J. Michael Millis

Outcomes of Kidney Transplantation in HIV-Infected Recipients

BACKGROUND The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood. METHODS We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy. RESULTS Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications. CONCLUSIONS In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression.

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

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.

Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection

Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)–infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV‐coinfected patients and 2 control groups: 235 HCV‐monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3‐year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%‐71%] and 53% (95% CI = 40%‐64%) for the HCV/HIV patients and 79% (95% CI = 72%‐84%) and 74% (95% CI = 66%‐79%) for the HCV‐infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney‐liver transplantation (HR = 3.8), an anti‐HCV–positive donor (HR = 2.5), and a body mass index < 21 kg/m2 (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3‐year incidence of treated acute rejection was 1.6‐fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV‐coinfected LT patients versus HCV‐monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV‐coinfected recipients versus HCV‐infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes. Liver Transpl 18:716–726, 2012.

Summary Report of a National Conference: Evolving Concepts in Liver Allocation in the MELD and PELD Era

A national conference was held to review and assess data gathered since implementation of MELD and PELD and determine future directions. The objectives of the conference were to review the current system of liver allocation with a critical analysis of its strengths and weaknesses. Conference participants used an evidence‐based approach to consider whether predicted outcome after transplantation should influence allocation, to discuss the concept of minimal listing score, to revisit current and potential expansion of exception criteria, and to determine whether specific scores should be used for automatic removal of patients on the waiting list. After review of data from the first 18 months since implementation, association and society leaders, and surgeons and hepatologists with wide regional representation were invited to participate in small group discussions focusing on each of the main objectives. At the completion of the meeting, there was agreement that MELD has had a successful initial implementation, meeting the goal of providing a system of allocation that emphasizes the urgency of the candidate while diminishing the reliance on waiting time, and that it has proven to be a powerful tool for auditing the liver allocation system. It was also agreed that the data regarding the accuracy of PELD as a predictor of pretransplant mortality were less conclusive and that PELD should be considered in isolation. Recommendations for the transplant community, based on the analysis of the MELD data, were discussed and are presented in the summary document. (Liver Transpl 2004;10:A6–A22.)

Portal vein thrombosis and stenosis in pediatric liver transplantation.

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P<0.0005 vs. reduced graft and < 0.03 vs. other LDLT groups). The incidence of late portal vein stenosis or thrombosis was significantly higher in the LDLT Group 2, (51%) than any of the other groups (LDLT 1, 16%; LDLT Group 3, 9%; RLT 4%;P<0.005 vs. cadaveric and < 0.02 vs. LDLT Group 1 and LDLT Group 3). Five year arterial graft and patient survival for patients who have experienced portal vein thrombosis or stenosis is 61% and 67%, respectively, versus 67% and 71% for those patients who have not experienced portal vein pathology, P=ns. Based on this experience, we recommend avoiding the use of cryopreserved iliac vein for portal vein reconstruction in liver transplantation. Every effort should be taken to eliminate the need for venous conduits in liver transplantation. If venous conduits must be utilized, cryopreserved femoral veins seem to provide superior patency rates. Careful clinical and ultrasonopraphic monitoring of patients at high risk for late venous thrombosis permits therapy with excellent graft and patient survival.

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.

Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: Three-year results

Background. Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell–depleting and interleukin-2 receptor antibodies. Methods. A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years. Results. At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell–depleting antibody induction (36.1%) when compared with those receiving anti–interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001). Conclusions. Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell–depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.

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.