The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy

Abstract

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.

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

“…Increased production of aldosterone and the activation of MR contribute to the development of CKD not only by increasing sodium retention and potassium loss, but also by causing tissue fibrosis and vascular damage (48)(49)(50)(51)(52). The renal protective effects of MR inhibitors are well documented (5,8,(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). However, systemic aldosterone or MR blockade causes hyperkalemia and acute renal insufficiency, thus requiring frequent assessment of serum electrolytes (63).…”

“…Excessive aldosterone production induces glomerulosclerosis, tubular cell injury, and interstitial fibrosis, independently of changes in arterial blood pressure and volume homeostasis, thus contributing to the development of end-stage renal failure (6,7). MR antagonists (e.g., spironolactone and eplerenone) slow the progression of CKD and decrease mortality in patients with hypertension, diabetic nephropathy, or congestive heart failure (8,9). However, their use is limited by hyperkalemia (10).…”

Improvements in the Management of Diabetic Nephropathy

“…Aldosterone antagonists seem to possess antiproteinuric effects when used alone and in combination with ACEI or ARB in both type 1 and type 2 diabetes, but involve a risk of hyperkalemia when applied in patients with reduced GFR [104][105][106]. However, there is no adequate long-term evidence of beneficial effects regarding the prevention of renal impairment through aldosterone antagonists [107,108].…”

The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: Progress and challenges

“…The other reason that aldosterone should be targeted in the treatment of diabetes before the onset of DKD is lying on its direct association with insulin resistance (IR) [24]. The mechanism of how aldosterone influences the insulin sensitivity was involved with the expression of insulin receptor substrate 1 (IRS-1) and IRS-2 [25][26][27].…”