Carcinogenic Effects of Nitrosodimethylamine Contamination in Ranitidine: Defining the Relationship With Renal Malignancies

Patients with renal cell carcinoma (RCC) often feel struck by lightning. Unsatisfied by relatively modest associations of RCC with advancing age, male sex, tobacco exposure, and Western diets rich in red meat,1,2 patients reach for causative connections to occupational exposures and drugs. Exposure to trichloroethylene and chronic analgesic use has perhaps the most compelling association with RCC.3 However, many other drugs have been implicated in contributing to RCC without convincing proof. Urologists must be prepared to field these questions from their patients when they arise. The cautionary tale of the rise and fall of ranitidine, once the highest-selling drug on the planet, is fascinating and of particular interest to patients with RCC and their physicians. The downfall of ranitidine derived from the detection of a known carcinogen in the medication, nitrosodimethylamine (NDMA), linked to RCC and other tumors in animals. The authors describe the preclinical evidence for NDMA contamination in ranitidine, its connection to carcinogenesis in animals, and the challenges inherent in asking the critical clinical question: “Did ranitidine ingestion contribute to RCC tumorigenesis in humans?” The available population cohort data exploring this association are clouded by short follow-up, inhomogeneous data collection, the lack of screening imaging to detect subclinical tumors, and a range of other confounders. Moreover, NDMA levels were not actually measured in any of these studies. The story highlights the inherent difficulty in connecting an extremely pervasive drug exposure to a specific type of cancer unless the associated risk is exceptionally high. For practicing urologists, the take home message of this well-written review is that no clear association between ranitidine exposure and the development of RCC currently exists.4 However, the authors appropriately recommend that we view this conclusion, based entirely on observational studies with significant weaknesses, with caution when counseling our patients.