Diabetics aided by spironolactone with ACE inhibitors, angiotensin receptor.

The renin-angiotensin-aldosterone system (RAAS) is a well-known regulator of BP, and angiotensin II (AII) plays the primary role in constricting the postglomerular arterioles. This increases both the glomerular hydraulic pressure and the ultrafiltration of plasma proteins—effects that may contribute to chronic renal damage. AII may stimulate renal cell growth, inflammation, and fibrosis.

Recent evidence has implicated aldosterone as another important pathogenic factor in renal pathology (Am J Med. 2006;119:912-919), ac-cording to Kasper Rossing, MD, of the Steno Diabetes Center in Gentofte, Denmark. He spoke about aldosterone blockade during the American Society of Nephrology’s Renal Week 2006 in San Diego.

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In addition to its classic role in increasing sodium reabsorption in the kidney, aldosterone exhibits several effects that may promote fibrosis, including inhibition of plasminogen activator inhibitor-1 and stimulation of transforming growth factor-beta-1. Experimental evidence suggests that aldosterone is an independent contributor to small- and medium-sized arterial injury and nephropathy.

Blockade of the RAAS with ACE inhibitors and angiotensin receptor-blockers (ARBs) decreases proteinuria and nephrosclerosis, but the drugs may not confer optimal protection from the effects of mineralocorticoids on smaller blood vessels. Growing evidence suggests that selective blockade of aldosterone provides renoprotection and de-creases proteinuria beyond the effects of ACE inhibitors and ARBs, independent of beneficial BP effects (Kidney Int. 2004;66:1-9).

The findings support the concept that add-on therapy with a mineralocorticoid receptor antagonist (MRA) may provide more complete inhibition of RAAS than ACE inhibitors or ARBs alone. An MRA may also more effectively reduce proteinuria and progression of renal nephropathy.

Aldosterone escape during long-term treatment with an ARB is associated with enhanced decline in glomerular filtration rate (GFR) in patients with diabetic nephropathy. In a recent study, a group of 63 hypertensive patients with type 1 diabetes and diabetic nephropathy were treated with 100 mg of losartan daily for a mean of 35 months (Diabetologia. 2004;47:1936-1939). Mean plasma aldosterone levels increased from 57 to 102 pg/mL in 26 patients (the “escape” group) and decreased from 83 to 49 pg/mL in 37 patients (the “non-escape” group) during 35 months of treatment with losartan.

The median rate of decline in the GFR was 5.0 mL/min-1/year-1 in the escape group and 2.4 mL/min-1/year-1 in the non-escape group, a significant difference. The increase in plasma aldosterone correlated significantly with the rate of decline in GFR. Levels of renin and angiotensin II increased similarly in both groups during follow-up.

RALES (Randomized Aldactone Evaluation Study) demonstrated that blockade of aldosterone receptors with spironolactone, in addition to standard therapy, significantly de-creases morbidity and mortality in patients with severe heart failure (N Engl J Med. 1999;341:709-717). In this study, 1,663 patients were randomly assigned to receive 25 mg of spironolactone or placebo daily in addition to standard therapy including an ACE inhibitor, a loop diuretic, and digoxin.

The trial was discontinued early, after a mean follow-up of 24 months, because an interim analysis revealed that spironolactone was associated with a 30% decrease in the risk of death and a 35% decrease in the risk of hospitalization for worsening heart failure. Patients treated with spironolactone also experienced significant improvement in heart failure symptoms. Adverse effects included gynecomastia and breast pain in men; the incidence of serious hyperkalemia was minimal in both patient groups.

The efficacy of aldosterone receptor blockade with spironolactone as add-on therapy has been examined in patients with CKD receiving ACE inhibitors or ARBs. Of 45 patients with type 2 diabetes and early nephropathy who were treated with an ACE inhibitor for 40 weeks, 18 patients (40%) had aldosterone escape and 27 patients (60%) were without aldosterone escape (Hypertension. 2003;41:64-68).

Urinary albumin excretion was significantly greater in patients with aldosterone escape than in those without escape. In the 18 patients with escape, spironolactone (25 mg/day) was added to ACE inhibitor treatment. After 24 weeks of combination treatment, urinary albumin excretion decreased 25% and left ventricular mass was significantly reduced without changes in BP.

A group of 59 patients with type 2 diabetes and macroalbuminuria resistant to ACE inhibitors or ARBs were allocated to spironolactone add-on therapy (25-50 mg/day) or placebo (J Hypertens. 2006;24:2285-2292). Albuminuria decreased 41% and BP by 7 mm Hg in the spironolactone group but did not change in the placebo group. During the one-year follow-up, mean estimated GFR decreased by 12.9 mL/min/1.73 m2 in the spironolactone group and by 4.9 mL/min/1.73 m2 in the placebo group.

Similar outcomes were observed in a study of 21 patients with type 2 diabetes and nephropathy during treatment with diuretics and maximally recommended doses of an ACE inhibitor or ARB who received spi-ronolactone add-on therapy (25 mg/day) for eight weeks (Diabetes Care. 2005;28:2106-2112). During the ad-dition of spironolactone, albuminuria decreased by 33%, fractional clearance of albumin decreased by 40%, and 24-hour ambulatory systolic and diastolic BP decreased by 6 and 4 mm Hg, respectively. Hyperkalemia developed in one patient during treatment with spironolactone.

The efficacy of triple therapy with an ACE inhibitor, ARB, and spironolactone was examined in 41 patients with persistent proteinuria during long-term ACE inhibitor therapy (Clin J Am Soc Nephrol. 2006;1:256-262). In patients randomized to receive an ACE inhibitor, ACE + ARB, ACE + spironolactone, or ACE + ARB + spironolactone, the reduction in proteinuria at three months was 1.4%, 15.7%, 42.0%, and 48.2%, respectively.

Triple therapy provided no significant advantage over dual therapy with an ACE inhibitor and spironolactone. The reductions in proteinuria among patients treated with spironolactone-containing regimens were sustained at 6 and 12 months.

Aldosterone blockade is generally well tolerated, but treatment with higher doses of MRA may raise the risk of hyperkalemia. A group of 215 hypertensive patients with diabetic proteinuria were treated with ep-lerenone (200 mg/day), enalapril (40 mg/day), or eplerenone and enalapril (200/10 mg/day) (Am J Hypertens. 2002;15[Part 2]:24A).

Urinary albumin excretion de-creased by 62% in the eplerenone group, 45% in the enalapril group, and 74% in the two-drug group. The proportion of patients withdrawn due to hyperkalemia was 6%, 2%, and 15% in the eprelenone, enalapril, and two-drug groups, respectively.

Strategies to reduce the risk of hyperkalemia during treatment with MRA include the withdrawal of potassium supplements and the use of lowest effective doses of MRA. Potassium levels should be monitored regularly in patients treated with MRA, and discontinuation of RAAS blockade should be considered in patients who become dehydrated. MRA should be used with caution in patients with a severely reduced GFR.