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Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan.

Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which

suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors,

failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the

reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and

discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering

effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to

an RAS inhibitor can help to maintain ‘long-term’ antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia.

Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects

if mineralocorticoid receptor antagonists are appropriately used.

Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy (DM nephropathy) is the most common primary disease necessitating dialysis treatment in the world

including Japan.1 In the management of DM nephropathy, particularly in preventing the onset and progression of early nephropathy, glycemic control is important. Comprehensive management

also includes treatment of hypertension and hyperlipidemia. Hypertension is about twice as common in diabetics as in non-diabetics, and is an important risk factor for macroangiopathy and

microangiopathy due to arteriosclerosis in diabetic patients. Therefore, strict 24-h control of hypertension is essential. Major guidelines for treatment of hypertension in Japan, the United

States and Europe recommend the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs), which suppress the renin–angiotensin system (RAS), as the

antihypertensive drugs of first choice in patients with coexisting diabetes.2, 3, 4 Many large-scale clinical studies have shown that, in patients with DM nephropathy, ACEIs and ARBs

decrease albuminuria and prevent nephropathy progression.5, 6, 7 However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric effects, renoprotective

effects and a reduction in cardiovascular events has also been reported.8, 9, 10, 11, 12

To achieve more complete RAS inhibition in patients with type 2 diabetes, concomitant treatment with different types of RAS inhibitors has been promising. However, some clinical studies,

including those in Japanese patients, have shown that concomitant treatment with an ACEI and ARB, or also including a direct renin inhibitor, may not provide a clinical synergistic effect in

reducing cardiovascular events or preventing a decline in renal function, but conversely, may cause an increase in the incidence of adverse reactions such as hyperkalemia and acute renal

insufficiency.13, 14, 15, 16 Although ACEIs and ARBs are cornerstone drugs for the treatment of DM nephropathy, new treatment strategies are necessary to achieve even better effectiveness.

We have previously reported aldosterone breakthrough as a clinical phenomenon that can occur with an RAS inhibitor.17 Aldosterone breakthrough is a phenomenon in which, after treatment with

an RAS inhibitor, plasma aldosterone levels, once they have decreased, can again rise to higher than pretreatment levels during relatively long-term treatment. Aldosterone breakthrough

usually does not influence the antihypertensive effects of RAS inhibitors, but breakthroughed aldosterone attenuates the organ-protective effects of RAS inhibitors through the actions of

mineralocorticoid receptors (MRs).18, 19, 20, 21, 22, 23 With relatively long-term treatment with RAS inhibitors, regardless of dose or combination of drugs, aldosterone breakthrough may be

impossible to prevent. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with DM

nephropathy. To achieve better treatment of DM nephropathy, in which RAS inhibitors are now the mainstay of treatment, investigation of aldosterone blockade is important.24, 25 In fact, in

the field of cardiology, large-scale clinical studies in which a MR antagonist is added to an RAS inhibitor to inhibit the effects of aldosterone breakthrough have shown marked effects in

patients with chronic heart failure who have decreased systolic function.26, 27, 28

This review focuses on treatment in DM nephropathy and discusses the significance of aldosterone blockade. MR antagonists used to treat refractory edema in patients with DM nephropathy as

potassium-sparing diuretics, but are rarely used in advanced stages of DM nephropathy because of concern for hyperkalemia. Moreover, the current guidelines in Japan for the treatment of

hypertension and CKD do not discuss the use of MR antagonists, but advise that extreme precautions when prescribing. However, early activation of the aldosterone/MR cascade, particularly in

patients with diabetes, has been reported, including the need to add a MR antagonist in stage 1 (pre-nephropathy) with normoalbuminuria and a normal estimated glomerular filtration rate

(eGFR). In the treatment of DM nephropathy, MR antagonists are effective and should be administered according to the stage of disease.

One reason why aldosterone should be targeted in the treatment of diabetes before clinical diagnosis of DM nephropathy is because aldosterone is directly associated with insulin resistance.

It has long been known that glucose intolerance is common in patients with primary aldosteronism (PA). This has been thought to be due to hypokalemia in PA, but, in addition, recent studies

have shown a direct association with aldosterone. Plasma renin activity and plasma angiotensin II levels are decreased in PA, and this is due to the unique effects of aldosterone. Patients

with PA, compared with those with essential hypertension or who are normotensive, have insulin resistance with decreased insulin sensitivity. Metabolic syndrome with insulin resistance due

to visceral fat accumulation is also common in PA.29, 30 Moreover, improvement in insulin resistance with normalization of plasma aldosterone levels after surgery for an

aldosterone-producing adenoma has also been reported. These reports suggest that plasma aldosterone levels alone may be the strongest determinant in insulin resistance.31, 32

The association between aldosterone and insulin resistance has been reported not only in PA patients with autonomic hypersecretion of aldosterone, but also in hypertensive patients without

PA.33 In a Japanese study over a 10-year observation period, plasma aldosterone levels were a predictive factor for the development of insulin resistance.34 As the number of risk factors for

metabolic syndrome increases, plasma aldosterone levels rise in a non-renin-dependent manner, thus plasma aldosterone levels are independently associated with metabolic syndrome.35 Plasma

aldosterone levels have often been reported to correlate with waist circumference, plasma insulin levels and the homeostasis model assessment (HOMA) index. In addition, plasma aldosterone

levels are significantly higher in patients with coexisting metabolic syndrome than without.36 In Caucasian patients with essential hypertension, plasma aldosterone levels are significantly

positively correlated with plasma glucose levels, C-peptide and the HOMA index, and, as plasma aldosterone levels increase, insulin sensitivity decreases.37 The relationship between

aldosterone with insulin resistance and metabolic syndrome has been shown in various conditions and ethnic groups.38, 39, 40, 41

The mechanism of how aldosterone influences insulin sensitivity as seen in clinical studies has been reported in basic research studies. This is summarized in Figure 1. Aldosterone directly

suppresses insulin signaling. These effects on insulin signaling are complex, including effects on insulin receptor expression as well as on insulin receptor substrate 1 (IRS-1) and

IRS-2.42, 43, 44, 45 In addition, aldosterone is directly associated with gluconeogenesis in the human and mouse liver; aldosterone increases glucose by stimulating gene expression of

enzymes involved in gluconeogenesis.46, 47 These actions of aldosterone cannot be fully suppressed by RAS inhibitors alone. This worsening of insulin resistance by aldosterone may have a

direct role in increase of the risk for nephropathy progression and the development of cardiovascular events.

The influence of aldosterone on glucose metabolism and metabolic syndrome. Aldosterone is involved in metabolic abnormalities by direct effects other than just hypokalemia.

Furthermore, nighttime hypertension and treatment-resistant hypertension are more likely to occur with decreased insulin sensitivity,48, 49, 50 and, when treatment with an RAS inhibitor is

started, a good blood pressure-lowering response is often absent.51, 52 In diabetic patients, suppression of aldosterone/MR effects before the onset of DM nephropathy can improve insulin

resistance, and this may also be promising for the management of hypertension that is difficult to control with RAS inhibitors alone.

Aldosterone directly contributes to insulin resistance, but conversely, the various actions of aldosterone in epithelial and non-epithelial tissues are enhanced in hyperglycemia. There is a

vicious cycle between the effects of aldosterone and a hyperglycemic state. In epithelial tissue, MR selectivity for aldosterone is regulated by 11β-hydroxysteroid dehydrogenase type 2

(11β-HSD2), and this overcomes the 100-fold difference with plasma levels, aldosterone selectively binds to MRs, and appropriate water and electrolyte balance is maintained. However, in

diabetic patients, renal tubular 11β-HSD2 activity is decreased before the onset of nephropathy; hence, cortisol can bind to MRs, sodium reabsorption is increased and salt-sensitive

hypertension occurs.

In type 2 diabetic patients, including those with early nephropathy, our group has investigated the urinary free cortisone/cortisol ratio as an index of renal 11β-HSD2 activity. In diabetic

patients, regardless of the presence or absence of nephropathy, this enzyme activity is decreased (Figure 2). A decreased intracellular NAD+/NADH ratio has been reported in diabetic rats in

basic experiments.53, 54 This suggests a decrease in activity of 11β-HSD2, for which NAD+ is a cofactor. In fact, decreased renal 11β-HSD2 activity has been shown in diabetic rats, and this

was reversed by treatment with insulin or a MR antagonist.55 Therefore, one mechanism of salt-sensitive hypertension in diabetes is a decrease in renal 11β-HSD2 activity, and this occurs

before the onset of nephropathy.

Changes in renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity in diabetic patients based on the free cortisone/cortisol (E/F) ratio as an index. In 40 patients with type 2

diabetes (DM) treated alone with diet or during oral antidiabetic drug therapy, 24-h urine was collected for measurement of free cortisone (E), free cortisol (F), total tetrahydrocortisone

(THE) and total tetrahydrocortisol (THF) by gas chromatography-mass spectrometry/selective ion monitoring (GC-MS/SIM). The free E/F and THE/THF ratios were compared with normal controls. The

free E/F ratio in diabetic patients significantly decreased regardless of the presence or absence of nephropathy, but the THE/THF ratio did not significantly differ. There was no

significant difference in age between control group and DM patients. Data represent the mean±s.d. (These data were presented at the 71st Annual Meeting of Japan Endocrine Society, 1998).

*P90% of MRs. However, these MRs are in general thought to be transcriptionally inactive and not activated. In this respect, this is very different than that in epithelial tissue. However,

by various mechanisms such as oxidative stress in hyperglycemia, MRs are activated without aldosterone and/or sensitivity of aldosterone for MRs increases, and organ injury by aldosterone

occurs in non-epithelial tissues.56, 57, 58 We previously reported that, in hyperglycemia, aldosterone increases protein synthesis via MRs in cultured cardiomyocytes from the heart, a

non-epithelial tissue.59 Therefore, early treatment with a MR antagonist in diabetic patients may prevent organ damage via MRs in non-epithelial tissue.

On the basis of the previous sections, we will now discuss the clinical use of MR antagonists in DM nephropathy. The Joint Committee on Diabetic Nephropathy in Japan classifies

pre-nephropathy as normoalbuminuria (