with a decrease in the percentage of p21+ BECs and the number of p21+ BECs per portal tract. In vitro, nuclear p21(WAF1/Cip1) expression is increased in large and multinucleated BECs, and is induced by transforming growth factor (TGF)-beta. TGF-beta1 also increases expression of TGF-beta receptor II, causes phosphorylation of SMAD-2 and nuclear translocation of p21(WAF1/Cip1), which inhibits BEC growth. Because conversion from cyclosporine to tacrolimus is an effective treatment for early CR, we next tested whether these two immunosuppressive drugs directly influenced BEC growth in vitro. The results show that cyclosporine, but not tacrolimus, stimulates BEC TGF-beta1 production, which in turn, causes BEC mito-inhibition and up-regulation of nuclear p21(WAF1/Cip1). In conclusion, expression of the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR and decreases with successful recovery. Replicative senescence accounts for the characteristic BEC cytological alterations used for the diagnosis of early CR and lack of a proliferative response to injury. The ability of cyclosporine to inhibit the growth of damaged BECs likely accounts for the relative duct sparing properties of tacrolimus.

Animals↗
PubMed2001

An analysis of early renal transplant protocol biopsies--the high incidence of subclinical tubulitis.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2+/-2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Adult↗
PubMed2001

Transplantation tolerance from a historical perspective.

Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy.

Animals↗
PubMed2001

Does tacrolimus offer virtual freedom from chronic rejection after primary liver transplantation? Risk and prognostic factors in 1,048 liver transplantations with a mean follow-up of 6 years.

Tacrolimus has proven to be a potent immunosuppressive agent in liver transplantation (LT). Its introduction has led to significantly less frequent and severe acute rejection. Little is known about the rate of chronic rejection (CR) in primary LT using tacrolimus therapy. The aim of the present study is to examine the long-term incidence of CR, risk factors, prognostic factors, and outcome after CR. The present study evaluated the development of CR in 1,048 consecutive adult primary liver allograft recipients initiated and mostly maintained on tacrolimus-based immunosuppressive therapy. They were evaluated with a mean follow-up of 77.3 +/- 14.7 months (range, 50.7 to 100.1 months). To assess the impact of primary diagnosis on the rate and outcome of CR, the population was divided into 3 groups. Group I included patients with hepatitis C virus (HCV)- or hepatitis B virus (HBV)-induced cirrhosis (n = 312); group II included patients diagnosed with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or autoimmune hepatitis (AIH; n = 217); and group III included patients with all other diagnoses (n = 519). Overall, 32 of 1,048 patients (3.1%) developed CR. This represented 13 (4.1%), 12 (5.5%), and 7 patients (1.3%) in groups I, II, and III, respectively. The relative risk for developing CR was 3.2 times greater for group I and 4.3 times greater for group II compared with group III. This difference was statistically significant (P =.004). The incidence of acute rejection and total number of acute rejection episodes were significantly greater in patients who developed CR compared with those who did not (P <.0001). Similarly, the mean donor age for CR was significantly older than for patients without CR (43.0 v 36.2 years; P =.02). Thirteen of the 32 patients (40.6%) who developed CR retained their original grafts for a mean period of 54 +/- 25 months after diagnosis. Seven patients (21.9%) underwent re-LT, and 12 patients (38.3%) died. Serum bilirubin levels and the presence of arteriopathy, arterial loss, and duct loss on liver biopsy at the time of diagnosis of CR were significantly greater among the 3 groups of patients. In addition, patient and graft survival for group I were significantly worse compared with groups II and III. We conclude that CR occurred rarely among patients maintained long term on tacrolimus-based immunosuppressive therapy. When steroid use is controlled, the incidence of acute rejection, mean donor age, HBV- and/or HCV-induced cirrhosis, or a diagnosis of PBC, PSC, or AIH were found to be predictors of CR. Greater values for serum bilirubin level, duct loss, arteriopathy, arteriolar loss, and presence of HCV or HBV were found to be poor prognostic factors for the 3 groups; greater total serum bilirubin value (P =.05) was the only factor found to be significant between patients who had graft loss versus those who recovered.

Adult↗
PubMed2001

Clinical intestinal transplantation: a decade of experience at a single center.

OBJECTIVE: To assess the long-term efficacy of intestinal transplantation under tacrolimus-based immunosuppression and the therapeutic benefit of newly developed adjunct immunosuppressants and management strategies. SUMMARY BACKGROUND DATA: With the advent of tacrolimus in 1990, transplantation of the intestine began to emerge as therapy for intestinal failure. However, a high risk of rejection, with the consequent need for acute and chronic high-dose immunosuppression, has inhibited its widespread application. METHODS: During an 11-year period, divided into two segments by a 1-year moratorium in 1994, 155 patients received 165 intestinal allografts under immunosuppression based on tacrolimus and prednisone: 65 intestine alone, 75 liver and intestine, and 25 multivisceral. For the transplantations since the moratorium (n = 99), an adjunct immunosuppressant (cyclophosphamide or daclizumab) was used for 74 transplantations, adjunct donor bone marrow was given in 39, and the intestine of 11 allografts was irradiated with a single dose of 750 cGy. RESULTS: The actuarial survival rate for the total population was 75% at 1 year, 54% at 5 years, and 42% at 10 years. Recipients of liver plus intestine had the best long-term prognosis and the lowest risk of graft loss from rejection (P =.001). Since 1994, survival rates have improved. Techniques for early detection of Epstein-Barr and cytomegaloviral infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, and most recently allograft irradiation may have contributed to the better results. CONCLUSION: The survival rates after intestinal transplantation have cumulatively improved during the past decade. With the management strategies currently under evaluation, intestinal transplant procedures have the potential to become the standard of care for patients with end-stage intestinal failure.

Adult↗
PubMed2001

Detection of infectious baboon cytomegalovirus after baboon-to-human liver xenotransplantation.

Xenotransplantation is considered to be a solution for the human donor shortage. However, there is a potential risk of transmitting animal infections from the transplanted organ. The known transmissibility and clinical significance of human cytomegalovirus (HCMV) infection after allotransplantation led us to evaluate whether baboon cytomegalovirus (BCMV) transmission could occur after a baboon-to-human liver xenotransplant. We examined serial blood samples from a baboon liver recipient and isolated replication-competent CMV-like agents on days 29, 36, and 42 after xenotransplantation. BCMV and HCMV DNAs were detected in the day 29 isolate, while only HCMV DNA was detected in the other isolates. This is the first report of detecting a replication-competent virus from a source animal after xenotransplantation and is a concern with regard to potential zoonotic transmission to others.

Adult↗
PubMed2000

Immunomodulation for intestinal transplantation by allograft irradiation, adjunct donor bone marrow infusion, or both.

BACKGROUND: The passenger leukocytes in the intestine have a lineage profile that predisposes to graft-versus-host disease (GVHD) in some animal models and have inferior tolerogenic qualities compared with the leukocytes in the liver, other solid organs, and bone marrow. Elimination by ex vivo irradiation of mature lymphoid elements from the bowel allografts is known to eliminate the GVHD risk. We hypothesized that infusion of donor bone marrow cells (BMC) in recipients of irradiated intestine would improve tolerogenesis without increasing the risk of GVHD. METHODS: Orthotopic small intestine transplantation was performed with the GVHD-prone Lewis (LEW)-to-Brown Norway (BN) combination and the reverse GVHD-resistant BN-to-LEW model under a short course of tacrolimus treatment (1 mg/kg/day, days 0-13, 20, 27). Grafts were irradiated ex vivo, using a 137Cs source. In selected experimental groups, donor BMC (2.5 x 10(8)) were infused on the day of small intestine transplantation. RESULTS: The unmodified LEW intestine remained intact, whether transplanted alone or with adjunct donor BMC infusion, but all of the BN recipients died of GVHD after approximately 2 months. Intestinal graft irradiation (10 Gy) effectively prevented the GVHD and prolonged survival to 92.5 days, but all of the BN recipients died with chronic rejection of the LEW grafts, which was prevented by infusion of adjunct donor BMC without causing GVHD. In the GVHD-resistant reverse strain direction (BN-->LEW), all intestinal recipients treated for 27 days with tacrolimus survived > or =150 days without regard for graft irradiation or adjunct BMC, but chronic rejection was severe in the irradiated intestine, moderate in the unaltered graft, and least in the irradiated intestine transplanted with adjunct BMC. Mild arteritis in the 150 day allografts of both strain combinations (i.e., LEW--> BN and BN-->LEW) may have been irradiation associated, but this was prevented when weekly doses of tacrolimus were continued for the duration of the experiment rather than being stopped at 27 days. CONCLUSIONS: Recipients are protected from GVHD by irradiating intestinal allografts, but the resulting leukocyte depletion leads to chronic rejection of the transplanted bowel. The chronic rejection is prevented with adjunct donor BMC without causing GVHD. Although application of the strategy may be limited by the possibility of radiation injury, the results are consistent with the paradigm that we have proposed to explain organ-induced graft acceptance, tolerance, and chronic rejection.

Animals↗
PubMed2000

Isolation of the regulatory regions and genomic organization of the porcine alpha1,3-galactosyltransferase gene.

BACKGROUND: Alpha1,3-galactosyltransferase (alpha1,3GT) is an enzyme that produces carbohydrate chains termed alphaGal epitopes found in most mammals, although some species of higher primates, including human, are notable exceptions. The evolutionary origin of the lost alpha1,3GT enzyme activity is not yet known, although it has been suggested that the promoter activity of this gene in the ancestors of higher primates was inactivated. METHODS: We used 5'-or 3'-RACE, GenomeWalking, reverse transcriptase polymerase chain reaction (RT-PCR) and dual Luciferase reporter assay for identification of the full-length cDNA, which includes the transcription initiation site and the promoter region of porcine alpha1,3GT gene. RESULTS: The region around exon 1 is guanine and cytosine (GC)-rich (about 70%), comprising a CpG island spanning more than 1.5 kbp. The 5'-flanking region of exon 1 contains multiple transcription factor consensus motifs, including GC-box, SP1, AP2, and GATA-box sites, in the absence of TATA or CAAT-box sequences. The entire gene consists of three 5' noncoding and six coding region exons spanning more than 52 kbp. Detailed analysis of alpha1,3GT transcripts revealed two major alternative splicing patterns in the 5'-untranslated region (5'-UTR) and evidence for minor splicing activity that occurs in a tissue-specific manner. Interspecies comparison of 5'-UTR shows minimal homology between porcine and murine sequences except for exon 2, which suggests that the regulatory regions differ among species. CONCLUSIONS: These observations have important implications for experiments involving genetic manipulation of the alpha1,3GT gene in transgenic animals in terms of promoter utilization, and particularly in genetically engineering cells for the animal cloning technology by nuclear transfer.

Animals↗