A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease

Abstract

Background: Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited.

Methods: To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypertension medication was discontinued for a 2-week period before randomization. We analyzed effects on BP, kidney function, and fluid balance and related this to renal clearance of diuretics.

Results: A total of 26 patients (with a mean eGFR of 39 ml/min per 1.73 m²) completed both treatments. Dietary sodium restriction reduced sodium excretion from 160 to 64 mmol per day. Diuretics produced a greater reduction in 24-hour systolic BP (SBP; from 138 to 124 mm Hg) compared with sodium restriction (from 134 to 129 mm Hg), as well as a significantly greater effect on extracellular water, eGFR, plasma renin, and aldosterone. Both interventions resulted in a similar decrease in body weight and NT-proBNP. Neither approaches decreased albuminuria significantly, whereas diuretics did significantly reduce urinary angiotensinogen and β2-microglobulin excretion. Although lower eGFR and higher plasma indoxyl sulfate correlated with lower diuretic clearance, the diuretic effects on body weight and BP at lower eGFR were maintained. During diuretic treatment, higher PGE2 excretion correlated with lower free water clearance, and four patients developed mild hyponatremia.

Conclusions: Distal diuretics are noninferior to dietary sodium restriction in reducing BP and extracellular volume in CKD. Diuretic sensitivity in CKD is maintained despite lower diuretic clearance.

Clinical trial registry name and registration number: DD-study: Diet or Diuretics for Salt-sensitivity in Chronic Kidney Disease (DD), NCT02875886.

Keywords: chronic kidney disease; clinical hypertension; clinical trial; diuretics; pharmacokinetics; water-electrolyte balance.

Graphical abstract

Figure 1.

Overview of the study design. HCTZ, hydrochlorothiazide; Na⁺, sodium; V, visit.

Figure 2.

Only dietary sodium (Na+) restriction reduced urinary Na+ excretion, while diuretics reduced urinary calcium (Ca2+) excretion more than Na+ restriction. Two-way repeated measures ANOVA was used for analysis. (C) Urine potassium (K⁺) was normally distributed, whereas (A) urine Na⁺ and (B) calcium (Ca²⁺) were not. *P<0.05 for difference before versus after treatment, and for difference between treatments.

Figure 3.

Sodium (Na+) restriction and diuretics lowered blood pressure and kidney function, but had no effect on albuminuria and plasma potassium (K+). Two-way repeated measures ANOVA was used for analysis. (A) SBP and (B) diastolic BP (DBP), (C) eGFR, and (E) plasma K⁺ were normally distributed, whereas (D) albuminuria was not. *P<0.05 for difference before versus after treatment, and for difference between treatments. FU, follow-up.

Figure 4.

Diuretics but not sodium (Na+) restriction caused persistent effects on BP and plasma potassium (K+) after washout. The data show that the effect of diuretics (A C) and but not Na⁺ restriction (B and D) persists after discontinuation of their use. A paired t test was used for analysis. *P<0.05 for difference before versus after treatment, or before treatment versus after washout.

Figure 5.

Both sodium (Na+) restriction and diuretics reduced indices of fluid balance and increased plasma renin and aldosterone. (A–E) All data were normally distributed. Two-way repeated measures ANOVA was used for analysis. *P<0.05 for difference before versus after treatment, and for difference between treatments. NT-pro-BNP, N-terminal–pro B-type natriuretic peptide.

Figure 6.

Lower eGFR reduced diuretic clearance and increased plasma indoxyl sulfate, while maintaining diuretic effects on BP and body weight. (A–F) Clearances were not normally distributed. Pearson correlation coefficient was calculated. Δ, change in; Cl_Amiloride, clearance of amiloride; Cl_HCTZ, clearance of hydrochlorothiazide.

Figure 7.

Diuretics but not sodium (Na+) restriction increased urinary PGE2 and this reduced free water clearance (ClH2O). Effects of dietary sodium (Na⁺) restriction and diuretics on the excretion of (A) PGE2 and its metabolite (PGE2+M), and (B) the correlation between urinary PGE2+M excretion with free water clearance (Cl_H2O) in patients treated with diuretics. Cl_H2O was normally distributed, whereas PGE2+M was not. Two-way repeated measures ANOVA and Pearson correlation coefficient were used for analysis. One patient had ten- to 100-fold higher PGE2 values and this outlier was excluded from the analysis; we suspect that his urine was contaminated with semen, which contains high PGE2 levels. ^*P<0.05, difference before versus after treatment.

Figure 8.

Diuretics but not sodium (Na+) restriction reduced (fractional) renin, angiotensinogen (AGT), and ß2-microglobulin excretion. (A–D) All data were normally distributed. Two-way repeated measures analysis was used for analysis. FE, fractional excretion. ^*P<0.05, difference before versus after treatment.