Cancer incidence in kidney transplant recipients: a study protocol

Cardiovascular illnesses and neoplasms are the two main causes of death with normal function of the graft in the long-term follow-up of patients who have received kidney transplants [1, 2]. The Australian-New Zealand register even suggests that the second factor could be growing at a faster rate than the first [3]. The presence of neoplasms is a major threat and cause of morbidity in kidney transplant patients.

According to data published in other countries, the accumulated incidence of neoplasms can reach 20% 10 years from the transplant [4] and nearly 30% after 20 years [5, 6]. The rate of expected cancers compared to those which are observed varies in the different registers. On average, it is estimated that the incidence of cancer in patients who have received kidney transplants is 3 times higher than that for the general population. By localizations, this ratio can reach an incidence rate of between 8 and 14 times more for kidney cancer in transplant patients, and an incidence of between 65 and 92 times more of non-melanoma skin tumours [4, 5, 7‐11]. In the largest study on the incidence rates of malignancies among first-time recipients of deceased or living donor kidney transplantation (n = 35765) the rates for most malignancies are higher after kidney transplantation compared with the general population [7]. Similar results were observed in studies from five national tumour registries in Denmark [11], Finland [12], Sweden [13], Australia [14], and Canada [15] with a total sample size of 31,977 transplant recipients.

Several factors may influence in the pathogenesis of tumours after transplantation: chronic uraemic status, cumulative exposure to immunosupression, and certain drugs which can be carcinogenic through independent mechanisms or as a result of immunosupression and viral infections. Some authors suggest that immune deficiency, rather than other risk factors for cancer, is responsible for the increased risk [16].

The use of immunosuppressive agents to prevent allograft rejection increases the long-term risk of malignancy compared with that of the general population. In this case, cyclosporine and tacrolimus have been identified as oncogenes in themselves, through a mechanism which involves TGF-β [17, 18]. However, the data published to date do not make it possible to obtain conclusive results.

Despite the increased risk, little is known about the overall cancer prognosis, screening, treatment strategies, and effectiveness in this population [19], and strategies to understand and minimize the risk of developing malignancy in the transplant population are needed [20]. Some authors describe this uncertainty as an "unmet medical need" [21].

Most of the information regarding the incidence of post-transplant tumours comes from multi-centre registries, in which the data gathering process may be incomplete, and which may lead to an underestimation of the true incidence of malignant cancers. Also, it is difficult to estimate the incidence of the majority of tumours and their associated factors based on studies carried out in a single hospital, which normally involve a small number of patients.

Knowledge of the true incidence of cancer in patients who have undergone kidney transplants in our surroundings could alert us to the need to establish tumour screening policies which permit early intervention, as has been established in the European Guidelines for kidney transplant follow-up [22‐24]. Promoting healthy lifestyles and carrying out regular tests on patients that permit the early diagnosis of tumour complications could contribute towards palliating the morbidity-mortality of these patients.

The aim of this study is to establish the incidence of cancer in recipients of renal transplants performed in a hospital in A Coruña (Spain) during the period 1981–2007 compared to that experienced by the general population. This centre, the University Hospital Complex of A Coruña, has the same level of activity as the national average, at around 50 interventions per million population per year.

An observational prospective follow-up study with a retrospective component, carried out in the health district of A Coruña (northwest Spain) during the period 1981–2007. During that period 1967 kidney transplants were performed in the University Hospital Complex of A Coruña, which corresponded to 1710 patients. Patients with pre-transplant neoplasms will be excluded from the analysis (n = 38). A follow-up study was designed in order to estimate cancer incidence after kidney transplantation. This sample size would make it possible to detect relative risks of ≥1.2 estimating an exposed proportion of 35% and a proportion of censured observations of 40%, with a security of 95% and a statistical power of 80%.

Patients who had received transplants were identified through the hospital's transplant registry. For each patient, information includes donor and recipient characteristics, patient and graft survival and cancer incidence after transplantation. The variables are summarized in the Appendix.

The study was approved by the region's Ethics Committee for Clinical Research (CEIC Galicia) and written informed consent was obtained from all of patients who have participated in the study.

This study will provide us with information on the risk of developing cancer in kidney transplant patients, and will allow us to increase the level of vigilance over the incidence of cancers in this population, especially for tumours for which there are no population-based screening programmes.

The interval between transplantation and diagnosis of cancer is time dependent, so the follow-up period will let us know if the incidence is modified with length of follow-up. Even though there is variability dependent on the type of tumour and age of the patient, it has been described that the average latency period is approximately three to five years after transplantation [31‐34].

Furthermore, this study will provide us with information on the variables associated with the presence of cancer in kidney transplant patients, and allow us to adapt the European Guidelines on post-kidney transplant follow-up on tumour screening to our environment[35].

Although the information will be taken from hospital records, which could lead to a bias in the information, the characteristics of these patients mean that they are subjected to more exhaustive follow-up than normal, not only during the immediate post-transplant period, but also during the years after the transplant. During the first year after the transplant they are seen at least every 3 months, every 6 months from one year after the transplant, and after 10 years are seen at least once a year. This fact would minimize any possible bias in the information. The use of data from a single centre could also hinder the calculation of the incidence of less frequent tumours. It is also true that as indicated in a number of publications, neither is the incidence of cancer in populational registries of transplant patients free from errors, as the reporting of cancer to the registry is often incomplete, and this could lead to an underestimation of the incidence [7].

Spain has the highest cadaver donor rate in the world, and is the leading country at international level in terms of performance in renal transplantations per million population (pmp) [36]. The hospital in which we are going to carry out this study, the University Hospital Complex of A Coruña, is located in the Autonomous Region of Galicia, which has the same level of activity as the national average, at around 50 interventions per million population per year [37].

Little is known about the advantages and disadvantages of cancer screening, treatment effectiveness, and overall cancer prognosis in renal transplant recipients [38].

This study will allow us to know the scale of the problem in kidney transplant patients, and to evaluate the impact of intervention measures for the prevention of cancer in these patients in the future.