Tailoring treatment of hyperkalemia Free

Abstract

Hyperkalemia is a common electrolyte disorder that may be rapidly life-threatening because of its cardiac toxicity. Hyperkalemia risk factors are numerous and often combined in the same patient. Most of the strategies to control serum potassium level in the short term have been used for decades. However, evidence for their efficacy and safety remains low. Treatment of hyperkalemia remains challenging, poorly codified, with a risk of overtreatment, including short-term side effects, and with the priority of avoiding unnecessary hospital stays or chronic medication changes. Recently, new oral treatments have been proposed for non-life-threatening hyperkalemia, with encouraging results. Their role in the therapeutic arsenal remains uncertain. Finally, a growing body of evidence suggests that hyperkalemia might negatively impact outcomes in the long term in patients with chronic heart failure or kidney failure through underdosing or withholding of cardiovascular medication (e.g. renin–angiotensin–aldosterone system inhibitors). Recognition of efficacy and potential side effects of treatment may help in tailoring treatments to the patient’s status and conditions. In this review we discuss how treatment of hyperkalemia could be tailored to the patient’s conditions and status, both on the short and mid term.

INTRODUCTION

Hyperkalemia is a frequent electrolyte disorder, potentially rapidly life-threatening due to the risk of cardiac arrhythmia or conduction disorders. The association between hyperkalemia and mortality has been well described in various populations. In the short term, the benefit of treating immediately life-threatening hyperkalemia with cardiac consequences is rather consensual. However, the best strategies to be applied and the indications for treatments in mild hyperkalemia or in the absence of cardiac consequences are much more uncertain. In addition to direct mortality due to its cardiac consequences, hyperkalemia might also be indirectly responsible for an increase in morbidity (and mortality) due to the side effects of treatments used and/or changes in chronic cardiovascular medications, occluding their benefits.

RISK FACTORS FOR HYPERKALEMIA: IMPORTANT CONSIDERATIONS FOR TREATMENT

The incidence of hyperkalemia depends on the studied population and exposure to risk factors, for example, variations in the proportions of patients receiving one or more hyperkalemic treatment, such as renin–angiotensin–aldosterone system inhibitors (RAASis) [1].

Altered renal function is the major risk factor for hyperkalemia [2–5]. The risk for hyperkalemia has been largely associated with a decrease in estimated glomerular filtration rate (eGFR), with a reported odds ratio of 1.25 for each 5 mL/min decrease of eGFR and up to 30% of kalemia >5.5 mmol/L in patients with Stage 4 chronic kidney disease (CKD) [3, 6]. Renal function is therefore a key factor to consider when assessing the risk of hyperkalemia and the likelihood of rapid control of serum potassium levels. In other words, the probability of pseudo-hyperkalemia and rapid reversal of mild hyperkalemia are the two situations more likely to occur in a patient with preserved renal function compared with a patient with renal failure.

The occurrence of hyperkalemia is a common adverse event after the introduction of treatments such as RAASi, with an incidence ranging from 6% up to 10% [7–10]. Severe hyperkalemia (>6 mmol/L) occurs in up to 3% of patients following mineralocorticoid receptor antagonist (MRA) introduction [11–14]. Once again, the impact of renal function on the risk of developing hyperkalemia is major. The incidence of hyperkalemia after angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) initiation in patients with preserved renal function is low, at 2–4% [3, 7, 15]. However, hyperkalemia was reported in ∼10% of patients with kidney disease on ACEIs/ARBs [4]. There is a stepwise increase of the incidence of hyperkalemia with CKD severity after the introduction of ACEIs/ARBs, reaching 51% and 29% for kalemia >5 mmol/L and >5.5 mmol/L, respectively, in CKD Stage 4 patients [6, 15, 16]. The occurrence of hyperkalemia after β-blockers introduction seems low and similar compared with after ACEIs/ARBs (4% for kalemia >5.5 mmol/L) in patients with preserved kidney function. This risk increases in patients with CKD [15]. Finally, the combination of these different risk factors in the same patient greatly increases the risk of hyperkalemia. Indeed, the reported incidence of hyperkalemia in patients receiving a combination of treatments including ACEIs/ARBs, β-blockers and MRAs reached 20% [12, 17].

IMPACT OF HYPERKALEMIA ON OUTCOMES VARIES ACROSS SETTINGS

Association of kalemia and outcomes

Many studies have reported an association between kalemia and mortality, following a U-shaped curve [2, 3, 5, 18]. A recent international meta-analysis found an adjusted hazard ratio for all-cause mortality of 1.22 [95% confidence interval (CI) 1.15–1.29] for kalemia >5.5 mmol/L compared with the mean kalemia of 4.2 mmol/L [2]. Mortality appeared to be lowest for kalemia levels between 4.0 and 4.5 mmol/L. For the same level of hyperkalemia, all-cause mortality has been reported higher for patients with associated comorbidities such as CKD, heart failure (HF) or diabetes mellitus compared with patients without these conditions [5]. Kalemia <4.5 mmol/L and ≥5.5 mmol/L has been associated with an increased risk of cardiovascular events [18]. How the treatment of hyperkalemia affects these outcomes is largely unknown.

BENEFITS AND RISKS OF TREATMENTS OF HYPERKALEMIA: WHO SHOULD BE TREATED?

Expert recommendations for the treatment of hyperkalemia include detection of electrical changes on electrocardiograms (EKGs), potassium levels (i.e. >6 mmol/L) and/or rapid changes that define severe or life-threatening hyperkalemia, requiring immediate treatment [19]. Two categories of patients need to be differentiated. The first category is patients with so-called immediate life-threatening hyperkalemia, in whom urgent treatment is required. The second category is represented by patients with non-severe hyperkalemia. In the second category, the objectives of the treatment of hyperkalemia, summarized in Table 1, are mostly to allow the maintenance of treatment over the long term while avoiding hospitalizations and unnecessary overtreatment. Decisions to perform an EKG to assess immediate cardiac consequences, to manage inpatient care or to determine the threshold(s) to allow outpatient treatment are debated and are still largely dependent on clinician assessment, medical history and the serum potassium level.

In our opinion, the diagnosis of hyperkalemia should fall under the umbrella of a ‘life-threatening’ condition in any unstable condition such as decompensated HF, acute kidney injury (AKI), other acute organ failures or shock (Table 1). The treatment of these associated conditions and causes of hyperkalemia is key (e.g. correction of shock, treatment of the cause of AKI and fluid status correction).

EKG changes or not?

In case of hyperkalemia, cardiac conduction modifications are induced by modification of the potassium ion (K⁺) gradient between intra- and extracellular compartments [20]. There is a very poor association between serum potassium level and EKG changes [21, 22], and the absence of EKG changes should not preclude treatment. However, observation of EKG changes should trigger urgent administration of cardiomyocyte membrane stabilization and serum potassium–lowering treatments. The first classic EKG manifestation of hyperkalemia is peaked T-waves that signal myocardial hyperexcitability [23]. Then myocardial conduction disorders appear (i.e. prolonged PR, QRS widening, loss of P-waves, bradycardia and ultimately electromechanical dissociation).

Cardiac membrane stabilization

Calcium salts stabilize the cardiomyocyte membrane by inducing intracellular sodium entry that restores a rapid depolarization slope [24]. The effect is fast (within 5 min) and expected to last between 30 and 60 min [22]. In case of calcium salt utilization, the clinician should check that the perfusion is not subcutaneous, due to the risk of skin necrosis in case of extravasation [25]. It is not recommended to use calcium salt in patients treated with digoxin; however, no human study has reported an increased risk of cardiac toxicity in case of co-administration [26]. Hypertonic sodium may be an alternative treatment to protect the heart from conduction disorders in patients with contraindications to calcium salts [24].

Potassium transfer

Three different treatments are commonly used to decrease serum potassium levels (i.e. insulin dextrose, β2-agonists and sodium bicarbonate). All three act by indirectly activating the sodium–potassium adenosine triphosphatase (Na⁺/K⁺ ATPase) pump [22].

Insulin dextrose

Insulin dextrose is efficient to decrease the serum potassium level via activation of Na⁺/K⁺ ATPase after insulin fixation to its receptor. Its use decreases the potassium level by ∼0.5–1 mmol/L [22]. The main side effects are glycemic variations (i.e. hyper- or hypoglycemia). In a recent review of the different scheme of insulin/glucose administration, the authors found no statistically significant difference in the mean decrease in serum potassium concentration at 60 min between studies in which insulin was administered as an infusion of 20 U over >60 min and studies in which 10 U of insulin were administered as a bolus or studies in which 10 U of insulin were administered as an infusion [27]. The incidence of hypoglycemia ranges from 5% up to 75% depending on the protocol and the definition used. A high dose of glucose (60 g with the administration of 20 U of insulin or 50 g with the administration of 10 U of insulin) was reported to be associated with less hypoglycemia [27]. The protocols associated with fewer hypoglycemic episodes appear to be 5 U of rapid insulin +25 g of glucose or 0.1 U/kg of body weight (to a maximum of 10 U) [28, 29]. Of note, the risk of hypoglycemia occurs within 2–3 h after the bolus and thus justifies close glycemic monitoring after the infusion [30]. The incidence of acute and transient hyperglycemia due to insulin dextrose and its consequences are not well documented and the potential consequences are poorly appreciated (i.e. vascular dysfunction, osmotic diuresis and organ injury) [31, 32].

β2-agonists

β2-agonists decrease the serum potassium level through two different pathways: first, via increased secretion of endogenous insulin and second, via the activation of Na⁺/K⁺ ATPase after stimulation of the β2-receptors in the muscle and liver. Albuterol is efficient to decrease the serum potassium level in a dose-dependent manner, 20 mg being more efficient than 10 mg [33]. There is no difference in the serum potassium level decrease between routes of administration (i.e. intravenous or inhaled), but intravenous administration is associated with more cardiovascular side effects. Inhaled salbutamol (10 mg) appears as effective as 10 U of insulin dextrose to decrease the serum potassium level [34]. Due to the increased risk of tachycardia and supraventricular tachycardia (i.e. auricular fibrillation), the risk:benefit ratio of β2-agonists should be weighed in patients with cardiomyopathy (e.g. non-stabilized coronary artery disease or HF). Furthermore, some patients (including but not limited to patients treated with β-blockers or elderly patients) may be resistant to β2-agonists [35]. Therefore insulin dextrose or an association of insulin/glucose and β2-agonists should probably be considered as first-line therapy in patients treated with β-blockers or patients with life-threatening hyperkalemia.

Sodium bicarbonate

Despite conflicting data in the literature about the ability of sodium bicarbonate to lower the serum potassium level, recent data suggest that sodium bicarbonate is efficient to decrease the serum potassium level. In an animal study (hyperkalemic calves), the kalemia decrease was immediate after the end of the perfusion of bicarbonate, with a mean decrease of kalemia of 1.5 mmol/L 30 min after the infusion in the bicarbonate group [36]. A recent randomized controlled trial (RCT) evaluated the effect of sodium bicarbonate (4.2%) on outcome in patients admitted to intensive care unit with a Sequential Organ Failure Assessment score >4 and/or lactatemia >2 mmol/L associated with severe acidemia (pH ≤7.20, partial pressure of carbon dioxide ≤45 mmHg and sodium bicarbonate concentration ≤20 mmol/L) [37]. In this study the authors observed a significant decrease in serum potassium level in patients receiving sodium bicarbonate 4 h after the beginning of the perfusion. Sodium bicarbonate in the treatment of patient with hyperkalemia should probably be restricted to patients with metabolic acidosis and hypovolemia. Due to the uncertainty of the serum potassium–lowering effect of sodium bicarbonate, it should probably be used in combination with other treatments (e.g. insulin glucose) in life-threatening hyperkalemia. When used, ionized calcemia should be monitored due to the risk of hypocalcemia [37].

Increased potassium urinary excretion with diuretics

Diuretic and kaliuretic responses to loop diuretics infusion are variable and unpredictable, exposing patients to the risk of failure to decrease serum potassium and inducing hypokalemia and hypovolemia. Therefore loop diuretics should not be considered as a first-line emergency treatment of hyperkalemia. They must be titrated and considered only in case of fluid overload (i.e. clinical oedema with turgescent jugular vena, high central venous pressure and dilated inferior vena cava on echography).

Renal replacement therapy

Renal replacement therapy (RRT) should be considered in patients with severe hyperkalemia associated with severe AKI or CKD and resistant to medical treatment. When the conduction method is used, a potassium concentration bath <2 mmol/L can lead to too fast a decrease in the serum potassium level, exposing the patient to the risk of hypokalemia and its cardiac consequences and to a hyperkalemic rebound [38].

WHICH TREATMENT FOR NON-LIFE-THREATENING HYPERKALEMIA?

To date, no consensus exists on which patients would/should benefit from treatment for non-life-threatening hyperkalemia. Our proposal is summarized in Tables 1 and 2.

While treatment options, especially in outpatients, were limited to ion exchange resins and kaliuretic diuretics (in addition to a low potassium diet), promising new treatments are emerging and could contribute to the optimization of cardiovascular treatments. Their cost and lack of comparative studies with available treatments, however, limit their wide implementation. Dedicated trials in acute hyperkalemia and cost–effectiveness analysis should be performed before generalizing the use of new potassium binders in acute hyperkalemia management.

Sodium polystyrene sulphonate

Sodium polystyrene sulphonate (SPS) exchanges sodium non-specifically with potassium in the colon (also exchanging sodium with magnesium, calcium and ammonium). To date, no RCT has evaluated SPS in the acute setting. Furthermore, SPS use has been associated with potentially severe side effects (e.g. colon necrosis, perforation) [39]. SPS should not be considered as a therapeutic option to treat acute hyperkalemia. In an RCT published in 2015 comparing SPS with placebo in 33 patients with CKD and treated for 7 days, SPS showed a significant reduction in the serum potassium level in patients receiving SPS compared with placebo (−1.25 ± 0.57 versus −0.21 ± 0.29 mmol/L, respectively; P < 0.001). More gastrointestinal side effects were observed with SPS [40]. SPS has not yet been compared with more recently released treatments of hyperkalemia [i.e. patiromer and sodium zirconium cyclosilicate (ZS-9)].

Patiromer

Compared with SPS, patiromer is a sodium-free, potassium-binding polymer that exchanges calcium for potassium. It is now available in North America and the European Union for hyperkalemia management. It has been evaluated for the management of chronic hyperkalemia in RCTs and has been shown to decrease the serum potassium level by −0.35 mmol/L (95% CI −0.48–0.22) to −1.01 (95% CI −1.07 to −0.95) within 4 weeks, depending on the dose and the clinical setting [41–44]. In a recently published double-blind randomized trial among patients with resistant hypertension and CKD, treatment with patiromer enabled more patients to continue treatment with spironolactone (86% versus 66%) with less hyperkalemia [45]. The most frequent side effects described are digestive (i.e. diarrhoea or constipation) and electrolytic disturbances (i.e. hypokalemia and hypomagnesemia). Patiromer has been evaluated in a trial in emergency departments, but the results are not yet available [Relypsa for ED Acute Hyperkalemia Control and Reduction (REDUCE study), NCT02933450].

ZS-9

ZS-9 selectively binds potassium in the gastrointestinal tract through ionic bonding with more specificity than SPS and patiromer. One gram of ZS-9 binds ∼3 mEq of potassium [46]. ZS-9 was developed for the treatment of hyperkalemia, and its efficacy in this setting has been demonstrated in Phase 2 and 3 trials [47, 48]. In a subgroup of patients with severe hyperkalemia (>6 mmol/L), Kosiborod et al. [49] observed a rapid decrease in the serum potassium level with a median time to obtain a serum potassium level <6.0 mmol/L of 1.1 h and 4.0 h to reach a level ≤5.5 mmol/L. These data suggest that ZS-9 could be part of the therapeutic arsenal for hyperkalemia management in acute settings, but this still needs confirmation in specific RCTs. To date, only minor side effects have been described (i.e. gastrointestinal disturbance and oedema). No study has yet evaluated the efficacy of ZS-9 compared with patiromer.

MANAGEMENT OF CHRONIC MEDICATIONS INDUCING HYPERKALEMIA

Several studies have shown that hyperkalemia is an important cause for modification or cessation of treatments, particularly for cardiovascular medications, including ACEIs/ARBs [4, 18, 50].

In a study by Chang et al. [6], among ACEIs/ARBs users, 11% of patients with kalemia >5 mmol/L and 24% of patients with kalemia >5.5 mmol/L had discontinuation of ACEI or ARB treatment, respectively, versus 4.8% of patients without hyperkalemia. In the same study, almost half of patients discontinued potassium-sparing diuretics in case of hyperkalemia. Up to 50% of ACEI/ARB treatment changes were described due to mild hyperkalemia (serum potassium <5.5 mmol/L) [4, 51]. Epstein reported RAASi discontinuation in 16% of patients with a maximum dose and mild hyperkalemia, while 22% of patients had their dose down-titrated [51]. In the Biology Study to Tailored Treatment in Chronic Heart Failure, baseline kalemia was independently associated with lower ACEI/ARB dosage [52, 53]. Hyperkalemia is also frequently associated with the absence of ACEI/ARB treatment in patients with CKD [54]. Hyperkalemia was reported as one of the main reasons for MRA non-use or suboptimal dosing (in 12% of the 53 known reasons) in HF patients [50, 55]. RAASi discontinuation or submaximum dose because of hyperkalemia is therefore a potential source of accelerated progression to chronic and end-stage renal disease and/or HF. A recent study evaluating the economic impact of maintaining normal kalemia, and thus optimal ACEI/ARB therapy, suggests benefits in life expectancy while also decreasing cost [56].

The impact of hyperkalemia on the prognosis in patients on RAASis appears highly uncertain. The impact on the long-term prognosis may be indirect due to therapeutic changes triggered by hyperkalemia, offsetting all or part of the benefits of these treatments [57]. In HF patients treated with ACEIs/ARBs, hyperkalemia (>5.0 mmol/L) was not associated with mortality and/or hospitalization for HF [52, 58]. Hyperkalemia (>5.0 mmol/L) was also not associated with the worst outcome in patients with CKD after ACEIs/ARBs initiation therapy [58]. However, the change in kalemia was mild, as <2% of patients had kalemia >5.5 mmol/L. The combination of ACEIs and ARBs was associated with an increased risk of acute renal failure and hyperkalemia (>6mmol/L) in patients with diabetic nephropathy (with a high prevalence of HF), while mortality was not affected [59]. However, our group reported that the association between serum potassium level and mortality remained in patients admitted to the emergency department for decompensated HF and treated with ACEIs/ARBs [60]. Hyperkalemia is also frequent with MRAs (33 and 15% of kalemia >5.0 and 5.5 mmol/L, respectively). It was not found to be associated with mortality after MRA introduction [12, 61]. Thus no death was attributable to hyperkalemia in the eplerenone group in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [12, 62]. However, modalities of hyperkalemia management were not reported. After publication of the Randomized Aldactone Evaluation Study, increased prescriptions of spironolactone were observed, with a simultaneous increased rate of hospitalization and mortality (from 0.3 to 2 for 1000 patients) [11]. This observation underlines the need for proper patient selection and monitoring with rigorous surveillance [63].

To summarize, the decision to down-titrate or interrupt chronic medication such as ACEis, ARBs or MRAs that could cause hyperkalemia must be weighed against the risk of cancelling their potential protective effects. We need studies evaluating strategies in these populations and guidance in these conditions. In the meantime, reintroduction should certainly be discussed on a case-by-case basis in stable patients once the risk of hyperkalemia has been evaluated and controlled.

CONCLUSION

Adequate identification of high-risk patients should allow early detection of hyperkalemia in order to minimize the risks associated with potassium cardiac toxicity. However, the best therapeutic strategies in the acute setting remain largely under- explored and the benefit:risk ratio poorly explored. Future research should explore the best therapeutic option for treatment of acute hyperkalemia (i.e. treatments lowering serum potassium and the need for hospitalization) (Table 3). In non-acute settings, the objective is often to maintain cardiovascular treatments at the optimal doses and in combination and avoid unnecessary hospitalizations.

ACKNOWLEDGEMENTS

This article was published as part of a supplement financially supported with an educational grant from Vifor Fresenius Medical Care Renal Pharma and AstraZeneca with no influence on its content.

CONFLICT OF INTEREST STATEMENT

M.C. declares no conflicts. F.D. received grants from the French Ministry of Health, research support from Sphingotec and lecture fees from Sedana Medical, all outside the submitted work. M.L. received grants from the French Ministry of Health, research support from Sphingotec, lecture fees from Baxter and Fresenius and consulting fees from Novartis, all outside the submitted work.

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