Hypertensive nephropathy and cancer: Is it the hypertension, the nephropathy, or both?

Hypertension (HTN) is a prominent preventable cause of premature morbidity and mortality and has been estimated to be the second leading risk factor for the global burden of disease.1 Classically, HTN has been mostly associated with cardiovascular disease2 and is a well-established major risk factor for ischemic and hemorrhagic stroke, myocardial infarction, heart failure, chronic kidney disease (CKD), peripheral vascular disease, cognitive decline, and premature death. Less is known about the association between HTN and cancer. However, interest into a possible link between HTN and cancer is not new. As early as 1958, a relationship was thought to be present between elevated systolic and diastolic blood pressures measured at study entry and subsequent 14-year mortality from cancer among 1233 white males originally aged 40-59.3 Other studies confirmed elevated standardized mortality ratios for cancer in middle-aged hypertensive men4, 5 but also in older cohorts.6, 7 Those findings were, however, refuted by others.8 Furthermore, some epidemiological studies found an increased incidence of cancer among hypertensives suggesting a causal effect.9, 10 Such a hypothesis could seem plausible as Norden et al11 studied repair synthesis of DNA in lymphocytes exposed to a carcinogen and showed that lymphocytes from subjects with raised diastolic pressure had a higher frequency of chromosomal aberrations than those from subjects with a diastolic pressure under 90 mm Hg. Moreover, it appears that lowering the BP could decrease the risk.12 However, the HTN could be secondary to the cancer itself rather than constitute a causal factor. It is now well recognized that ectopic adrenocorticotrophic hormone secretion, leading to hypercortisolism and BP elevation, is caused by various solid tumors.13 HTN is also the most commonly observed comorbidity among cancer survivors14, 15 with a prevalence of 20%-65%.16, 17 Finally, the risk could come from the hypertensive drugs used to treat the condition rather than the condition itself as a number of agents have been incriminated in the pathogenesis of cancer even if findings have been contradictory18 except maybe for skin cancer where calcium channel blockers and beta blockers have been found to play a role through drug-induced photosensitivity.19 In this issue, clinical data and cancer diagnoses for all patients with biopsy-proven hypertensive nephropathy between 1995 and 2015 were extracted by Heaf et al from four national registries in Denmark and compared with age- and sex-adjusted national rates, and the risk of cancer was twice the background population. It was more specifically significantly raised for renal cancer, multiple myeloma (MM), and skin cancers. The increased risk for renal cancer is consistent with the risk reported in other studies in association with HTN.10 Lipid peroxidation and formation of reactive oxygen species are elevated in hypertensive individuals and because in experimental animals lipid peroxidation of the proximal renal tubules is a necessary mechanistic pathway in renal carcinogenesis, they are hypothesized to play a role in renal cell cancer development.20 The choice of the investigators to try to link hypertensive nephropathy to cancer diagnoses could be explained in two different ways. The hypertensive nephropathy could be a hallmark of longstanding HTN with biopsy-proven end-organ damage of an entity whose diagnostic criteria are still hotly debated by the scientific community.21, 22 Moreover, it would eliminate any measurement bias, and in this case, it would solidify the findings of previous studies done in that regard. Alternatively, the risk could stem from the nephropathy per se. The increased risk of cancer for patients on dialysis and after transplantation is well documented23 most notably for colorectal cancer and renal cancer24 and is largely attributed to the immunosuppressed state of these patients. Furthermore, pre-dialysis CKD has also been associated with an increased incidence of malignancy25 most notably of kidney cancer in younger men26 but also of skin malignancies, gynecologic malignancies, and gastrointestinal malignancies.25 Cytogenetic changes in uremia, such as sister chromatid exchange and chromosomal aberration, may also play a role in the heightened risk of cancer.27 Conversely, it is worth to note that a large percentage of renal cell carcinoma survivors in the United States have an underlying kidney disease most commonly diabetic nephropathy or hypertensive nephrosclerosis.28 On the other hand, certain lesions seen on kidney biopsy such as focal and segmental glomerulosclerosis and commonly attributed to HTN can actually be paraneoplastic in the setting of solid tumors such as non–small-cell lung cancer29, 30 or seen in association with hematological malignancies31 and MM.32 That could also possibly account partially for the increased incidence of cancer and MM observed in the registries of Heaf et al. In summary, the observational nature of the study of Heaf et al, the possibility of multiple confounders, and the controversies associated with similar studies done before preclude the possibility of drawing firm conclusions. However, it does make attractive the option of reaching in the future the possibility of elaborating a cancer risk score similar to the Framingham risk score where risk factors such as HTN, obesity, and smoking would be computed with evidence of target organ damage such as hypertensive nephropathy in order to evaluate the necessity of early screening. None.