ABO-incompatible (ABOi) living-donor kidney transplantation is becoming increasingly common largely as a response to continuing shortage of kidney donors. Since 2006, ABOi transplants comprise 1.5% of all living-donor transplants in the United States (1). In most reports, ABOi recipients have similar patient and graft survival to their ABO-compatible (ABOc) counterparts (1–4). To achieve these results, most ABOi kidney recipients undergo more intense immunomodulatory protocols that include plasmapheresis, intravenous immunoglobulin, anti-CD20 treatment, and/or splenectomy (5, 6).
In general, the cancer risk for organ recipients is increased due largely to immunosuppression (7). This increased risk is particularly pronounced among infection-related cancers and ranges from 1.5-fold increased risk for stomach cancer to 61-fold increased risk for Kaposi sarcoma. Individual steps of ABOi protocols, including splenectomy and other forms of B-cell modulation, are associated with mildly increased cancer risk in other contexts (8–10). It is possible that these protocols might further increase the risk of cancer after transplantation, although this has never been studied.
As ABOi transplantation becomes more common and survival improves, it is necessary to evaluate the risks of long-term complications such as cancer to tailor patient selection, consent, screening, and prevention appropriately. Our objective was to compare cancer risk in equivalent ABOi versus ABOc living-donor kidney transplant recipients using the Transplant Cancer Match (TCM) Study, a linkage between the Scientific Registry of Transplant Recipients (SRTR) and U.S. population-based cancer registries (7). The TCM offers the first opportunity to study high-quality cancer follow-up data in a large, national cohort of ABOi recipients.
Comparing 318 living-donor ABOi kidney recipients with 37,643 ABOc recipients during the study period, age at transplantation, gender, race, percentage of retransplants, and zero human leukocyte antigen (HLA) mismatch status were similar. However, a higher percentage of ABOi recipients were African American (19.3% vs. 14.0%; P=0.02) and had received a retransplant (11.0% vs. 8.0%; P=0.03) (Table 1).
As expected, ABOi transplantation was skewed toward more recent years, with 55.4% of ABOi transplants performed between 2004 and 2008. The total time at risk for ABOi recipients was 990.7 person years (median, 2.00 years). An A donor to 0 recipient was the most common type of ABOi (27.0%) (Table 2).
Among ABOi recipients, there were seven cancers identified with one case each of non-Hodgkin lymphoma (NHL), Merkel cell carcinoma (MCC), gastric adenocarcinoma, hepatocellular carcinoma, papillary thyroid cancer, pancreatic cancer, and testicular germinoma. Four of these cancers were infection related (NHL, MCC, gastric adenocarcinoma, and hepatocellular carcinoma). The time to cancer diagnosis ranged from 0.9 to 9.2 years (median, 3.6 years). ABOi recipients had no demonstrable difference in overall cancer risk compared with ABOc recipients in unadjusted (incidence rate ratio [IRR], 0.83; 95% confidence interval [CI], 0.33–1.71; P=0.3) or matched (IRR, 0.99; 95% CI, 0.38–2.23) analyses (Table 3).
The NHL case diagnosed among the ABOi recipients was a nodal Burkitt lymphoma. The time to diagnosis was 5.9 years. ABOi recipients had no demonstrable difference in NHL risk compared with ABOc recipients in unadjusted (IRR, 0.86; 95% CI, 0.02–4.85; P=0.5) or matched (IRR, 1.02; 95% CI, 0.02–8.38; P=0.5) analyses.
In this first, limited exploration of cancer after ABOi transplantation using a national linkage of transplant registry to cancer registry data, we did not detect an elevated posttransplantation cancer risk associated with ABOi.
Only one ABOi recipient was diagnosed with NHL, typically the most common malignancy after transplantation (except for basal and squamous cell skin cancers). There was not a demonstrable difference between the incidence rate of NHL in ABOi and ABOc recipients. The single case of NHL was diagnosed at 5.9 years, consistent with the late peak of NHL risk after transplantation (11). Although, in general, late NHL is less likely to be Epstein-Barr virus associated and more likely to be extranodal (12), the NHL diagnosed among the ABOi recipients was Burkitt lymphoma and nodal. Burkitt lymphoma risk is increased in association with immunosuppression due to HIV infection or transplantation and possibly related to Epstein-Barr virus infection (13–15). Somewhat surprisingly, there were no diagnoses of early NHL (within 2 years after transplantation) among ABOi recipients. Anti-CD20 antibodies are given as part of incompatible desensitization protocols at certain centers and are also used in the treatment of NHL (16, 17). Anti-CD20 antibodies deplete B cells that may contribute to development of NHL. The peak period of B-cell immunomodulation with anti-CD20 is during the peak of early risk for NHL (18). It is possible that the anti-CD20 antibodies could decrease risk of NHL, particularly during this early period. More targeted research into the associations of this immunomodulation and NHL risk should be performed.
Of interest, MCC, a rare neuroendocrine tumor of the skin associated with immunosuppressed states and thought to be caused by Merkel cell polyomavirus (19), was diagnosed among the ABOi cohort. MCC risk is elevated among transplant recipients (20, 21). Increased risk has also been found in HIV-positive patients (22) and associated with chronic lymphocytic leukemia (23, 24). Prominent immune dysfunctions in chronic lymphocytic leukemia include B-cell dysfunction and hypogammaglobulinemia (25–27). B-cell deficits are also induced in ABOi recipients as part of desensitization protocols and may offer a mechanistic explanation for the development of this rare cancer.
Strengths of our study include the use of a national cohort of living-donor kidney recipients and accurate cancer ascertainment independent of transplant center follow-up and reporting. Using cancer registry linkage allowed for the greatest and most accurate follow-up time possible for each of the ABOi kidney transplant recipients captured; however, because the practice of ABOi transplantation is a relatively recent one, our median follow-up time could only be 2 years. It is possible that differences in cancer risk will become apparent when increasing numbers of ABOi recipients are followed for longer periods of time. Although our cohort is the largest to date used to answer this question, it is nonetheless too small to allow additional interesting analyses such as stratification by blood type, other recipient characteristics, or cancer types. Limitations also include lack of antibody titer in SRTR data, minimal information about desensitization protocols, and likely heterogeneity in practice patterns throughout the country. Another limitation is the lack of information on the incidence of nonmelanoma skin cancer, the most common cancer after transplantation.
Expansion of ABOi kidney transplantation offers hope for increasing available kidney donors and access to transplantation. As outcomes after ABOi transplantation improve, it will be necessary to closely study the possible long-term risks associated with this procedure. Using the largest, albeit not large, national cohort to date, we were unable to demonstrate differences in cancer risk associated with ABOi compared with ABOc kidney transplantation. Further efforts should be made to capture accurate information on additional incompatible transplants and to track the long-term outcomes in this unique cohort of recipients.
MATERIALS AND METHODS
Eligible living kidney recipients were identified in the TCM Study, a linkage of data from SRTR (1987–2008) with 14 population-based cancer registries throughout the United States (http://transplantmatch.cancer.gov/). The SRTR includes data on all U.S. solid organ transplants. Participating cancer registries, which together cover approximately 43% of the U.S. transplant population, ascertained the occurrence of malignancies (other than basal cell and squamous cell skin cancer) based on mandatory reporting from hospitals, medical providers, and pathology laboratories. After linkage with the SRTR, investigators retained only anonymized data from the cancer registries. The study was approved by human subjects committees at the National Cancer Institute and, as required, at participating cancer registries.
Eligible recipients were those that received an ABOi living-donor kidney transplant during a time period with available data on cancer from participating registries. We used the linked cancer registry data to identify first incident cancer cases after transplantation. Cancers were classified and recorded by cancer registries using topography and morphology codes. Follow-up started at transplantation and ended at death, graft failure, retransplantation, loss of follow-up, or end of cancer registry coverage.
Unadjusted IRRs and exact 95% CIs for ABOi versus ABOc living-donor kidney recipients were calculated for all cancers and separately for NHL. In addition, a matched control cohort was created by matching ABOc living kidney recipients 5:1 with ABOi recipients. Matches were drawn from 37,643 possible ABOc controls available in SRTR data. Using iterative expanding radius matching as previously described (28, 29), each control was matched on age at transplantation, gender, race, zero HLA mismatch status, retransplantation, and year of transplantation. Based on an incidence rate of 0.0085 per year in the ABOc cohort, we had 80% power to detect a threefold increase in cancer incidence based on our cohort of 318 ABOi patients.
All analyses were performed using Stata 12.0/MP for Linux (StataCorp, College Station, TX; www.stata.com).
The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (including Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, and Jon Snyder), and the following cancer registries: the states of California (Christina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Marc Goodman), Iowa (Charles Lynch), Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Karen Pawlish, Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson and Ruth Parsons). During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP000817-05), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP000808-05), New York (15-0351), North Carolina (U58DP000832), and Texas (5U58DP000824-04). The following cancer registries were supported by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (N01-PC-35143), New Jersey (HHSN261201000027C N01-PC-54405), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14–2491), Texas, and Washington as well as the Fred Hutchinson Cancer Research Center in Seattle, WA.
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