Nephrol Dial Transplant (2019) 34: iii62–iii68
doi: 10.1093/ndt/gfz220
Tailoring treatment of hyperkalemia
Maxime Coutrot1,2,3, Francois Dépret1,2,3 and Matthieu Legrand2,3,4,5
REVIEW
1
Department of Anesthesiology and Critical Care and Burn Unit, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris,
France, 2INSERM UMR-S942, Institut National de la Santé et de la Recherche Médicale, Lariboisiére Hospital, Paris, France, 3University of Paris,
Paris Diderot, France , 4Department of Anesthesiology and Peri-Operative Care, University of California, San Francisco, San Francisco, CA, USA
and 5INI-CRCT Network, Nancy, France
Correspondence to: Matthieu Legrand; E-mail: matthieu.legrand@ucsf.edu
ABSTRACT
Hyperkalemia is a common electrolyte disorder that may be
rapidly life-threatening because of its cardiac toxicity.
Hyperkalemia risk factors are numerous and often combined in
the same patient. Most of the strategies to control serum potas-
sium level in the short term have been used for decades.
However, evidence for their efficacy and safety remains low.
Treatment of hyperkalemia remains challenging, poorly codi-
fied, with a risk of overtreatment, including short-term side
effects, and with the priority of avoiding unnecessary hospital
stays or chronic medication changes. Recently, new oral treat-
ments have been proposed for non-life-threatening hyperkale-
mia, with encouraging results. Their role in the therapeutic
arsenal remains uncertain. Finally, a growing body of evidence
suggests that hyperkalemia might negatively impact outcomes
in the long term in patients with chronic heart failure or kidney
failure through underdosing or withholding of cardiovascular
medication (e.g. renin–angiotensin–aldosterone system inhibi-
tors). Recognition of efficacy and potential side effects of treat-
ment may help in tailoring treatments to the patient’s status
and conditions. In this review we discuss how treatment of
hyperkalemia could be tailored to the patient’s conditions and
status, both on the short and mid term.
Keywords: chronic kidney disease, hyperkalemia, renin–
angiotensin–aldosterone system inhibitor
INTRODUCTION
Hyperkalemia is a frequent electrolyte disorder, potentially rap-
idly life-threatening due to the risk of cardiac arrhythmia or
conduction disorders. The association between hyperkalemia
and mortality has been well described in various populations.
In the short term, the benefit of treating immediately life-
threatening hyperkalemia with cardiac consequences is rather
consensual. However, the best strategies to be applied and the
indications for treatments in mild hyperkalemia or in the ab-
sence of cardiac consequences are much more uncertain. In ad-
dition to direct mortality due to its cardiac consequences,
C The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
V iii62
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hyperkalemia might also be indirectly responsible for an in-
crease in morbidity (and mortality) due to the side effects of
treatments used and/or changes in chronic cardiovascular med-
ications, occluding their benefits.
RISK FACTORS FOR HYPERKALEMIA:
IMPORTANT CONSIDERATIONS FOR
TREATMENT
The incidence of hyperkalemia depends on the studied popula-
tion and exposure to risk factors, for example, variations in the
proportions of patients receiving one or more hyperkalemic
treatment, such as renin–angiotensin–aldosterone system
inhibitors (RAASis) [1].
Altered renal function is the major risk factor for hyperkale-
mia [2–5]. The risk for hyperkalemia has been largely associated
with a decrease in estimated glomerular filtration rate (eGFR),
with a reported odds ratio of 1.25 for each 5 mL/min decrease
of eGFR and up to 30% of kalemia >5.5 mmol/L in patients
with Stage 4 chronic kidney disease (CKD) [3, 6]. Renal func-
tion is therefore a key factor to consider when assessing the risk
of hyperkalemia and the likelihood of rapid control of serum
potassium levels. In other words, the probability of pseudo-
hyperkalemia and rapid reversal of mild hyperkalemia are the
two situations more likely to occur in a patient with preserved
renal function compared with a patient with renal failure.
The occurrence of hyperkalemia is a common adverse event
after the introduction of treatments such as RAASi, with an in-
cidence ranging from 6% up to 10% [7–10]. Severe hyperkale-
mia (>6 mmol/L) occurs in up to 3% of patients following
mineralocorticoid receptor antagonist (MRA) introduction
[11–14]. Once again, the impact of renal function on the risk of
developing hyperkalemia is major. The incidence of hyperkale-
mia after angiotensin-converting enzyme inhibitors (ACEIs) or
angiotensin receptor blockers (ARBs) initiation in patients with
preserved renal function is low, at 2–4% [3, 7, 15]. However,
hyperkalemia was reported in 10% of patients with kidney
disease on ACEIs/ARBs [4]. There is a stepwise increase of the
incidence of hyperkalemia with CKD severity after the
introduction of ACEIs/ARBs, reaching 51% and 29% for kale-
mia >5 mmol/L and >5.5 mmol/L, respectively, in CKD Stage
4 patients [6, 15, 16]. The occurrence of hyperkalemia after
b-blockers introduction seems low and similar compared with
after ACEIs/ARBs (4% for kalemia >5.5 mmol/L) in patients
with preserved kidney function. This risk increases in patients
with CKD [15]. Finally, the combination of these different risk
factors in the same patient greatly increases the risk of hyperka-
lemia. Indeed, the reported incidence of hyperkalemia in
patients receiving a combination of treatments including
ACEIs/ARBs, b-blockers and MRAs reached 20% [12, 17].
IMPACT OF HYPERKALEMIA ON OUTCOMES
VARIES ACROSS SETTINGS
Association of kalemia and outcomes
Many studies have reported an association between kalemia
and mortality, following a U-shaped curve [2, 3, 5, 18]. A recent
international meta-analysis found an adjusted hazard ratio for
all-cause mortality of 1.22 [95% confidence interval (CI) 1.15–
1.29] for kalemia >5.5 mmol/L compared with the mean kale-
mia of 4.2 mmol/L [2]. Mortality appeared to be lowest for kale-
mia levels between 4.0 and 4.5 mmol/L. For the same level of
hyperkalemia, all-cause mortality has been reported higher for
patients with associated comorbidities such as CKD, heart fail-
ure (HF) or diabetes mellitus compared with patients without
these conditions [5]. Kalemia <4.5 mmol/L and 5.5 mmol/L
has been associated with an increased risk of cardiovascular
events [18]. How the treatment of hyperkalemia affects these
outcomes is largely unknown.
BENEFITS AND RISKS OF TREATMENTS OF
HYPERKALEMIA: WHO SHOULD BE
TREATED?
Expert recommendations for the treatment of hyperkalemia in-
clude detection of electrical changes on electrocardiograms
(EKGs), potassium levels (i.e. >6 mmol/L) and/or rapid
changes that define severe or life-threatening hyperkalemia, re-
quiring immediate treatment [19]. Two categories of patients
need to be differentiated. The first category is patients with so-
called immediate life-threatening hyperkalemia, in whom ur-
gent treatment is required. The second category is represented
by patients with non-severe hyperkalemia. In the second cate-
gory, the objectives of the treatment of hyperkalemia, summa-
rized in Table 1, are mostly to allow the maintenance of
treatment over the long term while avoiding hospitalizations
and unnecessary overtreatment. Decisions to perform an EKG
to assess immediate cardiac consequences, to manage
inpatient care or to determine the threshold(s) to allow outpa-
tient treatment are debated and are still largely dependent on
clinician assessment, medical history and the serum potassium
level.
In our opinion, the diagnosis of hyperkalemia should fall un-
der the umbrella of a ‘life-threatening’ condition in any unstable
condition such as decompensated HF, acute kidney
injury (AKI), other acute organ failures or shock (Table 1).
The treatment of these associated conditions and causes of
Tailoring treatment of hyperkalemia
hyperkalemia is key (e.g. correction of shock, treatment of the
cause of AKI and fluid status correction).
EKG changes or not?
In case of hyperkalemia, cardiac conduction modifications
are induced by modification of the potassium ion (Kþ) gradient
between intra- and extracellular compartments [20]. There is a
very poor association between serum potassium level and EKG
changes [21, 22], and the absence of EKG changes should not
preclude treatment. However, observation of EKG changes
should trigger urgent administration of cardiomyocyte mem-
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brane stabilization and serum potassium–lowering treatments.
The first classic EKG manifestation of hyperkalemia is peaked
T-waves that signal myocardial hyperexcitability [23]. Then
myocardial conduction disorders appear (i.e. prolonged PR,
QRS widening, loss of P-waves, bradycardia and ultimately elec-
tromechanical dissociation).
Cardiac membrane stabilization
Calcium salts stabilize the cardiomyocyte membrane by in-
ducing intracellular sodium entry that restores a rapid depolari-
zation slope [24]. The effect is fast (within 5 min) and expected
to last between 30 and 60 min [22]. In case of calcium salt utili-
zation, the clinician should check that the perfusion is not sub-
cutaneous, due to the risk of skin necrosis in case of
extravasation [25]. It is not recommended to use calcium salt in
patients treated with digoxin; however, no human study has
reported an increased risk of cardiac toxicity in case of co-
administration [26]. Hypertonic sodium may be an alternative
treatment to protect the heart from conduction disorders in
patients with contraindications to calcium salts [24].
Potassium transfer
Three different treatments are commonly used to decrease
serum potassium levels (i.e. insulin dextrose, b2-agonists and
sodium bicarbonate). All three act by indirectly activating
the sodium–potassium adenosine triphosphatase (Naþ/Kþ
ATPase) pump [22].
Insulin dextrose. Insulin dextrose is efficient to decrease the
serum potassium level via activation of Naþ/Kþ ATPase after
insulin fixation to its receptor. Its use decreases the potassium
level by 0.5–1 mmol/L [22]. The main side effects are glycemic
variations (i.e. hyper- or hypoglycemia). In a recent review of
the different scheme of insulin/glucose administration, the
authors found no statistically significant difference in the mean
decrease in serum potassium concentration at 60 min between
studies in which insulin was administered as an infusion of 20
U over >60 min and studies in which 10 U of insulin were ad-
ministered as a bolus or studies in which 10 U of insulin were
administered as an infusion [27]. The incidence of hypoglyce-
mia ranges from 5% up to 75% depending on the protocol and
the definition used. A high dose of glucose (60 g with the ad-
ministration of 20 U of insulin or 50 g with the administration
of 10 U of insulin) was reported to be associated with less hypo-
glycemia [27]. The protocols associated with fewer hypoglyce-
mic episodes appear to be 5 U of rapid insulin þ25 g of glucose
or 0.1 U/kg of body weight (to a maximum of 10 U) [28, 29].
iii63
Table 1. Guidance proposal for hyperkalemia managementa

When kalemia should be monitored?b

Underlying pathology CKD, AKI, HF
Medications RAASi (ACEIs, ARBs, MRAs), b-blockers, diabetes mellitus
Hypokalemia drugs discontinuation (i.e. loop diuretics,
Kþ binders)
When performing EKG should be considered?
Any new Kþ >6.0 mmol/L
Kþ >5.5 mmol/L with unstable condition (i.e. AKI, shock, decompensated HF)
Which patients should be considered for hospitalization?
Kþ >6.5 mmol/L
Kþ >5.5 mmol/L with  EKG signs of hyperkalemia (cardiac monitoring in any case)

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 AKI, decompensated HF, and any unstable condition
 Outpatient monitoring not possible
Which treatment for hyperkalemia?
 Hospital management with cardiac and  Outpatient management possible
close Kþ monitoring
Assess need for membrane stabilization with  Potassium level monitoring
calcium salt (or hypertonic sodium if calcium  Kþ binders treatment
salt contraindicated or not available)  Consider loop diuretics if fluid overload
Emergency treatment:
 Insulin/glucose and/or nebulized b2-agonist
(combined if severe hyper Kþ >6.5 mmol/L or EKG signs)
 And consider hypertonic sodium bicarbonate
if severe metabolic acidosis
 Consider RRT if ESKD or severe AKI
 Consider loop diuretics as an adjunctive
treatment if fluid overload
How to manage patients with hyperkalemic chronic medications?
 Kþ >6.0 mmol/L or Kþ >5.5 mmol/L with EKG signs  Kþ ¼ 5.5–6.0 mmol/L without EKG signs
or unstable condition
 Temporary discontinuation of RAASis until regression  Temporary discontinuation of RAASis if mild worsening renal
of EKG signs and normokalemia (and eventually AKI resolution)c function or serum potassium level uncontrolledb
 Otherwise, maintenance of treatments such as RAASi
(or only a decrease in the dose) should be strongly considered
if not unstable condition
In all cases, target a serum potassium level between 4 and 4.5 mmol/L
a
Note these suggestions are informative and should be considered along with the patient condition and setting.
b
Adjust kalemia measurement intervals to the situation (closer monitoring after introduction or increasing dose of medication at risk of hyperkalemia, association of risks factors, acute
event).
c
We suggest reintroducing the treatments after resolution of the unstable condition (e.g. AKI) and up-titration under serum Kþ and renal function monitoring.
BMI, body mass index; ESKD, end-stage kidney disease.

Of note, the risk of hypoglycemia occurs within 2–3 h after the
bolus and thus justifies close glycemic monitoring after the in-
fusion [30]. The incidence of acute and transient hyperglycemia
due to insulin dextrose and its consequences are not well docu-
mented and the potential consequences are poorly appreciated
(i.e. vascular dysfunction, osmotic diuresis and organ injury)
[31, 32].
b2-agonists. b2-agonists decrease the serum potassium level
through two different pathways: first, via increased secretion of
endogenous insulin and second, via the activation of Naþ/Kþ
ATPase after stimulation of the b2-receptors in the muscle and
liver. Albuterol is efficient to decrease the serum potassium level
in a dose-dependent manner, 20 mg being more efficient than
10 mg [33]. There is no difference in the serum potassium level
decrease between routes of administration (i.e. intravenous or
inhaled), but intravenous administration is associated with
more cardiovascular side effects. Inhaled salbutamol (10 mg)
appears as effective as 10 U of insulin dextrose to decrease the
serum potassium level [34]. Due to the increased risk of tachy-
cardia and supraventricular tachycardia (i.e. auricular fibrilla-
tion), the risk:benefit ratio of b2-agonists should be weighed in
patients with cardiomyopathy (e.g. non-stabilized coronary ar-
tery disease or HF). Furthermore, some patients (including but
not limited to patients treated with b-blockers or elderly
patients) may be resistant to b2-agonists [35]. Therefore insulin
dextrose or an association of insulin/glucose and b2-agonists
should probably be considered as first-line therapy in patients
treated with b-blockers or patients with life-threatening
hyperkalemia.
Sodium bicarbonate. Despite conflicting data in the litera-
ture about the ability of sodium bicarbonate to lower the serum
potassium level, recent data suggest that sodium bicarbonate is
efficient to decrease the serum potassium level. In an animal
study (hyperkalemic calves), the kalemia decrease was immedi-
ate after the end of the perfusion of bicarbonate, with a mean
decrease of kalemia of 1.5 mmol/L 30 min after the infusion in

iii64 M. Coutrot et al.

the bicarbonate group [36]. A recent randomized controlled
trial (RCT) evaluated the effect of sodium bicarbonate (4.2%)
on outcome in patients admitted to intensive care unit with a
Sequential Organ Failure Assessment score >4 and/or lactate-
mia >2 mmol/L associated with severe acidemia (pH 7.20,
partial pressure of carbon dioxide 45 mmHg and sodium bi-
carbonate concentration 20 mmol/L) [37]. In this study the
authors observed a significant decrease in serum potassium
level in patients receiving sodium bicarbonate 4 h after the be-
ginning of the perfusion. Sodium bicarbonate in the treatment
of patient with hyperkalemia should probably be restricted to
patients with metabolic acidosis and hypovolemia. Due to the
uncertainty of the serum potassium–lowering effect of sodium
bicarbonate, it should probably be used in combination with
other treatments (e.g. insulin glucose) in life-threatening hyper-
kalemia. When used, ionized calcemia should be monitored
due to the risk of hypocalcemia [37].
Increased potassium urinary excretion with diuretics
Diuretic and kaliuretic responses to loop diuretics infusion are
variable and unpredictable, exposing patients to the risk of failure
to decrease serum potassium and inducing hypokalemia and
hypovolemia. Therefore loop diuretics should not be considered
as a first-line emergency treatment of hyperkalemia. They must
be titrated and considered only in case of fluid overload (i.e. clini-
cal oedema with turgescent jugular vena, high central venous
pressure and dilated inferior vena cava on echography).
Renal replacement therapy
Renal replacement therapy (RRT) should be considered in
patients with severe hyperkalemia associated with severe AKI
or CKD and resistant to medical treatment. When the conduc-
tion method is used, a potassium concentration bath <2 mmol/
L can lead to too fast a decrease in the serum potassium level,
exposing the patient to the risk of hypokalemia and its cardiac
consequences and to a hyperkalemic rebound [38].
Table 2. Treatments of hyperkalemia: doses and expected effects
Treatment Dose
Membrane stabilization
Calcium salt 10–20 mL (20%)
Hypertonic sodium 10–20 mL NaCl (20%)
100 mL of 8.4% intravenous sodium bicarbonate
Intracellular Kþ transfer
Insulin/dextrose 5 U/25 g
b2 mimetics 10 mg salbutamol
Elimination
Loop diuretics Depending on kidney function and fluid overload level
RRT Variable
Absorption
SPS 15–60 g/day
Patiromer 8.4–25.2 g/day
ZS-9 10 g three times/day
Tailoring treatment of hyperkalemia
WHICH TREATMENT FOR NON-LIFE-
THREATENING HYPERKALEMIA?
To date, no consensus exists on which patients would/should
benefit from treatment for non-life-threatening hyperkalemia.
Our proposal is summarized in Tables 1 and 2.
While treatment options, especially in outpatients, were lim-
ited to ion exchange resins and kaliuretic diuretics (in addition
to a low potassium diet), promising new treatments are emerg-
ing and could contribute to the optimization of cardiovascular
treatments. Their cost and lack of comparative studies with
available treatments, however, limit their wide implementation.
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Dedicated trials in acute hyperkalemia and cost–effectiveness
analysis should be performed before generalizing the use of new
potassium binders in acute hyperkalemia management.
Sodium polystyrene sulphonate
Sodium polystyrene sulphonate (SPS) exchanges sodium
non-specifically with potassium in the colon (also exchanging
sodium with magnesium, calcium and ammonium). To date,
no RCT has evaluated SPS in the acute setting. Furthermore,
SPS use has been associated with potentially severe side effects
(e.g. colon necrosis, perforation) [39]. SPS should not be con-
sidered as a therapeutic option to treat acute hyperkalemia. In
an RCT published in 2015 comparing SPS with placebo in 33
patients with CKD and treated for 7 days, SPS showed a signifi-
cant reduction in the serum potassium level in patients receiv-
ing SPS compared with placebo (1.25 6 0.57 versus
0.21 6 0.29 mmol/L, respectively; P < 0.001). More gastroin-
testinal side effects were observed with SPS [40]. SPS has not yet
been compared with more recently released treatments of
hyperkalemia [i.e. patiromer and sodium zirconium cyclosili-
cate (ZS-9)].
Patiromer
Compared with SPS, patiromer is a sodium-free, potassium-
binding polymer that exchanges calcium for potassium. It is
now available in North America and the European Union for
hyperkalemia management. It has been evaluated for the man-
agement of chronic hyperkalemia in RCTs and has been shown
Effect on kalemia Delay/peak of effect
None Immediate
0.47 6 0.31 mmol/L Immediate
0.79 6 0.25 mmol/L 15/60 min
0.5 6 0.1 mmol/L 5–30/60 min
Variable Variable
1 mmol/L Minutes
>1 mmol/L Hours
Unknown Variable
0.21 6 0.07 mmol/L 7h
0.6 6 0.2 mmol/L 2h
iii65
to decrease the serum potassium level by 0.35 mmol/L (95%
CI 0.48–0.22) to 1.01 (95% CI 1.07 to 0.95) within
4 weeks, depending on the dose and the clinical setting [41–44].
In a recently published double-blind randomized trial among
patients with resistant hypertension and CKD, treatment with
patiromer enabled more patients to continue treatment with
spironolactone (86% versus 66%) with less hyperkalemia [45].
The most frequent side effects described are digestive (i.e. diar-
rhoea or constipation) and electrolytic disturbances (i.e. hypo-
kalemia and hypomagnesemia). Patiromer has been evaluated
in a trial in emergency departments, but the results are not yet
available [Relypsa for ED Acute Hyperkalemia Control and
Reduction (REDUCE study), NCT02933450].
ZS-9
ZS-9 selectively binds potassium in the gastrointestinal tract
through ionic bonding with more specificity than SPS and
patiromer. One gram of ZS-9 binds 3 mEq of potassium [46].
ZS-9 was developed for the treatment of hyperkalemia, and its
efficacy in this setting has been demonstrated in Phase 2 and 3
trials [47, 48]. In a subgroup of patients with severe hyperkale-
mia (>6 mmol/L), Kosiborod et al. [49] observed a rapid de-
crease in the serum potassium level with a median time to
obtain a serum potassium level <6.0 mmol/L of 1.1 h and 4.0 h
to reach a level 5.5 mmol/L. These data suggest that ZS-9
could be part of the therapeutic arsenal for hyperkalemia man-
agement in acute settings, but this still needs confirmation in
specific RCTs. To date, only minor side effects have been
described (i.e. gastrointestinal disturbance and oedema). No
study has yet evaluated the efficacy of ZS-9 compared with
patiromer.
MANAGEMENT OF CHRONIC MEDICATIONS
INDUCING HYPERKALEMIA
Several studies have shown that hyperkalemia is an
important cause for modification or cessation of treatments,
particularly for cardiovascular medications, including ACEIs/
ARBs [4, 18, 50].
In a study by Chang et al. [6], among ACEIs/ARBs users,
11% of patients with kalemia >5 mmol/L and 24% of patients
with kalemia >5.5 mmol/L had discontinuation of ACEI or
ARB treatment, respectively, versus 4.8% of patients without
hyperkalemia. In the same study, almost half of patients discon-
tinued potassium-sparing diuretics in case of hyperkalemia. Up
to 50% of ACEI/ARB treatment changes were described due to
mild hyperkalemia (serum potassium <5.5 mmol/L) [4, 51].
Epstein reported RAASi discontinuation in 16% of patients
with a maximum dose and mild hyperkalemia, while 22% of
patients had their dose down-titrated [51]. In the Biology Study
to Tailored Treatment in Chronic Heart Failure, baseline kale-
mia was independently associated with lower ACEI/ARB dos-
age [52, 53]. Hyperkalemia is also frequently associated with the
absence of ACEI/ARB treatment in patients with CKD [54].
Hyperkalemia was reported as one of the main reasons for
MRA non-use or suboptimal dosing (in 12% of the 53 known
reasons) in HF patients [50, 55]. RAASi discontinuation or
iii66
submaximum dose because of hyperkalemia is therefore a po-
tential source of accelerated progression to chronic and end-
stage renal disease and/or HF. A recent study evaluating the
economic impact of maintaining normal kalemia, and thus op-
timal ACEI/ARB therapy, suggests benefits in life expectancy
while also decreasing cost [56].
The impact of hyperkalemia on the prognosis in patients on
RAASis appears highly uncertain. The impact on the long-term
prognosis may be indirect due to therapeutic changes triggered
by hyperkalemia, offsetting all or part of the benefits of these
treatments [57]. In HF patients treated with ACEIs/ARBs,
hyperkalemia (>5.0 mmol/L) was not associated with mortality
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and/or hospitalization for HF [52, 58]. Hyperkalemia
(>5.0 mmol/L) was also not associated with the worst outcome
in patients with CKD after ACEIs/ARBs initiation therapy [58].
However, the change in kalemia was mild, as <2% of patients
had kalemia >5.5 mmol/L. The combination of ACEIs and
ARBs was associated with an increased risk of acute renal failure
and hyperkalemia (>6mmol/L) in patients with diabetic ne-
phropathy (with a high prevalence of HF), while mortality was
not affected [59]. However, our group reported that the associa-
tion between serum potassium level and mortality remained in
patients admitted to the emergency department for decompen-
sated HF and treated with ACEIs/ARBs [60]. Hyperkalemia is
also frequent with MRAs (33 and 15% of kalemia >5.0 and
5.5 mmol/L, respectively). It was not found to be associated
with mortality after MRA introduction [12, 61]. Thus no death
was attributable to hyperkalemia in the eplerenone group in
the Eplerenone Post–Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study [12, 62]. However, mo-
dalities of hyperkalemia management were not reported.
After publication of the Randomized Aldactone Evaluation
Study, increased prescriptions of spironolactone were ob-
served, with a simultaneous increased rate of hospitalization
and mortality (from 0.3 to 2 for 1000 patients) [11]. This ob-
servation underlines the need for proper patient selection
and monitoring with rigorous surveillance [63].
To summarize, the decision to down-titrate or interrupt
chronic medication such as ACEis, ARBs or MRAs that could
cause hyperkalemia must be weighed against the risk of
cancelling their potential protective effects. We need studies
evaluating strategies in these populations and guidance in these
conditions. In the meantime, reintroduction should certainly be
discussed on a case-by-case basis in stable patients once the risk
of hyperkalemia has been evaluated and controlled.
CONCLUSION
Adequate identification of high-risk patients should allow early
detection of hyperkalemia in order to minimize the risks associ-
ated with potassium cardiac toxicity. However, the best
therapeutic strategies in the acute setting remain largely under-
explored and the benefit:risk ratio poorly explored. Future
research should explore the best therapeutic option for treat-
ment of acute hyperkalemia (i.e. treatments lowering serum po-
tassium and the need for hospitalization) (Table 3). In non-
acute settings, the objective is often to maintain cardiovascular
M. Coutrot et al.
Table 3. Examples of clinical scenarios and suggested therapeutic strategies
Clinical scenario Hospitalization
Patient with AKI and decompensated HF þ 
Plasma Kþ of 5.7 mmol/L
Patient with history of myocardial infarction, in sepsis þ þ
with AKI and hypovolemia
Plasma Kþ of 6.3 mmol/L
Patient with stable HF  Not available
Plasma Kþ of 5.4 mmol/L
Immediate stable postoperative kidney transplant with þ 
urine output of 300 mL >2 h
Plasma Kþ of 5.4 mmol/L
Immediate stable postoperative kidney transplant with þ 
urine output of 20 mL >2 h, history of unstable
diabetes
Plasma Kþ of 5.4 mmol/L
treatments at the optimal doses and in combination and avoid
unnecessary hospitalizations.
ACKNOWLEDGEMENTS
This article was published as part of a supplement financially
supported with an educational grant from Vifor Fresenius
Medical Care Renal Pharma and AstraZeneca with no influ-
ence on its content.
CONFLICT OF INTEREST STATEMENT
M.C. declares no conflicts. F.D. received grants from the
French Ministry of Health, research support from Sphingotec
and lecture fees from Sedana Medical, all outside the submit-
ted work. M.L. received grants from the French Ministry of
Health, research support from Sphingotec, lecture fees from
Baxter and Fresenius and consulting fees from Novartis, all
outside the submitted work.
REFERENCES
1. Truhlár A, Deakin CD, Soar J et al. European resuscitation council guide-
lines for resuscitation 2015. Resuscitation 2015; 95: 148–201
2. Kovesdy CP, Matsushita K, Sang Y et al. Serum potassium and adverse out-
comes across the range of kidney function: a CKD prognosis consortium
meta-analysis. Eur Heart J 2018; 39: 1535–1542
3. Nakhoul GN, Huang H, Arrigain S et al. Serum potassium, end-stage renal
disease and mortality in chronic kidney disease. Am J Nephrol 2015; 41:
456–463
4. Jun M, Jardine MJ, Perkovic V et al. Hyperkalemia and renin-angiotensin
aldosterone system inhibitor therapy in chronic kidney disease: a general
practice-based, observational study. PLoS One 2019; 14: e0213192
5. Collins AJ, Pitt B, Reaven N et al. Association of serum potassium with all-
cause mortality in patients with and without heart failure, chronic kidney
disease, and/or diabetes. Am J Nephrol 2017; 46: 213–221
6. Chang AR, Sang Y, Leddy J et al. Antihypertensive medications and the
prevalence of hyperkalemia in a large health system. Hypertension 2016; 67:
1181–1188
7. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe
congestive heart failure. Results of the Cooperative North Scandinavian
Tailoring treatment of hyperkalemia
EKG changes Preferred treatment options
Insulin/glucose
Loop diuretics if congestive
Avoid b2-agonists and sodium bicarbonate
Calcium slat
Insulin/glucose þ sodium bicarbonate
Avoid b2-agonists
RRT if persistent and severe AKI
Kþ binders
Recontrol serum potassium level
Decrease or stop chronic medication if hyperkalemia
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persists
Recontrol serum potassium level
Inhalated b2-agonists
Consider loop diuretics if congestive
RRT if delayed graft function confirmed
Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316:
1429–1435
8. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk
factors associated with myocardial infarction in 52 countries (the
INTERHEART study): case-control study. Lancet 2004; 364: 937–952
9. McMurray JJV, Ostergren J, Swedberg K et al. Effects of candesartan in
patients with chronic heart failure and reduced left-ventricular systolic func-
tion taking angiotensin-converting-enzyme inhibitors: the CHARM-Added
trial. Lancet 2003; 362: 767–771
10. Young JB, Dunlap ME, Pfeffer MA et al. Mortality and morbidity reduction
with Candesartan in patients with chronic heart failure and left ventricular
systolic dysfunction: results of the CHARM low-left ventricular ejection
fraction trials. Circulation 2004; 110: 2618–2626
11. Juurlink DN, Mamdani MM, Lee DS et al. Rates of hyperkalemia after pub-
lication of the randomized aldactone evaluation study. N Engl J Med 2004;
351: 543–551
12. Pitt B, Bakris G, Ruilope LM et al. Serum potassium and clinical outcomes
in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy
and Survival Study (EPHESUS). Circulation 2008; 118: 1643–1650
13. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbid-
ity and mortality in patients with severe heart failure. N Engl J Med 1999;
341: 709–717
14. Navaneethan SD, Nigwekar SU, Sehgal AR et al. Aldosterone antagonists
for preventing the progression of chronic kidney disease: a systematic re-
view and meta-analysis. Clin J Am Soc Nephrol 2009; 4: 542–551
15. Bandak G, Sang Y, Gasparini A et al. Hyperkalemia after initiating renin–
angiotensin system blockade: the Stockholm Creatinine Measurements
(SCREAM) project. J Am Heart Assoc 2017; 6: e005428
16. Bakris GL, Siomos M, Richardson D et al. ACE inhibition or angiotensin re-
ceptor blockade: impact on potassium in renal failure. VAL-K Study Group.
Kidney Int 2000; 58: 2084–2092
17. Pitt B, Pfeffer MA, Assmann SF et al. Spironolactone for heart failure with
preserved ejection fraction. N Engl J Med 2014; 370: 1383–1392
18. Luo J, Brunelli SM, Jensen DE et al. Association between serum potassium
and outcomes in patients with reduced kidney function. Clin J Am Soc
Nephrol 2016; 11: 90–100
19. Rossignol P, Legrand M, Kosiborod M et al. Emergency management of se-
vere hyperkalemia: guideline for best practice and opportunities for the fu-
ture. Pharmacol Res 2016; 113: 585–591
20. Winkler AW, Hoff HE, Smith PK. Electrocardiographic changes and
concentration of potassium in serum following intravenous injection of
potassium chloride. Am J Physiol Legacy Content 1938; 124: 478–483
21. Burchell HB. Electrocardiographic changes related to disturbances in
potassium metabolism. J Lancet 1953; 73: 235–238
iii67
22. Dépret F, Peacock WF, Liu KD et al. Management of hyperkalemia in the
acutely ill patient. Ann Intensive Care 2019; 9: 32
23. Lyons CJ, Burgess MJ, Abildskov JA. Effects of acute hyperkalemia on
cardiac excitability. Am Heart J 1977; 94: 755–763
24. Robert T, Burbach M, Joseph A et al. Sodium is the secret re-agent of
bicarbonate therapy during hyperkalemia. Kidney Int 2016; 90: 450–451
25. Pacheco Compa~ na FJ, Midón Mı́guez J, de Toro Santos FJ. Lesions
associated with calcium gluconate extravasation: presentation of 5 clini-
cal cases and analysis of cases published. Ann Plastic Surg 2017; 79:
444–449
26. Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in
patients with digoxin toxicity. J Emerg Med 2011; 40: 41–46
27. Harel Z, Kamel KS. Optimal dose and method of administration of intrave-
nous insulin in the management of emergency hyperkalemia: a systematic
review. PLoS One 2016; 11: e0154963
28. LaRue H, Peksa GD, Shah S. A comparison of insulin doses for the treat-
ment of hyperkalemia in patients with renal insufficiency. Pharmacotherapy
2017; 37: 1516
29. Wheeler DT, Schafers SJ, Horwedel TA et al. Weight-based insulin dosing
for acute hyperkalemia results in less hypoglycemia: hyperkalemia treat-
ment and hypoglycemia. J Hosp Med 2016; 11: 355–357
30. Long B, Warix JR, Koyfman A. Risks of hypoglycemia with insulin therapy
for hyperkalemia. J Emerg Med 2019; 56: 459–460
31. King JT, Goulet JL, Perkal MF et al. Glycemic control and infections in
patients with diabetes undergoing noncardiac surgery. Ann Surg 2011; 253:
158–165
32. Diebel LN, Liberati DM, Martin JV. Acute hyperglycemia increases sepsis
related glycocalyx degradation and endothelial cellular injury: a microfluidic
study. Am J Surg 2019; 217: 1076–1082
33. Allon M. Nebulized albuterol for acute hyperkalemia in patients on hemodi-
alysis. Ann Intern Med 1989; 110: 426
34. Liu M, Rafique Z. Acute management of hyperkalemia. Curr Heart Fail Rep
2019; 16: 67–74
35. Vestal RE, Wood AJ, Shand DG. Reduced beta-adrenoceptor sensitivity in
the elderly. Clin Pharmacol Ther 1979; 26: 181–186
36. Trefz FM, Constable PD, Lorenz I. Effect of intravenous small-volume hy-
pertonic sodium bicarbonate, sodium chloride, and glucose solutions in de-
creasing plasma potassium concentration in hyperkalemic neonatal calves
with diarrhea. J Vet Intern Med 2017; 31: 907–921
37. Jaber S, Paugam C, Futier E et al. Sodium bicarbonate therapy for patients
with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a
multicentre, open-label, randomised controlled, phase 3 trial. Lancet 2018;
392: 31–40
38. Pun PH, Lehrich RW, Honeycutt EF et al. Modifiable risk factors associated
with sudden cardiac arrest within hemodialysis clinics. Kidney Int 2011; 79:
218–227
39. Harel Z, Harel S, Shah PS et al. Gastrointestinal adverse events with sodium
polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med 2013;
126: 264.e9–264.e24
40. Lepage L, Dufour A-C, Doiron J et al. Randomized clinical trial of sodium
polystyrene sulfonate for the treatment of mild hyperkalemia in CKD. Clin J
Am Soc Nephrol 2015; 10: 2136–2142
41. Pitt B, Anker SD, Bushinsky DA et al. Evaluation of the efficacy and safety
of RLY5016, a polymeric potassium binder, in a double-blind, placebo-con-
trolled study in patients with chronic heart failure (the PEARL-HF) trial.
Eur Heart J 2011; 32: 820–828
42. Bakris GL, Pitt B, Weir MR et al. Effect of patiromer on serum potassium
level in patients with hyperkalemia and diabetic kidney disease: the
AMETHYST-DN randomized clinical trial. JAMA 2015; 314: 151
43. Weir MR, Bakris GL, Bushinsky DA et al. Patiromer in patients with kidney
disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;
372: 211–221
44. Pitt B, Bakris GL, Weir MR et al. Long-term effects of patiromer for hyper-
kalaemia treatment in patients with mild heart failure and diabetic nephrop-
athy on angiotensin-converting enzymes/angiotensin receptor blockers:
results from AMETHYST-DN. ESC Heart Fail 2018; 5: 592–602
45. Agarwal R, Rossignol P, Romero A et al. Patiromer versus placebo to enable
spironolactone use in patients with resistant hypertension and chronic
iii68
kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-
controlled trial. Lancet 2019; https://doi.org/10.1016/S0140-6736
(19)32135-X
46. Stavros F, Yang A, Leon A et al. Characterization of structure and function
of ZS-9, a Kþ selective ion trap. PLoS One 2014; 9: e114686
47. Ash SR, Singh B, Lavin PT et al. A phase 2 study on the treatment of hyper-
kalemia in patients with chronic kidney disease suggests that the selective
potassium trap, ZS-9, is safe and efficient. Kidney Int 2015; 88: 404–411
48. Kosiborod M, Rasmussen HS, Lavin P et al. Effect of sodium zirconium
cyclosilicate on potassium lowering for 28 days among outpatients with
hyperkalemia: the HARMONIZE randomized clinical trial. JAMA 2014;
312: 2223–2233
49. Kosiborod M, Peacock WF, Packham DK. Sodium zirconium cyclosilicate
for urgent therapy of severe hyperkalemia. N Engl J Med 2015; 372:
Downloaded from https://academic.oup.com/ndt/article-abstract/34/Supplement_3/iii62/5652183 by guest on 11 January 2020
1577–1578
50. Maggioni AP, Anker SD, Dahlström U et al. Are hospitalized or ambulatory
patients with heart failure treated in accordance with European Society of
Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart
Failure Long-Term Registry. Eur J Heart Fail 2013; 15: 1173–1184
51. Epstein M, Reaven NL, Funk SE et al. Evaluation of the treatment gap be-
tween clinical guidelines and the utilization of renin-angiotensin-
aldosterone system inhibitors. Am J Manag Care 2015; 21: S212–220
52. Beusekamp JC, Tromp J, van der Wal HH et al. Potassium and the use of
renin-angiotensin-aldosterone system inhibitors in heart failure with re-
duced ejection fraction: data from BIOSTAT-CHF: potassium and RAAS
inhibitors in HFrEF. Eur J Heart Fail 2018; 20: 923–930
53. Voors AA, Anker SD, Cleland JG et al. A systems BIOlogy Study to
TAilored Treatment in Chronic Heart Failure: rationale, design, and base-
line characteristics of BIOSTAT-CHF. Eur J Heart Fail 2016; 18: 716–726
54. Shirazian S, Grant CD, Mujeeb S et al. Underprescription of renin-
angiotensin system blockers in moderate to severe chronic kidney disease.
Am J Med Sci 2015; 349: 510–515
55. Rassi AN, Cavender MA, Fonarow GC et al. Temporal trends and predic-
tors in the use of aldosterone antagonists post-acute myocardial infarction.
J Am Coll Cardiol 2013; 61: 35–40
56. Evans M, Palaka E, Furuland H et al. The value of maintaining normokalae-
mia and enabling RAASi therapy in chronic kidney disease. BMC Nephrol
2019; 20: 31
57. Epstein M. Hyperkalemia constitutes a constraint for implementing renin-
angiotensin-aldosterone inhibition: the widening gap between mandated
treatment guidelines and the real-world clinical arena. Kidney Int Suppl
2016; 6: 20–28
58. Garlo KG, Bates DW, Seger DL et al. Association of changes in creatinine
and potassium levels after initiation of renin angiotensin aldosterone system
inhibitors with emergency department visits, hospitalizations, and mortality
in individuals with chronic kidney disease. JAMA Netw Open 2018; 1:
e183874
59. Fried LF, Emanuele N, Zhang JH et al. Combined angiotensin inhibition
for the treatment of diabetic nephropathy. N Engl J Med 2013; 369:
1892–1903
60. Legrand M, Ludes P-O, Massy Z et al. Association between hypo- and
hyperkalemia and outcome in acute heart failure patients: the role of medi-
cations. Clin Res Cardiol 2018; 107: 214–221
61. Rossignol P, Dobre D, McMurray JJV et al. Incidence, determinants,
and prognostic significance of hyperkalemia and worsening renal func-
tion in patients with heart failure receiving the mineralocorticoid recep-
tor antagonist eplerenone or placebo in addition to optimal medical
therapy: results from the Eplerenone in Mild Patients Hospitalization
and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail
2014; 7: 51–58
62. Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone
blocker, in patients with left ventricular dysfunction after myocardial infarc-
tion. N Engl J Med 2003; 348: 1309–1321
63. Bozkurt B, Agoston I, Knowlton AA. Complications of inappropriate use of
spironolactone in heart failure: when an old medicine spirals out of new
guidelines. J Am Coll Cardiol 2003; 41: 211–214
Received: 6.6.2019; Editorial decision: 23.9.2019
M. Coutrot et al.