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Current Drug Therapy

ACE INHIBITORS AND ARBS: MANAGING POTASSIUM AND RENAL FUNCTION

Tasnim Momoniat, MBCHB, MRCP (UK), Duha Ilyas, MBBS, MRCP (UK) and Sunil
Bhandari, MBCHB, FRCP, PhD, M CLIN EDU, FHEA
Cleveland Clinic Journal of Medicine September 2019, 86 (9) 601-607; DOI:
https://doi.org/10.3949/ccjm.86a.18024
Tasnim Momoniat
Department of Nephrology, Hull University Teaching Hospitals NHS Trust, East
Yorkshire, UK
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Duha Ilyas
Department of Nephrology, Hull University Teaching Hospitals NHS Trust, East
Yorkshire, UK
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Sunil Bhandari
Department of Nephrology, Hull University, Teaching Hospitals NHS Trust, East
Yorkshire, UK
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* For correspondence: Sunil.Bhandari@hey.nhs.uk

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ABSTRACT

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor
blockers (ARBs) are used primarily to treat hypertension and are also useful for
conditions such as heart failure and chronic kidney disease, independent of
their effect on blood pressure. This article reviews the indications for ACE
inhibitors and ARBs and offers advice for managing their adverse effects,
particularly declining renal function and hyperkalemia.

Key Points

* ACE inhibitors and ARBs reduce proteinuria by lowering the intraglomerular
pressure, reducing hyperfiltration.

* These drugs tend to raise the serum potassium level and reduce the glomerular
filtration rate (GFR). Monitoring the serum potassium and creatinine levels
and the GFR is therefore imperative.

* Despite the benefits, concern for adverse effects including hyperkalemia and
a rise in serum creatinine has led to reluctance to prescribe these drugs,
and they are underused in the patients who may derive the greatest benefit.

> A highly active, water-and alcohol-soluble, basic pressor substance is formed
> when renin and renin-activator interact, for which we suggest the name
> “angiotonin.”
>
> —Irvine H. Page and O. M. Helmer, 1940.1

The renin-angiotensin-aldosterone system regulates salt and, in part, water
homeostasis, and therefore blood pressure and fluid balance through its actions
on the heart, kidneys, and blood vessels.2 Drugs that target this
system—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II
receptor blockers (ARBs)—are used primarily to treat hypertension and also to
treat chronic kidney disease and heart failure with reduced ejection fraction.

Controlling blood pressure is important, as hypertension increases the risk of
myocardial infarction, cerebrovascular events, and progression of chronic kidney
disease, which itself is a risk factor for cardiovascular disease. However, the
benefit of these drugs is only partly due to their effect on blood pressure.
They also reduce proteinuria, which is a graded risk factor 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
glomerular afferent arteriole, reduced sodium delivery to the distal convoluted
tubule, or increased sympathetic activity stimulates the renal juxtaglomerular
apparatus to produce renin (Figure 1). This leads to a cascade of effects
culminating in sodium retention and potassium excretion, thus increasing blood
pressure.

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Figure 1

The renin-angiotensin-aldosterone system and drugs that inhibit it.

ACE inhibitors, as their name indicates, inhibit conversion of angiotensin I to
angiotensin II by ACE, resulting in vasodilation of the efferent arteriole and a
drop in blood pressure. Inhibition of ACE, a kininase, also results in a rise in
kinins. One of these, bradykinin, is associated with some of the side effects of
this class of drugs such as cough, which affects 5% to 20% of patients.4
Elevation of bradykinin is also believed to account for ACE inhibitor-induced
angioedema, an uncommon but potentially serious side effect. Kinins are also
associated with desirable effects such as lowering blood pressure, increasing
insulin sensitivity, and dilating blood vessels.

ARBs were developed as an alternative for patients unable to tolerate the
adverse effects of ACE inhibitors. While ACE inhibitors reduce the activity of
angiotensin II at both the AT1 and AT2 receptors, ARBs block only the AT1
receptors, thereby inhibiting their vasoconstricting activity on smooth muscle.
ARBs also raise the levels of renin, angiotensin I, and angiotensin II as a
result of feedback inhibition. Angiotensin II is associated with release of
inflammatory mediators such as tumor necrosis factor alpha, cytokines, and
chemokines, the consequences of which are also inhibited by ARBs, further
preventing renal fibrosis and scarring from chronic inflammation.3

WHAT IS THE EVIDENCE SUPPORTING THE USE OF ACE INHIBITORS AND ARBS?

ACE inhibitors and ARBs, used singly, reduce blood pressure and proteinuria,
slow progression of kidney disease, and improve outcomes in patients who have
heart failure, diabetes mellitus, or a history of myocardial infarction.5–11

While dual blockade with the combination of an ACE inhibitor and an ARB lowers
blood pressure and proteinuria to a greater degree than monotherapy, dual
blockade has been associated with higher rates of complications, including
hyperkalemia.12–17

RISK FACTORS FOR HYPERKALEMIA

ACE inhibitors and ARBs raise potassium, especially when used in combination.
Other risk factors for hyperkalemia include the following—and note that some of
them are also indications for ACE inhibitors and ARBs:

RENAL INSUFFICIENCY

The kidneys are responsible for over 90% of potassium removal in healthy
individuals,18,19 and the lower the GFR, the higher the risk of
hyperkalemia.3,20,21

Heart failure

Diabetes mellitus6,21–23

Endogenous potassium load due to hemolysis, rhabdomyolysis, insulin deficiency,
lactic acidosis, or gastrointestinal bleeding

Exogenous potassium load due to dietary consumption or blood products

Other medications, eg, sacubitril-valsartan, aldosterone antagonists,
mineralocorticoid receptor antagonists, potassium-sparing diuretics,
beta-adrenergic antagonists, non-steroidal anti-inflammatory drugs, heparin,
cyclosporine, trimethoprim, digoxin

Hypertension

Hypoaldosteronism (including type 4 renal tubular acidosis)

Addison disease

Advanced age

Lower body mass index.

Both hypokalemia and hyperkalemia are associated with a higher risk of
death,20,21,24 but in patients with heart failure, the survival benefit from ACE
inhibitors, ARBs, and mineralocorticoid receptor antagonists outweighs the risk
of hyperkalemia.25–27 Weir and Rolfe28 concluded that patients with heart
failure and chronic kidney disease are at greatest risk of hyperkalemia from
renin-angiotensin-aldosterone system inhibition, but the increases in potassium
levels are small (about 0.1 to 0.3 mmol/L) and unlikely to be clinically
significant.

Hyperkalemia tends to recur. Einhorn et al20 found that nearly half of patients
with chronic kidney disease who had an episode of hyperkalemia had 1 or more
recurrent episodes within a year.

ACE INHIBITORS, ARBS, AND RENAL FUNCTION

Another concern about using ACE inhibitors and ARBs, especially in patients with
chronic kidney disease, is that the serum creatinine level tends to rise when
starting these drugs,29 although several studies have shown that an acute rise
in creatinine may demonstrate that the drug is actually protecting the
kidney.30,31 Hirsch32 described this phenomenon as “prerenal success,” proposing
that the decline in GFR is hemodynamic, secondary to a fall in intraglomerular
pressure as a result of efferent vasodilation, and therefore should not be
reversed.

Schmidt et al,33,34 in a study in 122,363 patients who began ACE inhibitor or
ARB therapy, found that cardiorenal outcomes were worse, with higher rates of
end-stage renal disease, myocardial infarction, heart failure, and death, in
those in whom creatinine rose by 30% or more since starting treatment. This
trend was also seen, to a lesser degree, in those with a smaller increase in
creatinine, suggesting that even this group of patients should receive close
monitoring.

Whether renin-angiotensin-aldosterone system inhibitors provide a benefit in
advanced progressive chronic kidney disease remains unclear.35–37 The
Angiotensin Converting Enzyme Inhibitor (ACEi)/Angiotensin Receptor Blocker
(ARB) Withdrawal in Advanced Renal Disease trial (STOP-ACEi),38 currently under
way, will provide valuable data to help close this gap in our knowledge. This
open-label randomized controlled trial is testing the hypothesis that stopping
ACE inhibitor or ARB treatment, or a combination of both, compared with
continuing these treatments, will improve or stabilize renal function in
patients with progressive stage 4 or 5 chronic kidney disease.

NEED FOR MONITORING

Taken together, the above data suggest close and regular monitoring is required
in patients receiving these drugs. However, monitoring tends to be lax.34,37,39
A 2017 study of adherence to the guidelines for monitoring serum creatinine and
potassium after starting an ACE inhibitor or ARB and subsequent discontinuation
found that fewer than 10% of patients had follow-up within the recommended 2
weeks after starting these drugs.34 Most patients with a creatinine rise of 30%
or more or a potassium level higher than 6.0 mmol/L continued treatment. There
was also no evidence of increased monitoring in those deemed at higher risk of
these complications.

WHAT DO THE GUIDELINES SUGGEST?

ACE INHIBITORS AND ARBS IN CHRONIC KIDNEY DISEASE AND HYPERTENSION

Target blood pressures vary in guidelines from different organizations.4,40–45
The 2017 joint guidelines of the American College of Cardiology and American
Heart Association (ACC/AHA)40 recommend a target blood pressure of 130/80 mm Hg
or less in all patients irrespective of the level of proteinuria and whether
they have diabetes mellitus, based on several studies.46–48 In the elderly,
other factors such as the risk of hypotension and falls must be taken into
consideration in establishing the most appropriate blood pressure target.

In general, a renin-angiotensin-aldosterone system inhibitor is recommended if
the patient has diabetes, stage 1, 2, or 3 chronic kidney disease, or
proteinuria. For example, the guidelines recommend a
renin-angiotensin-aldosterone system inhibitor in diabetic patients with
albuminuria.

None of the guidelines recommend routine use of combination therapy.

ACE INHIBITORS AND ARBS IN HEART FAILURE

The 2017 ACC/AHA and Heart Failure Society of America (HFSA) guidelines for
heart failure49 recommend an ACE inhibitor or ARB for patients with stage C
(symptomatic) heart failure with reduced ejection fraction, in view of the known
cardiovascular morbidity and mortality benefits.

The European Society of Cardiology50 recommends ACE inhibitors for patients with
symptomatic heart failure with reduced ejection fraction, as well as those with
asymptomatic left ventricular systolic dysfunction. In patients with stable
coronary artery disease, an ACE inhibitor should be considered even with normal
left ventricular function.

ARBs should be used as alternatives in those unable to tolerate ACE inhibitors.

Combination therapy should be avoided due to the increased risk of renal
impairment and hyperkalemia but may be considered in patients with heart failure
and reduced ejection fraction in whom other treatments are unsuitable. These
include patients on beta-blockers who cannot tolerate mineralocorticoid receptor
antagonists such as spironolactone. Combination therapy should be done only
under strict supervision.50

STARTING ACE OR ARB THERAPY

Close monitoring of serum potassium is recommended during ACE inhibitor or ARB
use. Those at greatest risk of hyperkalemia include elderly patients, those
taking other medications associated with hyperkalemia, and diabetic patients,
because of their higher risk of renovascular disease.

Caution is advised when starting ACE inhibitor or ARB therapy in these high-risk
groups as well as in patients with potassium levels higher than 5.0 mmol/L at
baseline, at high risk of prerenal acute kidney injury, with known renal
insufficiency, and with previous deterioration in renal function on these
medications.3,41,51

Before starting therapy, ensure that patients are volume-replete and measure
baseline serum electrolytes and creatinine.41,51

The ACC/AHA and HFSA recommend starting at a low dose and titrating upward
slowly. If maximal doses are not tolerated, then a lower dose should be
maintained.49 The European Society of Cardiology guidelines52 suggest increasing
the dose at no less than every 2 weeks unless in an inpatient setting. Blood
testing should be done 7 to 14 days after starting therapy, after any titration
in dosage, and every 4 months thereafter.53

The guidelines generally agree that a rise in creatinine of up to 30% and a fall
in eGFR of up to 25% is acceptable, with the need for regular monitoring,
particularly in high-risk groups.40–42,51,52

WHAT IF SERUM POTASSIUM OR CREATININE RISES DURING TREATMENT?

If hyperkalemia arises or renal function declines by a significant amount, one
should first address contributing factors. If no improvement is seen, then the
dose of the ACE inhibitor or ARB should be reduced by 50% and blood work
repeated in 1 to 2 weeks. If the laboratory values do not return to an
acceptable level, reducing the dose further or stopping the drug is advised.

Give dietary advice to all patients with chronic kidney disease being considered
for a renin-angiotensin-aldosterone system inhibitor or for an increase in dose
with a potassium level higher than 4.5 mmol/L. A low-potassium diet should aim
for potassium intake of less than 50 or 75 mmol/day and sodium intake of less
than 60 mmol/day for hypertensive patients with chronic kidney disease.

Review the patient’s medications if the baseline potassium level is higher than
5.0 mmol/L. Consider stopping potassium-sparing agents, digoxin, trimethoprim,
and nonsteroidal anti-inflammatory drugs. Also think about starting a
non–potassium-sparing diuretic as well as sodium bicarbonate to reduce potassium
levels. Blood work should be repeated within 2 weeks after these changes.

Do not start a renin-angiotensin-aldosterone system inhibitor, or do not
increase the dose, if the potassium level is elevated until measures have been
taken to reduce the degree of hyperkalemia.51

In renal transplant recipients, renin-angiotensin-aldosterone system inhibitors
are often preferred to manage hypertension in those who have proteinuria or
cardiovascular disease. However, the risk of hyperkalemia is also greater with
concomitant use of immunosuppressive drugs such as tacrolimus and cyclosporine.
Management of complications should be approached according to guidelines
discussed above.51

Monitor renal function, potassium. The National Institute for Health and Care
Excellence guideline54 advocates that baseline renal function testing should be
followed by repeat blood testing 1 to 2 weeks after starting
renin-angiotensin-aldosterone system inhibitors in patients with ischemic heart
disease. The advice is similar when starting therapy in patients with chronic
heart failure, emphasizing the need to monitor after each dose increment and to
use clinical judgment when deciding to start treatment. The AHA advises caution
in patients with renal insufficiency or a potassium level above 5.0 mmol/L.49

Sick day rules. The National Institute for Health and Care Excellence encourages
discussing “sick day rules” with patients starting renin-angiotensin-aldosterone
system inhibitors. This means patients should be advised to temporarily stop
taking nephrotoxic medications, including over-the-counter nonsteroidal
anti-inflammatory drugs, in any potential state of illness or dehydration, such
as diarrhea and vomiting. There is, however, little evidence that this advice
can actually reduce the incidence of acute kidney injury.55,56

Potassium-lowering agents. Evidence is emerging to support the use of
potassium-lowering agents to manage hyperkalemia. New compounds such as
patiromer and zirconium cyclosilicate bind potassium in the gastrointestinal
tract so it is excreted fecally. Meaney et al56 performed a systematic review
and meta-analysis of current phase 2 and 3 trials and concluded that these drugs
lowered serum potassium levels by up to 0.70 mmol/L. There may be a significant
role for these novel agents in diseases such as chronic kidney disease and heart
failure, in which hyperkalemia is the limiting factor in the use of
renin-angiotensin-aldosterone system inhibitors.57

OUR RECOMMENDATIONS

Our advice for managing patients receiving ACE inhibitors or ARBs is summarized
in Table 1.

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TABLE 1

Our advice for managing patients receiving ACE inhibitors or ARBs

REFERENCES

1. ↵
1. Page IH,
2. Helmer OM

. A crystalline pressor substance (angiotonin) resulting from the reaction
between renin and renin-activator. Exp Med 1940; 71(1):29–42.
doi:10.1084/jem.71.1.29
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1. Steddon S,
2. Ashman N,
3. Chesser A,
4. Cunningham J

. Oxford Handbook of Nephrology and Hypertension. 2nd ed. Oxford: Oxford
University Press; 2016203–206, 508–509.
Google Scholar
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1. Barratt J,
2. Topham P,
3. Harris K

. Oxford Desk Reference. 1st ed. Oxford: Oxford University Press; 2008
Google Scholar
4. ↵
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ACE inhibitors and ARBs: Managing potassium and renal function
Tasnim Momoniat, Duha Ilyas, Sunil Bhandari
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* ACE INHIBITORS AND ARBs
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