Diuretic and Enhanced Sodium Restriction Results in Improved Antiproteinuric Response to RAS Blocking Agents

Abstract

P roteinuria is a major risk factor for progression to ESRD in both diabetic and nondiabetic nephropathies (1,2). Angiotensin II is a key player in the development of renal failure, either directly by promoting tissue fibrosis or indirectly through its action on glomerular hemodynamic and proteinuria (1,3-5). Therefore, inhibition of the renin-angiotensin system (RAS), through either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), may have a positive impact on proteinuria and renal failure progression (2). ACEI significantly slow down renal failure progression in type 1 diabetes (6), as well as in nondiabetic nephropathies (7)(8)(9)(10)(11)(12). ARB demonstrated a similar nephroprotective effect in type 2 diabetes (13,14). However, despite treatment with ACEI or ARB, many patients present residual proteinuria and progress to ESRD.ACEI and ARB antagonize the RAS at different levels, suggesting that their combination may be beneficial (15). Several studies have shown that dual blockade of RAS by ACEI and ARB can decrease proteinuria more than ACEI and ARB alone in IgA nephropathy (16,17), type 1 (18) and 2 (19) diabetes, and mixed primary nephropathies (20 -24). This dual blockade of the RAS is also more effective at preventing renal failure progression than each form of monotherapy (25). However, only one study has shown that combined half doses of ACEI and ARB decrease proteinuria better than optimal doses of ACEI or ARB, demonstrating a true synergistic antiproteinuric activity (26). This latter study included only nondiabetic patients who had well-equilibrated BP and were taking fewer than two antihypertensive drugs and no RAS blocking agent before their inclusion in the study. However, most patients with severe proteinuria and renal failure do not reach the targeted BP in the absence of multiple drug regimens including a RAS blocking agent (7,8), particularly in the case of diabetes (13,14). Furthermore, the antiproteinuric effect of ACEI may be blunted by high salt intake and can subsequently be restored by diuretics (27). The aim of this study was to determine (1) whether the synergistic effect of ACEI and ARB on proteinuria is general to patients with renal failure of various causes, including diabetes, irrespective of their baseline BP, and (2) whether the antiproteinuric effect of combined ACEI and ARB can be increased by raising diuretic dosage.

Double-Blind, Placebo-Controlled Study on the Effect of the Aldosterone Receptor Antagonist Spironolactone in Patients Who Have Persistent Proteinuria and Are on Long-Term Angiotensin-Converting Enzyme Inhibitor Therapy, with or without an Angiotensin II Receptor Blocker

“…Recently, there has been evidence to suggest that diuretics and low-salt diet may potentiate the effect of renin-aldosterone system-blocking agents (19,20). More than 70% of patients in every group were taking either a loop diuretic or thiazide diuretic, so the effect of spironolactone in reducing proteinuria is over and above that provided by concurrent use of diuretics.…”

Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy

“…Indeed, a lower serum potassium level would feed back to decrease serum aldosterone levels in the absence of hypovolemia (23). Sodium depletion may also be the link between high serum aldosterone levels and low UACR and eGFR at baseline, which was previously shown (24)(25)(26). Inversely, subsequent aldosterone breakthrough was more frequent if the patient had, at baseline, the opposite profile suggestive of hypervolemia (i.e., lower serum aldosterone levels and higher SBP in multivariate analysis as well as higher UACR in univariate analysis).…”

Are Two Better Than One? Angiotensin-Converting Enzyme Inhibitors Plus Angiotensin Receptor Blockers for Reducing Blood Pressure and Proteinuria in Kidney Disease

“…sive agents) than did patients in the other investigation, whose BP was controlled with fewer than two antihypertensive agents and no RAS blockade (6). In addition, patients in the negative study excreted less sodium than those in the study that showed a positive finding (mean sodium excretion 129 to 168 versus 192 to 204 mEq/d) (5,6).…”