Association between Use of Hydrochlorothiazide and Risk of Keratinocyte Cancers in Kidney Transplant Recipients

Abstract

Background and objectives: Keratinocyte cancers, which primarily comprise squamous cell carcinomas and basal cell carcinomas, represent a major concern and potential risk for kidney transplant recipients. Hydrochlorothiazide, a diuretic widely used to treat hypertension, has been implicated in skin photosensitivity reaction. Recent studies conducted in the general population have found that hydrochlorothiazide use is associated with a higher risk of keratinocyte cancer, especially squamous cell carcinomas. High-risk groups, however, including transplant recipients were excluded from these. Our aim was to investigate whether hydrochlorothiazide use was associated with keratinocyte cancer in kidney transplant recipients on immunosuppressive therapy.

Design, setting, participants, & measurements: In a single-center cohort of kidney (n=2155), combined kidney-pancreas (n=282), and pancreas (n=59) transplant recipients from the Données Informatisées VAlidées Transplantation (DIVAT) database transplanted between 2000 and 2017 in Nantes, France, we evaluated the association between hydrochlorothiazide exposure and keratinocyte cancers. Multivariable cause-specific, time-varying Cox models were used to estimate the relationship between hydrochlorothiazide exposure and the hazard of squamous cell carcinoma and basal cell carcinoma, with hydrochlorothiazide designated as the time-dependent variable.

Results: Among the participants, 279 of 2496 (11%) were exposed to hydrochlorothiazide after the transplantation. Cumulative incidence rates of keratinocyte cancer by 10 and 15 years were 7% and 9% for squamous cell carcinomas, respectively, and 8% and 11% for basal cell carcinomas, respectively. We found a relationship between exposure to hydrochlorothiazide and the risk of squamous cell carcinomas (hazard ratio, 2.04; 95% confidence interval, 1.27 to 3.28). In contrast, we found no association between hydrochlorothiazide exposure and basal cell carcinomas (hazard ratio, 0.63; 95% confidence interval, 0.35 to 1.15).

Conclusions: In a single-center cohort of kidney, combined kidney-pancreas, and pancreas transplant recipients, exposure to hydrochlorothiazide was associated with a two-fold higher risk of squamous cell carcinoma and no higher risk of basal cell carcinoma.

Keywords: Hydrochlorothiazide; cancer; diuretics; kidney transplantation; skin cancer; squamous cell carcinoma; thiazide diuretics; transplantation.

Graphical abstract

Figure 1.

Flow chart of eligibility criterion. BCC, basal cell carcinoma; mTOR, mammalian target of rapamycin; SCC, squamous cell carcinoma.

Figure 2.

Cumulative incidence curve of hydrochlorothiazide (HCTZ). Aalen–Johansen estimator, retransplantations, returns to dialysis, and deaths are competing events.

Figure 3.

Cumulative incidence curves. (A) Basal cell carcinoma and (B) squamous cell carcinoma. Aalen–Johansen estimator, retransplantations, returns to dialysis, and deaths are competing events.