Diabetic nephropathy-characterized by hypertension, macro-albuminuria, progressive loss of renal function, and a high incidence of cardiovascular morbidity and mortality-is the leading cause of end-stage renal failure in the US.^1-5 The predictive power of proteinuria for progressive renal function loss has been demonstrated in patients with and without diabetic nephropathy.^6,7 It has been suggested, therefore, that besides adequate blood pressure and metabolic control, suppression of proteinuria should be a goal of therapy aiming to achieve optimal renal protection in diabetic as well as non-diabetic nephropathy.⁶

According to guidelines, patients with diabetic nephropathy are treated with agents that interfere with the renin-angiotensin system (RAS), as several large intervention studies have demonstrated that these agents provide better renal protection than non-RAS antihypertensive agents.^8-10 Nevertheless, the renal protection provided by these agents is far from complete. For instance, in a study with irbesartan in diabetic nephropathy, end-stage renal failure during follow-up developed in 17.8% of patients on placebo and in 14.2% of patients on irbesartan (absolute reduction of 3.6%).⁹ In a study with losartan these values were 25.5% and 19.6%, respectively (absolute reduction of 4.9%).¹⁰ The development of new therapeutic strategies is therefore necessary. In this paper, the effects of aldosterone receptor antagonism on diabetic nephropathy will be discussed. In particular, we will focus on the results of clinical studies evaluating the role of aldosterone receptor antagonism on proteinuria.

Aldosterone and Nephropathy 
Aldosterone is now well recognized as a mediator of the progression of renal disease by causing perivascular inflammation.^12,13 In the rodent remnant kidney model, infusion of aldosterone during losartan administration was associated with hypertension, proteinuria, and glomerulosclerosis.¹⁴ Likewise, in the stroke-prone hypertensive rat on a high sodium intake, aldosterone infusion during ACE inhibition with captopril was associated with proteinuria and malignant nephrosclerosis,¹⁵ whereas in a hypertensive rat model subjected to angiotensin II and N-nitro-L-arginine methyl ester (L-NAME) infusion, renal and cardiac damage was prevented by aldosterone removal through adrenalectomy or administration of eplerenone.¹³ Moreover, in the streptozotocin-induced diabetic rat with increased renal protein excretion, administration of spironolactone markedly attenuated urinary protein excretion and prevented early renal injury, indirectly indicating involvement of aldosterone in this process of renal injury.¹⁶ Similar findings were obtained in the streptozotocin-induced diabetic rat and the db/db (a rodent model of type 1 diabetes) mouse when eplerenone was used as a mineralocorticoid receptor antagonist.¹⁷

A number of potential mechanisms has been put forward to explain the deleterious effect of aldosterone on the kidney.12 Recently, it has been demonstrated that the expression of the mineralocorticoid receptor and glucocorticoid-regulated kinase 1 (Sgk1) is significantly increased in renal biopsies obtained from patients with heavy proteinuria.¹⁸ Related to this increased expression, an enhanced expression of inflammatory parameters such as interleukin (IL)-6 and transforming growth factor (TGF) ß-1-known to promote renal inflammation-was also observed. Further evidence for the involvement of aldosterone in promoting proteinuria stems from a study in rats showing that aldosterone infusion damages glomerular visceral podocytes.¹⁹ These podocytes are essential for glomerular barrier function. They harbor mineralocorticoid receptors, and damage by aldosterone might be induced by oxidative stress through enhanced Sgk1 expression.¹⁹ Finally, it has been shown that aldosterone has a direct vasoconstrictor influence on afferent and efferent glomerular arterioles, with a higher sensitivity for efferent arterioles. This effect of aldosterone is non-genomic and is caused by activation of phospholipase C, resulting in calcium mobilization through L- or T-type voltage-dependent calcium channels.²⁰ Therefore, the adverse effects of aldosterone on renal function could be through direct (inflammatory) damage and through alteration of renal hemodynamics.

Although the synthesis and release of aldosterone by the adrenal gland is in part under the control of angiotensin II, escape of aldosterone has been reported to occur in a substantial proportion of patients with diabetic nephropathy treated with ACE inhibitors or angiotensin II receptor antagonists.^21,22 This aldosterone escape is not harmless as it has been shown to be associated with an enhanced excretion of urinary albumin and an enhanced decline of renal function.²² Because of this aldosterone escape and the knowledge from experimental studies that aldosterone is involved in the development of renal injury, it is not surprising that several clinical studies have been conducted in which the effect of add-on therapy of aldosterone receptor antagonism on proteinuria in (diabetic) nephropathy has been explored.

Table 1: Overview of Clinical Studies with Aldosterone-receptor Blockade in Type 1 or Type 2 Diabetic Nephropathy

DNP = deoxyribonucleoprotein; DM = diabetes mellitus; ARB = angiotensin receptor blocker