Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

Abstract

Background and objectives: Addition of aldosterone antagonists (AA) might provide renal benefits to proteinuric chronic kidney disease (CKD) patients over and above the inhibition of renin-angiotensin system blockers (RAS). We evaluated the benefits and harms of adding selective and nonselective AA in CKD patients already on RAS.Design, setting, participants, & measurements: MEDLINE, EMBASE, and Renal Health Library were searched for relevant randomized clinical trials in adult CKD patients. Results were summarized using the random-effects model.Results: Eleven trials (991 patients) were included. In comparison to angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) plus placebo, nonselective AA along with ACEi and/or ARB significantly reduced 24 h proteinuria (seven trials, 372 patients, weighted mean difference [WMD] ؊0.80 g, 95% CI ؊1.27, ؊0.33) and BP. This did not translate into an improvement in GFR (WMD ؊0.70 ml/min/1.73m 2 , 95% CI ؊4.73, 3.34). There was a significant increase in the risk of hyperkalemia with the addition of nonselective AA to ACEi and/or ARB (relative risk 3.06, 95% CI 1.26, 7.41). In two trials, addition of selective AA to ACEi resulted in an additional reduction in 24 h proteinuria, without any impact on BP and renal function. Data on cardiovascular outcomes, long-term renal outcomes and mortality were not available in any of the trials.Conclusions: Aldosterone antagonists reduce proteinuria in CKD patients already on ACEis and ARBs but increase the risk of hyperkalemia. Long-term effects of these agents on renal outcomes, mortality, and safety need to be established. Clin J Am Soc Nephrol 4: 542-551, 2009. doi: 10.2215 C hronic kidney disease (CKD) affects 25 to 30 million Americans and several million people across the globe in both developed and developing nations (1,2). A number of treatment options have been shown to delay the progression of kidney damage (3,4). To date, the major impact on delaying the progression of CKD and the risk of end-stage kidney disease (ESKD) has been provided by the use of renin-angiotensin system (RAS) blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-blocking agents (ARB). These agents have become standard of care in proteinuric CKD patients (5-8). Both ACEi and ARB significantly reduce proteinuria and the risk of ESKD by about 20 to 30% (9). But this is suboptimal given the higher costs and burden of ESKD (10). Thus, studies exploring interventions for traditional and nontraditional risk factors for CKD are advocated (11).Animal studies have shown that aldosterone has an independent role in the development of hypertensive nephropathy and vascular injury resulting in myocardial and renal fibrosis, and its blockade reduces proteinuria (12-16). In humans, RAS blockade with ACEi or ARB results in an incomplete suppression of serum aldosterone levels, a phenomenon known as "aldosterone escape" (17). When patients are treated with ACEi or ARB, aldosterone levels decrease during...

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…1). The selective aldosterone blocker eplerenone also ameliorates podocyte injury, proteinuria and salt-evoked nephropathy [30,31].…”

Assessment of Spironolactone Effects on the Prevention of Progression of Proteinuria in Chronic Kidney Diseases

“…The number of patients in the study was low, but the study was strong to show that spironolactone can reduce proteinuria in a short-duration (23). In 2009, Navaneethan and colleagues in a systematic review about the prevention of progression of kidney disease with aldosterone antagonists using Medline data base concluded that in patients who received ACEi or ARB, aldosterone antagonists reduced proteinuria, although the risk of hyperkalemia increased (24). In 2008, Bomback and colleagues in a systematic review showed that most studies about spironolactone have these characteristics in common: CKD with different causes, Low number of patients studied (less than 30), mean of GFR > 60 and potassium cutoff equal to 5.5.…”

“…Four weeks after discontinuation of spironolactone, proteinuria returned to its initial level. The level of proteinuria was directly related to the level of aldosterone (23,24).…”

“…The effects of spironolactone combined with ARBs and/or ACEIs in reducing proteinuria and the delay in the progression of CKD have been studied as well. These studies have shown that the combination is very useful and reduces proteinuria significantly (22)(23)(24), but there were doubts because of hyperkalemia as the side effect since it was increased in the studies. Four weeks after discontinuation of spironolactone, proteinuria returned to its initial level.…”

Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury

“…1 Accumulating evidence shows that Ald, an end product of that system, plays a key role in the progression of chronic kidney disease (CKD) due to salt-sensitive hypertension, [2][3][4] and that mineralocorticoid receptor (MR) blockers, which inhibit the injurious effect of Ald on the kidney, contribute to a reduction in albuminuria and proteinuria in CKD patients. 5,6 MR blockers are therefore considered to play a crucial role in preventing the progression of CKD with hypertension. However, treatment with MR blockers can induce hyperkalemia, which is a concern in patients with renal dysfunction and requires caution in prescribing MR blockers for advanced CKD patients.…”