Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy
in diabetic nephropathy: a randomised clinical trial.
Author(s): Kwakernaak AJ(1), Krikken JA(2), Binnenmars SH(3), Visser FW(2), Hemmelder MH(4),
Woittiez AJ(3), Groen H(5), Laverman GD(6), Navis G(2); Holland Nephrology Study
(HONEST) Group.
Collaborators: de Borst MH, Janssen WM, Lambers Heerspink HJ.
Affiliation(s): Author information:
(1)Department of Internal Medicine, Division of Nephrology, University of
Groningen, University Medical Center Groningen, Groningen, Netherlands.
Electronic address: a.kwakernaak@umcg.nl. (2)Department of Internal Medicine,
Division of Nephrology, University of Groningen, University Medical Center
Groningen, Groningen, Netherlands. (3)Department of Internal Medicine, Division
of Nephrology, ZGT Hospital Almelo, Netherlands. (4)Department of Internal
Medicine, Division of Nephrology, Medical Center Leeuwarden, Leeuwarden,
Netherlands. (5)Department of Epidemiology, University of Groningen, University
Medical Center Groningen, Groningen, Netherlands. (6)Department of Internal
Medicine, Division of Nephrology, University of Groningen, University Medical
Center Groningen, Groningen, Netherlands; Department of Internal Medicine,
Division of Nephrology, ZGT Hospital Almelo, Netherlands.
Publication date & source: 2014, Lancet Diabetes Endocrinol. , 2(5):385-95
BACKGROUND: Reduction of dietary sodium intake or diuretic treatment increases
renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic
nephropathy. We aimed to investigate the effect of sodium restriction and the
diuretic hydrochlorothiazide, separately and in combination, added to RAAS
blockade on residual albuminuria in patients with type 2 diabetic nephropathy.
METHODS: In this multicentre, double-blind, placebo-controlled, crossover
randomised trial, we included patients with type 2 diabetic nephropathy. Main
entry criteria were microalbuminaria or macroalbuminuria, and creatinine
clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous
year. We tested the separate and combined effects of sodium restriction (dietary
counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily),
added to standardised maximal angiotensin-converting enzyme (ACE) inhibition
(lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given
hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6
weeks. Both treatments were combined with regular sodium diet or sodium
restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment
periods were done consecutively in a random order. Patients were randomised in
blocks of two patients. The trial was analysed by intention to treat. The trial
is registered with TrialRegister.nl, number 2366.
FINDINGS: Of 89 eligible patients, 45 were included in the study. Both sodium
restriction and hydrochlorothiazide significantly reduced albuminuria,
irrespective of treatment sequence. Residual geometric mean albuminuria with
baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly
reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by
hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest
extent by their combination (306 mg per day [203-461], p<0·0001). Orthostatic
complaints were present in two patients (4%) during baseline treatment, five
(11%) during addition of sodium restriction, five (11%) during
hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No
serious adverse events occurred.
INTERPRETATION: We conclude that sodium restriction is an effective
non-pharmacological intervention to increase RAAS blockade efficacy in type 2
diabetic nephropathy.
FUNDING: None.
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