CURRENT DRUG THERAPY TASNIM MOMONIAT, MBCHB, MRCP (UK) DUHA ILYAS, MBBS, MRCP (UK) SUNIL BHANDARI, MBCHB, FRCP, PhD, Department of Nephrology, Hull University Department of Nephrology, Hull University M CLIN EDU, FHEA Teaching Hospitals NHS Trust, East Yorkshire, UK Teaching Hospitals NHS Trust, East Yorkshire, UK Department of Nephrology, Hull University Teaching Hospitals NHS Trust, East Yorkshire, UK ACE inhibitors and ARBs: Managing potassium and renal function ABSTRACT A highly active, water- and alcohol-soluble, basic pressor substance is formed when renin and renin- Angiotensin-converting enzyme (ACE) inhibitors and an- activator interact, for which we suggest the name giotensin II receptor blockers (ARBs) are used primarily to “angiotonin.” treat hypertension and are also useful for conditions such —Irvine H. Page and O. M. Helmer, 1940.1 as heart failure and chronic kidney disease, independent of their effect on blood pressure. This article reviews the he renin-angiotensin-aldosterone sys- indications for ACE inhibitors and ARBs and offers advice Ttem regulates salt and, in part, water ho- for managing their adverse effects, particularly declining meostasis, and therefore blood pressure and fluid renal function and hyperkalemia. balance through its actions on the heart, kid- neys, and blood vessels.2 Drugs that target this KEY POINTS system—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers ACE inhibitors and ARBs reduce proteinuria by lowering (ARBs)—are used primarily to treat hyperten- the intraglomerular pressure, reducing hyperfiltration. sion and also to treat chronic kidney disease and heart failure with reduced ejection fraction. These drugs tend to raise the serum potassium level and reduce the glomerular filtration rate (GFR). Monitoring See related editorial, page 608 the serum potassium and creatinine levels and the GFR is Controlling blood pressure is important, as therefore imperative. hypertension increases the risk of myocardial infarction, cerebrovascular events, and pro- Despite the benefits, concern for adverse effects including gression of chronic kidney disease, which itself hyperkalemia and a rise in serum creatinine has led to re- is a risk factor for cardiovascular disease. How- ever, the benefit of these drugs is only partly luctance to prescribe these drugs, and they are underused due to their effect on blood pressure. They also in the patients who may derive the greatest benefit. reduce proteinuria, which is a graded risk fac- tor for progression of kidney disease as well as morbidity and death from vascular events.3 Despite the benefits of ACE inhibitors and ARBs, concern about their adverse effects— especially hyperkalemia and a decline in renal function—has led to their underuse in patients likely to derive the greatest benefit.3 ■ ACE INHIBITORS AND ARBs The renin-angiotensin-aldosterone system is activated when hypoperfusion to the glomeru- lar afferent arteriole, reduced sodium delivery doi:10.3949/ccjm.86a.18024 to the distal convoluted tubule, or increased CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 9 SEPTEMBER 2019 601 ACE INHIBITORS AND ARBs Angiotensinogen also raise the levels of renin, angiotensin I, and angiotensin II as a result of feedback inhibi- Renin tion. Angiotensin II is associated with release Direct renin inhibitor (aliskiren) of inflammatory mediators such as tumor ne- crosis factor alpha, cytokines, and chemokines, Angiotensin I the consequences of which are also inhibited Angiotensin-converting enzyme (ACE) by ARBs, further preventing renal fibrosis and 3 ACE inhibitors (benazepril, captopril, enalapril, lisinopril, scarring from chronic inflammation. ramipril) What is the evidence supporting the use Angiotensin II of ACE inhibitors and ARBs? ACE inhibitors and ARBs, used singly, reduce Angiotensin II receptor blockers (ARBs) (candesartan, irbesartan, losartan, valsartan) blood pressure and proteinuria, slow progression of kidney disease, and improve outcomes in pa- Aldosterone tients who have heart failure, diabetes mellitus, Aldosterone antagonists (spironolactone, eplerenone) or a history of myocardial infarction.5–11 While dual blockade with the combina- Target cells tion of an ACE inhibitor and an ARB low- Mineralocorticoid antagonists ers blood pressure and proteinuria to a greater Increased sodium absorption, potassium excretion, degree than monotherapy, dual blockade has fluid retention been associated with higher rates of complica- tions, including hyperkalemia.12–17 Figure 1. The renin-angiotensin-aldosterone system and drugs that inhibit it. ■ RISK FACTORS FOR HYPERKALEMIA sympathetic activity stimulates the renal jux- ACE inhibitors and ARBs raise potassium, taglomerular apparatus to produce renin (Fig- especially when used in combination. Other ure 1). This leads to a cascade of effects cul- risk factors for hyperkalemia include the fol- The benefit minating in sodium retention and potassium lowing—and note that some of them are also of these drugs excretion, thus increasing blood pressure. indications for ACE inhibitors and ARBs: ACE inhibitors, as their name indicates, Renal insufficiency. The kidneys are re- is only partly sponsible for over 90% of potassium removal inhibit conversion of angiotensin I to angio- 18,19 due to their tensin II by ACE, resulting in vasodilation of in healthy individuals, and the lower the GFR, the higher the risk of hyperkalemia.3,20,21 the efferent arteriole and a drop in blood pres- effect on Heart failure sure. Inhibition of ACE, a kininase, also re- blood pressure Diabetes mellitus6,21–23 sults in a rise in kinins. One of these, bradyki- Endogenous potassium load due to hemo- nin, is associated with some of the side effects lysis, rhabdomyolysis, insulin deficiency, lactic of this class of drugs such as cough, which af- 4 acidosis, or gastrointestinal bleeding fects 5% to 20% of patients. Elevation of bra- Exogenous potassium load due to dietary dykinin is also believed to account for ACE consumption or blood products inhibitor-induced angioedema, an uncommon Other medications, eg, sacubitril-valsar- but potentially serious side effect. Kinins are tan, aldosterone antagonists, mineralocorti- also associated with desirable effects such as coid receptor antagonists, potassium-sparing lowering blood pressure, increasing insulin diuretics, beta-adrenergic antagonists, non- sensitivity, and dilating blood vessels. steroidal anti-inflammatory drugs, heparin, ARBs were developed as an alternative for cyclosporine, trimethoprim, digoxin patients unable to tolerate the adverse effects Hypertension of ACE inhibitors. While ACE inhibitors re- Hypoaldosteronism (including type 4 re- duce the activity of angiotensin II at both the nal tubular acidosis) AT1 and AT2 receptors, ARBs block only the Addison disease AT1 receptors, thereby inhibiting their vaso- Advanced age constricting activity on smooth muscle. ARBs Lower body mass index. 602 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 9 SEPTEMBER 2019 MOMONIAT AND COLLEAGUES Both hypokalemia and hyperkalemia are as- currently under way, will provide valuable sociated with a higher risk of death,20,21,24 but in data to help close this gap in our knowledge. patients with heart failure, the survival benefit This open-label randomized controlled trial from ACE inhibitors, ARBs, and mineralocor- is testing the hypothesis that stopping ACE ticoid receptor antagonists outweighs the risk inhibitor or ARB treatment, or a combina- of hyperkalemia.25–27 Weir and Rolfe28 conclud- tion of both, compared with continuing these ed that patients with heart failure and chronic treatments, will improve or stabilize renal kidney disease are at greatest risk of hyperka- function in patients with progressive stage 4 lemia from renin-angiotensin-aldosterone sys- or 5 chronic kidney disease. tem inhibition, but the increases in potassium levels are small (about 0.1 to 0.3 mmol/L) and ■ NEED FOR MONITORING unlikely to be clinically significant. Taken together, the above data suggest close Hyperkalemia tends to recur. Einhorn et and regular monitoring is required in patients al20 found that nearly half of patients with receiving these drugs. However, monitoring chronic kidney disease who had an episode tends to be lax.34,37,39 A 2017 study of adher- of hyperkalemia had 1 or more recurrent epi- ence to the guidelines for monitoring serum sodes within a year. creatinine and potassium after starting an ACE inhibitor or ARB and subsequent dis- ■ ACE INHIBITORS, ARBs, AND RENAL continuation found that fewer than 10% of FUNCTION patients had follow-up within the recom- Another concern about using ACE inhibitors mended 2 weeks after starting these drugs.34 and ARBs, especially in patients with chronic Most patients with a creatinine rise of 30% kidney disease, is that the serum creatinine or more or a potassium level higher than 6.0 level tends to rise when starting these drugs,29 mmol/L continued treatment. There was also although several studies have shown that an no evidence of increased monitoring in those acute rise in creatinine may demonstrate that deemed at higher risk of these complications. the drug is actually protecting the kidney.30,31 Cough affects Hirsch32 described this phenomenon as “pre- ■ WHAT DO THE GUIDELINES SUGGEST? 5% to 20% renal success,” proposing that the decline in ACE inhibitors and ARBs in chronic kidney GFR is hemodynamic, secondary to a fall in disease and hypertension of patients intraglomerular pressure as a result