Lynda Brady

Complications in 100 living-liver donors

OBJECTIVE A review of 100 living-liver donors was performed to evaluate the perisurgical complications of the procedure and thus to help quantify the risks to the donor. SUMMARY BACKGROUND DATA Despite the advantages of living-donor liver transplantation (LDLT), the procedure has received criticism for the risk it imposes on healthy persons. A paucity of data exists regarding the complications and relative safety of the procedure. METHODS One hundred LDLTs performed between November 1989 and November 1996 were reviewed. Donor data were obtained by chart review, anesthesia records, and the computerized hospital data base. Patient variables were compared by Fishers exact test and the Students t test. RESULTS There were 57 women and 43 men with a median age of 29. Donors were divided into two groups: group A (first 50 donors), and group B (last 50 donors). There were 91 left lateral segments and 9 left lobes. There were no deaths. Fourteen major complications occurred in 13 patients; 9 occurred in group A and 5 in group B. Biliary complications consisted of five bile duct injuries (group A = 4, group B = 1) and two cut edge bile leaks. Complications were more common in left lobe resections (55%) than in left lateral segment grafts (10%). Minor complications occurred in 20% of patients. A significant reduction in overall complications (major and minor) was observed between the groups (group A, n = 24 [45%] vs. group B, n = 10 [20%]). In addition, surgical time and hospital stay were both significantly reduced. CONCLUSIONS Although the procedure is safe, many LDLT donors have a perisurgical complication. Surgical experience and technical modifications have resulted in a significant reduction in these complications, however. To minimize the risks for these healthy donors, LDLT should be performed at institutions with extensive experience.

Experiences with leflunomide in solid organ transplantation.

BACKGROUND Leflunomide (Arava), a drug widely used for treatment of rheumatoid arthritis, has a very promising background in experimental transplantation. Its activity in experimental models of chronic rejection, its synergy with calcineurin phosphatase inhibitors, and its inhibitory effects on herpes virus replication are compelling reasons to pursue its clinical evaluation in transplantation. We report the use of this drug over the past 3 years in various clinical situations. METHODS A retrospective review was performed in 53 liver and kidney transplant recipients receiving Arava. A single-dose pharmacokinetic (PK) study was first performed in stable, renal transplant recipients, and an initially targeted serum level of 100 microg/mL (300 microM) was calculated to require a loading dose of 1200-1400 mg over a 7-day period. We correlate the appearance of toxicity with serum levels of active drug and review the outcomes in patients whose clinical condition required dose reductions of conventional immune suppressive drugs. RESULTS Fifty-three patients received leflunomide from 5 days to more than 430 days, and 37 patients received the drug for more than 60 days. The primary toxicity was anemia in the renal transplant patients and elevation of liver enzymes in the liver transplant patients. At comparable oral doses, serum levels were substantially lower and anemia more common in patients with serum creatinine >3 mg/dL. In liver and renal recipients with serum creatinine <3 mg/dL, the drug was well tolerated and dose-limiting side effects occurred in less than 15% when drug serum levels were less than 80 microg/ml. Patients with serum creatinine >3 mg/dL often required serum levels of active drug reduced to <60 microg/mL. In 12 of 18 renal patients treated for 200 days or more, the dose of cyclosporine or Prograf was reduced by a mean of 38.5% and stopped in one patient. The prednisone dose was reduced by a mean of 25% in these same 13 patients. Cyclosporine or FK506 was stopped completely in four liver recipients and reduced by 65% in another patient. No evidence of acute rejection developed in any of these liver or kidney transplant patients. CONCLUSION Leflunomide seems to possess substantial immune suppressive potency in renal and liver transplant recipients and may be safely dosed for more than 300 days. The data suggest that calcineurin phosphatase inhibitors and prednisone can be safely reduced in patients with serum levels of active drug above 50 microg/mL. Because of a wide inter-patient range of active metabolite terminal half-life (>300%), monitoring of serum levels would seem to be an important part of its evaluation.

De novo hepatitis with autoimmune antibodies and atypical histology : A rare cause of late graft dysfunction after pediatric liver transplantation

Background. Late graft dysfunction after orthotopic liver transplantation is commonly due to chronic rejection, recurrence of primary disease, sepsis, lymphoproliferative disease, or vascular or biliary complications. Herein we describe a subset of pediatric liver transplant patients in whom late graft dysfunction was associated with autoimmune markers, bile ductular proliferation, and portal infiltrates, which progress to fibrosis. This subset of patients has not been previously described. Methods. Six of the 115 children followed for greater than 5 years after transplantation developed this unusual form of graft dysfunction. All children were on a low-dose single immunosuppressive therapy (mean trough cyclosporine concentration 89 &mgr;g/L) and had been tapered off steroids for a median duration of 1.5 year. Liver biopsies were performed in all children to evaluate the graft dysfunction, and the histologic findings were interpreted by an experienced hepato-pathologist. All patients were tested for antibodies to hepatitis C virus, hepatitis B surface antigen, and IgM antibodies to hepatitis A. Smooth muscle antibody, antinuclear antibody, and antibody to liver/kidney microsome type 1 were sought by indirect immunofluorescence. International Autoimmune Hepatitis Group scores were calculated. All patients underwent ultrasonography with doppler studies at the onset of graft dysfunction. Three patients with marked bile duct proliferation on histology had cholangiograms. Results. Histology in all patients showed mononuclear cell infiltrates in the portal area with interface hepatitis, portal fibrosis, and ductular proliferation without duct damage or loss. All six patients had positive antinuclear antibody or smooth muscle antibody titers. Viral studies for hepatitis A, B, and C were negative in all patients. On the International Autoimmune Hepatitis Group scoring system, five patients had probable autoimmune hepatitis (score of 10–15) and one had definite autoimmune hepatitis (score >15) at the onset of graft dysfunction. All were treated with azathioprine and prednisone similar to treatment for autoimmune hepatitis. However, despite aggressive treatment, four patients developed bridging portal fibrosis resulting in graft loss in two patients. Conclusion. This clinical constellation is associated with worse outcome then that previously described for pediatric patients with posttransplantation de novo autoimmune hepatitis. Further studies are needed to find an optimal treatment regimen for these patients.

Risk factors for chronic rejection after pediatric liver transplantation.

Background. Chronic rejection is a major cause of graft failure and a frequent reason for retransplantation after pediatric liver transplantation. Identification of risk factors for chronic rejection in pediatric transplant recipients is vital to understanding the pathogenesis of chronic rejection and may help prevent further graft loss. Methods. The study population consisted of 285 children with 385 liver transplants performed at University of Chicago between 1991 and 1999. Logistic regression analysis was used to evaluate risk factors for chronic rejection, including age, sex, race, type of graft (living related vs. cadaveric), native liver disease, acute rejection episodes, cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD). Results. The chronic rejection rate was significantly lower in recipients of living-related grafts than in recipients of cadaveric grafts (4% vs. 16%, P =0.001). African-American recipients had a significantly higher rate of chronic rejection than did Caucasian recipients (26% vs. 8%, P <0.001). Numbers of acute rejection episodes, transplantation for autoimmune disease, occurrence of PTLD, and CMV infection were also significant risk factors for chronic rejection. However, recipient age, gender, donor-recipient gender mismatch, and donor-recipient ethnicity mismatch were not associated with higher incidence of chronic rejection Conclusion. We have identified a number of risk factors for chronic rejection in a large group of pediatric liver allograft recipients. We believe that donor-recipient matching for gender or race is not likely to reduce the incidence of chronic rejection. The elucidation of the mechanisms by which living-related liver transplantation affords protection against chronic rejection may provide insight into the immunogenetics of chronic rejection and help prevent further graft loss.

Use of barbiturates in the treatment of cyclic vomiting during childhood

BACKGROUND Cyclic vomiting is an uncommon disorder that can be described as recurrent, self-limiting, fairly uniform episodes of intractable nausea and vomiting with no identifiable organic cause, separated by symptom-free intervals. There is no established therapeutic regimen for this disorder. METHODS Fourteen children referred to the Pediatric Gastroenterology Clinic were diagnosed with cyclic vomiting from May 1984 to January 1995. Vomiting, the predominant symptom, was present in all children and was severe enough to require hospitalization in 11. Associated symptoms included abdominal ain, headache, nausea, aura, and fever. Diagnostic studies were done to rule out organic causes as indicated in individual patients. Daily phenobarbital was prescribed in all 14 patients. The dose ranged from 30 to 120 mg/hs, (mean 2 mg.kg-1.day-1), with a median dose of 60 mg/hs [corrected]. Prior therapy with propranolol (3 patients) and butalbital (2 patients) had been ineffective. RESULTS Eleven patients had complete resolution of their symptoms, and 3 patients had marked improvement in their symptoms with infrequent attacks of reduced severity. The only side effects associated with long-term phenobarbital therapy were behavioral in nature, namely hyperactivity and disruptive behavior at school. CONCLUSIONS The results of our series of 14 patients, all of whom received barbiturates, support the usefulness of this therapeutic approach. Hence we feel that daily low-dose phenobarbital therapy is a safe and effective therapy in preventing episodes of cyclic vomiting in children.