In the Literature: Cancer Incidence Before and After Kidney Transplantation

What Did This Important Study Show? 

To differentiate between the risk of cancer associated with kidney disease per se, treatment with dialysis, and the effects of immunosuppression, Vajdic et al conducted a cohort study following 28,855 patients over two decades (1982-2003).5 Cancer incidence after transplantation was compared with incidence during dialysis and during a 5-year period before initiation of renal replacement therapy (RRT) in the same patient population. Record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House was performed to compare these rates to those in the general Australian population based on standardized incidence ratios (SIRs) using cancer rates specific to age, gender, and calendar year. Even after excluding nonmelanoma skin cancer and cancers known to frequently cause kidney disease (ie, multiple myeloma and urinary tract cancers), Vajdic et al found a significant increase in the overall incidence of cancer after transplantation. The SIR for malignancy was 3.27 (95% confidence interval [CI], 3.09 to 3.46) after transplant, as compared to 1.35 (95% CI, 1.27 to 1.45) during dialysis and 1.16 (95% CI, 1.08 to 1.25) before renal replacement therapy.

Comparison to the general population revealed an increased risk of cancer at 25 body sites after kidney transplantation (Fig 1). At 18 of these sites, the risk was increased more than 3-fold. The majority of these 18 sites represented cancers of known or suspected viral etiology. For example, human papillomavirus has been associated with cancers of the tongue, mouth, vulva, vagina, and penis, and may be an etiologic agent in some cancers of the eye, lip, salivary gland, and esophagus; Epstein-Barr virus has been causally linked to non-Hodgkin lymphoma; hepatitis B and C are linked to liver cancer; human herpesvirus 8 is a cause of Kaposi sarcoma. The authors concluded that kidney transplantation is associated with a marked increase in cancer risk at a wide variety of sites, and that immunosuppression may be responsible for the increased risk by increasing susceptibility to causative viral infections.

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Figure 1. Standardized incidence ratios and 95% confidence intervals for various cancers in Australian patients with end-stage kidney disease. Reprinted with permission from page 2827 of reference 5, © 2006 American Medical Association.

How Does This Study Compare With Prior Studies? 

Compared to the earlier studies cited above, this analysis of cancer risk in kidney transplant recipients is superior in terms of the large number of patients included, the long duration of follow-up, and the unique effort to determine whether chronic kidney disease itself poses a risk of neoplasia. The authors speculate that the modest increase in the risk of cancer prior to RRT and during dialysis might reflect the immunosuppressive effects of uremia or the influence of immunosuppressive therapy sometimes used to treat kidney disease. The study’s main conclusion, that transplantation and immunosuppression dramatically increase the risk of cancer at multiple body sites, largely confirms the results of 2 recent registry analyses from the United States6 and Canada.7 Kasiske et al linked data from the United States Renal Data System to Medicare billing claims to determine rates of malignancy among 35,765 first-time recipients of kidney transplants performed between 1995 and 2001, and compared them to site-specific rates observed in the general population.6 Similar to the Australian experience, but with a follow-up of only 3 years, the authors found a 2-fold increase in the incidence of colon, lung, prostate, stomach, esophagus, pancreas, ovary, and breast cancer. Melanoma, leukemia, hepatobiliary cancer, and cervical/vulvovaginal cancer were 5-fold more common. Kidney cancer was increased 15-fold, while Kaposi sarcoma, non-Hodgkin lymphoma, and nonmelanoma skin cancers were increased more than 20-fold compared to the general population.6 Subsequent to the report from Vajdic et al, a Canadian study linking data from the Canadian Organ Replacement Registry and the Canadian Cancer Registry reported cancer rates in 11,155 patients who underwent kidney transplantation between 1981 and 1998, and reached similar conclusions.7 Non-melanoma skin cancers were not included in the analysis. Site-specific SIRs were highest for cancer of the lip, non-Hodgkin lymphoma, and kidney cancer.7

Among these 3 recent large registry analyses, only the study of Kasiske et al made an effort to assess the effects of specific immunosuppressive regimens on the risk of cancer and found no correlations between the use of induction antibodies or initial maintenance immunosuppressive regimens and subsequent risk of cancer. However, the authors did not attempt to link specific agents to site-specific tumors. Other studies suggest that induction antibody therapy increases the risk of non-Hodgkin lymphoma.8, 9, 10 Reliance on initial maintenance immunosuppression in such retrospective registry analyses is flawed, as recent studies indicate that a majority of kidney transplant recipients are converted from one regimen to another within the first 4 years after transplantation.11 Only 6% of patients in the US study were treated initially with sirolimus.6 Based on the timing of the analyses, it is likely that few, if any, of the patients in the Australian or Canadian studies were treated with TOR (target of rapamycin) inhibitors. This is relevant because recent studies in animals12, 13, 14 indicate that the TOR inhibitors have anti-neoplastic properties including inhibition of cell-to-cell adhesions required for metastatic growth and inhibition of tumor angiogenesis mediated by VEGF (vascular endothelial growth factor).12, 13, 14 Furthermore, preliminary studies in humans indicate that patients receiving TOR-inhibitor-based immunosuppression exhibit lower rates of malignancy than patients receiving other regimens.15, 16

What Should Clinicians and Researchers Do? 

Studies in the general population have led to the development of guidelines for screening and prevention of common cancers. The studies of Vajdic et al5 and Kasiske et al6 suggest that the incidence of such “screenable” malignancies is 2-fold to 3-fold higher in kidney transplant recipients than in the general population. However, the wisdom of applying screening guidelines to kidney transplant recipients depends on the life expectancy of the individual patient.17 Further research is needed to ascertain the costs and benefits of screening for specific tumors in specific subsets of kidney transplant recipients. On the other hand, the findings of the recent registry analyses underscore the need for increased vigilance among kidney transplant recipients to detect cancers at sites for which there are no population-based screening programs in place (eg, skin cancer, lymphoma, kidney cancer, and Kaposi sarcoma). Considering the preeminence of cancers related to viral infections in the posttransplant setting, additional research also is needed to study the benefits of antiviral therapies, including vaccinations, in preventing cancer after kidney transplantation. The potential anti-neoplastic benefits of the TOR inhibitors require further attention in prospective studies. In the long run, there is a need for developing new immunosuppressants that do not increase the risk of cancer. In the meantime, a number of strategies to minimize long-term immunosuppression are being tested in randomized trials and it will be of great interest to determine if such regimens effectively reduce the currently disturbing incidence of malignancy in kidney transplant recipients.