J May Ocp 202006014

REVIEW
Clinical Management of Hyperkalemia

Biff F. Palmer, MD; Juan Jesus Carrero, PharmD, PhD; Deborah J. Clegg, PhD;
Gates B. Colbert, MD; Michael Emmett, MD; Steven Fishbane, MD;
Debra J. Hain, PhD, APRN, AGPCNP-BC; Edgar Lerma, MD;
Macaulay Onuigbo, MD; Anjay Rastogi, MD; Simon D. Roger, MD;
Bruce S. Spinowitz, MD; and Matthew R. Weir, MD
Abstract
Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite

various guidelines, no universally accepted consensus exists on best practices for hyperkalemia
monitoring, with variations in precise potassium (Kþ) concentration thresholds or for the manage-
ment of acute or chronic hyperkalemia. Based on the available evidence, this review identifies several
critical issues and unmet needs with regard to the management of hyperkalemia. Real-world studies
are needed for a better understanding of the prevalence of hyperkalemia outside the clinical trial
setting. There is a need to improve effective management of hyperkalemia, including classification and
Kþ monitoring, when to reinitiate previously discontinued renin-angiotensin-aldosterone system in-
hibitor (RAASi) therapy, and when to use oral Kþ-binding agents. Monitoring serum Kþ should be
individualized; however, increased frequency of monitoring should be considered for patients with
chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and for those receiving
RAASi therapy. Recent clinical studies suggest that the newer Kþ binders (patiromer sorbitex calcium
and sodium zirconium cyclosilicate) may facilitate optimization of RAASi therapy. Enhancing the
knowledge of primary care physicians and internists with respect to the safety profiles of these newer
Kþ binders may increase confidence in managing patients with hyperkalemia. Lastly, the availability of
newer Kþ-binding agents requires further study to establish whether stringent dietary Kþ restrictions
are needed in patients receiving Kþ-binder therapy. Individualized monitoring of serum Kþ among
patients with an increased risk of hyperkalemia and the use of newer Kþ-binding agents may allow for
optimization of RAASi therapy and more effective management of hyperkalemia.
ª 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc. 2020;nn(n):1-19
From the Department of
H
yperkalemia, defined as an elevated binders and their use in patients with hyperka-
Internal Medicine, Univer-
serum potassium (Kþ) concentra- lemia due to CKD or the adverse effects of sity of Texas South-
tion of greater than 5.0 or greater RAASis, a widely used drug class with signifi- western Medical Center,
than 5.5 mEq/L (mmol/L), is an electrolyte cant cardiorenal benefits.1 Thus, new manage- Dallas (B.F.P.); Depart-
ment of Medical Epidemi-
abnormality with potentially life-threatening ment guidelines are needed to incorporate ology and Biostatistics,
consequences.1 The risk for development of these Kþ binders into hyperkalemia treatment. Karolinska Institutet,
Stockholm, Sweden (J.J.C.);
hyperkalemia is increased in patients with This review summarizes the physiology of Drexel University College
chronic kidney disease (CKD), diabetes, and hyperkalemia and suggests evidence-based of Nursing and Health
Professions, Philadelphia,
heart failure (HF) and in individuals clinical considerations that may provide im-
PA (D.J.C.); Baylor Uni-
receiving renin-angiotensin-aldosterone sys- provements in care and outcomes in patients versity Medical Center,
tem inhibitors (RAASis).1-3 with an increased hyperkalemia risk. Dallas, TX (G.B.C., M.E.);
Department of Medicine,
Guidelines/consensus statements for hyper- Zucker School of Medi-
kalemia management have been devel- METHODS cine at Hofstra/Northwell,
oped.1,2,4-9 However, no universally accepted We conducted a literature search of the Great Neck, NY (S.F.);
consensus exists regarding best practices, PubMed database for articles published be- Affiliations continued at
particularly in consideration of newer Kþ tween January 1, 2000, and October 14, the end of this article.
Mayo Clin Proc. n XXX 2020;nn(n):1-19 n https://doi.org/10.1016/j.mayocp.2020.06.014 1

www.mayoclinicproceedings.org n ª 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
MAYO CLINIC PROCEEDINGS
diabetes.14,15 A U-shaped curve exists between

ARTICLE HIGHLIGHTS serum Kþ and mortality, with both hyperkale-
mia and hypokalemia associated with adverse
d An unmet need exists for new hyperkalemia management
clinical outcomes (Figure 2).14 However, the
guidelines that effectively incorporate classification and moni-
exact Kþ concentration that clinicians should
toring for hyperkalemia, optimization of renin-angiotensin- consider to be life-threatening remains contro-
aldosterone system inhibitor (RAASi) therapy, and use of the versial. The risk of hyperkalemia and the
newer potassium (Kþ) binders. optimal range for serum Kþ concentrations
d Treatment gaps exist between guideline recommendations and vary according to individual patient comorbid-
RAASi use in clinical practice among patients with an increased ities, such as CKD, HF, or diabetes. For
risk of hyperkalemia; if discontinued, RAASi therapy should be example, a patient with atrioventricular heart
block may experience worsening of cardiac
reinitiated after acute hyperkalemia has resolved.
symptoms at a lower Kþ concentration than
d The frequency of Kþ monitoring should be individualized on the another patient without the same condition.16
basis of patient comorbidities and medications (eg, RAASi), partic- The rate of increase in Kþ concentrations must
ularly in patients at high risk for development of hyperkalemia. also be considered, as a rapid increase in serum
d Patients with chronic hyperkalemia may benefit from long-term Kþ is more likely to result in cardiac abnormal-
Kþ-binding therapy, initiated at the recommended dose and ities than a slow steady rise over several
titrated according to serum Kþ levels. months.17 In patients with CKD, compensa-
tory mechanisms may result in tolerance to
Use of the newer Kþ binders may enable the optimization of
elevated circulating Kþ, and several studies
d
RAASi therapy in more patients with hyperkalemia. have suggested that hyperkalemia is a less
threatening condition in CKD.15,18-22 A retro-
spective study found a stronger association be-
tween hyperkalemia (Kþ 5.5 mEq/L) and
2019. Search terms included chronic kidney 1-day mortality among inpatients and outpa-
disease, diabetes, heart failure, hyperkalaemia, tients with normal kidney function than in
hyperkalemia, patiromer, potassium, renin- those with CKD (estimated glomerular filtra-
angiotensin-aldosterone system inhibitor, so- tion rate [eGFR] <60 mL/min per 1.73
dium polystyrene sulfonate, SPS, sodium zirco- m2).18 A U-shaped correlation was found
nium cyclosilicate, SZC, and ZS9. The results between serum Kþ and overall mortality
of this literature search were reviewed by re- risk in patients with nonedialysis-dependent
searchers, epidemiologists, clinicians, dieti- CKD,19 and in a study of consecutive hospital-
tians, and trialists in the field of hyperkalemia. izations for severe hyperkalemia, a graded
decrease in the risk of mortality was observed
POTASSIUM HOMEOSTASIS AND as CKD stage worsened.20 In a cohort study
HYPERKALEMIA of patients with stage 3 to 5 CKD, the risk of
Potassium homeostasis is largely maintained by preeend-stage renal disease (ESRD) mortality
the kidneys, although the gastrointestinal tract was lower when serum Kþ concentrations
and other systems are also involved to a lesser were 4.0 to 5.5 mEq/L compared with 4.0
extent (Figure 1).7,10 Hyperkalemia has depola- mEq/L or less and was not increased with
rizing effects on the heart,10 causing shortened serum Kþ levels of 5.5 mEq/L or greater.21
action potentials and increasing the risk of ar- Lastly, in a large cohort study evaluating the
rhythmias.11 Hyperkalemia causes neuromus- potential reduction in mortality risk from
cular symptoms,10,12 metabolic acidosis, and hyperkalemia with worsening CKD in more
suppression of ammoniagenesis.13 than 800,000 individuals, an evaluation of
The risk of mortality, cardiovascular 90-day mortality risk in relation to Kþ concen-
morbidity, progression of CKD, and hospitali- trations revealed that the observed optimal Kþ
zation is increased in patients with hyperkale- range was broader toward higher Kþ concen-
mia, especially those with CKD, HF, and tration in patients with stage 4 to 5 CKD
n n
2 Mayo Clin Proc. XXX 2020;nn(n):1-19 https://doi.org/10.1016/j.mayocp.2020.06.014
www.mayoclinicproceedings.org
HYPERKALEMIA MANAGEMENT
(optimal range, 3.3 to 5.5 mEq/L) than in those United States,31 observed higher rates of hyper-
with stage 1 to 2 CKD (optimal range, 3.5 to kalemia (7%30 and 11% [>5.0 mEq/L] and 2%
5.0 mEq/L).15 [>5.5 mEq/L],31 respectively). The worldwide
The mechanisms underlying this possible incidence of hyperkalemia could be underesti-
increase in tolerance to hyperkalemia among mated because of the lack of routine Kþ moni-
patients with advanced CKD are not fully un- toring even in some high-risk patient
derstood. It has been suggested that patients populations. Therefore, further epidemiolog-
with CKD adapt to elevated Kþ concentra- ical research in real-world populations is
tions through modifications in gastrointes- needed to more accurately estimate hyperkale-
tinal Kþ secretions10,23 which may favor mia incidence, which may be higher than
intracellular Kþ storage,24 or by increasing observed in clinical trials because of the lack
insulin-mediated intracellular Kþ uptake in of consistent Kþ monitoring and the lack of a
splanchnic and peripheral muscle tissues.25 standardized hyperkalemia definition (eg,
However, it is unknown whether these adap- serum Kþ >5.0, >5.5, or >6.0 mEq/L).
tations to increased serum Kþ exist in other
cells (eg, cardiomyocytes). Potassium chan- Risk Factors
nels in the myocardium are known to be sen- Certain patient populations have an increased
sitive to shifts in endogenous factors and may risk of hyperkalemia-associated morbidity and
change in number or functioning in response mortality, including patients with advanced
to structural26,27 and environmental28 alter- stages of CKD, HF, resistant hypertension, dia-
ation. Therefore, future studies should inves- betes, myocardial infarction (MI), and/or com-
tigate whether these changes in myocardial binations of these conditions.14,32,33 Additional
Kþ channels may explain the observed reduc- risk factors include RAASi usage, advanced
tions in the relative risk of death from hyper- age,2 and drugs such as heparin, b-blockers,
kalemia in patients with advanced CKD. In nonsteroidal anti-inflammatory drugs, calci-
addition, given the relationship between neurin inhibitors, trimethoprim, pentamidine,
serum Kþ, acidosis, and calcium/magnesium and Kþ-sparing diuretics.10,34 The risk of
concentrations,29 it would be interesting to hyperkalemia progressively increases as eGFR
examine whether metabolic acidosis affects decreases.15 Because chronic loss of kidney
the association between serum Kþ and mor- function is associated with an adaptive
tality risk in patients with CKD. response in the remaining functional nephrons,
allowing for an increase in fractional Kþ excre-
tion and maintenance of serum Kþ levels of less
EPIDEMIOLOGY OF HYPERKALEMIA
than 5.5 mEq/L, the risk of hyperkalemia is
Hyperkalemia Incidence generally increased once the eGFR is less than
Hyperkalemia is rare in the general popula- 15 mL/min per 1.73 m2.35 Furthermore, pa-
tion.7 However, because it is a transient condi- tients receiving RAASi therapy who have an
tion, no prospective studies monitoring eGFR of less than 60 mL/min per 1.73 m2
intraindividual serum Kþ concentrations have have an elevated hyperkalemia risk, which pro-
been conducted, and therefore, the exact inci- gressively increases as eGFR decreases.3,36 In
dence of hyperkalemia in the general popula- patients with CKD and/or chronic HF receiving
tion is unclear. Different Kþ thresholds also RAASi, risk factors for repeated hyperkalemia
affect the reported incidence of hyperkalemia. within 6 months of the first event include mod-
Among hospitalized patients, hyperkalemia erate to severe initial hyperkalemia (5.6
incidence has been reported as 3.5% (>5.5 mEq/L), low eGFR (<45 mL/min per 1.73
mEq/L) in Canada16 and 4.9% (>5.0 mEq/L) m2), diabetes, and spironolactone use.37
in Ireland.17 However, the likelihood of detect- Hyperkalemia risk is slightly higher in
ing hyperkalemia depends on the frequency of men than in women after initiation of RAASi
Kþ monitoring. Two studies of inpatients and/ therapy3 and differs among racial groups, in
or outpatients undergoing Kþ testing over 3 whom ethnicity, diet, and socioeconomic fac-
years, one in Sweden30 and another in the tors may contribute.38 These factors currently
FIGURE 1. Regulation of potassium (Kþ) homeostasis. Absorbed Kþ is largely redistributed from the blood to the intracellular space
by active transport (Naþ/Kþ-ATPase), which is stimulated by insulin and catecholamines. In individuals with normal kidney function, Kþ
is filtered through the glomerulus and reabsorbed in the proximal tubule and loop of Henle; less than 10% of filtered Kþ reaches the
distal nephron. Potassium excretion in the distal nephron and collecting duct is stimulated by aldosterone, increased urine flow, and
increased delivery of sodium to the distal nephron. Increased Kþ intake may also promote renal excretion via enteric sensing and
stimulation of aldosterone release from the adrenal gland. Excess extracellular Kþ is usually managed by increased renal excretion of
Kþ; however, impaired kidney function can cause dysregulation of Kþ homeostasis and increase the risk of hyperkalemia.
GI ¼ gastrointestinal; Naþ/Kþ-ATPase ¼ sodium-potassium pump.
do not impact hyperkalemia management; including blood pressure reductions and

however, the potentially additive effects of reduced risks of CKD progression, cardiovas-
these differences may increase hyperkalemia cular disease, and stroke.41 Restriction of die-
risk. tary Kþ as a general approach to preventing
A low-Kþ diet is recommended in patients hyperkalemia may therefore deprive patients
with advanced-stage CKD to reduce hyperka- of these benefits.40
lemia risk39; however, a recent Kidney Disease:
Improving Global Outcomes (KDIGO) confer- RAASi TherapydBenefits and Hyper-
ence found that direct evidence supporting a kalemia Risk
link between dietary Kþ intake and serum Renin-angiotensin-aldosterone system inhib-
Kþ concentrations is limited and that interven- itors are recommended for patients with hy-
tional trials are needed to determine optimal pertension,42 HF,43,44 stable coronary artery
recommendations for dietary Kþ in patients disease,45 CKD, diabetic kidney disease
with CKD.40 A low-Kþ diet is difficult for pa- (DKD),46 and diabetes.47,48 They improve
tients to adhere to, particularly those who survival in patients with CKD,49 HF,50,51
may have additional dietary restrictions due and post-MI status52 and also provide kidney
to diabetes and reduced sodium intake for benefits in patients with non-DKD53 and
CKD or HF. Furthermore, evidence indicates DKD.54,55 Many patients who would other-
that a Kþ-rich diet has multiple health benefits wise benefit from RAASis either do not receive
n n
these medications, receive suboptimal doses,

1.0
or discontinue therapy because of the associ-
Predicted probability of mortality

0.9
ated increased risk of recurrent hyperkale- 0.8
mia.1 Treatment gaps exist between 0.7 HF, CKD, DM
guideline recommendations and RAASi use 0.6
in clinical practice in patients with increased CKD
0.5 HF
hyperkalemia risk.36,56,57 Compared with 0.4
those for maximum RAASi dosing, mortality 0.3 DM
0.2 Control group
rates are higher with suboptimal dosing
among patients with CKD, diabetes or HF 0.1
0
and are highest among patients who discon-
2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
tinue RAASis.57 In one study, 74% of patients
Baseline serum potassium level (mEq/L)
who discontinued mineralocorticoid receptor
antagonists (MRAs) because of hyperkalemia
FIGURE 2. The risk of hypokalemia- or hyperkalemia-associated mortality
did not reinitiate therapy during the subse- (a) in patients with chronic kidney disease (CKD) and other comorbidities
quent year.36 Many patients who have had over 18 months. DM ¼ diabetes mellitus; HF ¼ heart failure. From Am J
acute MI are not prescribed MRAs at hospital Nephrol,14 with permission.
discharge because of hyperkalemia risk.56
Additionally, patients with HF are often pre-
scribed subtherapeutic MRA doses despite hyperkalemia. Other potential risk factors for
guideline recommendations.58 hyperkalemia should be identified and
Although hyperkalemia represents a signif- removed, whenever possible, and patients
icant barrier to effective use of RAASis,1,59,60 should be monitored closely, with reassess-
RAASi therapy is associated with improved sur- ment of Kþ concentrations within 1 week.
vival in patients with HF, particularly in those
at risk for hyperkalemia.61,62 Despite a lack of HYPERKALEMIA MANAGEMENT
randomized controlled trial data to document Management of hyperkalemia occurs across a
improved clinical outcomes with correction of continuum ranging from urgent to short-term
hyperkalemia and reinitiation of RAASi therapy treatment and then long-term treatment
in patients with an increased hyperkalemia and involves both inpatient and outpatient
risk, there is an increasing body of real-world settings. Different management strategies
evidence of increased morbidity and mortality are utilized in patients with acute vs chronic
among patients with CKD, HF, or diabetes hyperkalemia (Figure 3).
who receive suboptimal or no RAASi therapy
because of hyperkalemia.63-65 For example, in Classification of Hyperkalemia
a cohort study of patients who experienced a Although the precise Kþ concentration thresh-
decline in eGFR to less than 30 mL/min per olds for mild, moderate, and severe hyperkale-
1.73 m2 while receiving RAASi therapy, discon- mia vary among current guidelines,1,4-6 a serum
tinuation of RAASi therapy was associated with Kþ level of 5.5 mEq/L or greater is widely
a higher risk of mortality or major adverse car- accepted as the threshold for hyperkalemia.6
diovascular events than continuation of RAA- Hyperkalemia-associated adverse outcomes
Sis.63 In addition, a recent consensus report9 may extend beyond hyperkalemia thresholds
and a position paper66 suggest that treatment (serum Kþ >5.0 or >5.5 mEq/L) and include
with the newer Kþ binders (discussed subse- high “normal” Kþ concentrations in patients
quently) may allow for optimization of RAASi with acute or chronic HF,32,67 hypertension,33
therapy in patients with HF. Therefore, or CKD.15 When deciding how to treat hyper-
maximum RAASi therapy, as tolerated, should kalemic episodes, it may be useful to focus on
be considered when RAASis are indicated. hyperkalemia with clinical impact, as well as
Hyperkalemia should be treated if it develops, rapid fluctuations in serum Kþ, rather than
and reinitiation of RAASis (if discontinued) rigid and somewhat arbitrary serum Kþ
should be considered after resolution of acute thresholds.
Hyperkalemia
Acute Chronic
Dietary K+ counseling
IV calcium
(avoid salt substitutes)
Monitor: (10 mL of 10%)
Monitor:
• K+ trajectory • Serum K+ ¾2 times/year
• ECG changes • Comorbidities
• Other symptoms Manage RAASi therapy
IV insulin/glucose (reinitiate and titrate to optimal dose after
• Medications (OTC NSAIDs
(10 U + 50 mL dextrose) serum K+ stabilizes) and herbal supplements)
• Exclude pseudohyperkalemia
Educate:
• Health care professionals
Nebulized salbutamol Effective diuretic therapy • Patients
(20 mg in 4 mL) (loop diuretics with eGFR <30 mL/min)
Multidisciplinary care:
• Dietitian input
• Pharmacist input
IV sodium
Diureticsb Hemodialysisc Oral sodium bicarbonatea
bicarbonatea
Consider K+ binders
Consider K+ binders
(may facilitate RAASi dose optimization)
aIn patients with metabolic acidosis Stabilize myocardial cell membrane

bIn patients with hypervolemia (nonoliguric)
cIn patients with oliguria or ESRD K+ redistribution into intracellular space
Total body K+ elimination
Reduction of K+ intake
Identification/removal of medications that inhibit renal K+ excretion
FIGURE 3. Treatment options for the management of acute and chronic hyperkalemia. In patients with acute hyperkalemia, intravenous
(IV) calcium reduces membrane excitation in cardiac tissue within 1 to 3 minutes, while insulin and b-agonists redistribute potassium (Kþ)
to the intracellular space (30 to 60 minutes) but do not reduce total body Kþ. b-Agonists have a short duration of effect (2 to 4 hours),
and glucose must be administered with insulin to prevent hypoglycemia. Sodium bicarbonate use, which promotes Kþ elimination
through increased urinary Kþ excretion, is limited to patients with metabolic acidosis, and effective diuretic therapy depends on residual
kidney function. Hemodialysis increases total Kþ elimination and may be used for resistant acute hyperkalemia. ECG ¼ electrocardi-
ography; eGFR ¼ estimated glomerular filtration rate; ESRD ¼ end-stage renal disease; NSAIDs ¼ nonsteroidal anti-inflammatory drugs;
OTC ¼ over-the-counter; RAASi ¼ renin-angiotensin-aldosterone system inhibition.
Potassium concentration thresholds for Frequency of Kþ Monitoring

the classification of mild, moderate, and severe The use of serum or plasma for determination
hyperkalemia are useful; however, patient of Kþ concentrations affects laboratory results.
risk- and clinical impact-based classification Plasma Kþ concentrations are usually 0.1- to
may also guide clinical intervention. Clinicians 0.4-mEq/L lower than serum levels,7 which is
should consider using individualized serum caused by the release of Kþ from platelets dur-
Kþ concentration thresholds that take into ac- ing coagulation.68 The methods used for Kþ
count patient comorbidities and “normal” Kþ determination are not standardized, with
concentration ranges, as well as the rate or de- wide variations in reference ranges.7 Compli-
gree of change in serum Kþ levels over time, cations such as pseudohyperkalemia (result-
which enables proactive or preventive inter- ing from repeated fist clenching and poor
ventions and is a useful clinical variable for phlebotomy techniques), hemolysis, slow
hyperkalemia management. specimen processing, and other factors7,10,69
n n
need to be assessed prior to hyperkalemia the clinical relevance of elevated serum Kþ,
treatment. The timing of sample collection ECG findings can be highly variable and not
may influence Kþ results because of the circa- as sensitive as a laboratory test in predicting
dian rhythm of Kþ homeostasis.7 hyperkalemia or its associated complications.
Clinical guidelines recommend Kþ mea- A deep learning model that may allow for
surement in at-risk patients prior to initia- noninvasive screening for hyperkalemia using
tion of drugs that influence hyperkalemia ECG is currently being developed73; however,
risk and periodically thereafter.4,46,70,71 For this tool is not yet available for use in routine
example, the 2012 KDIGO guidelines advo- clinical practice. Therefore, Kþ measurements
cate serum Kþ measurement within 1 week should be conducted on the basis of the pa-
of starting or dose escalation of RAASis in tient’s risk factors rather than clinical symp-
patients with CKD.46 Repetitive consecutive toms (Figure 3).
measurements facilitate determination of The goal of managing acute hyperkale-
whether hyperkalemia is a chronic or tran- mia is to prevent or minimize electrophysio-
sient event5; however, there is no consensus logic effects on the heart to reduce the
on the number of tests required to document immediate risk of arrhythmias.2,5,7 Treat-
chronic hyperkalemia risk.59 Potassium ment options for acute hyperkalemia include
monitoring frequency should vary depend- intravenous calcium gluconate, insulin/
ing on patient comorbidities (eg, diabetes, glucose, inhaled b-agonists (eg, salbutamol),
HF, CKD stage, and the need for dialysis) intravenous sodium bicarbonate, and hemo-
and medications (eg, RAASi therapy). dialysis (Figure 3). Intravenous calcium glu-
Individualized Kþ monitoring frequency conate administration rapidly reduces the
based on the presence of comorbidities and membrane excitatory effects of Kþ on car-
medications should be considered, with diac tissue within 1 to 3 minutes, thereby
more frequent monitoring in patients with minimizing the potential for cardiac
increased hyperkalemia risk (eg, those with arrhythmia, but only minimally reduces
CKD, diabetes, HF, or a history of hyperka- serum Kþ concentrations.2,74 If no effect is
lemia and those taking RAASis). In partic- observed within 5 to 10 minutes, another
ular, serum Kþ concentrations should be dose of calcium gluconate may be given.75
assessed 7 to 10 days after starting RAASi Intravenous insulin (plus glucose) and
therapy and increasing RAASi doses. inhaled b-agonists act within 30 minutes to
promote redistribution of serum Kþ into
Acute Hyperkalemia the intracellular space but do not change to-
Acute hyperkalemia is defined as a serum Kþ tal body Kþ levels.74 Short-term treatment
concentration exceeding the upper limit of with oral sodium bicarbonate may be used
normal that is not known to be chronic.40 Man- to promote Kþ elimination through
agement of acute hyperkalemia depends on the increased urinary Kþ excretion in patients
magnitude or severity of the increase in Kþ con- with concurrent metabolic acidosis,2 coun-
centration, especially when combined with tering the release of Kþ into the blood that
marked electrocardiographic (ECG) changes is caused by metabolic acidosis by decreasing
and severe muscle weakness.4,40 The most blood acidity and promoting Kþ excretion
commonly observed changes in ECG are through increased distal sodium delivery.76
peaked T waves and prolonged QRS com- Dialysis increases Kþ elimination from the
plexes.40 However, as noted in the observa- body and may be used as an adjunctive ther-
tional REVEAL-ED (Real World Evidence apy in acute hyperkalemia after instituting
for Treatment of Hyperkalemia in the other approaches.2
Emergency Department) study of emergency Several deficiencies associated with current
department patients who presented with Kþ management of acute hyperkalemia were high-
concentrations of 5.5 mEq/L or greater,72 the lighted by the REVEAL-ED study, including a
symptoms of hyperkalemia can be nonspecific, lack of standard, universally accepted treat-
and although recommended for determining ment protocols or algorithms for managing
hyperkalemia in the emergency department.72 recommendations on when to reinitiate RAASi

The study documented the use of different (Table 1).4,44,46,71 Recently US Food and Drug
treatments, alone or in combination, depend- Administrationeapproved Kþ-binding agents
ing on the institution and initial blood Kþ con- may provide benefits for the management of
centration, including intravenous calcium, chronic hyperkalemia while avoiding these
inhaled b2-agonists, oral sodium polystyrene limitations. Educational initiatives on the
sulfonate (SPS), intravenous sodium bicarbon- safety and efficacy of the newer Kþ binders
ate, dialysis, and intravenous diuretics. Insulin/ are needed for primary care physicians and in-
glucose (alone or in combination with other ternists to increase their knowledge of hyper-
therapy) was the most commonly utilized kalemia management, especially in regions
option (64% of patients) within the first 4 where specialist services may not be readily
hours,72 whereas the treatment option most available. A team approach for chronic hyper-
likely to achieve normokalemia within 4 hours kalemia management is optimal, which may
was dialysis. include specialists (eg, cardiologists, nephrol-
ogists), primary care physicians, nurses, phar-
Chronic Hyperkalemia macists, social workers, or dietitians.
Chronic hyperkalemia is defined as recurrent
episodes of elevated serum Kþ concentrations Potassium Binders
that require ongoing maintenance therapy; All Kþ binders used for hyperkalemia manage-
however, based on the recent KDIGO report,40 ment are nonabsorbed and consist of a coun-
there is no consensus on the frequency, terion that is exchanged for Kþ, facilitating
severity, or duration of these episodes that de- the elimination of bound Kþ in feces.77-79 Until
scribes chronicity. In general, chronic hyper- recently, SPS (Kayexalate)78,80 was the only
kalemia is more likely to be identified in Kþ binder available for hyperkalemia manage-
individuals who have more frequent testing ment and may continue to be the only agent
and is often asymptomatic.40 Current recom- available in parts of the world. However, 2
mendations regarding the management of other Kþ binders, patiromer sorbitex calcium
chronic hyperkalemia (long-term elevated (Veltassa)77 and sodium zirconium cyclosili-
serum Kþ) include the use of loop or thiazide cate (SZC; Lokelma [formerly ZS-9]),79 are
diuretics, modification of RAASi dose, and now approved in the United States and the Eu-
removal of other hyperkalemia-causing medi- ropean Union. The characteristics of these 3
cations (Figure 3).2,34,40 Diuretics promote Kþ-binding agents are summarized in
urinary excretion of Kþ in patients with CKD Table 2.12,59,60,79-81 The efficacy of patiromer
or DKD by stimulating the flow and delivery and SZC has been documented in clinical tri-
of Kþ to the renal collecting ducts.76 Fludro- als, whereas clinical data for SPS is limited (dis-
cortisone can also increase Kþ excretion but cussed subsequently and summarized in
is associated with an increased risk of fluid Table 3).82-94 The newer Kþ-binding agents
retention, hypertension, and vascular are also more palatable than SPS, facilitating
injury.2,11 adherence and efficacy and potentially leading
These long-term treatment options have to improved outcomes.89,90,92,95 The National
limitations.2 Despite the beneficial effects of di- Institute for Health and Care Excellence has
uretics on volume status and blood pressure in recently provided recommendations regarding
patients with CKD or HF, these agents may in- SZC and patiromer use for the treatment of
crease the risk of gout, volume depletion, acute life-threatening hyperkalemia, stating
decreased distal nephron flow, worsening kid- that these agents may be considered for use
ney function, and reduced Kþ excretion, and in conjunction with standard care.95,96
their effectiveness in managing hyperkalemia The initiation of newer Kþ-binding agents
relies on residual kidney function. Discontinu- should be considered in patients with chronic
ation or dose reduction of RAASi therapy may hyperkalemia despite optimized diuretic ther-
lead to adverse cardiorenal outcomes, and cur- apy and correction of metabolic acidosis. After
rent guidelines differ with regard to starting therapy at the recommended dose, Kþ
n n
TABLE 1. Summary of Guideline Recommendations for RAASi Therapya

Society Serum Kþ (mEq/L) Recommendations for RAASi therapy
American College of Cardiology/American Heart >5.0 Use ACEis and ARBs with caution
Association/ Heart Failure Society of America44 MRAs are not recommended
Canadian Cardiovascular Society4 Mild HK (Kþ 5.0-5.5) RAASi not usually stopped
If RAASi therapy is stopped, reinitiate therapy once any
concurrent condition contributing to changes in Kþ is
under control AND serum Kþ has decreased to <5.0
mEq/L or to within patient’s usual range (whichever is
higher)
Moderate (Kþ 5.6-5.9) or Reinitiate RAASi therapy once any concurrent condition
severe (Kþ >5.9) HK contributing to changes in Kþ is under control AND
serum Kþ has decreased to <5.0 mEq/L or to within
patient’s usual range (whichever is higher)
Reintroduce RAASi agents one at a time with monitoring
of kidney function and electrolytes
European Society of Cardiology1 4.5-5.0b If not taking maximum-tolerated guideline-recommended
dose, initiate/up-titrate RAASi therapy and closely
monitor Kþ; start Kþ-lowering therapy if Kþ increases to
>5.0 mEq/L
>5.0 to 6.5 If receiving maximum-tolerated guideline-recommended
RAASi dose, initiate Kþ-lowering therapy; closely
monitor Kþ and continue Kþ-lowering therapy unless
another treatable etiology for hyperkalemia is identified
If not taking maximum-tolerated guideline-recommended
RAASi dose, start Kþ-lowering therapy and titrate
RAASi when Kþ is <5.0 mEq/L; closely monitor Kþ and
maintain Kþ-lowering therapy unless another etiology
for hyperkalemia is identified
>6.5 Discontinue or reduce RAASi therapy; Kþ-lowering
therapy may be started as soon as Kþ is >5.0 mEq/L;
closely monitor serum Kþ
Kidney Disease: Improving Global Outcomes46 NS Assess GFR and measure serum Kþ within 1 week of
starting RAASi or following any dose escalation
National Institute for Health and Care Excellence71 >5.0 Do not initiate RAASi therapy in patients with CKD
6.0 Discontinue RAASi therapy once other drugs known to
increase the risk of hyperkalemia have been stopped
a
ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CKD ¼ chronic kidney disease; GFR ¼ glomerular filtration rate; HK¼ hyperkalemia;
Kþ ¼ potassium; MRA ¼ mineralocorticoid receptor antagonist; NS ¼ not specified; RAASi ¼ renin-angiotensin-aldosterone system inhibitor.
b
Serum or plasma Kþ.
binders should be titrated for optimization of Although such data are limited, cost-
serum Kþ concentration, with individualized effectiveness analysis from the US payer
monitoring of serum or plasma Kþ. Long- perspective found that the benefits of adding
term Kþ-binder therapy may be considered patiromer to treatment in patients with HF
in patients with chronic hyperkalemia. The and hyperkalemia outweighed the incremental
use of one of the newer Kþ-binding agents total costs, with lower hospitalization costs,
(patiromer or SZC) may allow for the continu- improved survival, and increased quality of
ation and optimization of RAASi therapy in pa- life.97
tients with hyperkalemia. Consideration of the
costs of patiromer or SZC may influence their Sodium Polystyrene Sulfonate. Sodium
use in clinical practice for some patients. polystyrene sulfonate is a polymeric cation-
TABLE 2. Selected Characteristics of Kþ-Binding Agents for Hyperkalemia

Characteristic SPS Patiromer SZC
Approval date 1958 US, 2015; EU, 2017 US, 2018; EU, 2018
Mechanism of action Kþ binding in exchange for Naþ in Kþ binding in exchange for Ca2þ in Kþ binding in exchange for Hþ and
GI tract ([ fecal excretion) GI tract ([ fecal excretion) Naþ in GI tract ([ fecal
excretion)
Site of action Colon Colon Small and large intestines
Selectivity for Kþ Nonselective; also binds Ca2þ and Nonselective; also binds Naþ and Highly selective; also binds NH4þ
Mg2þ Mg2þ
Onset of action Variable; several hours 7h 1h
Naþ content 1500 mg per 15-mg dose None 400 mg per 5-g dose
Ca2þ content None 1.6 g per 8.4-g dose None
Sorbitol content 20,000 mg per 15-g dose 4000 mg per 8.4-g dose No sorbitol content
Dosing 15 g 1-4 times (oral); 30-50 g 8.4 g QD (oral), titrate up to 16.8 g 10 g TID (oral) for initial correction
1-2 times (rectal) or 25.2 g QD of hyperkalemia (for 48 h),
then 5 g QOD to 15 g QD for
maintenance
Serious AEs Cases of fatal GI injury reported None reported None reported
Most common AEs GI disorders (constipation, GI disorders (abdominal GI disorders (constipation,
diarrhea, nausea, vomiting, discomfort, constipation, diarrhea, nausea, vomiting), mild
gastric irritation), diarrhea, nausea, flatulence), to moderate edema
hypomagnesemia, hypokalemia, hypomagnesemia
hypocalcemia, systemic alkalosis
AE ¼ adverse event; Ca2þ ¼ calcium; EU ¼ European Union; GI ¼ gastrointestinal; Hþ ¼ hydrogen ion; Kþ ¼ potassium; Mg2þ ¼ magnesium; Naþ ¼ sodium; NH4þ ¼
ammonium; QD ¼ once daily; QOD ¼ every other day; SPS ¼ sodium polystyrene sulfonate; SZC ¼ sodium zirconium cyclosilicate; TID ¼ three times daily; US ¼ United
States; [ ¼ increased.
Data from references 12, 59, 60, and 79 to 81.
exchange resin that binds Kþ ions in for patients with serious gastrointestinal
exchange for sodium ions in the distal co- injury.103 However, although cohort studies
lon.12,78 It is nonselective for Kþ, with have reported a higher relative risk of gastro-
affinity for calcium and magnesium ions. intestinal AEs with SPS use, the incidence of
Sodium polystyrene sulfonate may be events with SPS was rare (16 or 23 events
administered either orally or rectally,78 per 1000 person-years).101,102 Because of its
although the oral suspension has poor potential to cause constipation, SPS was often
palatability.98 With only one small random- previously coadministered with the laxative
ized, double-blind, 7-day trial, clinical sorbitol.12 However, in 2009, the US Food
studies supporting its long-term use in pa- and Drug Administration added a warning la-
tients with hyperkalemia are lacking bel to SPS regarding the concomitant use of
(Table 3).82 Its short-term efficacy is also sorbitol and the associated risk of colonic ne-
inconsistent,2 and the onset of action is crosis and other serious gastrointestinal AEs
variable (hours to days).78 Its use varies (bleeding, ischemic colitis, and perfora-
widely among countries, ranging from 42% tion).104 Coadministration of SPS with sorbi-
of patients in France to less than 1% in the tol is currently not recommended,78 although
United Kingdom, Spain, and Japan.99 gastrointestinal injury has been reported in
Sodium polystyrene sulfonate has been patients receiving SPS without sorbitol.101-103
associated with adverse events (AEs), The nonselective binding properties of
including intestinal ischemia and colonic ne- SPS may also lead to hypocalcemia and hypo-
crosis,100,101 a doubling in the risk of hospi- magnesemia,12 and because orally adminis-
talization for serious gastrointestinal AEs,102 tered SPS potentially binds to other oral
and a reported overall mortality rate of 33% medications, their administration should be
n n
TABLE 3. Summary of Key Clinical Studies of Kþ-Binding Agentsa

Study name; design (duration) Patient population Study treatment Primary efficacy outcomes
SPS
Phase 4, randomized, Outpatients with CKD and SPS 30 g or placebo QD Mean change in serum Kþ:
double-blind, placebo- mild hyperkalemia (Kþ 1.25 mEq/L with SPS
controlled (7 d)82 5.0-5.9 mEq/L); N¼33 0.21 mEq/L with placebo
Mean difference (95% CI) vs placebo:
1.04 mEq/L (1.37 to 0.71
mEq/L); P<.001
Patiromer
Phase 4, randomized, open- Emergency department Single dose of patiromer Adjusted mean serum Kþ at 6 h:
label, single-blind (10 h)83 patients with ESRD and 25.2 g þ SOC or SOC alone 5.81 mEq/L with patiromer þ SOC
serum Kþ 6.0 mEq/L; 6.32 mEq/L with SOC alone; P¼.155
N¼43 vs SOC alone
Adjusted mean serum Kþ at 2 h:
5.90 mEq/L with patiromer þ SOC
6.51 mEq/L with SOC alone; P¼.009
vs SOC alone
PEARL-HF; phase 2, Patients with chronic HF Patiromer 15 g or placebo BID LS mean change in serum Kþ:
randomized, double-blind, with (1) history of (þ spironolactone 25 mg/db) 0.22 mEq/L with patiromer
placebo-controlled (28 d)84 hyperkalemia leading to þ0.23 mEq/L with placebo
RAASi and/or b-blocker LS mean difference vs placebo:
withdrawal or (2) CKD; 0.45 mEq/L; P<.001
N¼105
AMETHYST-DN; phase 2, Outpatients with DKD and Mild hyperkalemia: patiromer 4.2, Mild hyperkalemia:
randomized, open-label mild (Kþ 5.0-5.5 mEq/L) 8.4, or 12.6 g BIDc LS mean change in serum Kþ:
(28 d)85 or moderate (Kþ 5.5-6.0 0.35 mEq/L with patiromer 4.2 g
mEq/L) hyperkalemia; 0.51 mEq/L with patiromer 8.4 g
N¼306 0.55 mEq/L with patiromer 12.6 g
Moderate hyperkalemia: Moderate hyperkalemia:

patiromer 8.4, 12.6, or 16.8 g LS mean change in serum Kþ:
BIDc 0.87 mEq/L with patiromer 8.4 g
0.97 mEq/L with patiromer 12.6 g
0.92 mEq/L with patiromer 16.8 g
AMBER; phase 2, Patients with CKD, Kþ 4.3- Patiromer 8.4 g or placebo QD Patients remaining on spironolactone:
randomized, double-blind, 5.1 mEq/L, and resistant (þ open-label spironolactone 86% with patiromer
placebo-controlled hypertension; N¼295 25 mg/dd) 66% with placebo
(12 wk)86 Difference vs placebo:
19.5%; P<.0001
More patients in placebo vs patiromer
with serum
Kþ 5.5 mEq/L:
P<.001
OPAL-HK; phase 3, 2 stages: Patients with CKD on Treatment stage: patiromer 4.2 g Treatment stage:
(1) treatment, single-group, RAASi therapy with mild (mild hyper-kalemia) or 8.4 g Mean change in serum Kþ at wk 4:
single-blind (4 wk) and (2) (Kþ 5.1-5.5 mEq/L) or (moderate to severe hyper- Overall: 1.01 mEq/L (P<.001 vs
with-drawal, randomized, moderate to severe (Kþ kalemia) BID baseline)
single-blind, placebo- 5.5-6.5 mEq/L) Mild hyperkalemia: 0.65 mEq/L
controlled (8 wk)87 hyperkalemia; N¼237 Moderate to severe hyperkalemia:
1.23 mEq/L
Continued on next page

TABLE 3. Continued
Withdrawal stage: patiromer (at Withdrawal stage:
same dosage) or placebo Median change in Kþ to wk 4:
(Kþ 3.8-5.1 mEq/L) 0 mEq/L with patiromer
þ0.72 mEq/L with placebo
P<.001 vs placebo
SZC
ENERGIZE; phase 2, Emergency department SZC 10 g (3 doses in 10 h) or LS mean change in serum Kþ at 4 h:
randomized, double-blind, patients with serum Kþ placebo (þ insulin þ glucose) 0.41 mEq/L with SZC
placebo-controlled (24 h)88 5.8 mEq/L; N¼70 0.27 mEq/L with placebo
LS mean difference vs placebo:
0.13 mEq/L (95% CI 0.44 to
0.17 mEq/L)
Phase 3, 2-stage, randomized, Patients with hyperkalemia Correction phase: Correction phase:
double-blind, placebo- (Kþ 5.0-6.5 mEq/L); SZC 1.25, 2.5, 5, or 10 g or Exponential rate of change in mean
controlled (14 d)89 N¼754 placebo TID for 48 h serum Kþ at 48 h:
0.11% with SZC 1.25 g
0.16% with SZC 2.5 g
0.21% with SZC 5 g
0.30% with SZC 10 g
0.09% with placebo
P<.001 vs placebo for 3 highest doses
Maintenance phase: Maintenance phase:

SZC (same dose) or placebo Exponential rate of change in mean
QD (Kþ 3.5-4.9 mEq/L) serum Kþ:
for 14 d þ0.14% per hour with
SZC 10 g þ1.04% per hour with
placebo
P<.001
þ0.09% per hour with SZC 5 g þ0.47%
per hour with placebo
P¼.008
HARMONIZE; phase 3, 2- Outpatients with hyper- Initial phase (open-label): Initial phase (open-label):
stage, randomized, kalemia (Kþ 5.1 mEq/ SZC 10 g TID for 48 h Mean change in serum Kþ over 48 h:
double-blind, placebo- L); N¼258 1.1 mEq/L; P<.001 vs baseline
controlled (28 d)90
Maintenance phase (double-blind): Maintenance phase (double-blind):
SZC 5, 10, or 15 g or placebo QD Mean serum Kþ during days 8-29:
for 28 d (Kþ 3.5-5.0 mEq/L) 4.8 mEq/L with SZC 5 g QD
4.5 mEq/L with SZC 10 g QD
4.4 mEq/L with SZC 15 g QD
5.1 mEq/L with placebo
P<.001 vs placebo for each dose
HARMONIZE-OLE; phase Patients from SZC 10 g QD, titrated in 5-g 93% of patients achieved mean serum
3, open-label (11 mo)91 HARMONIZE with Kþ amounts to maintain Kþ Kþ 5.1 mEq/L across days 8-337
3.5-6.2 mEq/L; N¼123 3.5-5.0 mEq/L (min, 5 g QD;
max, 15 g QD)
HARMONIZE-Global; Correction phase (open-label): Correction phase (open-label):
phase 3, randomized, SZC 10 g TID for 48 h Mean change in serum Kþ over 48 h:
Continued on next page
n n
TABLE 3. Continued
double-blind, placebo- Outpatients with 1.28 mEq/L; P<.001 vs baseline
controlled (28 d)92 hyperkalemia (Kþ 5.1
mEq/L); N¼267
Maintenance phase (double- Maintenance phase (double-blind):
blind): Mean serum Kþ during days 8-29:
SZC 5 or 10 g or placebo QD 4.8 mEq/L with SZC 5 g QD
for 28 d (Kþ 3.5-5.0 mEq/L) 4.4 mEq/L with SZC 10 g QD
5.3 mEq/L with placebo
P<.001 vs placebo for each dose
ZS-005; phase 3, 2-stage, Outpatients with Correction phase: Correction phase:

open-label (12 mo)93 hyperkalemia (Kþ 5.1 SZC 10 g TID for 24-72 h 78% of patients had serum Kþ 3.5-5.0
mEq/L); N¼751 mEq/L at 72 h
Maintenance phase: Maintenance phase:

SZC 5 g QDe 88% of patients had serum
Kþ <5.1 mEq/L over 3-12 mo
DIALIZE; phase 3b, Patients with ESRD on SZC 5, 10, or 15 g or placebo Maintenance of predialysis serum Kþ
randomized, double-blind, hemodialysis with QD on nondialysis days 4.0-5.0 mEq/L during 3 of 4 hemo-
placebo-controlled hyperkalemiaf; N¼196 for 4 wk dialysis sessions after long interdialytic
(4 wk)94 interval without requiring rescue
therapy:
41% with SZC
1% with placebo
P<.001 vs placebo
a
AMBER ¼ Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease; AMETHYST-DN ¼ Patiromer in the Treatment of
Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; BID ¼ twice daily; CKD ¼ chronic kidney disease; DIALIZE ¼ A Study to Test Whether ZS
(Sodium Zirconium Cyclosilicate) Can Reduce the Incidence of Increased Blood Potassium Levels Among Dialized Patients; DKD ¼ diabetic kidney disease; ENERGIZE ¼ A
Study to Evaluate a Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate (ZS) Among Patients With S-K 5.8; ESRD ¼ end-stage renal
disease; HARMONIZE ¼ Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance; HARMONIZE-OLE ¼ HARMONIZE open-label extension; HF ¼ heart
failure; Kþ ¼ potassium; LS ¼ least squares; max ¼ maximum; min ¼ minimum; OPAL-HK ¼ A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of
Patiromer for the Treatment of Hyperkalemia; PEARL-HF ¼ Evaluation of Patiromer in Heart Failure Patients; QD ¼ once daily; RAASi ¼ renin-angiotensin-aldosterone
system inhibitor; SOC ¼ standard of care; SPS ¼ sodium polystyrene sulfonate; SZC ¼ sodium zirconium cyclosilicate; TID ¼ three times daily.
b
Spironolactone dosage increased to 50 mg/d after 2 weeks in patients with serum Kþ >3.5 to 5.1 mEq/L.
c
Patiromer was titrated to achieve and maintain serum Kþ 5.0 mEq/L.
d
Spironolactone dosage increased to 50 mg/d after 3 weeks in patients with systolic blood pressure 120 mm Hg and serum Kþ 5.1 mEq/L.
e
SZC was titrated to maintain serum Kþ 3.5-5.0 mEq/L.
f
Defined as predialysis serum Kþ >5.4 mEq/L after the long interdialytic interval and predialysis serum Kþ >5.0 mEq/L after 1 short interdialytic interval.
separated by 3 or more hours.78 Of note, the patients with hyperkalemia, including those
release of sodium from SPS during Kþ with CKD and HF, and/or receiving RAASis
exchange may potentially increase sodium (Table 3). In a pilot study of emergency
and volume load. Sodium polystyrene sulfo- department patients with ESRD and serum Kþ
nate should be used with caution in patients levels of 6.0 mEq/L or higher, single-dose
with congestive HF, severe hypertension, administration of patiromer, 25.2 g, in addi-
edema, or decreased kidney function who tion to standard of care effectively reduced
may not tolerate increased sodium loads.12,78 serum Kþ concentrations over 6 hours.83 In
patients with chronic hyperkalemia, patiromer,
Patiromer Sorbitex Calcium. The efficacy of 4.2 to 16.8 g twice daily, provided significant
patiromer was established in randomized, dose-dependent reductions in serum Kþ levels
placebo-controlled, phase 2 and 3 trials of by 0.2 to 1.0 mEq/L over 4 weeks84,85,87 and

effectively maintained normokalemia (Kþ efficacy and safety established in phase 2 and
levels of 3.8 to 5.1 mEq/L) for a further 4 3 clinical trials of patients with hyperkalemia
weeks.87 In patients with advanced CKD and including those with CKD, HF, and/or diabetes
resistant hypertension, significantly more pa- or those receiving RAASis (Table 3).88-94 In a
tients continued spironolactone, 25 to 50 mg study of emergency department patients with
once daily, while receiving patiromer, 8.4 g serum Kþ concentrations of 5.8 mEq/L or
once daily, vs placebo for 12 weeks.86 Among higher, SZC therapy (up to three 10-g doses
patients with diabetes and CKD, including within 10 hours) added to insulin plus glucose
those with HF receiving RAASis, normokale- provided reductions in mean serum Kþ levels
mia was maintained with patiromer therapy for of 0.72 mEq/L within 2 hours.88 In studies of
up to 12 months.105 In a real-world study of patients with chronic hyperkalemia, 3-times-
patients undergoing long-term hemodialysis, daily SZC significantly reduced serum Kþ
serum Kþ concentrations were significantly concentrations within 48 hours, and a once-
reduced following initiation of patiromer over daily 5- or 10-g SZC dose effectively main-
three 30-day periods, and the proportion of tained normokalemia over 14 to 28
patients with serum Kþ levels of 6.0 mEq/L or days.89,90,92 Significant reductions in serum
higher decreased from approximately 50% Kþ levels were observed within 1 hour of a
before patiromer initiation to 22% at 90 days single SZC 10-g dose in the overall patient
after patiromer initiaton.106 populations89,90,92 and in those with severe
Oral patiromer contains a calcium- hyperkalemia (6.0 mEq/L).111 The efficacy
sorbitol counterion that exchanges calcium and safety of SZC over 12 months have also
for Kþ as it passes through the colon.77 been documented.91,93 In the DIALIZE (A
Similar to SPS, patiromer is a polymer that Study to Test Whether ZS [Sodium Zirconium
is nonselective for Kþ and may also bind Cyclosilicate] Can Reduce the Incidence of
magnesium and small amounts of so- Increased Blood Potassium Levels Among
dium.77,107 The time to onset of action Dialized Patients) study of patients with ESRD
with patiromer is approximately 7 hours.108 and persistent hyperkalemia, once-daily SZC
Patiromer administration should also be on nondialysis days effectively maintained
separated from other oral medications by 3 normal predialysis serum Kþ levels over 8
or more hours because of the potential for weeks.94 Sustained increases in serum bicar-
binding with patiromer.77 bonate have been observed with SZC,112 which
No serious AEs have been associated may provide an added benefit for patients with
with patiromer therapy in randomized trials. metabolic acidosis.
The most common AEs include gastrointes- Unlike SPS and patiromer, SZC is nonpoly-
tinal events (constipation, diarrhea, nausea/ meric with high selectivity for Kþ and ammo-
vomiting, abdominal discomfort, and flatu- nium ions (1.25-fold higher affinity for Kþ
lence) and electrolyte disturbances (hypoka- than ammonium) in exchange for hydrogen
lemia and hypomagnesemia).12,77,81 Because and sodium throughout the gastrointestinal
patiromer exchanges calcium for Kþ in the tract.79 Sodium zirconium cyclosilicate binds
colon, theoretically it may also increase the monovalent cations (Kþ) as opposed to diva-
risk of hypercalcemia.12 Although rare, cases lent cations (eg, calcium and magnesium).113
of patiromer-induced hypercalcemia have Because SZC may affect absorption of other
been reported,109,110 suggesting that it may oral medications with pH-dependent solubility
be an underreported AE that clinicians due to a transient increase in gastric pH, SZC
should be aware of when initiating patiromer administration should be separated from these
therapy. Currently, there are no real-world medications by 2 or more hours.79
safety data for patiromer. Sodium zirconium cyclosilicate has not
been associated with any serious AEs in ran-
Sodium Zirconium Cyclosilicate. Sodium domized trials. The most common AEs were
zirconium cyclosilicate (SZC) is the most hypokalemia and a dose-dependent increase
recently approved Kþ-binding agent, with its in edema.89,90,93 Because SZC was only
n n
recently launched in US and other markets, ACKNOWLEDGMENTS

postmarketing safety data are currently very All named authors meet the International
limited. Committee of Medical Journal Editors
criteria for authorship for this article and
take responsibility for the integrity of the
Hyperkalemia Education
work as a whole. Medical writing support
The National Kidney Foundation recom-
was provided by Sarah Greig, PhD (Auck-
mends improvements in patient awareness
land, New Zealand), and Meri Pozo, PhD
of hyperkalemia.114 These actions include us-
(New York, NY), of inScience Communica-
ing educational tools to facilitate communica-
tions, Springer Healthcare, in accordance
tion about hyperkalemia (eg, https://www.
with Good Publication Practice and funded
kidney.org/atoz/content/what-hyperkalemia)
by AstraZeneca. The authors had full edito-
and encouraging nurse practitioners, physi-
rial control of the submitted manuscript,
cians, physician assistants, pharmacists, and
reviewed and edited successive drafts, pro-
dietitians to proactively engage patients in
vided final approval of all content and sub-
dialogue about the associated risk of hyperka-
mission of the manuscript, and are fully
lemia and provide ongoing dietary and other
accountable for all aspects of the work.
lifestyle information relevant to patients with
increased hyperkalemia risk.114
Abbreviations and Acronyms: AE = adverse event; CKD =
Educational initiatives and campaigns are
chronic kidney disease; DKD = diabetic kidney disease; ECG
needed to improve patient awareness of hyper- = electrocardiographic; eGFR = estimated glomerular
kalemia risk and its potentially life-threatening filtration rate; HF = heart failure; Kþ = potassium; KDIGO =
consequences, including awareness that hyper- Kidney Disease: Improving Global Outcomes; MI =
myocardial infarction; MRA = mineralocorticoid receptor
kalemia is often asymptomatic and that routine
antagonist; RAASi = renin-angiotensin-aldosterone system
Kþ monitoring is important. Allied health care inhibitor; SPS = sodium polystyrene sulfonate; SZC = so-
professional involvement in patient education dium zirconium cyclosilicate
may help to increase awareness of the hyperka-
Affiliations (Continued from the first page of this
lemia risk associated with RAASi and other article.): Christine E. Lynn College of Nursing, Florida
medications. Health care practitioners should Atlantic University, and Cleveland Clinic Florida, Weston,
be involved in patient education regarding FL (D.J.H.); Department of Medicine, University of Illinois
at Chicago/Advocate Christ Medical Center, Oak Lawn
hyperkalemia to promote shared care responsi-
(E.L.); Robert Larner College of Medicine, University of Ver-
bility and treatment planning. mont Medical Center, Burlington (M.O.); David Geffen
School of Medicine, University of California, Los Angeles
(A.R.); Renal Research, Gosford Hospital, Gosford, Australia
CONCLUSION (S.D.R.); Nephrology Associates P.C., New Rochelle, NY
Critical unmet needs exist regarding effective (B.S.S.); and Department of Medicine, University of Mary-
hyperkalemia management, including classifi- land School of Medicine, Baltimore (M.R.W.).
cation and monitoring for hyperkalemia, rein-
itiation and maximization of RAASi therapy, Grant Support: This work was supported in part by
and use of Kþ-binding agents. Hyperkalemia AstraZeneca.
incidence may be higher than previously re- Potential Competing Interests: Dr Carrero has received
ported, and the risks associated with acute advisory board fees and travel support from AstraZeneca
and chronic hyperkalemia may be reduced and research grants and advisory board fees from Astellas
through vigilant individualized serum Kþ Pharma Inc, Merck Sharp & Dohme Corp, and Vifor Pharma.
Drs Colbert, Emmett, Hain, and Onuigbo have received
monitoring. With the availability of newer advisory board fees from AstraZeneca. Dr Fishbane has
Kþ-binding agents, clinicians have increased received research funding and consulting fees from AstraZe-
need for education on their use as well as to neca. Dr Lerma has received research grants from ZS
increase patient awareness about the signs, Pharma, Inc. Dr Rastogi has received advisory board and
speakers bureau fees from AstraZeneca and Relypsa Inc
symptoms, and risks of hyperkalemia. Newer and research grants from AstraZeneca. Dr Roger has
Kþ-binding agents may enable the optimiza- received consulting and speakers bureau fees and travel sup-
tion of RAASi therapy in more patients with port from AstraZeneca and Vifor Pharma. Dr Spinowitz has
hyperkalemia. received grant support and personal fees from Akebia

Therapeutics, Inc, AstraZeneca, FibroGen, Inc, and Reata 11. Pochineni V, Rondon-Berrios H. Electrolyte and acid-base dis-
Pharmaceuticals, Inc, and fees from Fresenius Medical orders in the renal transplant recipient. Front Med (Lausanne).
Care. Dr Weir has received personal fees as scientific 2018;5:261.
advisor for AbbVie Inc, Akebia Therapeutics, Inc, AstraZe- 12. Chaitman M, Dixit D, Bridgeman MB. Potassium-binding
agents for the clinical management of hyperkalemia. P T.
neca, Bayer AG, Boehringer Ingelheim International
2016;41(1):43-50.
GmbH, Boston Scientific Corporation, Janssen Pharmaceuti- 13. Lee Hamm L, Hering-Smith KS, Nakhoul NL. Acid-base and
cals, Inc, Merck Sharp & Dohme Corp, Relypsa Inc, and Vifor potassium homeostasis. Semin Nephrol. 2013;33(3):257-264.
Pharma. The other authors report no competing interests. 14. Collins AJ, Pitt B, Reaven N, et al. Association of serum potas-
sium with all-cause mortality in patients with and without
Correspondence: Address to Biff F. Palmer, MD, Depart- heart failure, chronic kidney disease, and/or diabetes. Am J
ment of Internal Medicine, University of Texas South- Nephrol. 2017;46(3):213-221.
western Medical Center, 5323 Harry Hines Blvd, Dallas, 15. Gasparini A, Evans M, Barany P, et al. Plasma potassium ranges
TX 75390 (biff.palmer@utsouthwestern.edu). associated with mortality across stages of chronic kidney dis-
ease: the Stockholm CREAtinine Measurements (SCREAM)
ORCID project. Nephrol Dial Transplant. 2019;34(9):1534-1541.
Biff F. Palmer: https://orcid.org/0000-0002-7322-4692; 16. Fleet JL, Shariff SZ, Gandhi S, Weir MA, Jain AK, Garg AX. Val-
Juan Jesus Carrero: https://orcid.org/0000-0003-4763- idity of the International Classification of Diseases 10th revision
code for hyperkalaemia in elderly patients at presentation to
2024; Macaulay Onuigbo: https://orcid.org/0000-0002-
an emergency department and at hospital admission. BMJ
2601-5791; Matthew R. Weir: https://orcid.org/0000- Open. 2012;2(6):e002011.
0001-8820-5702 17. Conway R, Creagh D, Byrne DG, O’Riordan D, Silke B. Serum
potassium levels as an outcome determinant in acute medical
admissions. Clin Med (Lond). 2015;15(3):239-243.
REFERENCES 18. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyper-
kalemia and its significance in chronic kidney disease. Arch
1. Rosano GMC, Tamargo J, Kjeldsen KP, et al. Expert consensus
Intern Med. 2009;169(12):1156-1162.
document on the management of hyperkalaemia in patients with
19. Nakhoul GN, Huang H, Arrigain S, et al. Serum potassium,
cardiovascular disease treated with renin angiotensin aldosterone
end-stage renal disease and mortality in chronic kidney dis-
system inhibitors: coordinated by the Working Group on Cardio-
ease. Am J Nephrol. 2015;41(6):456-463.
vascular Pharmacotherapy of the European Society of Cardiology.
20. An JN, Lee JP, Jeon HJ, et al. Severe hyperkalemia requiring hos-
Eur Heart J Cardiovasc Pharmacother. 2018;4(3):180-188.
pitalization: predictors of mortality. Crit Care. 2012;16(6):R225.
2. Rafique Z, Weir MR, Onuigbo M, et al. Expert panel recom-
21. Korgaonkar S, Tilea A, Gillespie BW, et al. Serum potassium
mendations for the identification and management of hyper-
and outcomes in CKD: insights from the RRI-CKD cohort
kalemia and role of patiromer in patients with chronic kidney
study. Clin J Am Soc Nephrol. 2010;5(5):762-769.
disease and heart failure. J Manag Care Spec Pharm. 2017;
22. Grodzinsky A, Goyal A, Gosch K, et al. Prevalence and prog-
23(4-a, suppl):S10-S19.
nosis of hyperkalemia in patients with acute myocardial infarc-
3. Bandak G, Sang Y, Gasparini A, et al. Hyperkalemia after initi-
tion. Am J Med. 2016;129(8):858-865.
ating renin-angiotensin system blockade: the Stockholm
23. Mathialahan T, Maclennan KA, Sandle LN, Verbeke C,
Creatinine Measurements (SCREAM) project. J Am Heart
Sandle GI. Enhanced large intestinal potassium permeability
Assoc. 2017;6(7):e005428.
in end-stage renal disease. J Pathol. 2005;206(1):46-51.
4. Howlett JG, Chan M, Ezekowitz JA, et al; Canadian Cardiovas-
24. Sterns RH, Feig PU, Pring M, Guzzo J, Singer I. Disposition of
cular Society Heart Failure Guidelines Panels. The Canadian
intravenous potassium in anuric man: a kinetic analysis. Kidney
Cardiovascular Society heart failure companion: bridging
Int. 1979;15(6):651-660.
guidelines to your practice. Can J Cardiol. 2016;32(3):296-310.
25. Alvestrand A, Wahren J, Smith D, DeFronzo RA. Insulin-medi-
5. National Kidney Foundation. Best practices in managing
ated potassium uptake is normal in uremic and healthy sub-
hyperkalemia in chronic kidney disease. National Kidney Foun-
jects. Am J Physiol. 1984;246(2, pt 1):E174-E180.
dation website. https://www.kidney.org/sites/default/files/02-
26. Berti C, Zsolnay V, Shannon TR, Fill M, Gillespie D. Sarco-
10-7259%20Hyperkalemia%20Tool.pdf. Accessed August
plasmic reticulum Ca2þ, Mg2þ, Kþ, and Cl concentrations
21, 2019.
adjust quickly as heart rate changes. J Mol Cell Cardiol. 2017;
6. UK Renal Association. Clinical practice guidelines: treatment of
103:31-39.
acute hyperkalaemia in adults. https://renal.org/wp-content/
27. Stillitano F, Lonardo G, Zicha S, et al. Molecular basis of funny
uploads/2017/06/hyperkalaemia-guideline-1.pdf. Accessed
current (If) in normal and failing human heart. J Mol Cell Cardiol.
August 21, 2019.
2008;45(2):289-299.
7. Kovesdy CP, Appel LJ, Grams ME, et al. Potassium homeosta-
28. Wang X, Fitts RH. Ventricular action potential adaptation to
sis in health and disease: a scientific workshop cosponsored by
regular exercise: role of b-adrenergic and KATP channel func-
the National Kidney Foundation and the American Society of
tion. J Appl Physiol (1985). 2017;123(2):285-296.
Hypertension. Am J Kidney Dis. 2017;70(6):844-858.
29. Martin HE, Wertman M. Serum potassium, magnesium, and
8. Bianchi S, Aucella F, De Nicola L, Genovesi S, Paoletti E,
calcium levels in diabetic acidosis. J Clin Invest. 1947;26(2):
Regolisti G. Management of hyperkalemia in patients with kid-
217-228.
ney disease: a position paper endorsed by the Italian Society
30. Nilsson E, Gasparini A, Ärnlöv J, et al. Incidence and determi-
of Nephrology. J Nephrol. 2019;32(4):499-516.
nants of hyperkalemia and hypokalemia in a large healthcare
9. Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice
system. Int J Cardiol. 2017;245:277-284.
update on heart failure 2019: pharmacotherapy, procedures,
31. Chang AR, Sang Y, Leddy J, et al. Antihypertensive medica-
devices and patient management: an expert consensus
tions and the prevalence of hyperkalemia in a large health sys-
meeting report of the Heart Failure Association of the Euro-
tem. Hypertension. 2016;67(6):1181-1188.
pean Society of Cardiology. Eur J Heart Fail. 2019;21(10):
32. Krogager ML, Eggers-Kaas L, Aasbjerg K, et al. Short-term mor-
1169-1186.
tality risk of serum potassium levels in acute heart failure
10. Palmer BF, Clegg DJ. Physiology and pathophysiology of potas-
following myocardial infarction. Eur Heart J Cardiovasc Phar-
sium homeostasis: core curriculum 2019. Am J Kidney Dis.
macother. 2015;1(4):245-251.
2019;74(5):682-695.
n n
33. Krogager ML, Torp-Pedersen C, Mortensen RN, et al. Short- 48. American Diabetes Association. 9. Cardiovascular disease and
term mortality risk of serum potassium levels in hypertension: risk management: Standards of Medical Care in Dia-
a retrospective analysis of nationwide registry data. Eur Heart J. betese2018. Diabetes Care. 2018;41(suppl 1):S86-S104.
2017;38(2):104-112. 49. Molnar MZ, Kalantar-Zadeh K, Lott EH, et al. Angiotensin-
34. Palmer BF. Managing hyperkalemia caused by inhibitors of the converting enzyme inhibitor, angiotensin receptor blocker
renin-angiotensin-aldosterone system. N Engl J Med. 2004; use, and mortality in patients with chronic kidney disease.
351(6):585-592. J Am Coll Cardiol. 2014;63(7):650-658.
35. Palmer BF, Clegg DJ. Hyperkalemia across the continuum of 50. Tai C, Gan T, Zou L, et al. Effect of angiotensin-converting
kidney function. Clin J Am Soc Nephrol. 2018;13(1):155-157. enzyme inhibitors and angiotensin II receptor blockers on car-
36. Trevisan M, de Deco P, Xu H, et al. Incidence, predictors and diovascular events in patients with heart failure: a meta-
clinical management of hyperkalaemia in new users of miner- analysis of randomized controlled trials. BMC Cardiovasc Dis-
alocorticoid receptor antagonists [published correction ap- ord. 2017;17(1):257.
pears in Eur J Heart Fail. 2019;21(4):540]. Eur J Heart Fail. 51. Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study
2018;20(8):1217-1226. Group. Eplerenone in patients with systolic heart failure and
37. Adelborg K, Nicolaisen SK, Hasvold P, Palaka E, Pedersen L, mild symptoms. N Engl J Med. 2011;364(1):11-21.
Thomsen RW. Predictors for repeated hyperkalemia and po- 52. Xu Y, Qiu Z, Yang R, Wu Y, Cheng X. Efficacy of mineralo-
tassium trajectories in high-risk patients e a population-based corticoid receptor antagonists in postmyocardial infarction pa-
cohort study. PLoS One. 2019;14(6):e0218739. tients with or without left ventricular dysfunction: a meta-
38. Kim T, Rhee CM, Streja E, et al. Racial and ethnic differences in analysis of randomized controlled trials. Medicine (Baltimore).
mortality associated with serum potassium in a large hemodi- 2018;97(51):e13690.
alysis cohort. Am J Nephrol. 2017;45(6):509-521. 53. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting
39. Kidney Disease Outcomes Quality Initiative. K/DOQI clinical enzyme inhibitors and progression of nondiabetic renal dis-
practice guidelines on hypertension and antihypertensive ease: a meta-analysis of patient-level data [published correc-
agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5, tion appears in Ann Intern Med. 2002;137(4):299]. Ann Intern
suppl 1):S1-S290. Med. 2001;135(2):73-87.
40. Clase CM, Carrero J-J, Ellison DH, et al. Potassium homeostasis 54. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study
and management of dyskalemia in kidney diseases: conclusions Investigators. Effects of losartan on renal and cardiovascular
from a Kidney Disese: Improving Global Outcomes (KDIGO) outcomes in patients with type 2 diabetes and nephropathy.
Controversies Conference. Kidney Int. 2020;97(1):42-61. N Engl J Med. 2001;345(12):861-869.
41. Palmer BF, Clegg DJ. Achieving the benefits of a high- 55. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study
potassium, paleolithic diet, without the toxicity. Mayo Clin Group. Renoprotective effect of the angiotensin-receptor
Proc. 2016;91(4):496-508. antagonist irbesartan in patients with nephropathy due to
42. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guide- type 2 diabetes. N Engl J Med. 2001;345(12):851-860.
lines for the management of arterial hypertension: the Task 56. Rassi AN, Cavender MA, Fonarow GC, et al. Temporal trends
Force for the Management of Arterial Hypertension of the and predictors in the use of aldosterone antagonists post-acute
European Society of Hypertension (ESH) and of the Euro- myocardial infarction. J Am Coll Cardiol. 2013;61(1):35-40.
pean Society of Cardiology (ESC). Eur Heart J. 2013;34(28): 57. Epstein M, Reaven NL, Funk SE, McGaughey KJ, Oestreicher N,
2159-2219. Knispel J. Evaluation of the treatment gap between clinical guide-
43. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines lines and the utilization of renin-angiotensin-aldosterone system
for the diagnosis and treatment of acute and chronic heart fail- inhibitors. Am J Manag Care. 2015;21(11, suppl):S212-S220.
ure: the Task Force for the Diagnosis and Treatment of Acute 58. Savarese G, Carrero J-J, Pitt B, et al. Factors associated with
and Chronic Heart Failure of the European Society of Cardi- underuse of mineralocorticoid receptor antagonists in heart
ology (ESC); developed with the special contribution of the failure with reduced ejection fraction: an analysis of 11 215 pa-
Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. tients from the Swedish Heart Failure Registry. Eur J Heart Fail.
2016;18(8):891-975. 2018;20(9):1326-1334.
44. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA 59. De Nicola L, Di Lullo L, Paoletti E, Cupisti A, Bianchi S.
focused update of the 2013 ACCF/AHA guideline for the Chronic hyperkalemia in non-dialysis CKD: controversial is-
management of heart failure: a report of the American Col- sues in nephrology practice. J Nephrol. 2018;31(5):653-664.
lege of Cardiology/American Heart Association Task Force 60. Tamargo J, Caballero R, Delpón E. New therapeutic ap-
on Clinical Practice Guidelines and the Heart Failure Society proaches for the treatment of hyperkalemia in patients treated
of America. J Am Coll Cardiol. 2017;70(6):776-803. with renin-angiotensin-aldosterone system inhibitors. Cardio-
45. Task Force Members, Montalescot G, Sechtem U, et al. 2013 vasc Drugs Ther. 2018;32(1):99-119.
ESC guidelines on the management of stable coronary artery 61. Beusekamp JC, Tromp J, van der Wal HH, et al. Potassium and
disease: the Task Force on the management of stable coro- the use of renin-angiotensin-aldosterone system inhibitors in
nary artery disease of the European Society of Cardiology heart failure with reduced ejection fraction: data from BIO-
[published correction appears in Eur Heart J. 2014;35(33): STAT-CHF. Eur J Heart Fail. 2018;20(5):923-930.
2260-2261]. Eur Heart J. 2013;34(38):2949-3003. 62. Rossignol P, Dobre D, McMurray JJV, et al. Incidence, determi-
46. Kidney Disease: Improving Global Outcomes Work Group. nants, and prognostic significance of hyperkalemia and wors-
KDIGO 2012 clinical practice guideline for the evaluation and ening renal function in patients with heart failure receiving the
management of chronic kidney disease. Kidney Int Suppl. 2013; mineralocorticoid receptor antagonist eplerenone or placebo
3(1):1-150. in addition to optimal medical therapy: results from the Eplere-
47. Rydén L, Grant PJ, Anker SD, et al. ESC guidelines on dia- none in Mild Patients Hospitalization and Survival Study in Heart
betes, pre-diabetes, and cardiovascular diseases developed Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7(1):51-58.
in collaboration with the EASD e summary: the Task Force 63. Qiao Y, Shin J-I, Chen TK, et al. Association between renin-
on diabetes, pre-diabetes, and cardiovascular diseases of angiotensin system blockade discontinuation and all-cause
the European Society of Cardiology (ESC) and developed mortality among persons with low estimated glomerular filtra-
in collaboration with the European Association for the tion rate. JAMA Intern Med. 2020;180(5):718-726.
Study of Diabetes (EASD). Diab Vasc Dis Res. 2014;11(3): 64. Epstein M, Alvarez PJ, Reaven NL, et al. Evaluation of clinical
133-173. outcomes and costs based on prescribed dose level of

renin-angiotensin-aldosterone system inhibitors. Am J Manag 82. Lepage L, Dufour A-C, Doiron J, et al. Randomized clinical trial
Care. 2016;22(11, suppl):s311-s324. of sodium polystyrene sulfonate for the treatment of mild
65. Rossignol P, Lainscak M, Crespo-Leiro MG, et al; Heart Failure hyperkalemia in CKD. Clin J Am Soc Nephrol. 2015;10(12):
Long-Term Registry Investigators Group. Unravelling the 2136-2142.
interplay between hyperkalaemia, renin-angiotensin- 83. Rafique Z, Liu M, Staggers KA, Minard CG, Peacock WF.
aldosterone inhibitor use and clinical outcomes: data from Patiromer for treatment of hyperkalemia in the emergency
9222 chronic heart failure patients of the ESC-HFA-EORP department: a pilot study. Acad Emerg Med. 2020;27(1):54-60.
Heart Failure Long-Term Registry [published online ahead 84. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F,
of print April 3, 2020]. Eur J Heart Fail, https://doi.org/10. Huang I-Z; PEARL-HF Investigators. Evaluation of the efficacy
1002/ejhf.1793. and safety of RLY5016, a polymeric potassium binder, in a
66. Butler J, Khan MS, Anker SD. Novel potassium binders as double-blind, placebo-controlled study in patients with
enabling therapy in heart failure. Eur J Heart Fail. 2019;21(5): chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;
550-552. 32(7):820-828.
67. Aldahl M, Jensen A-SC, Davidsen L, et al. Associations of 85. Bakris GL, Pitt B, Weir MR, et al; AMETHYST-DN Investiga-
serum potassium levels with mortality in chronic heart failure tors. Effect of patiromer on serum potassium level in patients
patients. Eur Heart J. 2017;38(38):2890-2896. with hyperkalemia and diabetic kidney disease: the
68. Ranjitkar P, Greene DN, Baird GS, Hoofnagle AN, AMETHYST-DN randomized clinical trial [published correc-
Mathias PC. Establishing evidence-based thresholds and labo- tion appears in JAMA. 2015;314(7):731]. JAMA. 2015;314(2):
ratory practices to reduce inappropriate treatment of pseudo- 151-161.
hyperkalemia. Clin Biochem. 2017;50(12):663-669. 86. Agarwal R, Rossignol P, Romero A, et al. Patiromer versus pla-
69. Don BR, Sebastian A, Cheitlin M, Christiansen M, cebo to enable spironolactone use in patients with resistant
Schambelan M. Pseudohyperkalemia caused by fist clenching hypertension and chronic kidney disease (AMBER): a phase
during phlebotomy. N Engl J Med. 1990;322(18):1290-1292. 2, randomised, double-blind, placebo-controlled trial. Lancet.
70. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA 2019;394(10208):1540-1550.
guideline for the management of heart failure: a report of 87. Weir MR, Bakris GL, Bushinsky DA, et al; OPAL-HK Investiga-
the American College of Cardiology Foundation/American tors. Patiromer in patients with kidney disease and hyperkalemia
Heart Association Task Force on Practice Guidelines. J Am receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221.
Coll Cardiol. 2013;62(16):e147-e239. 88. Peacock WF, Rafique Z, Vishnevskiy K, et al. Emergency po-
71. National Institute for Health and Care Excellence. Chronic tassium normalization treatment including sodium zirconium
kidney disease in adults: assessment and management; clinical cyclosilicate: a phase II, randomized, double-blind, placebo-
gudiance. National Institute for Health and Care Excellence controlled study (ENERGIZE). Acad Emerg Med. 2020;27(6):
website. https://www.nice.org.uk/guidance/cg182. Published 475-486.
July 23, 2014. Updated January 16, 2015. Accessed August 89. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirco-
21, 2019. nium cyclosilicate in hyperkalemia. N Engl J Med. 2015;
72. Peacock WF, Rafique Z, Clark CL, et al; REVEAL-ED Study In- 372(3):222-231.
vestigators. Real world evidence for treatment of hyperkale- 90. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium
mia in the emergency department (REVEAL-ED): a zirconium cyclosilicate on potassium lowering for 28 days
multicenter, prospective, observational study. J Emerg Med. among outpatients with hyperkalemia: the HARMONIZE ran-
2018;55(6):741-750. domized clinical trial [published correction appears in JAMA.
73. Galloway CD, Valys AV, Shreibati JB, et al. Development and 2015;313(5):526]. JAMA. 2014;312(21):2223-2233.
validation of a deep-learning model to screen for hyperkale- 91. Roger SD, Spinowitz BS, Lerma EV, et al. Efficacy and safety of
mia from the electrocardiogram. JAMA Cardiol. 2019;4(5): sodium zirconium cyclosilicate for treatment of hyperkalemia:
428-436. an 11-month open-label extension of HARMONIZE. Am J
74. Kovesdy CP. Management of hyperkalaemia in chronic kidney Nephrol. 2019;50(6):473-480.
disease. Nat Rev Nephrol. 2014;10(11):653-662. 92. Zannad F, Hsu B-G, Maeda Y, et al. Efficacy and safety of so-
75. Lindner G, Burdmann EA, Clase CM, et al. Acute hyperkale- dium zirconium cyclosilicate for hyperkalaemia: the random-
mia in the emergency department: a summary from a Kidney ized, placebo-controlled HARMONIZE-Global study. ESC
Disease: Improving Global Outcomes conference [published Heart Fail. 2020;7(1):54-64.
online ahead of print March 24, 2020]. Eur J Emerg Med, 93. Spinowitz BS, Fishbane S, Pergola PE, et al; ZS-005 Study In-
https://doi.org/10.1097/MEJ.0000000000000691. vestigators. Sodium zirconium cyclosilicate in individuals with
76. Palmer BF, Clegg DJ. Diagnosis and treatment of hyperkalemia. hyperkalemia: a 12-month phase 3 study. Clin J Am Soc Neph-
Cleve Clin J Med. 2017;84(12):934-942. rol. 2019;14(6):798-809.
77. US Food and Drug Administration websiteRelypsa Inc. Veltassa 94. Fishbane S, Ford M, Fukagawa M, et al. A phase 3b, ran-
[package insert]. Redwood City, CA: Relypsa, Inc; 2018., domized, double-blind, placebo-controlled study of so-
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/ dium zirconium cyclosilicate for reducing the incidence
205739s016lbl.pdf. Accessed August 21, 2019. of predialysis hyperkalemia. J Am Soc Nephrol. 2019;
78. Kayexalate [package insert]. Laval. Quebec: Sanofi-Aventis; 30(9):1723-1733.
2018. https://products.sanofi.ca/en/kayexalate.pdf. Accessed 95. National Institute for Health and Care Excellence. Sodium zirco-
August 21, 2019. nium cyclosilicate for treating hyperkalaemia: guidance. National
79. Lokelma [package insert]. Wilmington, DE: AstraZeneca; 2018., Institute for Health and Care Excellence website. https://www.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/ nice.org.uk/guidance/ta599. Accessed September 12, 2019.
207078s000lbl.pdf. Accessed August 21, 2019. 96. National Institute for Health and Care Excellence. Patiromer
80. Beccari MV, Meaney CJ. Clinical utility of patiromer, sodium for treating hyperkalaemia. National Institute for Health and
zirconium cyclosilicate, and sodium polystyrene sulfonate for Care Excellence website. https://www.nice.org.uk/guidance/
the treatment of hyperkalemia: an evidence-based review ta623. Accessed April 23, 2020.
[published correction appears in Core Evid. 2019;14:1]. Core 97. Bounthavong M, Butler J, Dolan CM, et al. Cost-effectiveness
Evid. 2017;12:11-24. analysis of patiromer and spironolactone therapy in heart fail-
81. Georgianos PI, Agarwal R. Revisiting RAAS blockade in CKD ure patients with hyperkalemia [published correction appears
with newer potassium-binding drugs. Kidney Int. 2018;93(2): in Pharmacoeconomics. 2019;37(8):1071]. Pharmacoeconomics.
325-334. 2018;36(12):1463-1473.
n n
98. Zann V, McDermott J, Jacobs JW, et al. Palatability and physical blockers: results from AMETHYST-DN. ESC Heart Fail.
properties of potassium-binding resin RDX7675: comparison 2018;5(4):592-602.
with sodium polystyrene sulfonate. Drug Des Devel Ther. 2017; 106. Kovesdy CP, Rowan CG, Conrad A, et al. Real-world evalua-
11:2663-2673. tion of patiromer for the treatment of hyperkalemia in hemo-
99. Jadoul M, Karaboyas A, Goodkin DA, et al. Potassium-binding dialysis patients. Kidney Int Rep. 2018;4(2):301-309.
resins: associations with serum chemistries and interdialytic 107. Epstein M, Pitt B. Recent advances in pharmacological treat-
weight gain in hemodialysis patients. Am J Nephrol. 2014; ments of hyperkalemia: focus on patiromer. Expert Opin Phar-
39(3):252-259. macother. 2016;17(10):1435-1448.
100. Parks M, Grady D. Sodium polystyrene sulfonate for hyperka- 108. Bushinsky DA, Williams GH, Pitt B, et al. Patiromer induces rapid
lemia [published online ahead of print June 10, 2019]. JAMA and sustained potassium lowering in patients with chronic kidney
Intern Med, https://doi.org/10.1001/jamainternmed.2019.1291. disease and hyperkalemia. Kidney Int. 2015;88(6):1427-1433.
101. Laureati P, Xu Y, Trevisan M, et al. Initiation of sodium poly- 109. Bhattarai S, Pupillo S, Man Singh Dangol G, Sarac E. Patiromer
styrene sulphonate and the risk of gastrointestinal adverse acetate induced hypercalcemia: an unreported adverse effect.
events in advanced chronic kidney disease: a nationwide study Case Rep Nephrol. 2019;2019:3507407.
[published online ahead of print August 4, 2019]. Nephrol Dial 110. Wiederkehr MR, Mehta AN, Emmett M. Case report:
Transplant, https://doi.org/10.1093/ndt/gfz150. patiromer-induced hypercalcemia. Clin Nephrol Case Stud.
102. Noel JA, Bota SE, Petrcich W, et al. Risk of hospitalization for 2019;7:51-53.
serious adverse gastrointestinal events associated with sodium 111. Kosiborod M, Peacock WF, Packham DK. Sodium zirconium
polystyrene sulfonate use in patients of advanced age. JAMA cyclosilicate for urgent therapy of severe hyperkalemia [letter].
Intern Med. 2019;179(8):1025-1033. N Engl J Med. 2015;372(16):1577-1578.
103. Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastroin- 112. de Francisco A, Rasmussen H, Lavin P, et al. Normalization of
testinal adverse events with sodium polystyrene sulfonate serum bicarbonate with sodium zirconium cyclosilicate (ZS-9)
(Kayexalate) use: a systematic review. Am J Med. 2013; in the phase 3 randomized, double-blind, placebo-controlled
126(3):264.e9-264.e24. HARMONIZE study. Nephrol Dial Transplant. 2015;
104. US Food and Drug Administration. Kayexalate (sodium poly- 30(suppl_3). iii6. Abstract FO012.
styrene sulfonate, USP) powder approval letter (2009). US 113. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Charac-
Food and Drug Administration website. https://www. terization of structure and function of ZS-9, a Kþ selective ion
accessdata.fda.gov/drugsatfda_docs/appletter/2009/011287s trap. PLoS One. 2014;9(12):e114686.
022ltr.pdf. Accessed August 21, 2019. 114. National Kidney Foundation. Hyperkalemia: survey of aware-
105. Pitt B, Bakris GL, Weir MR, et al. Long-term effects of ness and experience among adults with CKD; a report of find-
patiromer for hyperkalaemia treatment in patients with ings. National Kidney Foundation website. https://www.kidney.
mild heart failure and diabetic nephropathy on org/sites/default/files/HyperkalemiaReport1.pdf. Published
angiotensin-converting enzymes/angiotensin receptor March 6, 2017. Accessed August 21, 2019.


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REVIEW

Clinical Management of Hyperkalemia

Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite

From the Department of

Mayo Clin Proc. n XXX 2020;nn(n):1-19 n https://doi.org/10.1016/j.mayocp.2020.06.014 1

diabetes.14,15 A U-shaped curve exists between

do not impact hyperkalemia management; including blood pressure reductions and

these medications, receive suboptimal doses,

Predicted probability of mortality

aIn patients with metabolic acidosis Stabilize myocardial cell membrane

Potassium concentration thresholds for Frequency of Kþ Monitoring

hyperkalemia in the emergency department.72 recommendations on when to reinitiate RAASi

TABLE 1. Summary of Guideline Recommendations for RAASi Therapya

TABLE 2. Selected Characteristics of Kþ-Binding Agents for Hyperkalemia

TABLE 3. Summary of Key Clinical Studies of Kþ-Binding Agentsa

Moderate hyperkalemia: Moderate hyperkalemia:

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Maintenance phase: Maintenance phase:

ZS-005; phase 3, 2-stage, Outpatients with Correction phase: Correction phase:

Maintenance phase: Maintenance phase:

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recently launched in US and other markets, ACKNOWLEDGMENTS

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