Hyperkalaemia (HPK) is an electrolyte disorder that occurs in advanced stages of chronic kidney disease (CKD) and cardiovascular disease (CVD; arterial hypertension, heart failure [HF] and atherosclerotic disease). This is directly related to the decrease in estimated glomerular filtration rate (eGFR) and the use of medications that interfere with the renin–angiotensin–aldosterone system (RAAS); these decrease potassium excretion and favour potassium retention. HPK has a high prevalence with the development of eGFR <15 ml/min/m² (CKD stage 5). However, there are extrinsic factors that modify this pathophysiological principle, and it can be found in CKD stages 3 and 4, in which diet, comorbidities and medication play a determining role. The incidence of HPK is variable, depending on the group of patients studied, the therapy used and the serum potassium levels considered.1,2
Potassium is the main intracellular cation, with an average concentration of 50–55 mEq/kg body weight. It is located mainly in the intracellular space (98%), with 2% in the extracellular space, corresponding to 135–145 mEq/l intracellularly and 4–5 mEq/l extracellularly. Potassium is regulated by its uptake, distribution in different cellular spaces, and excretion. Eighty per cent of potassium is excreted by the kidneys, 15% by the intestines, and 5% in perspiration. In advanced CKD, intestinal excretion increases to 25%. Ninety per cent of filtered potassium is reabsorbed in the proximal tubule and the thick portion of the ascending limb of the loop of Henle. Excretion occurs in the principal cells of the distal convoluted tubule and collecting duct by independent and aldosterone-dependent mechanisms. There are risk factors for the development of HPK, which are more relevant when eGFR is <30 ml/min (Box 1 ).3,4
Definition of the Problem
HPK presents a therapeutic challenge due to its generally asymptomatic course, which limits its identification.5–7 There is no direct relationship between HPK and clinical or ECG manifestations; however, higher levels of HPK require treatment due to the potential development of arrhythmias, muscle weakness and cardiac arrest.8,9 The prevalence of HPK>5 mEq/l is 1.5% in the general population, 5.6% in individuals taking angiotensin receptor blockers (ARBs), and 19% in patients with HF and left ventricular ejection fraction (LVEF) <35% who have started spironolactone treatment. The prevalence of HPK varies in different countries. For example, in Switzerland, where HPK is defined as a potassium level >4.7 mEq/l, the prevalence is 8.8%, whereas in North America, where HPK is defined as a potassium level >5 mEq/l, the prevalence is 3.6%.6–8 In the US, its prevalence in patients with stage 4 CKD is 1.8%, while in the same population in Italy, it is 4–5%.6–8 The reported prevalence of HPK in dialysis patients ranges from 2% to 28%, while in emergency departments, it ranges from 3% to 13%. These figures are influenced by the varying prevalence of comorbidities that necessitate the use of specific medications and dietary habits across different regions.10–12
RAAS inhibitors are a mainstay in the treatment of CVD and HF. This is a broad group of drugs that includes angiotensin-converting enzyme inhibitors (ACEIs), ARBs, angiotensin receptor/neprilysin inhibitors (ARNIs) and mineralocorticoid receptor antagonists (MRAs).13,14
A 1-year follow-up study conducted by the Spanish registry of the European Society of Cardiology included patients with HF from 28 hospitals.15 The aim was to examine changes in potassium levels and their impact on treatment. The study found that 3.76% of 3,587 patients with chronic HF and 6.0% of 881 patients with acute HF had potassium levels between 5.5 and 5.9 mEq/l, which is clinically defined as HPK. In patients with HPK with potassium level >6 mEq/l, the prevalence of chronic HF was 0.59% and that of acute HF was 2.2%.15
Aim
The aim of this study is to present a consensus document regarding the management of adult patients with HPK of cardiorenal origin. This consensus has been developed by a group of expert cardiologists and nephrologists, who are opinion leaders in Mexico, and it will enable healthcare professionals to optimise therapeutic decision-making.
Users
The purpose of this consensus document is to provide a practical and up-to-date tool for primary care physicians, cardiologists, nephrologists, internal medicine practitioners, endocrinologists, emergency medicine specialists and first-contact practitioners. These medical professionals, due to the nature of their daily work, are in a unique position to treat patients with HPK and contribute to reducing mortality rates.
Justification
The increased life expectancy in recent decades has also been accompanied by a rise in the prevalence of chronic non-communicable diseases, which have been linked to the development of a range of cardiovascular, cerebral and renal outcomes. A principal component of the treatment regimen for these disorders is RAAS inhibitors. These drugs have been demonstrated to reduce the advance of renal injury, albuminuria and glomerular sclerosis, and to defer the commencement of dialysis. They have also been shown to reduce cardiovascular mortality, hospitalisation and mortality due to HF, in addition to improving functional class in patients with HF and reduced LVEF. In both groups, there is indisputable improvement in life expectancy and quality of life. However, there is still a risk of developing HPK. The probability of mortality is contingent upon potassium levels between 2.5 and 8.0 mEq/l, with elevated risks observed at the upper and lower limits of this range. Compared with a control group, the risk is elevated in the presence of diabetes, followed by HF and CKD. However, the risk is further elevated in patients presenting with all three comorbidities.16,17 The management of patients with HF or CKD has traditionally been the responsibility of the cardiologist or nephrologist. However, a better understanding of the cardio-renal pathophysiology has clearly demonstrated that joint intervention provides greater clinical benefit, even more so with the incorporation of new molecules that modify the natural history of the disease.18,19
Methods
A group of specialists in the fields of nephrology and cardiology, coordinated by a leading cardiologist and a nephrologist, was established. Using a Delphi panel, a questionnaire addressing general aspects of HPK and therapeutic behaviour based on evidence and experience was developed and shared. The responses were integrated and consensus was reached for each specialty. The concentrated responses were considered in a virtual meeting, where they were agreed upon based on the review of the available scientific information. The final consensus is presented based on a search and selection of scientific information, to incorporate information that is the most clinically relevant, methodological and adaptable to the local environment. The preliminary version was reviewed and approved by all participants, and the final version was adapted by a medical writer.
Consensus
Incidence of Acute and Chronic Hyperkalaemia
The incidence of HPK varies depending on the form of kidney disease, whether acute or chronic. This study focuses on the chronic form, in which comorbidity and medication play determining roles. There are series reporting serum potassium levels determined with different thresholds and patient types. This makes it challenging to ascertain the precise frequency of HPK. In the absence of CKD or HF, the prevalence of acute HPK is 2–3%. In the presence of CKD, it ranges from 40% to 50%. In individuals with eGFR between 60 and 20 ml/min, the prevalence is 2–42%. In those undergoing dialysis and with potassium levels above 6 mEq/l, it is 4–6.3%.17–19
The prevalence of chronic HPK is estimated to be between 3.6% and 8.8%.20,21 The Gulf Cooperation Group report indicated a prevalence of 7.3–72% specifically in CKD with eGFR<30 ml/min, from 2.9% to 40% in stage 4 CKD, and from 8.3% to 11% in stage 5 CKD. In hospitalised patients, the prevalence was 1–10%.20,22,23
In a multicentre trial conducted in Mexico involving dialysis patients who were taking RAAS inhibitors, the prevalence of mild HPK was 21.7%, moderate HPK was 21.6%, and severe HPK was 17.2%.24
The occurrence of HPK is influenced by a number of factors, even in the presence of elevated eGFR. These include the daily intake of potassium from food, the use of associated medication, and the presence of comorbidities.22
Classification of Hyperkalaemia
HPK can manifest in an acute or chronic form or as a recurrent condition with two episodes in a year. Patients with diabetes, HF or CKD have increased risk of mortality with HPK, and hence levels between 4.5 and 5 mEq/l are considered safer. In patients with all three comorbidities, the mortality risk increases up to sevenfold. Therefore, the recommended classification is as follows:14,15,20–22
- Normal potassium: <5 mEq/l
- Mild HPK: 5–5.4 mEq/l
- Moderate HPK: 5.5–6 mEq/l
- Severe HPK: >6 mEq/l.
Anti-hyperkalaemia Measures
It is essential to differentiate between acute and chronic HPK as well as to identify any accompanying ECG changes, clinical manifestations and comorbidities. In both cases it is important to identify the causal factor, whether it is the drug or any co-existing medical condition. The current management guidelines recommend the implementation of a low-potassium diet, the initiation or increase of non-potassium-sparing diuretics, the elimination of potassium supplements, and the discontinuation of drugs that have a deleterious effect on renal function or that elevate potassium levels, such as non-steroidal anti-inflammatory drugs or RAAS inhibitors.25–29
Box 2 presents the nutritional recommendations for the reduction of HPK.30–32
The flowchart for managing HPK of cardiorenal origin is shown in Figure 1.30,31,33–37
In patients with an indication for an ACEI or ARB, the medication can be initiated when potassium is <5 mEq/l. However, when potassium is between 5 mEq/l and 6 mEq/l, sodium zirconium cyclosilicate should be considered as an alternative. At levels >6 mEq/l, an acute HPK protocol should be initiated.
In outpatients with chronic HF and mild-to-moderate HPK treated with anti-hyperkalaemic drugs, serum potassium should be monitored every 48–72 hours. In the event of a decrease to <5 mEq/l, the RAAS inhibitor should be restarted (Figure 2 ).
Strategies to Avoid Hyperkalaemia without Discontinuing ACEIs or ARBs
A nutritional assessment is an essential component of reducing the potassium load in food. The use of a loop diuretic is indicated in accordance with the clinical condition and an eGFR of <30 ml/min.22 The benefit of adding a sodium–glucose cotransporter 2 inhibitor (SGLT2I) in patients with diabetes, congestive HF or CKD was demonstrated in a meta-analysis that included six studies involving 49,875 participants.38 It was associated with a reduction in the likelihood of developing severe HPK and provided additional pleiotropic benefits without increasing the risk of hypokalaemia.39 The dosage of the RAAS inhibitor can be reduced to 50% or discontinued temporarily or permanently. Discontinuation is associated with a decrease in HPK; however, it is also associated with an increased risk of death from cardiovascular events.38,40,41
Anti-hyperkalaemic Drugs by Mechanism of Action
- Antagonisation of the effects of potassium on the cell membrane: calcium gluconate or calcium chloride.
- Transportation of potassium into the cell: insulin and glucose, β2-adrenergic agonists, sodium bicarbonate (if metabolic acidosis is present). Used in acute HPK.
- Potassium scavenging: loop diuretics and thiazides increase urinary excretion, especially if hypervolaemia is present; SGLT2Is also have this effect. Sodium polystyrene sulfonate, calcium polystyrene sulfonate, patiromer, sodium zirconium cyclosilicate (Table 1 ), and finally, dialysis increase intestinal clearance.
Timing of Discontinuation of RAAS Inhibitors in the Presence of Hyperkalaemia
Activation of the RAAS in HF leads to increased water retention, ventricular remodelling, disease progression and increased mortality. The use of RAAS inhibitors is class 1 recommended for treating HF. These drugs should be titrated to the maximum dose to obtain the greatest benefit; the main reason for not doing so is precisely the risk of generating symptomatic hypotension and HPK, a situation that seems to be attenuated when an SGLT2I is used.38,41–43 Therefore, before discontinuing a RAAS inhibitor due to HPK, consideration should be given to initiating new medications such as sodium zirconium cyclosilicate, among others.
Hyperkalaemic Emergency
A potassium level >6 mEq/l plus ECG changes, arrhythmia (bradycardia, non-sinus tachycardia, junctional rhythm), prolonged PR or QRS interval, decreased P wave amplitude, ST segment or T wave changes (elevation, depression, and pointy T wave) are considered an emergency.28,33,34
It is suggested that any outpatient with acute HPK with a potassium level <6 mEq/l or any HPK with new ECG changes should be referred to the emergency department for management of this problem.6
The goals of treatment in hyperkalaemic emergencies are cell membrane stabilisation, potassium redistribution and potassium excretion.
Treatment of Chronic Hyperkalaemia
Treatment of chronic HPK requires moderate potassium intake and elimination of potential causative agents. In general, discontinuation of the RAAS inhibitor should be avoided due to the described cardiovascular risks, and potassium excretion should be promoted, for example, by sodium zirconium cyclosilicate. Other alternatives that are less effective in the long term but may be considered are loop diuretics and oral sodium bicarbonate.
Conclusion
It is imperative to monitor potassium levels in patients at risk for HPK, especially those with CKD, HF, diabetes, and those being treated with RAAS inhibitors. This will enable optimal decision-making regarding appropriate follow-up and management plans, taking into account the cardiovascular risk profile of the patients. The concomitant presence of diabetes, HF and stage 3 or greater CKD is associated with a two- to fivefold increased risk of HPK.
HPK is a frequently underestimated and underappreciated problem that carries inherent risks associated with serum potassium levels. In addition, it is associated with decision-making in response to these alterations, which often results in the interruption of therapy and an increased risk of complications and mortality. It is recommended that strategies for the rapid identification and intentional search for ECG changes should be established, particularly in patients with advanced renal disease or HF.
At present, discontinuation of cardioprotective and nephroprotective medications (e.g. MRAs, ARNI, ACEIs or ARBs) should not be an option in the management of patients with HPK, especially in the long term, given that there is strong evidence that they improve cardiovascular outcomes in patients with pathologies such as HF, ischaemic heart disease, hypertension or CKD.
New medications are now available that can quickly, effectively and safely lower serum potassium levels and help maintain them within a safe range, thus avoiding the need to discontinue or reduce necessary and often essential therapies in the management of these patients.