Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury.

The purine nucleoside adenosine is clinically employed in the treatment of supraventricular tachycardia. In addition, it has direct coronary vasodilatory effects, and may influence platelet aggregation. Experimental observations mechanistically link extracellular adenosine to cellular adaptation to hypoxia. Adenosine generation has been implicated in several pathophysiologic processes including angiogenesis, tumor defenses and neurodegeneration. In solid organ transplantation, prolonged tissue ischemia and subsequent reperfusion injury may lead to profound graft dysfunction. Importantly, conditions of limited oxygen availability are associated with increased production of extracellular adenosine and subsequent tissue protection. Within the rapidly expanding field of adenosine biology, several enzymatic steps in adenosine production have been characterized and multiple receptor subtypes have been identified. In this review, we briefly examine the biologic steps involved in adenosine generation and chronicle the current state of adenosine signaling in hepatic ischemia and reperfusion injury.

Complications of living donor hepatic lobectomy--a comprehensive report.

A wider application of living donor liver transplantation is limited by donor morbidity concerns. An observational cohort of 760 living donors accepted for surgery and enrolled in the Adult-to-Adult Living Donor Liver Transplantation cohort study provides a comprehensive assessment of incidence, severity and natural history of living liver donation (LLD) complications. Donor morbidity (assessed by 29 specific complications), predictors, time from donation to complications and time from complication onset to resolution were measured outcomes over a 12-year period. Out of the 760 donor procedures, 20 were aborted and 740 were completed. Forty percent of donors had complications (557 complications among 296 donors), mostly Clavien grades 1 and 2. Most severe counted by complication category; grade 1 (minor, n = 232); grade 2 (possibly life-threatening, n = 269); grade 3 (residual disability, n = 5) and grade 4 (leading to death, n = 3). Hernias (7%) and psychological complications (3%) occurred >1 year postdonation. Complications risk increased with transfusion requirement, intraoperative hypotension and predonation serum bilirubin, but did not decline with the increased center experience with LLD. The probability of complication resolution within 1 year was overall 95%, but only 75% for hernias and 42% for psychological complications. This report comprehensively quantifies LLD complication risk and should inform decision making by potential donors and their caregivers.

Evidence of recurrent autoimmunity in human allogeneic islet transplantation.

We transplanted 10,000 isolated, handpicked human pancreatic islets into the subfascial compartment of the forearm muscle of a type I diabetic recipient who had received a successful renal transplant one year prior. The recipient was maintained on his usual immunosuppressive therapy of cyclosporine, azathioprine, and prednisone. A biopsy performed 7 days after transplantation showed normal islets with both insulin- and glucagon-staining cells present and no lymphocytic infiltration. A second biopsy performed 14 days after transplantation showed a dense mononuclear cell infiltrate with a preferential loss of insulin-staining cells relative to glucagon-staining cells in the islets. These data are consistent with recurrent autoimmune diabetes in an isolated islet allograft in an immunosuppressed type I diabetic recipient. In addition, this forearm subfascial site may be a useful means to monitor islet rejection and autoimmune recurrence in therapeutic intraportal islet allografts.

Combined liver-pancreas transplantation in a patient with primary sclerosing cholangitis and insulin-dependent diabetes mellitus.

Combined liver-pancreas transplantation is a relatively uncommon procedure. We report successful combined liver-pancreas transplantation in a patient with primary sclerosing cholangitis and insulin-dependent diabetes mellitus and review the literature on this topic.

Canine liver transplantation under Nva2-cyclosporine versus cyclosporine.

The immunosuppressive qualities and other features of a new cyclosporine (CsA) analogue, Nva2-cyclosporine (Nva2-CsA) were examined using canine orthotopic liver allografts. The mean survival time was 11.8 +/- 9.6 (SD) days in dogs without treatment, 60.8 +/- 4.4 days with Nva2-CsA and 65.1 +/- 33.0 days with CsA. Functional abnormalities indicating toxic side effects were not noted either with Nva2-CsA or with CsA. Using the same oral dose, the rate of blood level rise and the amount of the rise were greater with Nva2-CsA. Histopathologically, Nva2-CsA treatment was associated with the same degree of hydropic vocuolation in the pars recta of the proximal tubules as CsA treatment. Thus, in the dog, Nva2-CsA had identical immunosuppressive properties as CsA, with no functionally detectable toxicity affecting the liver and kidney.

Metabolic complications after liver transplantation. Diabetes, hypercholesterolemia, hypertension, and obesity.

We retrospectively studied the incidence of diabetes, hypercholesterolemia, hypertension, and obesity in 123 consecutive adult liver transplant recipients (61 men and 62 women) who were alive at least 1 year after transplantation. We also studied the change in these metabolic complications in 61 patients who subsequently were able to be tapered to 5 mg prednisone per day. One year after transplantation--a point at which almost all patients were on maintenance immunosuppression and had stable graft function--the incidence of diabetes was 13% and hypertension was 69.1%. The overall incidence of hypercholesterolemia (serum cholesterol > 240 ng/ml) was 31% and was more frequent in women than in men (38.7% vs. 23.0%, P < 0.06). The incidence of obesity at 1 year was 41.9% in women and 39.3% in men. With tapering of prednisone from 10 mg to 5 mg per day in 61 patients, the mean serum cholesterol decreased from 224.6 +/- 65.2 mg/dl to 203.3 +/- 65.5 mg/dl, P < 0.005. With steroid tapering, 8 patients were able to discontinue antihypertensive medications and 4 were able to discontinue insulin treatment for diabetes. Five patients became obese during the steroid-tapering period. No patient developed irreversible rejection with steroid tapering and no immunologic graft losses occurred more than a year after transplantation. Nine patients who lived a year subsequently died. Of these, 7 patients were diabetic and 2 died of cardiac disease. We conclude that metabolic complications such as diabetes, hypertension, and hypercholesterolemia are common later after liver transplantation and that these may contribute to patient morbidity and mortality. In addition, we conclude steroid tapering to 5 mg/day does not lead to graft loss and may decrease the incidence and severity of late metabolic complications.

Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.

Fatal transfer of malignant melanoma from multiorgan donor to four allograft recipients.

BACKGROUND: In this report we describe the transfer of malignant melanoma from a single donor to four solid organ transplant recipients, all of whom died from metastatic melanoma. METHODS AND CASE HISTORIES: The donor of a heart, liver, and two kidneys to four separate recipients died of intracerebral hemorrhage. The donor had no history or clinical evidence of melanoma. All four recipients, treated with standard immunosuppression protocols, developed metastatic malignant melanoma within 1 year after transplantation Three patients died within 14 months after transplantation, although the fourth, whose immunosuppressive therapy was discontinued, died of metastatic melanoma 30 months after renal transplantation. FINDINGS: Tumors from all recipients were histologically identical. Donor origin of tumor cells was confirmed by polymerase chain reaction (PCR)-based DNA analysis for polymorphic short tandem tetrameric repeats (Geneprint STR, Promega Corp., Madison, WI). DNAs from nontumorous donor tissue and tumor tissue available from three recipients tested positive for CSF1P0 alleles 10 and 12 and for TH01 alleles 6 and 7, although DNAs from nonneoplastic recipient tissues all exhibited different allelotypes. INTERPRETATION: Transmission of fatal or potentially fatal malignant tumors, notably malignant melanoma, from donor to recipient is an uncommon complication of solid organ transplantation. PCR-based genetic analysis permits definitive assignment of the source of posttransplant tumors.

Adult living donor liver transplantation using a right hepatic lobe.

BACKGROUND: Living donor liver transplantation has gained wide acceptance as an alternative for children with end-stage liver disease. The standard left lateral segment used in this operation does not provide adequate parenchymal mass to broaden its application to larger children or adults. METHODS: We report two cases of adult to adult living donor liver transplantation using a right hepatic lobe in patients with chronic liver disease. RESULTS: Both recipients experienced excellent initial graft function and have normal liver function 4 and 9 months postoperatively. Both donors are alive and well and returned to normal life 4 weeks postoperatively. CONCLUSIONS: Our initial experience suggests that this technique is a safe and reliable option for adults with chronic end-stage liver disease. A conservative application of this procedure in the adult population could significantly reduce the mortality on the adult waiting list.

Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus.

BACKGROUND: The long-term complications of immunosuppressive therapy such as diabetes, hypercholesterolemia, and hypertension are a major source of morbidity in liver transplant recipients. In this prospective, randomized, open-label study we completely withdrew prednisone (PRED) 14 days after liver transplantation in an effort to decrease these metabolic complications. Patients were maintained on mycophenolate mofetil (MMF) in combination with either cyclosporine (CsA; Neoral formulation) or tacrolimus (TAC). Thus, we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy, toxicity, and effect on posttransplant metabolic complications. METHODS: A total of 71 patients were randomized to receive either TAC-MMF (n=35) or CsA-MMF (n=36) after liver transplantation and were analyzed for patient and graft survival. Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes, hypertension, and hypercholesterolemia. RESULTS: The 6-month patient survival rates were 94.4% for CsA-MMF and 88.6% for TAC-MMF. Corresponding 6-month graft survival rates were 88.7% and 85.71% with no immunologic graft losses in either group. The incidence of biopsy-proven acute rejection was 46% for CsA-MMF and 42.3% for TAC-MMF. Six patients were converted from CsA to TAC (four for recurrent rejection) and seven patients were converted from TAC to CsA (four for neurotoxicity). Only one patient (in the TAC-MMF group) developed new-onset posttransplant diabetes. In contrast, four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant. The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group (145.2+/-41.8 mg/dl and 190.3+/-62.2, respectively; P<0.001) and the incidence of hypertension was lower in the TAC-MMF group (12% vs. 30.3% in the CsA-MMF group, P<0.01). Both groups had a lower incidence of metabolic complications compared with a historical group (n=100) maintained on CsA and PRED (10 mg/day at 6 months). CONCLUSIONS: MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses. Early PRED withdrawal decreases posttransplant diabetes, hypercholesterolemia, and hypertension, but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients.

Prolongation of islet allograft survival with an antibody to vascular cell adhesion molecule 1.

BACKGROUND: The purpose of this study was to determine whether an antibody to vascular cell adhesion molecule 1 (VCAM1) prolongs the survival of neovascularized pancreatic islet allografts. METHODS: We treated CBA (H-2k) recipients of BALB/c (H-2d) islet allografts with anti-VCAM1 antibody (400 micrograms/day for 20 days). Sensitized recipients of islet grafts also were treated with anti-VCAM1. To study mechanism we performed mixed lymphocyte reactions (MLRs) with anti-VCAM1 and studied the graft infiltrate in treated recipients. RESULTS: Anti-VCAM1-treated CBA recipients showed prolonged graft survival with indefinite survival in five of nine cases. Anti-VCAM1 prevented proliferation in an MLR but not when added 36 hours after the beginning of the MLR. Anti-VCAM1 did not prolong allograft survival in sensitized recipients and did not prevent lymphocytic infiltration of the graft at 7 days. CONCLUSIONS: Anti-VCAM1 prolongs allograft survival in neovascularized islets in which the donor vascular endothelium plays little or no role in immunogenicity. VCAM1 appears to be important in the afferent phase (lymphocyte activation) of the allograft response. Once activated, either late in an MLR or in sensitized recipients, lymphocytes are not dependent on VCAM1 for function. Finally, anti-VCAM1 does not appear to affect the homing of lymphocytes to the allograft.

Sirolimus reduces the risk of significant hepatic fibrosis after liver transplantation for hepatitis C virus: a single-center experience.

INTRODUCTION: Hepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant. METHODS: Among 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0-4); significant fibrosis was defined as fibrosis ≥ stage 2. RESULTS: Overall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration. CONCLUSIONS: This retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.