Is End-Stage Renal Disease Tumor Suppressive? Dispelling the Myths

Abstract

The prevalence of end-stage renal disease is increasing worldwide. Malignancies accompanying end-stage renal disease are detected in approximately 120 individuals per 10,000 person-years. Most studies have suggested that end-stage renal disease causes carcinogenesis and promotes tumor development; however, this theory remains questionable. Contrary to the theory that end-stage renal disease is predominantly carcinogenic, recent findings have suggested that after controlling for biases and sampling errors, the overall cancer risk in patients with end-stage renal disease might be lower than that in the general population, except for renal and urothelial cancer risks. Additionally, mortality rates associated with most cancers are lower in patients with end-stage renal disease than in the general population. Several biological mechanisms have been proposed to explain the anticancer effects of end-stage renal disease, including premature aging and senescence, enhanced cancer immunity, uremic tumoricidal effects, hormonal and metabolic changes, and dialysis therapy-related factors. Despite common beliefs that end-stage renal disease exacerbates cancer risk, emerging evidence suggests potential tumor-suppressive effects. This review highlights the potential anticancer effects of end-stage renal disease, proposing reconsideration of the hypothesis that end-stage renal disease promotes cancer development and progression.

Keywords: cancer immunity; carcinogenesis; dialysis; end-stage renal disease; tumor suppression; uremic immunosuppression.

Figure 1

Trends in mortality in the general population and patients with end-stage renal disease in Japan. (a) Line graph depicting the rate of deaths per 100,000 people from various causes in the Japanese population between 1986 and 2016. Data are extracted from the Statistical Handbook of Japan 2017 [37]. Reproduced with permission from the Statistics Bureau, Ministry of Internal Affairs and Communications; published by Statistics Japan, 2017. (b) Line graph depicting the percentage of deaths in patients on dialysis from various causes in Japan between 1983 and 2016. Data are extracted from the publication of Masakane et al. [38]. Reproduced with permission from Renal Replacement Therapy; published by Springer Nature, 2018.

Figure 2

Mechanisms of the tumor-suppressive effects of ESRD. ESRD inhibits cancer initiation and progression at multiple stages. ESRD inhibits carcinogenesis in early cancerous lesions via tumoricidal effects, growth inhibition, and senescence. Moreover, it eliminates circulating cancer cells via cytotoxicity and/or activated cancer immunosurveillance and enhances aging and fibrosis in most organs, preventing cancer cells from metastasizing to distant organs. Overall, ESRD can affect all stages of tumor development. ESRD, end-stage renal disease.

Figure 3

Clinical course of cancer in patients with ESRD. Cancer develops at a relatively high frequency among the healthy population and grows rapidly. These patients ultimately die from cancer with a maximum tumor burden. A certain number of patients with cancer will have ESRD independent of the cancer. In these cases, the growth of cancer cells slows down following ESRD development owing to various mechanisms described in Figure 2. In the presence of ESRD, cancer develops less frequently because carcinogenesis is inhibited at almost all potential sites of cancer development. Nevertheless, once cancer develops in the ESRD milieu, the growth of cancer cells is usually slow, and metastasis to other organs rarely occurs. Although patients with ESRD develop concomitant cancer, most of them die from ESRD-related comorbidities and not from cancer. ESRD, end-stage renal disease.