Wida S. Cherikh

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.

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.

Transplant tumor registry: donor related malignancies.

Background. Transmission of donor malignancies has been intermittently reported since the early days of clinical transplantation. The incidence of United States donor related malignancies has not previously been documented. Methods. All donor related malignancies reported to the Organ Procurement and Transplantation Network/United Network for Organ Sharing from 4/1/94–7/1/01 in a cohort of 34,933 cadaveric donors and 108,062 recipients were investigated by contacting the transplant centers to verify that the reported tumors were of donor origin. Time and mode of discovery, as well as graft and patient outcome, were determined. The status of other recipients from the donor was investigated. Results. A total of 21 donor related malignancies from 14 cadaveric and 3 living donors were reported. Fifteen tumors were donor transmitted and 6 were donor derived. Transmitted tumors are malignancies that existed in the donor at the time of transplantation. Derived tumors are de novo tumors that develop in transplanted donor hematogenous or lymphoid cells after transplantation. The cadaveric donor related tumor rate is 0.04% (14 of 34,993). The donor related tumor rate among transplanted cadaveric organs is 0.017% (18 of 108,062). Among patients developing donor related malignancies, the overall mortality rate was 38%, with that of transmitted tumors being 46% and derived tumors being 33%. The cadaveric donor related tumor mortality rate is 0.007% (8 of 108,062). Conclusions. The United States incidence of donor related tumors is extremely small. The donor related tumor death rate is also extremely small, particularly when compared with waiting-list mortality.

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.

An Optn Analysis of National Registry Data on Treatment of Bk Virus Allograft Nephropathy in the United States

Introduction. Published data for BK virus allograft nephropathy, a recently emerged graft-threatening complication of kidney transplantation, are from limited-center series. Since June 30, 2004, the Organ Procurement Transplant Network national registry in the United States started collecting data on treatment of BK virus (TBKV) on the kidney follow-up forms. This study determined the rates of TBKV within 24 months posttransplant time and elucidated the risk factors for TBKV from this multicenter database. Methods. We queried the database for all primary and solitary kidney transplant recipients transplanted between January 1, 2003 and December 31, 2006, followed through July 18, 2008, and who were reported to have TBKV. Cumulative incidence of TBKV over time was estimated using Kaplan-Meier (K-M) method to reduce potential under reporting. A Cox proportional hazards regression model was fitted to determine risk factors for TBKV development, and time dependent Cox model was fitted to determine if TBKV was associated with higher risk of graft loss. Results. We included 48,292 primary and solitary kidney transplants from the US Organ Procurement Transplant Network database. The cumulative K-M incidence of BKVAN kept rising over time (0.70% at 6 months posttransplant to 2.18% at 1 year, 3.45% at 2 years and 6.6% at 5 years). Risk for BKVAN was higher with certain immunosuppressive regimens that included rabbit antithymocyte globulin or tacrolimus/mycophenolate combinations. Higher center volume and living kidney donation exerted a protective effect. Of concern, TBKV rates were significantly higher in more recent transplant years. TBKV report was associated with higher risk of subsequent graft loss (adjusted hazard ratio=1.69, P<0.001).

Risk factors for renal allograft survival from pediatric cadaver donors : an analysis of united network for organ sharing data

BACKGROUND The shortage of cadaveric donors for kidney transplantation has prompted many centers to use cadaver kidneys from pediatric donors. Use of kidneys from pediatric donors has been shown to have a lower graft survival. METHODS Recipients receiving cadaver kidneys from pediatric and adult donors between 1988 and 1995 were analyzed. The data were obtained from United Network of Organ Sharing database. The actuarial kidney transplant graft survival was estimated by the Kaplan-Meier method. A logistic regression analysis was used to identify various risk factors for 1-year graft failure. Odds ratios (OR) were estimated for various risk factors. RESULTS Kidney transplant survival rates for donor age <18 years (n=12,838) at 1, 2, 3, 4, and 5 years were 81.5%, 76.3%, 71.3%, 66.4%, and 61.7%, respectively. The corresponding results for adult donors from age 18 to 50 years (n=35, 442) were 83.5%, 78.4%, 73.1%, 67.9%, and 62.4%, respectively, Log-rank test P<0.01. Pediatric donors were further divided into three groups according to donor age: group I (0-5 years), group II (6-11 years), and group III (12-17 years). The actuarial survival rates for 1, 3, and 5 years for group I (n=2198) were 73.6%, 63.3%, and 55.6%, respectively. The corresponding values for group II (n=2873) were 78.0%, 67.5%, and 57.8% and for group III (n=7767) were 85%, 75.0%, and 64.8%, respectively, P<0.01. Although the recipients of group I had lower graft survival, en bloc grafts (n=751) had much better 1-, 3-, and 5-year graft survival rates (76.3%, 67.7%, and 60.7%, respectively) compared with single grafts (n=1447; 72.2%, 61.1%, and 53.2%, P=0.02) from donors 0 to 5 years. Graft thrombosis as a cause of graft failure was seen in 10% of group I compared with 6% in group II and 5% in group III. In group I, lower OR were seen when an en bloc transplant was performed (0.688, P<0.01) and when donor body weight was>15 kg (0.547, P<0.01). However, OR were elevated in recipients of previous transplants (1.556, P<0.01), with prolonged cold ischemic time (1.097, P=0.03), for black recipients (1.288, P=0.03), and for recipients with body mass index> or =25 (1.286, P=0.02). Progressive increase in the donor age was associated with lower OR in group II (0.894, P<0.01). CONCLUSIONS (1) Overall, poorer graft survival was seen in pediatric donor transplants, (2) transplant kidney survival with en bloc kidneys was better than a single kidney from donors 0-5 years, (3) progressive increase in donor age was associated with improved graft survival when the donors were 6-11 years, whereas progressive increase in donor weight was associated with improved graft survival when the donors were 0-5 years.

Transplant tumor registry: donors with central nervous system tumors1.

BACKGROUND Despite 13,000 central nervous system (CNS) tumor deaths per year in the United States, CNS tumor donors comprise only 1% of cadaveric donors recovered per year. Concern about tumor transmission may be a possible reason for this very small percentage. Both the size of the candidate waiting list and the number of deaths on the waiting list are progressively increasing because of the donor shortage. METHODS During a 96-month period, the United Network for Organ Sharing recorded 42,340 cadaver donors of whom 397 had a past history of a CNS tumor or the cause of death listed as a CNS tumor. A total of 1,220 organs were transplanted from these 397 donors. All recipients who reported a posttransplant malignancy during a mean follow-up of 36 months were identified. RESULTS There was no difference in patient survival of organs from CNS tumor donors when compared to donors with no CNS tumors. CNS tumor donors were not used more often for either urgent or older recipients. A total of 39 patients reported posttransplant malignancies but none of these tumors were donor-derived. There is a wide variation in the number of CNS tumor donors utilized by individual organ procurement organizations. CONCLUSIONS The risk of tumor transmission from donors with CNS malignancies seems to be small. Certain tumors, such as glioblastoma multiforme and medulloblastoma, carry a high risk of transmission and should be avoided. The risk of tumor transmission should be weighed against the risk of the patient dying on the waiting list without a transplant.

The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time

This year marks the 50th anniversary of the first heart transplant, performed in 1967. Since then, and in particular since the introduction of cyclosporine immunosuppression in the 1970s, heart transplantation has grown worldwide. This 34th adult heart transplant report is based on data submitted to the International Society for Heart and Lung Transplantation (ISHLT) Registry on 135,387 heart transplants in recipients of all ages (including 120,991 adult heart transplants) through June 30, 2016. With each year’s report we now also provide more detailed analyses on a particular focus theme. Since 2013, these have been donor and recipient age, retransplantation, early graft failure, indication for transplant, and in 2017, allograft ischemic time.

Malignant Melanoma in Solid Transplant Recipients Collection of Database Cases and Comparison With Surveillance, Epidemiology, and End Results Data for Outcome Analysis

OBJECTIVE To determine malignant melanoma cause-specific and overall survival among patients with melanoma diagnosed after organ transplantation compared with a national sample with malignant melanoma. DESIGN Retrospective review. SETTING Mayo Clinic sites. PATIENTS Immunosuppressed organ transplant recipients with malignant melanoma identified from surgical and medical databases at Mayo Clinic (1978-2007), the Organ Procurement and Transplantation Network/United Network for Organ Sharing database (1999-2006), and the Israel Penn International Transplant Tumor Registry (1967-2007). MAIN OUTCOME MEASURES Prognostic analyses by Breslow thickness and Clark level of overall and melanoma cause-specific survival. Expected survival rates were estimated by applying the age-, sex-, and calendar year-specific survival rates of patients with malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program to the study cohort. RESULTS Malignant melanoma was diagnosed in 638 patients (724 cases) after transplantation. Breslow thickness was available for 123 patients; Clark level, for 175. Three-year overall survival rates for patients stratified by Breslow thickness (≤ 0.75, 0.76-1.50, 1.51-3.00, and >3.00 mm) were 88.2%, 80.8%, 51.2%, and 55.3%, respectively, and 3-year cause-specific survival rates (95% confidence intervals) were 97.8% (93.7%-100%), 89.4% (76.5%-100%), 73.2% (53.2%-100%), and 73.9% (56.4%-96.6%), respectively. Three-year cause-specific survival rates (95% confidence intervals) for patients stratified by Clark level (I-IV) were 100%, 97.4% (92.4%-100%), 82.8% (65.3%-100%), and 65.8% (51.8%-83.7%), respectively. For patients with Breslow thickness of 1.51 to 3.00 mm and Clark level III or IV, the cause-specific survival rate in the study sample was significantly different from the expected estimates for patients with the same Breslow thickness or Clark level. CONCLUSIONS Compared with the expected survival rates derived from malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program, immunosuppressed organ transplant recipients with thicker melanomas (ie, with a Clark level of III or IV or a Breslow thickness of 1.51 to 3.00 mm) had a significantly poorer malignant melanoma cause-specific survival rate. The overall survival rate was worse among patients with a prior history of transplantation, regardless of Breslow thickness or Clark level.

Retransplantation After Post‐Transplant Lymphoproliferative Disorders: An OPTN/UNOS Database Analysis

Post‐transplant lymphoproliferative disorders (PTLD) are a life‐threatening complication of immunosuppressive therapy. Retransplantation of survivors remains controversial. The Organ Procurement and Transplant Network/United Network for Organ Sharing database was reviewed for individuals who developed PTLD and underwent retransplant from 1987 through 2004. Sixty‐nine retransplants have been performed: 27 kidney, 22 liver, 9 lung, 6 heart, 4 intestine and 1 pancreas. At first transplant, most subjects (63.8%) were <17 years of age and was similar at retransplant with 50.7% less than 17 years. Time from transplant to PTLD was <1 year in 33.3%, 1–3 years in 21.7%, 3–5 years in 21.7%, 5–10 years in 21.7% and >10 years in 1.4%. Time from PTLD to retransplant was <1 year in 24.6%, 1–3 years in 37.7%, 3–5 years in 17.4% and 5–10 years in 20.3%. Induction agents were used in 21.7% of first and 47.8% of retransplants. Immunosuppression for first transplant was cyclosporine (CSA) in 55.1%, tacrolimus (TAC) in 27.5% versus CSA in 26.1%, TAC in 66.7% of retransplants. At last follow‐up, patient and graft survival are 85.5% and 73.9%, respectively. Most subjects retransplanted after PTLD are <17 years on TAC‐based immunosuppression. Patient/graft survival is excellent and retransplantation in PTLD subjects should be considered acceptable.