What is Hyperkalaemia?

Hyperkalaemia, elevated serum K+ levels >5.0 mEq/L, is a serious condition associated with high morbidity and mortality1-6

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Adverse events should be reported to the Vifor Pharma group.

K+ homeostasis is critical

K+ is the most abundant cation in the body. Approximately 2% of total body K+ is in extracellular fluid, with 98% in the intracellular compartment.7,8

  • This concentration gradient is partially responsible for membrane potential and is critical for normal cell function.1,8,9
  • Its maintenance is therefore particularly important for excitable cells such as nerve and muscle.9


K+ homeostasis is critical for normal cell function

K+ homeostasis is achieved by long- and short-term control mechanisms.7,10

Short-term control of K+ homeostasis10
Long-term control of K+ homeostasis10
Role of skeletal muscle cells in potassium homeostasis
  • Short-term regulation takes place over only seconds or minutes.3 Skeletal muscles play an important role as the largest single pool of K+ in the body.3 K+ fluctuations are reduced by moving K+ between the blood and skeletal muscle cells until the kidney excretes the K+ load. This buffering is regulated by insulin and catecholamines.9
Role of renal excretion in potassium homeostasis
  • Long-term regulation of K+ homeostasis takes place over hours to days3 and in healthy subjects is achieved by moderating renal excretion via the renin−angiotensin−aldosterone system.7,9 The colon is responsible for the remaining few percent of K+ excretion.3 In patients with end-stage renal disease, however, the capacity for the colon to excrete K+ increases.3,11

Hyperkalaemia is typically defined as elevated serum K+ levels >5.0 mEq/L1,2

  • Chronic hyperkalaemia is defined as serum K+ levels >5.0 mEq/L repetitively measured over a 1-year period12
  • Mild, moderate and severe hyperkalaemia are defined as serum K+ levels of >5−5.5, >5.5−6.0 and >6.0 mEq/L, respectively1

What causes hyperkalaemia?

Hyperkalaemia is caused by the complex interplay of physiological and environmental factors.3,13

  • The most common underlying cause of hyperkalaemia is reduced or impaired renal excretion of K+.14

Chronic kidney disease

In CKD, K+ homeostasis, established mostly by excretion of K+ via urine, is deregulated and can result in hyperkalaemia 


Heart failure

In HF, the RAAS is up-regulated, renal perfusion is reduced and Na+ is often excreted due to usage of diuretics 


Diabetes mellitus

Due to the lack of insulin-stimulated Na+/K+ pump-mediated K+ uptake in skeletal muscles



Age-dependent reduction in the availability of nephrons further increases the risk for hyperkalaemia



Background use of RAASi, beta blockers and aldosterone antagonists are associated with an increase in K+ levels 



Because skeletal muscles constitute the major reservoir for K+ in the body, K+ levels may increase markedly and reach values up to ~8 mEq/L during exercise  


Intake of K+

Oral K+ intake combined with reduced K+ excretion can increase risk of hyperkalaemia 

HYPERKALAEMIA is a serious medical condition

Hyperkalaemia is one of the most clinically important electrolyte abnormalities and is a serious medical condition associated with increased mortality and high rates of hospitalisation.1,3,4,6

In a targeted retrospective chart review of 1,457 patients with hyperkalaemia in 5 centres in Europe, hyperkalaemia was responsible for over one-third of hospitalisations over a 12-month period.6





Baseline comorbidities/treatment


With HTN


With CKD


With HF


With T2DM


With RAASi

The effects of hyperkalaemia can vary widely between patients,15 with symptoms ranging from mild and non-specific (e.g. muscle weakness, twitching, cramping, nausea, vomiting) to arrhythmias, palpitations, dizziness and syncope, and sudden cardiac death.3,16

Elevated serum K+ is associated with an increase in all-cause mortality in at-risk populations4

Graph: hyperkalaemia is associated with increased risk of mortality

Although severity of clinical presentation generally correlates with degree of hyperkalaemia,2 physiological adaptation, structural cardiac disease, medication use, and degree of concurrent illness might predispose certain patients with hyperkalaemia to a lower or higher threshold for toxicity.17


Importantly, hyperkalaemia is often asymptomatic until the patient experiences serious consequences.2,16 ECG changes are not always present but can progress rapidly without warning, making hyperkalaemia with ECG changes a true medical emergency.2

Progressive changes in ECG with increasing severity of hyperkalaemia

Progressive ECG changes with increasing severity of hyperkalaemia

CKD and HF patients are at risk of hyperkalaemia

Renal function is key to K+ homeostasis, and patients with conditions associated with disturbance of the renin−angiotensin−aldosterone system, reduction of renal perfusion and/or reduction in sodium availability are at high risk of hyperkalaemia.13

  • Patients who are particularly prone are those with chronic kidney disease, heart failure and those with comorbid conditions, such as type 2 diabetes.7,12

Prevalence of hyperkalaemia in CKD

CKD is the most common risk factor for hyperkalaemia.

  • In clinical practice, up to 73% of patients with advanced CKD have hyperkalaemia12, with prevalence increasing with disease severity,18 and a large proportion of these are likely to have chronic hyperkalaemia.19
  • Results of a retrospective, observational study in more than 55,000 non-dialysis patients demonstrated incidence of hyperkalaemia of 13–32%, with greater prevalence at lower eGFR.20

Patients with CKD may spend up to one-third of their time in a chronic state of hyperkalaemia20

Graph: lower eGFR is associatd with more time in state of hyperkalaemia

Mechanism behind hyperkalaemia in CKD

In patients with CKD, the ability to maintain K+ homeostasis is compromised as a result of reduced GFR, leading to an increased risk of hyperkalaemia.

  • RAASi use in the management of CKD and associated comorbidities exacerbates the situation.10

Compromised nephron function leading to a reduced glomerular filtration rate increases the risk of hyperkalaemia in CKD patients10

Normal long-
term K+ control
ESRD-induced HK
Diagram: normal long-term potassium control with normal nephron function
Diagram: diabetic nephropathy leads to reduced renin and lower K+ excretion
Diagram: reduced renal perfusion results in impaired K+ excretion

Hyperkalaemia and clinical outcomes

Chronic hyperkalaemia requires ongoing management to correct the underlying disturbances in K+ balance.21

  • Even a small increase in K+ levels may increase risk of mortality,4 and in patients with CKD this risk extends across all disease stages.

Onset of hyperkalaemia symptoms can be sudden22 and require urgent treatment.

  • Visits to the emergency department are significantly higher in patients with hyperkalaemia than in those without.23
  • New onset or chronic hyperkalaemia in non-dialysis CKD patients predicts higher end-stage renal disease risk.24 

Hyperkalaemia often leads to RAASi down-titration or discontinuation, and this is associated with poor outcomes in patients with CKD.25,26

Hyperkalaemia is associated with increased all-cause mortality across all CKD stages5

Graph: hyperkalaemia is associated with increased mortality in all CKD stages

Prevalence of hyperkalaemia in HF

Almost 4 in 10 patients with HF develop hyperkalaemia27,28 and many have recurrent episodes, with time between episodes becoming progressively shorter.27

Diagram: almost 4 in 10 patients with heart failur develop hyperkalaemia

*Median follow-up

Mechanism behind hyperkalaemia in HF 

Patients with HF are at risk of hyperkalaemia as approximately one-third to one-half have impaired renal function (eGFR <60 mL/min/1.73 m2).29 

  • In addition, use of guideline-recommended RAASi further increases the risk of hyperkalaemia.27,29 

Declining renal function and RAASi therapy in HF disrupt the renin−angiotensin−aldosterone system, resulting in depleted K+ excretion and hyperkalaemia10

Normal long-
term K+ control
HF-induced HK
Diagram: normal long-term potassium control with normal nephron function
Diagram: Heart failure-induced hyperkalaemia
Diagram: RAASI-induced heart failure

Hyperkalaemia and clinical outcomes

Even a small increase in K+ levels may increase risk of mortality.4 

  • In a study evaluating 16,116 serum K+ measurements taken from 2,164 patients with HF, a U-shaped association between serum K+ values and mortality was observed.30 
  • Analysis of serum K+ dynamics revealed that persistence of abnormal K+ levels was linked to a higher risk of death in comparison with patients who maintained or returned to normal values.30

Compared with normokalaemia, hyperkalaemia is an independent predictor of mortality30

Graph: versus normokalaemia, hyperkalaemia is a predictor of mortality

Onset of hyperkalaemia symptoms can be sudden22 and require urgent treatment.

  • Visits to the emergency department are significantly higher in patients with hyperkalaemia than in those without.23 

Hyperkalaemia is a risk marker for poor outcomes in patients with HF through suboptimal use of RAASi.25,31,32

References & footnotes

ACEi, angiotensin II converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; cAMP, cyclic adenosine monophosphate; CI, confidence interval; CKD, chronic kidney disease; ECG, electrocardiogram; (e)GFR, (estimated) glomerular filtration rate; HF, heart failure; HK, hyperkalaemia; HTN, hypertension; K+, potassium ions; mEq/L, milliequivalents per litre; MRA, mineralocorticoid-receptor antagonist; Na+, sodium ions; RAASi, renin−angiotensin−aldosterone system inhibitors; T2DM, type 2 diabetes mellitus.


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