Ask the Expert: What conditions benefit from renin-angiotensin-aldosterone system suppression?
The renin-angiotensin-aldosterone system (RAAS) is an important, complex system that helps regulate systemic blood pressure, vascular volume, and electrolyte balance. The RAAS is activated in cases in which hypotension, hypovolemia, or hyponatremia result in decreased renal perfusion and/or decreased sodium delivery to the renal distal convoluted tubule or in cases in which sympathetic tone is increased. RAAS activation is initially beneficial, but chronic activation may result in detrimental effects (eg, systemic hypertension, cardiac disease, proteinuria). Medications that suppress the RAAS (includingangiotensin-converting enzyme [ACE] inhibitors [eg, enalapril, benazepril], angiotensin II receptor blockers [ARBs; eg, telmisartan], and mineralocorticoid receptor antagonists [eg, spironolactone]) are used for treatment of the detrimental effects of chronic RAAS activation (Table 1).1-7
Indications for Renin-Angiotensin-Aldosterone System Suppression
Proteinuria
Persistent, significant renal proteinuria has been associated with kidney disease progression and poorer outcomes in dogs and cats,8,9 and reduction of proteinuria may decrease kidney disease progression and improve outcomes.10-12
Renal proteinuria may occur in the presence of intraglomerular hypertension, inflammation, amyloid or immune complexes in the glomerular capillaries, or decreased tubular reabsorption of protein.13 RAAS suppression is included in the treatment for proteinuria due to glomerular etiologies. The target urine protein:creatinine ratio (UPCR) with therapy is <0.5 or ≥50% reduction from baseline.14
ACE inhibitors have historically been recommended for RAAS suppression in dogs and cats with proteinuria14-16; however, the International Renal Interest Society (IRIS) and other organizations now preferentially recommend an ARB (eg, telmisartan) over an ACE inhibitor for dogs with proteinuria.17-22 Advantages of ARBs compared with ACE inhibitors include preservation of the beneficial actions of the angiotensin II receptors and a greater reduction in proteinuria.21,22 Similar evidence is available in cats,23 but ACE inhibitors and ARBs are currently equally recommended by IRIS for cats with proteinuria.19
Systemic Hypertension
Systemic hypertension is defined as a systolic blood pressure >160 mm Hg in patients in which situational hypertension (ie, white coat syndrome) is not suspected.24 An ACE inhibitor or ARB is typically the first-choice treatment to control systemic hypertension in dogs. If hypertension is severe (>200 mm Hg) or there is no response to medication, a calcium channel blocker (eg, amlodipine [0.1-0.25 mg/kg PO or up to 0.5 mg/kg PO every 24 hours]) can be added.1,17,24,25
In cats with systemic hypertension without proteinuria, amlodipine (usually 0.625-1.25 mg/cat PO every 24 hours) has historically been the first-choice treatment. Alternatively, recent studies have demonstrated that telmisartan is safe and effective when used for treatment of hypertension in cats with systolic blood pressure <200 mm Hg; an FDA-approved product is available.26,27 In cats with both hypertension and proteinuria, an ACE inhibitor or telmisartan can be added to amlodipine therapy if proteinuria is not adequately controlled with amlodipine therapy and resulting correction of hypertension.24
Hyperaldosteronism
Primary hyperaldosteronism (ie, Conn’s syndrome) in cats may result in hypokalemia and/or systemic hypertension that may be unresponsive to standard therapy. Hyperaldosteronism in cats is caused by an adrenal gland tumor or adrenal gland hyperplasia. Adrenalectomy is the treatment of choice for an adrenal gland tumor. If an adrenal gland tumor is not present or surgery is not an option, medical therapy with spironolactone can be prescribed along with oral potassium supplementation and amlodipine as needed; hypokalemia and/or hypertension typically resolve.28
Cardiac Disease
RAAS suppression with an ACE inhibitor may be included as part of therapy for chronic management of congestive heart failure (CHF) secondary to valvular disease or dilated cardiomyopathy in dogs; these medications are recommended by some but not all cardiologists.29-32 The role of ACE inhibitors for treatment of canine cardiac disease has been extensively researched, with some evidence supporting the benefits of ACE inhibitorsand some evidence indicating ACE inhibitors are not beneficial compared with or when added to pimobendan.33-36 In addition, studies vary on whether ACE inhibitors delay the onset of CHF in dogs with valvular disease or cardiomyopathy.37-39
Spironolactone may be beneficial as part of chronic management of CHF to block the effects of aldosterone.29-32 Although 2 studies have shown benefits of spironolactone for treatment of CHF caused by valvular disease in dogs,40,41 another study did not demonstrate benefit in dogs with CHF caused by valvular disease or dilated cardiomyopathy.42
At the time of writing, there is no evidence that ACE inhibitors are beneficial in cats with subclinical cardiomyopathy or CHF; however, some cardiologists include these drugs as part of chronic therapy for CHF.43 To avoid renal compromise, ACE inhibitors should not be administered to dogs or cats with acute presentation of CHF.29-32,43
Some studies have investigated potential benefits of ARBs instead of ACE inhibitors for treatment of cardiac disease in dogs, but more information is needed before clear recommendations can be made.44-46
Dietary Therapy
The role of dietary therapy in RAAS manipulation, specifically sodium restriction (which has been shown to stimulate the RAAS47), is not well defined in veterinary medicine. Sodium restriction can be beneficial in dogs with CHF caused by valvular disease,48 and modest dietary sodium restriction is recommended as part of medical management of CHF.29 Sodium restriction has not been shown to decrease blood pressure in dogs or cats with hypertension.49,50
Risks of Renin-Angiotensin-Aldosterone System Suppression, Monitoring, & Drug Interactions
RAAS suppression decreases glomerular transcapillary hydraulic pressure, which helps control proteinuria, but can also decrease the glomerular filtration rate, possibly resulting in increased azotemia. RAAS suppression also reduces the effects of aldosterone, which could result in hyperkalemia. Serum creatinine, potassium, and systolic blood pressure should thus be rechecked 1 to 2 weeks after initiation of RAAS suppression or an increase in dose. Monitoring is recommended every 3 months during chronic therapy. Creatinine increase of ≥30%, severe increase in potassium level >6 mEq/L (6 mmol/L), or systolic blood pressure <120 mm Hg may indicate that therapy should be modified.14,24
The safety of RAAS suppression is not known in patients with severe creatinine elevation (late IRIS stage 3 or stage 4). RAAS suppression should therefore be used judiciously with close monitoring or avoided.14,51 ACE inhibitors and ARBs should be avoided in dehydrated or anorexic patients to avoid a severe decrease in glomerular filtration rate.19,24 The safety of a dual RAAS blockade using a combination of an ACE inhibitor with an ARB has been evaluated in multiple studies in human medicine and in one study in veterinary medicine. Due to potential resultant worsening of azotemia and renal function, dual RAAS blockade is currently not recommended.1,21,24,52-56
Concurrent therapy with an ACE inhibitor or ARB and an NSAID may increase the risk for acute kidney injury, and the antihypertensive effect of the ACE inhibitor or ARB may be decreased.57
Conclusion
RAAS suppression is an important part of the management of several conditions in dogs and cats, but the RAAS is complex and incompletely understood. Additional studies are needed to further define RAAS actions, refine the specifics of therapy, and identify any additional indications for RAAS suppression.