DOI: 10.1097/01.hjh.0000249690.88865.90

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PMID: 17053534

Issn Print: 0263-6352

Publication Date: 2006/11/01


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Use of antagonists of aldosterone in patients with chronic kidney disease: potential advantages and risks

Vito M Campese; Jeanie Park

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The question of whether or not to use aldosterone antagonists in subjects with proteinuria and chronic kidney disease (CKD) is assuming increasing clinical relevance. The role of the renin–angiotensin–aldosterone system (RAAS) in the progression of CKD is undisputed [1,2] as is the notion that inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin type 1 receptor antagonists (ARBs) may retard but not abrogate CKD progression [3–6]. More recently, studies suggest that antagonists of aldosterone may also mitigate proteinuria and progression of CKD. Although aldosterone is partly controlled by angiotensin II expression, many patients exhibit ‘aldosterone escape’ in which aldosterone levels remain high despite inhibition of the RAAS with ACEIs or ARBs [7]. In addition, many diabetic patients continue to have proteinuria despite recommended doses of ACEIs and ARBs. Because proteinuria is an independent risk factor for progressive renal disease, investigators are searching for additional pathogenic mechanisms and alternative therapeutic tools, such as aldosterone blockade, to arrest or abrogate proteinuria and CKD progression.
Aldosterone may lead to progression of CKD and proteinuria through a variety of mechanisms. Studies in experimental rat models have shown that aldosterone participates in the progression of kidney disease through hemodynamic and direct cellular actions [8–10]. ACEIs and ARBs do not suppress aldosterone predictably, leaving potentially detrimental effects of aldosterone unabated [11], and antagonists of aldosterone retard the progression or cause regression of existing glomerulosclerosis independently of effects on blood pressure (BP) [12]. In rats with subtotal nephrectomy and adrenalectomy, proteinuria, hypertension and structural renal injury were less pronounced than in rats with intact adrenal glands [13]. Aldosterone infusion abrogated the beneficial effects of ACEIs in stroke-prone spontaneously hypertensive rats (SHRSP), whereas spironolactone reduced vascular injury and proteinuria in these animals [14,15].
The clinical evidence supporting a role of aldosterone in CKD progression is scanty but involves both diabetic and non-diabetic patients with CKD [7,16–18]. In an uncontrolled trial of eight patients with various renal diseases and proteinuria >1 g/day, spironolactone consistently reduced proteinuria by 53% [19]. In a short-term (8-week) uncontrolled study, Bianchi et al. [20] observed that 25 mg/day of spironolactone effectively reduced proteinuria by approximately 37% in 42 non-diabetic CKD patients already treated with ACEI and/or ARBs. In this study [20], baseline levels of aldosterone were significantly correlated with the degree of reduction in proteinuria following treatment with spironolactone. In 13 patients with early diabetic nephropathy and ‘aldosterone escape’ from ACEIs, Sato et al. [7] observed a significant reduction in urinary albumin excretion after 24 weeks of treatment with spironolactone. Of note, the decrease in urine albumin excretion was more pronounced among patients with aldosterone escape. Rachmani et al. [18] compared the antiproteinuric effects of spironolactone with those of cilazapril in 60 women with diabetic nephropathy. Spironolactone reduced proteinuria more effectively than ACEIs, and the combined administration of ACEIs and spironolactone was more effective than either drug alone. Similar findings were observed by Epstein et al. [21]. These investigators showed that eplerenone reduced proteinuria more effectively than an ACE inhibitor in patients with type 2 diabetes mellitus. A combination of eplerenone and ACE inhibitor was more effective than either drug given alone in reducing proteinuria. In 41 patients with CKD, Chrysostomou et al. [22] showed a significant reduction in proteinuria with spironolactone, which persisted 6–12 months after initiation of therapy. Spironolactone treatment in addition to recommended antihypertensive drugs reduced BP and proteinuria in type 1 and type 2 diabetic patients with nephropathy [23,24].
In this issue of the Journal of Hypertension, van den Meiracker et al.

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