HYPERKALEMIA

DISEASE STATE

Outline
What is hyperkalemia?
Prevalence and causes
Symptoms and diagnosis
Management of hyperkalemia in the
acute and chronic stages

Outline
What is hyperkalemia?
Prevalence and causes
Symptoms and diagnosis
Management of hyperkalemia in the
acute and chronic stages

K+ homeostasis is maintained by a balance

between absorption and excretion1,2
Daily dietary K+ intake
100 mEq/L
Bone
50 mEq/L

Liver
250 mEq/L

Extracellular fluid
70 mEq/L

Muscle
2650 mEq/L

Normal K+ excretion
100 mEq/L

Erythrocytes
250 mEq/L

Normal K+ range
3.55.5 mEq/L
Gut (10%)

Kidneys (90%)
1. Giebisch G, et al. AJP Centennial 1998;274(5 Pt 2):F822F833
2. Greenlee M, et al. Ann Intern Med 2009;150(9):619625

The kidney is critical in regulating K+ levels

in the body
The distal tubule
is the site of K+/Na+/
Ca+2/Mg+2 excretion

6075% of K+ re-absorbed in
the proximal tubule Bowmans
capsule

Glomerulus

Regulation of K+ secretion
occurs in the distal nephron

Cortex

Nephron function is
influenced by:1

Medulla

1520% of K+
re-absorbed in
the loop of Henle

Any alteration in kidney

function results in renal
retention of K+ ions1

Collecting
tubule

Flow rate to the nephron

Solute delivery

To
ureter

Effects of aldosterone

1. Weisberg, LS. Crit Care Med 2008;36(12):32463251

Hyperkalemia is the result of excess

potassium levels in serum

Risk of hyperkalemia is increased with:

6.0

Hyperkalemia

5.5
5.0

Normal
3.8

% of CKD patients K+ >5.5 mEq/L*

Serum K+ (mEq/L)

CKD
RAASi medications (ACEIs, ARBs, AAs)
60
50
40

CKD-3

30

CKD-4

20

CKD-5

10
0

*Retrospective analysis of 245,808 people

AA=aldosterone antagonists; ACEIs=angiotensin-converting enzyme inhibitors; ARBs=angiotensin II receptor blockers;
CKD=chronic kidney disease; RAASi=renin-angiotensin aldosterone system inhibitor
Adapted from Einhorn LM, et al. Arch Intern Med 2009;169(12):11561162

The definition of hyperkalemia varies,

depending on studies and guidelines

Serum K+ (mEq/L)

6.0

Hyperkalemia

5.5
5.0

Normal

4.0

Target Range: K+=3.85.0

Serum K+ levels of >5.0 to >5.5

mmol/L are commonly used cutoffs for ULN across publications
and guidelines17

Low
Low

3.5
3.0

A reference range indicates degree

of severity:

Hypokalemia

ULN=upper limit of normal

1. Einhorn LM, et al. Arch Intern Med 2009;169(12):11561162; 2. Yancy CW, et al. J Am Coll Cardiol 2013;62(16):e147239; 3. McMurray JJ. Eur Heart J 2012;33(14):17871847; 4.
National Kidney Foundation. Guideline 11: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in CKD. In: K/DOQI Clinical Practice Guidelines on
Hypertension and Antihypertensive Agents in Chronic Kidney Disease. 2002. http://www2.kidney.org/professionals/kdoqi/guidelines_bp/guide_11.htm;
5. National Institute for Health and Care Excellence (NICE) [UK]. Chronic kidney disease (CG73): Early identification and management of chronic kidney disease in adults in primary
and secondary care. 2008. http://www.nice.org.uk/CG73; 6. Lindenfeld J, et al. J Card Fail 2010;16(6):e1e194; 7. Spironolactone PI 2011.

Outline
What is hyperkalemia?
Prevalence and causes
Symptoms and diagnosis
Management of hyperkalemia in the
acute and chronic stages

Prevalence of hyperkalemia in the

general population is unknown1,2

No population-wide studies have evaluated the

incidence and prevalence of hyperkalemia2

Studies in hospitalised patients report incidence

rates of hyperkalemia ranging approximately
between 110%1,3
Majority (3575%) of hyperkalemia cases is due to
use of medications1

1. Evans KJ, Greenberg A. J Intensive Care Med 2005;20(5):272290

2. Kovesdy CP. Kidney Int Suppl 2016;6:36
3. Dunn JD, et al. Am J Manag Care 2015;21(15 Suppl):S307S315

Development of hyperkalemia requires a defect in at

least one mechanism that maintains K+ homeostasis

1. Increased potassium load (dietary)

2. Intracellular to extracellular shifts (uncommon)

3. Decreased renal elimination

(the most common cause)

Evans KJ, Greenberg A. J Intensive Care Med 2005;20(5):272290

Hyperkalemia is a common complication in

patients with co-morbidities

Advanced CKD
Hyperkalemia is common in patients with CKD owing
to a combination of kidney dysfunction and existing
co-morbidities

Diabetes and diabetic nephropathies

Heart failure and hypertension
Mineralocorticoid receptor antagonists

On concomitant medication
RAASi
NSAIDs
CKD=chronic kidney disease; RAASi=renin-angiotensin aldosterone system inhibitor;
NSAIDs=non-steroidal anti-inflammatory drugs
Kovesdy CP. Nat Rev Nephrol 2014;10(11):653662

Hyperkalemia is associated with higher mortality

rates, especially in older patients with co-morbidities

Predicted Probability of Mortality

0,9
0,8

Adjusted mortalities* by serum K+ levels in patients aged

4564 year-old and in patients aged 65 years
with and without co-morbid disease

0,7

+ Co-morbidities
65 yrs
Control 65 yrs

0,6
+ Co-morbidities
4564 yrs

0,5
0,4

Normal Range

0,3

Control
4564 yrs

0,2
0,1
0
2,5

3,0

3,5

4,0

4,5
5,0
5,5
6,0
Levels of Serum K+ (mEq/L)

6,5

7,0

7,5

8,0

* Evaluated through de-identified medical records (20072012) of individuals with 2 mEq/L serum K+ readings (Humedica, Cambridge, MA).
Spline analyses were performed to assess mortality at 0.1 mEq/L increments of serum K+ after adjusting for covariates and interactions.
Co-morbid patients are those with diabetes, heart failure, CKD stages 35, cardiovascular disease, or hypertension
Adjusted mortality probability rates in patients with and without co-morbidities (controls) were calculated with 95% confidence intervals
CKD=chronic kidney disease

Pitt B, et al. American Heart Association. 2014

Rates of hyperkalemia increase with

severity of CKD

Linear relationship observed between hyperkalemia rates

and CKD stage (serum K+ levels 5.5 mEq/L)
Hyperkalemia rates in real-world observational studies
and stage of CKD (serum K+ 5.5 mEq/L)*
56,7

Hyperkalemia rate as a %
of CKD population

60
50
42,1

40
30
20,7

20
10

8.9

0
No CKD
* Retrospective analysis of 245,808 people
CKD=chronic kidney disease

Stage 3

Stage 4

Stage 5

CKD stage

Einhorn LM, et al. Arch Intern Med 2009;169(12):11561162

Increasing severity of hyperkalemia is

associated with higher mortality in CKD

CKD patients with serum K+ levels 5.5 mEq/L have a

10-fold increase in mortality rate within 24 hours*
Odds of death within 24 hour period
Odds ratio of death
from hyperkalemia

25
19.52

20
15

11.56

10
5
0

5.7

5.4

1.0

1.1
CKD 3

<5.5
* Retrospective analysis of 245,808 people
CKD=chronic kidney disease

CKD 4

5.5 and <6.0

6.0

K+ level, mEq/L

Einhorn LM, et al. Arch Intern Med 2009;169(12):11561162

Outline
What is hyperkalemia?
Prevalence and causes
Symptoms and diagnosis
Management of hyperkalemia in the
acute and chronic stages

Hyperkalemia is often asymptomatic

Hyperkalemia is usually discovered on routine

laboratory tests,1 but may also be accompanied by
non-specific symptoms:2

Palpitations
Nausea
Weakness
Muscle pain

Clinical manifestations are related to changes in

neuromuscular and cardiac arrhythmias1,2
Serum K+ >6.0 mEq/L can become life-threatening2
1. Rastegar A, Soleimani M. Postgrad Med J 2001;77(914):759764
2. Kraft MD, et al. Am J Health Syst Pharm 2005;62(16):16631682

Changes in ECG may indicate the

severity of hyperkalemia1

ECG monitoring is mandatory in patients with

serum K+ >6.5 mmol/L2

Figure from McCullough PA, et al. Rev Cardiovasc Med 2014;15(1):1123

ECG=electrocardiogram
1. Levis TJ. Perm J 2013;17(1):69
2. Lehnhardt A, Kemper MJ. Pediatr Nephrol 2011;26(3):377384

Outline
What is hyperkalemia?
Prevalence and causes
Symptoms and diagnosis
Management of hyperkalemia in the
acute and chronic stages

Main principles of management hyperkalemia aim

to protect the heart and lower K+ levels in the body

1. Stabilise myocardial membrane potential

(antagonise the effects of K+ levels)
2. Redistribute K+ around the body
(shift extracellular K+ into cells)

3. Increase excretion of K+

Weisberg LS. Crit Care Med 2008;36(12):32463251

Various options are available for managing

acute and chronic hyperkalemia
Emergent
Insulin1

Intermediate

Maintenance

Calcium gluconate1

-adrenergic
receptor
antagonists1
SPS1
Loop
diuretics1

Dialysis1
Sodium
bicarbonate1

Low K+ diet2
RAASi reduction2
Dialysis*1

K+ redistribution

K+ elimination

Membrane stabilisation

Removal of potassium-retaining/increasing drugs

*Refers to HD-CKD patients where K+ is removed during the dialysis procedure (i.e. not true maintenance therapy for hyperkalemia)
RAASi=renin-angiotensin aldosterone system inhibitor; SPS=sodium polystyrene sulfonate
1. Weisberg LS. Crit Care Med 2008;36(12):32463251
2. Palmer BF. N Engl J Med 2004;351(6):585592

Chronic hyperkalemia can be managed by

a low K+ diet as a first step

Restricting K+ to 4060 mmol/day is difficult, as K+-rich

foods are pervasive

Angiotensin II can exert effects on

several target organs and tissues

ACE

ACE=angiotensin-converting enzyme

Figure from Givertz G. Circulation 2001;104(5):e14e18

RAAS inhibition provides additional renal and

cardiovascular benefits, beyond treating hypertension
Death, progression to dialysis, or doubling of serum creatinine

50

Risk reduction, 16%

P=0.02

40

Placebo

Losartan

30
20
10
0
0

12

24

36

48

Months of study

No. at Risk
Placebo
Losartan

IDNT
Proportion with primary endpoint

Primary composite endpoint (%)

RENAAL

762
751

698
692

554
583

Irbesartan
Amlodipine
Placebo

0.6
0.5
0.4
0.3
0.2

RR
0.80
Irbesartan vs placebo
Irbesartan vs amlodipine 0.77

0.1
0.0
0

36
52

12 18 24 30 36 42 48 54

Months of study

No. at Risk
295
329

P
0.023
0.006

Irbesartan 579
Amlodipine 565

555 528 496 400 304 216 146

542 508 474 385 287 187 128

65
46

Placebo

551 512 471 401 280 190 122

53

568

1. Brenner BM, et al. N Engl J Med 2001;345(12):861869

2. Lewis EJ, et al. N Engl J Med 2001;345(12):851860

RAAS inhibition is associated with an

increased risk of hyperkalemia

ACEi=angiotensin-converting enzyme inhibitor; ARBs=angiotensin receptor blockers;

MRAs=mineralocorticoid receptor antagonists

Figure from Guichard JL, et al. G. Vasc Health Risk Manag 2013;9:321331

A conundrum: hyperkalemia versus RAASi

The catch-22 of managing diseases that benefit from RAASi therapy

Prescribe RAASi and

accept presence of
hyperkalemia?

RAASi=renin-angiotensin aldosterone system inhibitor

Avoid/discontinue
proven RAASi
therapies?

Current K+ binders in clinical use today are

associated with gastrointestinal toxicity

1Current formulations of cation exchange resins include:

CPS
SPS

Act by exchanging K+ for Ca2+ (CPS) or Na+ (SPS) in

the lumen of the colon1

Serious gastrointestinal adverse events have been

reported with SPS, especially colonic necrosis2

Despite a long history in clinical use, no systematic,

long-term clinical trial data on the safety of these agents

exist3

CPS=calcium polystyrene sulfonate

SPS=sodium polystyrene sulfonate

1. Pitt, B, Bakris, L. Hypertension 2015;66:731738

2. Harel, Z et al. Am J Med 2013;126:264.e9e24
3. Sterns RH, et al. Kid Int 2016;89(3):546554

Desirable clinical attributes of a K+ binder

Clear and
sustained efficacy

Markedly lower serum K+ levels

Fast-acting (within hours) and maintain longterm efficacy (months to years)
Efficacy across diverse patient populations
with co-morbidities (CKD, diabetes, heart
failure, elderly, and combination of these)

Palatable drug with good patient acceptance

of dose form

Good tolerability
and safety

Compatible with commonly-used drugs in

target population
Demonstrate low adverse event rates and
clear long-term safety

Summary
Hyperkalemia is a common complication in patients with co

morbidities (e.g. CKD and diabetes) and who take certain

medications (e.g. RAASi)
The frequency and severity of hyperkalemia increases with
increasing stage of CKD, and is associated with higher mortality
RAAS inhibition increases the risk of hyperkalemia
A low-K+ diet can be used to manage chronic hyperkalemia, but
is difficult to maintain
Cation exchange resins used to treat hyperkalemia are
unsuitable for long-term use owing to gastrointestinal side effects
There is an unmet need for a K+ binder that demonstrates longterm efficacy and safety across a range of co-morbidities

CKD=chronic kidney disease

RAAS(i)=renin-angiotensin aldosterone system (inhibitor)