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.
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