A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease
Authors: Bovée Dominique M. , Visser Wesley J. , Middel Igor , De Mik–van Egmond Anneke , Greupink Rick , Masereeuw Rosalinde , Russel Frans G. M. , Danser A. H. Jan , Zietse Robert , Hoorn Ewout J. 
Published: January 2020

Significance Statement
CKD is characterized by increased extracellular volume and salt-sensitive hypertension, but it is unknown whether dietary or pharmacologic approaches are preferable to reduce sodium in CKD, and if distal diuretics are still effective at lower eGFRs. In a randomized crossover trial in patients with CKD stage G3 or G4 and hypertension, the authors compared dietary sodium restriction with a combination of distal diuretics (hydrochlorothiazide and amiloride). Both interventions effectively lowered 24-hour BP and extracellular volume, with diuretics exerting a stronger effect. Although the tubular secretion of diuretics was impaired at a lower eGFR, the reductions in body weight and BP effect were maintained. These findings indicate that even at lower eGFRs, use of distal diuretics is as effective as dietary sodium restriction in treating hypertension and volume overload in CKD.

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