Risk of Malignancy After Renal Transplantation

Abstract

Wong et al. attempted to answer an interesting and important question in their analysis using the Australian and New Zealand Dialysis and Transplant Registry, looking at all cancers other than nonmelanocytic skin cancer using a competing risk survival analysis model over a median of 4.4 years: Does the duration of end-stage renal disease (ESRD) requiring hemodialysis before transplantation influence the risk of malignancies seen after transplantation (1)? The elevated risk of malignancies in patients with ESRD and subsequent to transplantation is well recognized. It has been suggested that this is related to the uremic milieu, oncogenic viral infections, and/or immunosuppression (2, 3). Although the risk of most malignancies is elevated among renal transplant recipients compared with the general population (1), there does not appear to be an increase for most cancers relative to other patients with ESRD, such as those waitlisted for transplantation (4). The risk of skin cancer (melanoma and nonmelanoma), Kaposi’s sarcoma, lymphoma (Hodgkin’s and non-Hodgkin’s), posttransplantation lymphoproliferative disorder, and cervical cancer appears to be more common after transplantation, whereas the incidence of cancers of the kidney and the urinary tract appears to be more common among patients on dialysis compared with patients after transplantation (4, 5). The results reported by Wong et al. suggest that an extended duration of dialysis before transplantation increases the risk of malignancies, especially those of the urinary tract, after transplantation. Patients with malignancies in their cohort were marginally older, more likely to be white and former smokers, and were recipients of organs from deceased donors. Of note, the only site-specific adjusted hazard ratio that was significant in their analysis was that for malignancies of the renal parenchyma and the urinary tract—a site that has been shown previously to be associated with a higher risk of malignancies among dialysis patients than after transplantation (6). Although an extended period of dialysis may contribute to the overall risk of malignancy, by using the transplantation time as the point of origin for survival analysis, this study fails to acknowledge the risk continuum that patients with ESRD have, most notably for malignancies of the kidney and the urinary tract. The period of increased risk begins at the time of ESRD, or perhaps even earlier during periods with chronic kidney disease, and using the period before transplantation for stratification without including it in the time at risk introduces a potential bias akin to a lead-time bias. Others have also shown a higher incidence of renal cell carcinoma among renal transplant recipients in the same database, but it remains difficult to separate the effects of renal failure from the effects introduced by the treatment choices for this conditions, that is, dialysis or transplantation (6). Given that the risk of most types of malignancies has been shown to be higher after transplantation than in the general population, one might even see longer durations of dialysis as being potentially protective (5, 7). In the analysis from the Danish registry on regular dialysis and transplantation, for example, transplanted patients who were compared with patients who remained on dialysis were found to have significantly higher risk of cancer; the excess cancer risk appeared to occur after transplantation and not during dialysis (7). Contrary to the results reported by Wong et al. (2), this would suggest that, among patients who have the same total time at risk, those with longer time on dialysis would actually be expected to have a lower cumulative risk of malignancy than those transplanted soon after requiring renal replacement therapy. Conceivably then, if time origin at risk in the present study were modified to begin at dialysis initiation, we would see lower rates of malignancy in patients who remain on dialysis for a longer period of time. Then again, if the risk of malignancy were primarily driven by the duration of relative uremia before transplantation, using the onset of ESRD as the starting point for the time-to-event analysis would serve to widen the differences being reported for these patients. How much of the excess burden of malignancy can be attributed to uremia preceding transplantation versus the immunosuppression and oncogenic viral infections associated with transplantation remains an important, but difficult question to answer conclusively.