Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease: an observational study

Abstract

Background: In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin-angiotensin-aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions.

Methods: We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death.

Results: A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference -0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) -0.83 to -0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5-4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI -0.46 to -0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05-2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50-1.29), P = 0.4].

Conclusions: These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Keywords: ADPKD; diuretics; hypertension; polycystic kidney disease; thiazide diuretics.

FIGURE 1

Percentage of participants that use specific antihypertensives and combinations of antihypertensives. Of thiazide diuretic users, 91% also used an RAAS inhibitor. Of calcium channel blocker users, this was 83% and of β-blocker users it was 77%. Percentages are of the total analysed population (N = 533).

FIGURE 2

Association of the use of thiazide diuretics and eGFR decline and the composite kidney endpoint. (A) The predicted annual eGFR decline. The boxplot shows predicted mean and 25th and 75th percentiles, lower and upper limit error bars show predicted 2.5th and 97.5th percentiles as derived from the adjusted mixed model analyses (Model 5 of the primary analysis, adjusted for use of other antihypertensives, age, sex, BMI, systolic blood pressure, DNA mutation, baseline eGFR, htTKV and albuminuria). (B) The cumulative survival of thiazide users (n = 111) and participants not using thiazides (n = 360) in the Cox proportional hazards model at the mean of the covariates of the final model (age, sex, BMI, systolic blood pressure, number of antihypertensives used, baseline eGFR, htTKV, albuminuria and DNA mutation).

FIGURE 3

Association of the use of thiazide diuretics with the slope of estimated GFR (mL/min/1.73 m² per year) in subgroups. Analyses were adjusted for use of specific other antihypertensives, age, sex, BMI, systolic blood pressure, number of antihypertensives used, baseline eGFR, htTKV, albuminuria and DNA mutation. The analyses were performed in the 471 patients without missing values in any of these variables.