What is Hyperkalaemia?

Hyperkalaemia, elevated serum K⁺ levels >5.0 mEq/L, is a serious condition associated with high morbidity and mortality^1-6

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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

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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/L^1,2

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

Physiological

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

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

Environmental

Medication

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

Exercise

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

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36%
Hyperkalaemia
related

1,457
Patients

Baseline comorbidities/treatment

icon

72%
With HTN

icon

68%
With CKD

icon

40%
With HF

icon

36%
With T2DM

icon

60.5%
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

Discover MORE ABOUT HYPERKALAEMIA IN PATIENTS WITH CKD

Discover MORE ABOUT HYPERKALAEMIA IN PATIENTS WITH HF

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

DIABETIC
NEPHROPATHY-
INDUCED HK

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.⁵

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

Read up on the HK challenge in your patients with CKD

Prevalence of hyperkalaemia in HF

Almost 4 in 10 patients with HF develop hyperkalaemia^27,28 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

RAASi-INDUCED HK

Diagram: Heart failure-induced hyperkalaemia

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

Read up on the HK challenge in your patients with HF

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.

References:

1. Di Lullo L, et al. Cardiorenal Med 2019;9(1):8−21. 2. Rastegar A, Soleimani M. Postgrad Med J 2001;77(914):759−64. 3. Kjeldsen KP, Schmidt TA. Eur Heart J 2019;21(Suppl A):A2−A5. 4. Collins AJ, et al. Am J Nephrol 2017;46(3):213−21. 5. Kovesdy CP, et al. Eur Heart J 2018;39(17):1535−42. 6. Rossignol P, et al. Clin Kidney J 2020;13:714−9. 7. Clase CM, et al. Kidney Int 2020;97(1):42−61. 8. Youn JH, McDonough AA. Annu Rev Physiol 2009;71:381−401. 9. Palmer BF. Clin J Am Soc Nephrol 2015;10(6):1050−60. 10. Palmer BF. N Engl J Med 2004;351:585−92. 11. Mathialahan T, et al. J Pathol 2005;206:46−51. 12. Rosano GMC, et al. Eur Heart J Cardiovasc Pharmacother 2018;4(3):180−8. 13. Tromp J, van der Meer P. Eur Heart J 2019;21(Suppl A):A6−A11. 14. Palmer BF. In: Kimmel PL, Rosenberg M (Eds). 2015:386−7. 15. Welch A, et al. Nephrol Dial Transplant 2013;28(1):15−16. 16. Kraft MD, et al. Am J Health Syst Pharm 2005;62(16):1663−82. 17. Montford JR, Linas S. J Am Soc Nephrol 2017;28(11):3155−65. 18. Kashihara N, et al. Kidney Int Rep 2019;4(9):1248−60. 19. Einhorn LM, et al. Arch Intern Med 2009;169(12):1156−62. 20. Luo J, et al. Clin J Am Soc Nephrol 2016;11(1):90−100. 21. Kim GH. Electrolyte Blood Press 2019;17(1):1−6. 22. Dasgupta A. E-Journal of Cardiology Practice 2016;14, No 13. https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-14/fourteen-thirteen. 23. Betts KA, et al. Kidney Int Rep 2018;3(2):385−93. 24. Provenzano M, et al. J Clin Med 2018;7:499. DOI:10.3390/jcm7120499. 25. Epstein M, et al. Am J Manag Care 2015;21(11 Suppl):S212−S220. 26. Yildirim T, et al. Ren Fail 2012;34(9):1095−9. 27. Thomsen RW, et al. J Am Heart Assoc 2018;7(11):e008912. 28. Savarese G, et al. JACC Heart Fail 2019;7(1):65−76. 29. Shlipak MG. Ann Intern Med 2003;138(11):917−24. 30. Núñez J, et al. Circulation 2018;137:1320–30. 31. Lund LH, Pitt B. Eur J Heart Fail 2018;20:931–2. 32. Martens P, et al. Acta Cardiol 2020; doi: 10.1080/00015385.2020.1771885.

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Vifor Fresenius Medical Care Renal Pharma (VFMCRP) Ltd, a company of the Vifor Pharma Group, is the partner of choice for renal pharmaceutical and innovative, patient-focused solutions. The Vifor Pharma Group is a global pharmaceuticals company. It aims to become the global leader in iron deficiency, nephrology and cardio-renal therapies. The Vifor Pharma Group strives to help patients around the world with severe and chronic diseases lead better, healthier lives. The company develops, manufactures and markets pharmaceutical products for precision patient care. The Vifor Pharma Group holds a leading position in all its core business activities and consists of the following companies: Vifor Pharma; Vifor Fresenius Medical Care Renal Pharma, a joint company with Fresenius Medical Care; Relypsa; and 0M Pharma. For more information about Vifor Pharma, please visit www.viforpharma.com

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© 2019 Vifor Fresenius Medical Care Renal Pharma

HQ-PAT-2000046 | Date of preparation: December 2020

What is Hyperkalaemia?

Report adverse events:

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

K⁺ homeostasis is critical for normal cell function

Hyperkalaemia is typically defined as elevated serum K⁺ levels >5.0 mEq/L^1,2

What causes hyperkalaemia?