Douglas W. Hanto

Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de Novo malignancies

Background. Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. Methods. A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for nonskin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. Results. The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24–0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24–0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. Conclusions. Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and nonskin solid malignancy.

Epstein-Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Clinical, pathologic, and virologic findings and implications for therapy.

Nineteen renal allograft recipients developed B-cell lymphoproliferative diseases. Clinically there were two groups: a) young patients (mean age, 23 years) who presented soon (mean, 9 months) after transplantation or antirejection therapy with fever, pharyngitis, and lymphadenopathy resembling infectious mononucleosis, and b) older patients (mean age, 48 years) who presented later (mean, 6 years) after transplantation with localized tumor masses. Histologically, the diseases were classified as polymorphic diffuse B-cell hyperplasia (PDBH) or polymorphic B-cell lymphoma (PBL). Immunologic cell typing revealed either polyclonal or monoclonal B-cell proliferations. Malignant transformation of polyclonal proliferations in two patients was suggested by the finding of clonal cytogenetic abnormalities. Epstein-Barr virus (EBV) specific serology, staining of biopsy specimens for the Epstein-Barr nuclear antigen, and EBV DNA molecular hybridization studies implicated EBV as the cause of both PDBH and PBL. Acyclovir, an antiviral agent that blocks EBV replication in vitro, inhibited oropharyngeal shedding of EBV and caused complete remission in four patients with polyclonal B-cell proliferations. The monoclonal tumors were acyclovir resistant. We suggest that surgical treatment, radiotherapy, or chemotherapy may be more appropriate therapy in selected patients with acyclovir resistant tumors. Therapeutic decisions require not only documentation of the viral etiology of these tumors, but also immunologic and cytogenetic analysis to determine the stage of tumor evolution in individual patients.

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.

Aims/hypothesisPostprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved.MethodsGlucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients.ResultsAll three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass.Conclusions/interpretationThese findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.

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.).

Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation

Background. The use of antilymphocyte antibodies for induction therapy or for treatment for rejection has been associated with an increased risk of posttransplant lymphoproliferative disorder (PTLD). The authors investigated the incidence of PTLD after monoclonal antilymphocyte, polyclonal antilymphocyte, interleukin (IL)-2 receptor antibody, or no induction therapy in primary kidney transplant recipients. Methods. A multivariate Cox analysis of 38,519 primary kidney transplants from January 1, 1997, to December 31, 2000, was performed to compare the incidence of PTLD, graft survival, and patient survival among the induction groups. Results. The actual incidence of PTLD was 0.85% in 2,713 recipients with monoclonal, 0.81% in 4,343 with polyclonal, 0.50% in 7,800 with IL-2, and 0.51% in 23,663 recipients with no induction therapy (P =0.02). The Cox model indicated that as compared with no induction, the increased risk of PTLD was 72% with monoclonal (P =0.03), 29% with polyclonal (P =0.27), and 14% with IL-2 induction (P =0.52). IL-2 receptor antibody was associated with a 17% reduced risk of graft loss (P =0.002) and a 21% reduced risk of mortality (P =0.005) compared with no induction. Monoclonal and polyclonal induction therapies were not associated with a reduced risk of graft loss or mortality. Mycophenolate mofetil discharge maintenance immunosuppression was associated with a significantly reduced risk of PTLD and graft loss compared with azathioprine. Conclusions. Among induction therapies, IL-2 receptor antibody induction was associated with the smallest risk of PTLD and improved graft and patient survival. Monoclonal or polyclonal induction was not associated with improved graft or patient survival, and monoclonal induction was associated with an increased risk of PTLD.

ASTS recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation

The American Society of Transplant Surgeons (ASTS) champions efforts to increase organ donation. Controlled donation after cardiac death (DCD) offers the family and the patient with a hopeless prognosis the option to donate when brain death criteria will not be met. Although DCD is increasing, this endeavor is still in the midst of development. DCD protocols, recovery techniques and organ acceptance criteria vary among organ procurement organizations and transplant centers. Growing enthusiasm for DCD has been tempered by the decreased yield of transplantable organs and less favorable posttransplant outcomes compared with donation after brain death. Logistics and ethics relevant to DCD engender discussion and debate among lay and medical communities. Regulatory oversight of the mandate to increase DCD and a recent lawsuit involving professional behavior during an attempted DCD have fueled scrutiny of this activity. Within this setting, the ASTS Council sought best‐practice guidelines for controlled DCD organ donation and transplantation. The proposed guidelines are evidence based when possible. They cover many aspects of DCD kidney, liver and pancreas transplantation, including donor characteristics, consent, withdrawal of ventilatory support, operative technique, ischemia times, machine perfusion, recipient considerations and biliary issues. DCD organ transplantation involves unique challenges that these recommendations seek to address.

The Medical Evaluation of Living Kidney Donors: A Survey of US Transplant Centers

The use of living donors for kidney transplantation in the United States is common, and long‐term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long‐term outcomes in various types of donors with potential morbidities related to donation.

Post‐transplant de novo malignancies in renal transplant recipients: the past and present

Post‐transplant de novo malignancies are reviewed in three time periods: (i) the azathioprine (AZA) era from 1962 to 1980–1981, (ii) the cyclosporine (CYA) era (1980 to present) in which the calcineurin inhibitors, CYA and tacrolimus (TAC), were the mainstay of recipient immunosuppression, and (iii) the TOR inhibitor era starting in the year 2000. Both transplant registry and transplant center reports on malignancies occurring in the AZA era are reviewed. Reports from transplant centers and from the Cincinnati Transplant Tumor Registry (CTTR) in both the early CYA era (1980s) and the 1900–2000 CYA era are reported. Cancer incidence associated with AZA versus CYA, CYA versus TAC, and AZA versus mycophenolate mofetil (MMF) is compared in both transplant center and registry reports including new, unreported Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 1998 to 2003. The malignancy incidence associated with lymphocyte‐depleting antibody and corticosteroid immunosuppression is discussed. Reduced malignancy incidence recently reported with TOR inhibitors is compared with that of conventional immunosuppression. Important nondrug factors influencing the incidence of post‐transplant malignancies from seven single and three registry reports are detailed. The substantial role that de novo malignancies play in post‐transplant mortality is discussed. Finally, management recommendations for recipients who develop de novo post‐transplant malignancies are briefly presented.

Evaluating living kidney donors: relationship types, psychosocial criteria, and consent processes at US transplant programs.

We conducted a survey of 132 US kidney transplant programs to examine how they evaluate and select potential living kidney donors, focusing on donor‐recipient relationships, psychosocial criteria, and consent processes. There is heterogeneity in donor‐recipient relationships that are considered acceptable, although most programs (70%) will not consider publicly solicited donors. Most programs (75%) require a psychosocial evaluation for all potential living donors. Most programs agree that knowledge of financial reward (90%), active substance abuse (86%), and active mental health problems (76%) are absolute contraindications to donation. However, there is greater variability in how other psychosocial issues are considered in the selection process. Consent processes are highly variable across programs: donor and recipient consent for the donor evaluation is presumed in 57% and 76% of programs, respectively. The use of 13 different informed consent elements varied from 65% (alternative donation procedures) to 86% (description of evaluation, surgery and recuperative period) of programs. Forty‐three percent use a ‘cooling off’ period. Findings demonstrate high variability in current practice regarding acceptable donor‐recipient relationships, psychosocial criteria, and consent processes. Whether greater consensus should be reached on these donor evaluation practices, especially in the context of more expansive use of living donor kidney transplantation, is discussed.

Confirmation of the heterogeneity of posttransplant Epstein-Barr virus-associated B cell proliferations by immunoglobulin gene rearrangement analyses.

Immunoglobulin gene rearrangement analysis is a sensitive method for determining clonality of B cell proliferations. We have examined tissue obtained from five renal and one cardiac allograft recipient with Epstein-Barr virus-associated B cell proliferations for immunoglobulin gene rearrangements. Biopsies from two patients with lesions that were hyperplastic morphologically, polyclonal by cellular immunoglobulin staining, and had diploid karyotypes, had no detectable gene rearrangements and were, therefore, consistent with benign reactive processes. These patients are alive without evidence of disease 37 and 57 months after diagnosis. In a biopsy from one patient with a lesion that was malignant lymphoma morphologically, monoclonal by cellular immunoglobulin staining, and had clonal cytogenetic abnormalities, clonal gene rearrangements were detected in a majority of cells, confirming their neoplastic nature. In biopsies from an intermediate group of three patients with morphologically malignant proliferations that were composed predominantly of a polyclonal population of B cells, clonal gene rearrangements were also found, consistent with early malignant transformation in a subpopulation of cells. These findings confirm the heterogeneity of the posttransplant EBV-associated lymphoproliferative diseases and have significant implications for our understanding of the pathogenesis of EBV-induced infections and related lymphomas.