Burdening a frail patient
James Fleck, MD, PhD: Anticancerweb 7 (01), 2022
Cancer and cardiovascular disease are the leading causes of death in transplant recipients. Physicians are well advised about the increased risk of cardiovascular disease and already have a structured patient information program on preventive interventions. Although there are well-designed guidelines for preventing cancer in the general population, they do not necessarily apply to kidney transplant recipients, whose risk is increased due to immunosuppression. When kidney failure occurs, kidney transplantation is the most cost-effective intervention, improving the quality of life and overall survival of patients when compared to those kept on dialysis. However, kidney transplant recipients must remain immunosuppressed for life in order to maintain allograft function. Unfortunately, immunosuppression is one of the main mechanisms related to oncogenesis. Retrospective studies have shown an increased risk of kidney and urothelial cancer in chronic kidney disease (CKD), especially with eGFR<30. Patients with severe CKD have a more than 2-fold increase rate of kidney cancer, especially with clear cell morphology. CKD is also associated with a 48% increase in the adjusted rate of urothelial cancer. Duration of dialysis before transplantation is also associated to an increased cancer risk. Highly sensitized kidney transplant recipients should also be identified and closely monitored, as high levels of panel reactive antibodies (PRA), greater than 80%, represent an increased risk of rejection, graft failure, cancer and death, regardless of dialysis time. Dampening the immune system may create a favorable microenvironment for viral replication and eventually new oncogenic downstream pathways, leading to Kaposi’s sarcoma (HHV8), lymphoproliferative diseases (EBV), hepatocellular carcinoma (HBV), lip and anal cancer (HPV). Another mechanism is through accumulation of radiation-induced mutations favoring skin cancer. Most of the currently used immunosuppression is carcinogenic, except for the mTOR inhibitors, which may have potential antitumor effects through cell-cycle arrest and inhibition of apoptosis. There is evidence based on clinical trials supporting the conversion of immunosuppression to an mTOR inhibitor (everolimus) in transplant recipients with squamous cell carcinoma. This practice has also been used in patients who develop Kaposi's sarcoma and melanoma. Judicious reduction in the total immunosuppression load is the most used recommendation for patients with early and moderate-stage tumors. Although the treatment of renal carcinoma, non-small cell lung cancer, and melanoma with immunological checkpoint inhibitors (anti-PD1, anti-PDL1, anti-CTLA4) has shown excellent outcomes in general population, these results cannot be extrapolated to emerging cancer in organ transplant recipients.
Some patients with CKD maintained only on dialysis may have a worse prognosis, with a lower survival expectancy, which does not justify a cancer screening program. However, for kidney transplant recipients with a better prognosis, cancer screening should at least be conducted with shared decision-making. The evidence level is still low, since it is not based on prospective randomized trials. However, long-term survival observed after renal transplantation encourages some personalized guidelines on cancer screening. Historically, American and European transplantation societies have suggested some general recommendations, summarized in the table below. Cost-effectiveness is also provided for some specific tumors.
References:
1. David Al-Adra, Talal Al-Qaoud, Kevin Fowler and Germaine Wong: De Novo Malignancies after Kidney Transplantation, Clinical Journal of the American Society of Nephrology, March 29th, 2021
2. Wong, G; Chapman, J; Craig, J: Cancer Screening in Renal Transplant Recipients: What Is the Evidence? Clinical Journal of the American Society of Nephrology 3(2): S87-S100, 2008
3. Lim, Wai H; Chapman, Jeremy R; Wong, Germaine: Peak Panel Reactive Antibody, Cancer, Graft, and Patient Outcomes in Kidney Transplant Recipients, Transplantation 99(5): 1043 – 1050, 2015
4. William T. Lowrance, Juan Ordoñez, Natalia Udaltsova, Paul Russo and Alan S. Go: CKD and the Risk of Incident Cancer. Journal of the American Society of Nephrology 25 (10): 2327 – 2334, 2014
5. Photo by Robina Weermeijer on Unsplash (modified)
6. Photo by National Cancer Institute on Unsplash (modified)
e-GFR = Estimated Glomerular Filtration Rate, HHV8 = Human Herpes Virus 8, EBV = Epstein- Barr Virus, HBV = Chronic Hepatitis B Virus, HPV = Human Papilloma Virus, mTOR = Mammalian Target of Rapamycin
In patients of a solid organ transplant, the chronic use of immunosuppressive agents to prevent allograft rejection, especially calcineurin inhibitors (CNIs), increases the long-term risk of malignancy compared with that of the general population. Because of the risk factors that may lead to malignancy some preventive measures can be taken in order to avoid this outcome. In this way, a careful screening of the donor and the patient can be used before transplantation, in addition to protective measures from sun exposure or other forms of radiation, vaccination against HPV in patients with age indication and mainly avoid excess immunosuppression. Thus, immunosuppression should be used strategically to obtain target values and avoid toxicity.
The weighting of risks and benefits is, perhaps, the core of clinical medicine and this practice becomes progressively refined as the repertoire of medical science grows. It is, then, indispensable that, for exemple, the protocols for cancer screening keep up with this growth in the best interest of patients. Once imunnosupression is imperative for transplant recipients, it is also imperative that its implications in cancer risks are taken in consideration. Fortunatly, as reported in this article, different medical societies are already starting to recommend specific screening protocols for specific kinds of transplant recipients.
it´s really interesting that the article brings up the fact thet kidney transplant recipients are, indeed, more likely to develop cancer, needing a more careful follow up and sometimes screening. This strongly suggests, therefore, that physicians should be as concerned by that as they are regarding the cardiovascular risks that are higher in this population too.
We learn in our classes the importance of patient autonomy and a shared decision between doctor and patient. We cannot expect, however, that this decision will be taken without adequate information on all the processes involved. The Anticancer Tutorial is an innovative tool because it provides, in an accessible and didactic way, the necessary information for the active participation of the patient in his healing process.
Transplanted patients are provided with individualized care that must be maintained throughout their lives. Thus, associating this with the increased risk of developing cancer should be a factor to be widely discussed, given the whole scenario already evidenced. Patients should primarily be informed about possible complications, so that the decision is consistent with their judgment.
Patients with renal failure benefit from kidney transplantation, and have a better quality of life and survival compared to patients who need dialysis, however they must remain immunosuppressed until the end of life to maintain the function of the new kidney and this predisposes to neoplasms. Studies have shown an increase in cancer in patients with chronic kidney disease and also in kidney dialysis patients, so kidney transplant recipients should be monitored to avoid rejection, graft failure, cancer and death. The cause of oncogenesis is given by the suppression of the immune system, which can allow viral reapplication, new oncogenic pathways downstream, leading to Kaposi's Sarcoma, lymphoproliferative diseases, hepatocellular carcinoma, and lip and anal cancer. For this reason, we must research drugs that allow immunosuppression but that are not oncogenic.
Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries and represents a rapidly growing public health problem. The increased risk of cancer in transplant recipients is multifactorial and attributed to oncogenic viruses, immunosuppression and altered T-cell immunity. In view of the presented scenario, it is relevant to adapt, in a personalized way, the process of evaluation of the transplanted patient, from effective strategies for cancer screening after kidney transplantation and treatment, considering the individual's risk of cancer, the comorbidities, general prognosis and patient preferences. It is essential that the patient has knowledge and education about cancer risk in the context of transplantation.
Imunosupression is a hallmark of transplanted patients, given that a weakened immune system provides less protection against the growth of tumors. Hence, the medical establishment has been faced with a decisive conundrum: how to decide when the benefits outweight the risks, that is, how to assess the viability of a transplantation in every specific instance, taking into consideration the higher propensity for oncogenesis allied with other factors, such as comorbidities and the affected individual's personal values and wishes.
Although imunosupression is a crucial intervention to the success of the kidney transplant, it has a huge oncogenic potencial. Therefore, physisians must be aware of the risk transplanted patients are exposed to and should engage in different cancer tracking strategies. Combined with good medical practice, it is possible to enable CKD patients to appreciate the best medical treatment with less harm.
Immunosuppression is an indispensable intervention with regard to kidney transplants, as it reduces the chances of graft rejection. Nevertheless, using immunosuppressants can lead to severe outcomes, cancer being an example, as it reduces the capacity of the body to respond properly to procarcinogenic metabolism. Because of this panorama, the medical follow-up and the monitorization of these patients must be emphatic and a priority, especially considering the prevalent types of cancer in this population. Therefore, more studies are needed to properly track the disease in these patients and build adequate guidelines for this purpose.
Unfortunately, the imunossupression that comes with kidney transplantation increases the risk of cancer development. That said, kidney transplant patients should be informed about this fact, health professionals should be aware and screening tests should be made when considered appropriate.
It's amazing how much kidney transplantation has led to increased survival of patients with CKD, but the challenges don't stop, considering the increased risk of cancer due to immunosuppression. Although renal cancer screening is not cost-effective for everyone, it can be an extremely beneficial decision for the health of certain patients with major risk factors.
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