Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.

We previously suggested that in patients with heptocellular carcinoma (HCC), the conventional Milan criteria (T1/T2) for orthotopic liver transplantation (OLT) could be modestly expanded based on pathology (UCSF criteria). The present study was undertaken to prospectively validate the UCSF criteria based on pretransplant imaging. Over a 5-year period, the UCSF criteria were used as selection guidelines for OLT in 168 patients, including 38 patients exceeding Milan but meeting UCSF criteria (T3A). The 1- and 5-year recurrence-free probabilities were 95.9% and 90.9%, and the respective survivals without recurrence were 92.1% and 80.7%. Patients with preoperative T1/T2 HCC had 1- and 5-year recurrence-free probabilities of 95.7% and 90.1%, respectively, versus 96.9% and 93.6%, respectively, for preoperative T3A stage (p = 0.58). Under-staging was observed in 20% of T2 and 29% of T3A HCC (p = 0.26). When explant tumor exceeded UCSF criteria (15%), the 1- and 5-year recurrence-free probabilities were 80.4% and 59.5%, versus 98.6% and 96.7%, respectively, for those within UCSF criteria (p < 0.0001). In conclusion, our results validated the ability of the UCSF criteria to discriminate prognosis after OLT and to serve as selection criteria for OLT, with a similar risk of tumor recurrence and under-staging when compared to the Milan criteria.

Mixed allogeneic chimerism as a reliable model for composite tissue allograft tolerance induction across major and minor histocompatibility barriers.

BACKGROUND: Although prolonged composite tissue allograft (CTA) survival is achievable in animals using immunosuppressive drugs, long-term immunosuppression of CTAs in the clinical setting may be unacceptable for most patients. The purpose of this study was to develop a model for reliable CTA tolerance induction in the adult rat across a major MHC mismatch without the need for long-term immunosuppression. METHODS: Mixed allogeneic chimeras were prepared by using rat strains with strong MHC incompatibility [WF (RT1Au), ACI (RT1Aa)] WF + ACI-->WF, n=23. The bone marrow (BM) of recipient animals was pretreated with low-dose irradiation (500-700 cGy), followed by reconstitution with a mixture of T cell-depleted syngeneic (WF) and allogeneic (ACI) cells. Additionally, the recipient animals received a single dose of anti-lymphocyte serum (10 mg) 5 days before bone marrow transplantation (BMT) and tacrolimus (1 mg/kg/day) from the day before BMT to 10 days post-BMT. Hindlimb transplants were performed 12 months after BMT. Five animals received a limb allograft irradiated (1000 cGy) just before transplantation. Rat chimeras were characterized (percentage of donor cells present within the bloodstream) by flow cytometry at 3 and 12 months after BM reconstitution and after hindlimb transplantation. RESULTS: Peripheral blood lymphocyte chimerism (WF/ACI) remained stable >12 months after BM reconstitution in 18/23 animals. Multi-lineage chimerism of both lymphoid and myeloid lineages was present, suggesting that engraftment of the pluripotent rat stem cell had occurred. In animals with donor chimerism >60% (n=18) no sign of limb rejection was present for the duration of the study. All animals with chimerism <20% (n=5) developed moderate signs of rejection clinically and histologically. Gross motor and sensory reinnervation (weight bearing, toe spread) developed at >60 days in 14/21 rats. Postoperative flow cytometry studies demonstrated stable chimerism in all animals studied (n=10). Five out of five animals with irradiated limb transplants showed no sign of GVHD at >100 days. CONCLUSIONS: Stable mixed allogeneic chimerism can be achieved in a rat hindlimb model of composite tissue allotransplantation. Hindlimb allografts to mixed allogeneic chimeras exhibit prolonged, rejection-free survival. Partial functional return should be expected. The BM transplanted as part of the hindlimb allograft plays a role in the etiology of GVHD. Manipulating that BM before transplantation may influence the incidence of GVHD. This represents the first reliable rat hindlimb model demonstrating rejection-free CTA survival in an adult animal across a major MHC mismatch without the long-term need for immunosuppressive agents.

Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.

The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P =.87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P =.0001). An alpha-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > or = 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < or = 6.5 cm, or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P =.0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT.

Posttransplantation lymphoproliferative disorders in pediatric patients undergoing liver transplantation.

OBJECTIVES: To study the clinicopathologic and molecular genetic findings in posttransplantation lymphoproliferative disorders (PTLDs) following pediatric liver transplantation and to determine the applicability of a recently proposed consensus classification system. DESIGN: The clinical, pathologic, and molecular genetic findings of 11 PTLDs that occurred in 10 patients are presented. These 10 patients were derived from a group of 121 pediatric patients who underwent liver transplantation at the University of California, San Francisco. The PTLDs were classified using the proposed Society for Hematopathology scheme. Clonality was determined by immunohistochemical detection of monotypic immunoglobulin or by using polymerase chain reaction-based methods to detect monoclonal immunoglobulin heavy-chain gene rearrangements. Epstein-Barr virus (EBV) was detected by immunohistochemistry, in situ hybridization, or polymerase chain reaction. Epstein-Barr virus typing and the presence of LMP1 gene deletions were also analyzed by polymerase chain reaction. RESULTS: There were 3 early lesions, 4 polymorphic PTLDs, and 4 monomorphic PTLDs. Monoclonality was demonstrated in 8 of 9 cases assessed. Epstein-Barr virus was present in all cases; of 9 cases assessed by polymerase chain reaction, the virus was type A in 8 and type B in 1. No EBV LMP1 gene deletions were identified. The corresponding liver explants were negative for EBV in 8 cases and positive in 1 case. Greater than 3 foci of disease and monomorphic PTLD were associated with decreased actuarial survival (P <.05). CONCLUSIONS: The prognosis of pediatric patients with PTLD is favorable for early lesions and polymorphous PTLD, particularly in patients with localized disease. Multifocal disease and monomorphic PTLD are associated with an unfavorable prognosis.

Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated.

Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 +/- 4.6 and 26.8 +/- 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 +/- 1.1 and 1.2 +/- 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor-avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation.

Surgical anatomy of the left lateral segment as applied to living-donor and split-liver transplantation: a clinicopathologic study.

OBJECTIVE: To evaluate intrahepatic vascular and biliary anatomy of the left lateral segment (LLS) as applied to living-donor and split-liver transplantation. SUMMARY BACKGROUND DATA: Living-donor and split-liver transplantation are innovative surgical techniques that have expanded the donor pool. Fundamental to the application of these techniques is an understanding of intrahepatic vascular and biliary anatomy. METHODS: Pathologic data obtained from cadaveric liver corrosion casts and liver dissections were clinically correlated with the anatomical findings obtained during split-liver, living-donor, and reduced-liver transplants. RESULTS: The anatomical relation of the left bile duct system with respect to the left portal venous system was constant, with the left bile duct superior to the extrahepatic transverse portion of the left portal vein. Four specific patterns of left biliary anatomy and three patterns of left hepatic venous drainage were identified and described. CONCLUSIONS: Although highly variable, the biliary and hepatic venous anatomy of the LLS can be broadly categorized into distinct patterns. The identification of the LLS duct origin lateral to the umbilical fissure in segment 4 in 50% of cast specimens is significant in the performance of split-liver and living-donor transplantation, because dissection of the graft pedicle at the level of the round ligament will result in separate ducts from segments 2 and 3 in most patients, with the further possibility of an anterior segment 4 duct. A connective tissue bile duct plate, which can be clinically identified, is described to guide dissection of the segment 2 and 3 biliary radicles.

Prolonged cold ischemia time obviates the benefits of 0 HLA mismatches in renal transplantation.

HYPOTHESIS: Recipients of 0 HLA mismatch kidneys with prolonged cold ischemia times of longer than 36 hours do not have superior outcomes compared with recipients of kidneys with 1 or more mismatches. DESIGN: Retrospective review. SETTING: Transplanation centers. PATIENTS AND METHODS: A total of 63,688 recipients who underwent transplantation between January 1, 1990, and July 31, 1998. MAIN OUTCOME MEASURES: Delayed graft function, serum creatinine level, and patient and renal graft survival. RESULTS: Recipients of 0 HLA mismatch kidneys with fewer than 36 hours of cold ischemia time had better 5-year graft survival (75%) when compared with recipients with 1 or more mismatches (67%) (P<.001). However, recipients of 0 HLA mismatch kidneys with longer than 36 hours of cold ischemia time did not have any graft survival advantage (71% in 0 HLA mismatch kidneys vs 72% in 1 or more mismatches, P =.24). CONCLUSIONS: Cold ischemia times of longer than 36 hours obviate the benefits of better graft survival conferred by better matching.

A non-cleavable mutant of Fas ligand does not prevent neutrophilic destruction of islet transplants.

BACKGROUND: Fas ligand (FasL) mediates apoptosis of susceptible Fas-expressing lymphocytes, and may contribute to the maintenance of peripheral tolerance. In transplantation models, however, artificial expression of FasL on cellular as well as islet transplants results in accelerated rejection by neutrophils. The mechanism of the neutrophilic response to FasL expression is unknown. FasL, like other members of the tumor necrosis factor family, is cleaved to a soluble form by metalloproteases. We tested the hypothesis that soluble FasL (sFasL) was responsible for neutrophil migration by creating a non-cleavable mutant of FasL. METHODS: Three mutants of FasL with serial deletions in the putative proteolytic cleavage site of human FasL were made using inverse polymerase chain reaction. The relative fractions of sFasL and membrane-bound FasL were assessed by Western blot and immunoprecipitation, as well as by cytotoxicity assay using Fas-expressing target cells. The fully non-cleavable mutant was transduced into murine islets as well as myoblasts and tumor cell lines, and tested in a murine transplantation model. RESULTS: Serial deletions in the putative metalloprotease site of FasL resulted in a fully non-cleavable mutant of FasL (ncFasL). Expression of ncFasL in tumor lines induced higher levels of apoptosis in Fas bearing targets than wild-type FasL. Transplantation of ncFasL-expressing islets under the kidney capsule of allogenic mice resulted in accelerated rejection identical to that seen with wild-type Fas ligand-expressing islets. Myoblasts and tumor cell lines expressing ncFasL also induced neutrophil infiltration. CONCLUSIONS: Membrane-bound Fas ligand is fully capable of inducing a neutrophilic response to transplants, suggesting an activation by Fas ligand of neutrophil chemotactic factors.

A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival.

BACKGROUND: Dendritic cells are potent antigen-presenting cells that bind allogeneic T cells. They are thus candidates for targeting immunoregulatory molecules to the alloreactive T cell compartment and suppressing the alloimmune response. METHOD: A dendritic cell line derived from the BALB/c mouse (H2d) was genetically modified to express the immunoregulatory molecule CTLA4-Ig. The ability of these dendritic cell transfectants to downregulate the alloimmune response was tested in an islet transplant model. Allogeneic C57Bl/6 (H2b) mice were rendered diabetic with streptozocin, and they received BALB/c islet (H2d) transplants. Mice were administered 25 million untransfected or CTLA4-Ig-transfected D2SC/1 cells i.v. on the day of islet transplantation and 6 days later[fnc]. RESULT: Mice treated with CTLA4-Ig-transfected D2SC/1 cells demonstrated prolonged allograft survival (mean = 20 days, median = 17 days, SD = 9.39) compared with mice treated with untransfected D2SC/1 cells (mean = 12 days, median = 11 days, SD=2.74) or untreated control mice (mean = 11 days, median = 11 days SD = 1.41). Third party allograft survival was not prolonged in mice receiving similar treatment. CONCLUSIONS: These results demonstrate that a genetically modified dendritic cell line can suppress the alloimmune response and prolong islet allograft survival in an allospecific manner. The findings also suggest that genetically modified dendritic cells may be useful in targeting alloreactive T cells and prolonging allograft survival.

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants.

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.

Mycophenolate mofetil, microemulsion cyclosporine, and prednisone as primary immunosuppression for pediatric liver transplant recipients.

Triple immunosuppressive therapy using mycophenolate mofetil (MMF), microemulsion cyclosporine (me-CsA), and prednisone offers the potential for potent immunosuppression without intravenous drug therapy or anti-T-cell antibody induction therapy. This report describes the application of an immunosuppressive protocol (CNp) using MMF, me-CsA, and prednisone as primary immunosuppression for pediatric liver transplant recipients at the University of California at San Francisco. From August 1995 through December 1996, 26 children (17 boys, 9 girls) aged 1 month to 16 years (mean +/- standard deviation, 58 +/- 62 months; median, 31 months) underwent liver transplantation at our institution, receiving CNp as primary immunosuppression. Posttransplantation renal function, incidence of leukopenia, and drug tolerance within the group receiving CNp as primary immunosuppression were compared with those of 19 children who received primary immunosuppression consisting of azathioprine, oil-based gel-encapsulated cyclosporine, and prednisone with anti-T-cell antibody induction therapy at the same institution from October 1993 through July 1995. No significant difference was observed between immunosuppressive protocols in serum creatinine level or incidence of leukopenia requiring medical therapy during the first year posttransplantation. Whereas gastrointestinal symptoms were observed in approximately 30% of CNp recipients during initial immunotherapy, tolerance of CNp primary immunotherapy was routinely achieved by the dose reduction of MMF. At 1 year posttransplantation, 20 children (77%) remained on CNp primary immunotherapy, 5 children (19%) were receiving tacrolimus-based immunotherapy secondary to rejection, and 1 patient (4%) converted to tacrolimus-based immunotherapy secondary to persistent gastrointestinal intolerance. In conclusion, CNp provides an alternative immunosuppressive protocol that eliminates the necessity of intravenous and induction immunosuppressive therapy with no increased incidence of posttransplantation renal dysfunction or leukopenia and is well tolerated in children.

Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma.

BACKGROUND: Long-term results after liver transplantation for hepatocellular carcinoma have been disappointing, largely because of the high recurrence rate. It is controversial whether the immunosuppressed state of the recipient contributes to this recurrence rate. We have developed a model in the rat system to examine the effect of immunosuppression on tumor recurrence after transplantation, as well as to evaluate other treatment strategies to decrease the recurrence rate. METHODS: A 2-mm3 nodule of Morris hepatoma 3924a was implanted intrahepatically at day 0. At postimplant day 16, the animals underwent syngeneic orthotopic liver transplantation. Two treatment groups were established. Group I received saline injections subcutaneously for 2 weeks, while group II received subcutaneous cyclosporine injections at 3 mg/kg/day for 14 days. Animal survival, tumor recurrence rate, and sites of recurrence and number of pulmonary nodules were recorded. RESULTS: Overall survival rate was reduced in animals receiving cyclosporine. The mean survival time was 74.4 days (SEM 6.39 days) in saline-treated animals and 50.4 days (SEM 7.63 days) in the cyclosporine-treated animals. The proportion surviving in group 1 was 47% and in group 2 was 18%. This difference in survival was statistically significant (P=0.025). The incidence of pulmonary nodules was increased in the cyclosporine-treated animals, and tumor recurrence in extrapulmonary sites was seen only in the cyclosporine-treated animals. CONCLUSION: Results from this study suggest that cyclosporine has an adverse effect on tumor recurrence after transplantation. This model will be useful to further examine treatment strategies to improve the outcome of transplantation for hepatocellular carcinoma.

Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression. METHODS: Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity. RESULTS: Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)]. CONCLUSIONS: MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.

Hepatic artery pseudoaneurysm with hemobilia following angioplasty after liver transplantation.

A 58-yr-old female with primary biliary cirrhosis underwent an uncomplicated orthotopic liver transplantation. Elevated liver function tests 2 months post-transplantation were evaluated with Doppler ultrasound and a hepatic artery stricture was documented. The hepatic artery stenosis was treated with angioplasty. She developed hemobilia 1 d after the procedure, which was confirmed by angiography. Emergent exploratory laparotomy revealed a pseudoaneurysm at the hepatic artery anastomosis. The pseudoaneurysm was resected and the proper hepatic artery of the graft was anastomosed to the splenic artery of the host using preserved homograft. Her post-operative course was uneventful and liver function tests returned to normal quickly after the surgery. This report will discuss the unusual nature of this complication, and review the problem of hemobilia and pseudoaneurysms in liver transplant recipients.

Hepatitis after liver transplantation: the role of the known and unknown viruses.

This study was designed to determine the cause of posttransplantation hepatitis in patients undergoing transplantation for liver disease of nonviral cause; the role of acquired hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis G virus (HGV) in posttransplantation hepatitis; and the course of posttransplantation hepatitis of unknown cause. Two hundred forty-three patients underwent transplantation for nonviral liver diseases (mean age, 48 years; 103 men, 140 women). Serological and virological assays for HBV and HCV were performed pretransplantation to exclude preexisting infection and posttransplantation to investigate the cause of posttransplantation hepatitis. Histology was graded on all available biopsy specimens; posttransplantation hepatitis was assessable in 150 patients. Posttransplantation hepatitis was present in 29% (44 of 150) of the patients after a median follow-up of 47 months (range, 1 to 101 months). Actuarial survival was significantly lower in patients with posttransplantation hepatitis compared with patients without (71% v 89% at 5-year follow-up; P = .03). HCV and HBV were identified posttransplantation in 14% and 9% of patients with hepatitis, respectively. After the exclusion of HCV and HBV infection, 22% (33 of 150) of the patients had posttransplantation hepatitis of unknown cause. HGV was present in 58% of these patients, but HGV was equally prevalent in patients without posttransplantation hepatitis. When patients with HBV and HCV were excluded, there was no difference in survival between patients with posttransplantation hepatitis compared with patients without (P = .08, log-rank test). Posttransplantation hepatitis was present in approximately 30% of the patients undergoing transplantation for nonviral diseases, with a median follow-up of 47 months. Known hepatitis viruses (HBV, HCV) were present in one fourth of the patients with posttransplantation hepatitis; 22% (33 of 150) of the patients had hepatitis of unknown cause, suggesting that other, as yet undiscovered, hepatitis viruses may exist.

Biliary complications of reduced-organ liver transplantation.

Reduced-organ liver transplantation for children is effective in lowering pretransplantation morbidity and mortality. Improvements in surgical technique have reduced vascular complications; however, biliary complications continue to account for significant posttransplantation morbidity. This investigation chronicles the incidence and type of biliary complications encountered with reduced-organ liver transplantation. Retrospective review of reduced-organ liver recipients over a 59-month period was performed, and biliary complications were classified as (1) missed biliary radicle, (2) anastomotic leak requiring revision, and (3) biliary stricture. From July 1992 to May 1997, 42 children received reduced-organ grafts: 32 living-donor, 8 cadaveric-reduced, 1 split-liver, and 1 auxiliary orthotopic liver transplant. Of the 42 grafts, 41 were Couinaud segments II/III and 1 was segments II/III/IV. Ten biliary complications were identified in 9 recipients (24%). Biliary complications included parenchymal radicle leaks, 5 (50%); biliary strictures, 3 (30%); and anastomotic leaks, 2 (20%). Although technical advances have reduced the incidence of biliary complications secondary to organ ischemia, parenchymal radicle leaks continue to be a source of morbidity for reduced-organ recipients. Planned exploration on posttransplantation day 7 was performed on the most recent 26 of the 42 total reduced-organ procedures as a mechanism to identify and treat early technical complications. Planned exploration as a routine component of reduced-organ transplantation has yielded a 15% incidence of discovered parenchymal leaks and a 5% incidence of discovered anastomotic leaks. This series underscores the necessity for improved anatomical studies to correctly identify duct territories and the development of accurate noninvasive methods to assess the biliary system preoperatively and intraoperatively in the application of reduced-organ liver transplantation.

Single-center long-term results of renal transplantation for IgA nephropathy.

BACKGROUND: Previous reports with short-term follow-up after renal transplantation for IgA nephropathy (IgAN) have suggested an incidence of recurrence up to 50%, an increased recurrence with living-related donors, and the rarity of graft loss due to recurrence. In this study, the long-term results of renal transplantation for IgAN were examined. METHODS: Between June 1980 and December 1994, 54 patients (61 renal transplants) with end-stage renal disease due to IgA nephropathy were performed at the University of California San Francisco. Actuarial patient and graft survival were compared with a matched reference group. Correlates of recurrent disease (biopsy confirmed) and graft loss were determined. RESULTS: Patient and graft survival for IgA patients were good (100% and 75%, respectively, at 5 years after transplant). Graft survival was lower in IgA recipients with living-related compared with cadaveric renal allografts (P<0.09) and also with renal allografts well matched at HLA-AB (< or =2 AB mismatches) (P<0.09) or HLA-DR (< or =1 mismatch) (P<0.01). Recurrence was not correlated with donor status, recipient age, race, gender, or immunosuppression. Recurrence (18 of 61) resulted in substantial graft loss (6 of 18) or deteriorating renal function (4 of 18) at a mean follow-up of 61 months. Mean time to diagnosis of recurrence and subsequent graft loss was 31 and 63 months, respectively. Despite re-recurrence of IgAN in three of five patients who were retransplanted, all have good long-term renal function. CONCLUSIONS: Substantial graft loss due to recurrent disease after renal transplantation for IgAN occurs with long-term follow-up. Living-related transplantation and HLA matching do not appear to confer an advantage for graft survival in patients with IgAN. Despite the potential for recurrence, IgAN patients enjoy good long-term graft survival.

Risks associated with conversion of stable patients after liver transplantation to the microemulsion formulation of cyclosporine.

BACKGROUND: Neoral is a microemulsion formulation of cyclosporine that has a better pharmacokinetic profile than the standard formulation (Sandimmune). To prove the safety of converting stable liver transplant patients from Sandimmune to Neoral, we conducted a prospective trial involving 54 patients. METHOD: The average time from transplantation to conversion was 48.5+/-21.6 months. Thirty of 54 patients (55%) required a dose reduction during the study for various reasons. Five of 30 patients had the first dose reduction because of increased levels of cyclosporine. Seven patients required more than one dose reduction. RESULTS: Sixteen patients suffered serious adverse events. Six patients had a biopsy-proven rejection. Four of 6 patients had trough cyclosporine levels within 20% of baseline value immediately before developing rejection. CONCLUSION: Converting patients from the standard formulation to the microemulsion formulation of cyclosporine seems to expose stable patients to unnecessary risks.