Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan

Abstract

There is large interindividual variability in the antiproteinuric response to blockade of the renin-angiotensin-aldosterone system (RAAS). A low-sodium diet or addition of diuretics enhances the effects of RAAS blockade on proteinuria and BP, but the efficacy of the combination of these interventions is unknown. Therefore, this randomized, double-blind, placebo-controlled trial to determine the separate and combined effects of a low-sodium diet and hydrochlorothiazide (HCT) on proteinuria and BP was performed. In 34 proteinuric patients without diabetes, mean baseline proteinuria was 3.8 g/d, and this was reduced by 22% by a low-sodium diet alone. Losartan monotherapy reduced proteinuria by 30%, and the addition of a low-sodium diet led to a total reduction by 55% and the addition of HCT to 56%. The combined addition of HCT and a low-sodium diet reduced proteinuria by 70% from baseline (all P < 0.05). Reductions in mean arterial pressure showed a similar pattern (all P < 0.05). In addition, individuals who did not demonstrate an antiproteinuric response to losartan monotherapy did respond when a low-sodium diet or a diuretic was added. In conclusion, a low-sodium diet and HCT are equally efficacious in reducing proteinuria and BP when added to a regimen containing losartan and especially seem to benefit individuals who are resistant to RAAS blockade. Combining these interventions in sodium status is an effective method to maximize the antiproteinuric efficacy of RAAS blockade.

Figure 1.

Intensified intervention in sodium status by combining LS and HCT is an effective tool to maximize the antiproteinuric efficacy of RAAS blockade. Proteinuria (A) and MAP (B) compared with baseline (placebo-HS) after 6-wk treatment with losartan and losartan+HCT combined with HS (▪) and LS (). Data are means (SE). Drug effects in all periods were evaluated by a linear mixed-effect model. Tukey tests were used to localize the differences. *P < 0.05 versus all periods; ^#P < 0.05 versus same treatment on HS (effect of LS); ^†P < 0.05 versus losartan treatment on same diet (effect of HCT); ^‡P < 0.05 versus placebo on same diet.

Figure 2.

Conservative therapy is equally effective in patients with primary glomerulopathies as in patients with secondary nephropathies. Patients with primary glomerulopathies (membranous glomerulopathy [n = 7], FSGS [n = 7], membranoproliferative glomerulonephritis [n = 2], minimal-change disease with secondary glomerulosclerosis [n = 2], and Alport syndrome [n = 1]) were compared with patients with secondary renal damage (hypertensive nephropathy [n = 5] and IgA nephropathy [n = 5]), excluding the patients with nonconclusive diagnoses (n = 4). It is shown that conservative therapy was equally effective in the patients with primary glomerulopathies (n = 19) as in the patients with IgA or hypertensive nephropathies (n = 10). los, losartan.

Figure 3.

The antiproteinuric response of LS during losartan is not dependent on BP, in contrast to the antiproteinuric response of HCT during losartan, which correlates significantly with BP. There was no concordance between the change in proteinuria and the change in MAP when patients were switched from HS to LS during losartan (A), whereas the antiproteinuric response of HCT during losartan correlated significantly with the effects on BP (R = 0.382, P < 0.05; B).

Figure 4.

In proteinuric patients without diabetes, sodium depletion by LS or a diuretic is specifically beneficial in those who are resistant to RAAS blockade. We examined the effects of LS, HCT, and their combination (LS+HCT) on proteinuria (top) and antiproteinuric response (bottom) during losartan treatment (los). According to their antiproteinuric response to losartan from baseline (BL; on placebo-HS), patients were divided into three groups: Resistant (<25% reduction in proteinuria; n = 16), intermediate (25 to 50% reduction; n = 10), and good responders (>50% reduction; n = 7). Data are means ± SEM. ∧P < 0.05 versus resistant patients on same treatment; ∨P < 0.05 versus losartan on HS.