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Hyperkalaemia is common in patients with chronic kidney disease, diabetes and heart failure. Novel oral binders to correct serum potassium levels are currently under evaluation for approval by the European Medicines Agency (EMA).
Patients at high cardiovascular risk are more susceptible to developing hyperkalaemia. This is partly attributable to the widespread use of drugs inhibiting the renin–angiotensin system: angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Data from large clinical trials indicate that the incidence of hyperkalaemia, defined as serum potassium of >5.0mmol/l, is between 3% and 9% following the initiation of an ACE inhibitor.1,2
In specific high-risk groups, especially those with chronic kidney disease including diabetic nephropathy, the prevalence of hyperkalaemia can even reach up to a third of all patients, as observed in the RENAAL trial.3 The fact that hyperkalaemia also occurred in 23% of patients in the placebo arm of RENAAL, who were not exposed to an ACEI or ARB, underline that diabetes and renal impairment also contribute to the development of hyperkalaemia.
Because ACE inhibitors and ARBs have been shown to provide important renal and cardiovascular benefits in these high-risk patient populations, the risk of hyperkalaemia must always be weighted against the cardio-renal benefits of these drugs.
Potassium regulation
Potassium in the diet is absorbed via the gastrointestinal tract, mainly in the small intestine. The majority (98%) of potassium in the body is stored within the intracellular compartment. Potassium uptake from the blood into the intracellular space is regulated by the ion transporter, sodium–potassium ATPase. The sympathetic nervous system, through beta receptors and insulin, can increase the expression of sodium–potassium ATPase, thereby promoting potassium uptake from the circulation to the intracellular space.
Excretion of potassium is regulated by the kidneys through the hormone, aldosterone. Within the kidney, potassium is freely filtered by the glomerulus and subsequently (fully) re-absorbed in the proximal tubules. The secretion of potassium at the distal tubules, under the influence of aldosterone, is essential to remove sufficient amounts of potassium from the body. As a consequence, impaired renal potassium excretion is central to the pathophysiology of hyperkalaemia.
Potential causes of hyperkalaemia
Several diseases and drugs may contribute to the development of hyperkalaemia. Because aldosterone is an important regulator of potassium excretion, conditions that lead to low aldosterone levels, such as diabetes, impair renal potassium excretion. Furthermore, the presence of sufficient amounts of sodium at the distal tubules in the kidney is essential to excrete potassium. During intensive diuretic therapy, for example, in patients with advanced heart failure, volume depletion leads to reduced sodium delivery at the distal nephron, and subsequently to hyperkalaemia. Other drugs that interfere with renal sodium transport include amiloride, triamterene, trimethoprim, and calcineurin inhibitors (that is tacrolimus and cyclosporine). Some drugs (for example, digitalis and beta-blockers) or conditions (such as insulin deficiency) directly interfere with the availability of sodium-potassium ATPase. In addition, there are several other drugs and conditions that can promote the development or aggravation of hyperkalaemia. Therefore it is not surprising that high-risk patients that are receiving treatment for diabetes, chronic kidney disease, heart failure, or a combination of these disorders are prone to develop hyperkalaemia.
Current management of hyperkalaemia
Because severe hyperkalaemia can lead to potentially life-threatening cardiac arrhythmias, rapid correction is warranted. Acute management of hyperkalaemia aims for a quick reduction of serum potassium levels, preferably towards <5.0mmol/l. One option to achieve this is by combined treatment with insulin and glucose, promoting a transient potassium shift towards the intracellular compartment. Treatment with salbutamol and correction of metabolic acidosis, which may be concomitantly present, will also lower serum potassium levels. Furthermore, intravenous calcium infusion reduces the excitability of the myocardium, lowering the risk of arrhythmias within minutes. Although these measures act relatively quickly, they are all temporary and after a few hours hyperkalaemia may recur. Strategies aimed at removing potassium from the body are needed in case of more severe hyperkalaemia.
One approach to effectively remove potassium from the circulation is by haemodialysis (or haemofiltration), which may correct severe hyperkalaemia in minutes. Alternatively, treatment with loop diuretics may promote renal excretion of potassium, although this requires conserved renal function as well as more time.
In the longer term, some additional options are available to reduce serum potassium levels and/or to prevent the development of hyperkalaemia (Figure 1). If possible, medication impairing renal potassium excretion may be stopped, and patients may be recommended to restrict dietary potassium intake (for example, by refraining from potassium-rich fruits such as bananas, and green vegetables). However, avoiding these foods on a daily basis may not be beneficial as these also contain vitamins, fibre and other nutrients that are essential for a healthy diet.
The intestinal excretion of potassium can be promoted by the cation-exchange resins sodium polystyrene sulphonate (SPS) or calcium polystyrene sulphonate (CPS). Both compounds promote intestinal potassium excretion by exchanging potassium for sodium (SPS) or calcium (CPS). The clinical data for SPS in the management of hyperkalaemia are limited, with small open-label studies reporting reductions in serum potassium by >1mmol/l.4,5 A recent, small, randomised controlled trial demonstrated a reduction in serum potassium by 1.0mmol/l in outpatients with chronic kidney disease and mild hyperkalaemia.6 Safety data did not reveal clear differences in tolerability between SPS and placebo in this study, although this analysis may have been hampered by the study’s limited sample size.6 The tolerability of SPS (and CPS) may be an important issue in many patients, rendering its long-term application suboptimal in this setting. In many European countries, SPS and CPS are not widely used for the long-term management of chronic hyperkalaemia.
Novel strategies for hyperkalaemia management
Recently, two novel drugs have been developed for the treatment of hyperkalaemia. Patiromer is a spherical non-absorbed polymer that exchanges potassium for calcium, while zirconium cyclosilicate (ZS-9) is a non-absorbed oral powder that acts as a potassium selective ion trap.7,8 In the US, patiromer was approved by the Food and Drug Administration (FDA) for the treatment of hyperkalaemia in 2015, whereas ZS-9 has so far not received FDA approval.
Patiromer
Two recent clinical trials evaluated the efficacy and safety of patiromer in patients with chronic kidney disease. In the OPAL-HK trial, the short-term efficacy of patiromer was evaluated (n=237).9 Patients who had chronic kidney disease, using an ACEI or ARB with a serum potassium level of between 5.1 and <6.5mmol/l were initially treated with patiromer for four weeks. Patiromer reduced serum potassium levels by approximately 1mmol/l (5.6 to 4.6mmol/l).
Subsequently, patients who reached the target potassium level of 3.8 to <5.1mmol/l were randomised to patiromer or placebo for another eight weeks during the second part of the trial. Recurrent hyperkalaemia was reported in 60% of placebo recipients, compared with 15% of patiromer recipients, at the end of the study.
The longer term efficacy of patiromer was evaluated in the open-label AMETHYST-DN trial in 306 patients.10 In this trial, patients with type 2 diabetes and kidney disease received one of three patiromer dosages, titrated to reach serum potassium <5.1mmol/l, and were treated for 52 weeks. At four weeks after randomisation, a reduction in serum potassium was observed which lasted until week 52. Patiromer withdrawal at the end of the trial forced potassium levels to return to approximately 5.0mmol/l. Safety data in both patiromer clinical trials pointed towards gastrointestinal complaints (constipation, diarrhoea and nausea) as the most common adverse events, which occurred in approximately 3–5% of patients.9,10 Hypomagnesaemia was reported in 7% of patients in the AMETHYST-DN trial.10
Zirconium cyclosilicate
Two randomised controlled trials have addressed the efficacy and safety of ZS-9. First, the HARMONIZE trial evaluated the drug’s short-term efficacy in 258 patients with hyperkalaemia (serum potassium ≥5.1mmol/l).11 Interestingly, during an initial 48-hour open-label phase, ZS-9 reduced serum potassium from 5.6mmol/l to 4.5mmol/l. During the subsequent randomised, placebo-controlled phase, ZS-9 provided a dose-dependent reduction in serum potassium at day 29, compared with placebo. In the second clinical trial of 753 patients with hyperkalaemia, initial treatment with ZS-9 also effectively reduced serum potassium levels in a dose-dependent manner at 48 hours from baseline.12 This effect persisted over 12 days of maintenance therapy compared with placebo. At the end of the study, stopping ZS-9 treatment resulted in a significant increase in serum potassium levels.
Treatment with ZS-9 was well tolerated in the two aforementioned studies, although safety data beyond 29 days of treatment are not yet available. The rate of adverse events increased during the maintenance phases of both trials (29.4% and 25.1%, respectively), but remained similar to placebo. Gastrointestinal side effects were the most common adverse events, as for patiromer. However, in the HARMONIZE study, oedema was also more frequently reported in the high-dose ZS-9 arm, compared with placebo.11
On 23 February 2017, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorisation for ZS-9 in the EU.13
Conclusions
Hyperkalaemia is common, particularly in patients at high risk of cardiovascular disease, such as patients with diabetes, chronic kidney disease, and heart failure. Most, if not all, of these patients have an indication for treatment with an ACEI or ARB, and optimal management of their cardio-renal risk is hindered by the tendency to develop hyperkalaemia.
Current options available for chronic management of hyperkalaemia are limited, particularly in the longer term. It is anticipated that novel compounds including patiromer and ZS-9 will improve hyperkalaemia management. At the same time, this may open up new opportunities for cardiovascular and renoprotective therapy. Randomised controlled trials have shown that patiromer and ZS-9 effectively reduce serum potassium levels in patients with hyperkalaemia. Unfortunately, no studies have so far compared these novel players with SPS/CPS in a head-to-head design. Furthermore, the possibility of interactions with the uptake or bioavailability of other medications is currently subject of discussion. Yet, if patiromer and ZS-9 could enhance currently available therapeutic strategies, including uptitration of ACE-inhibitors or ARBs, without the burden of hyperkalaemia, this may provide an important step forward in the treatment of high-risk patients with heart and kidney disease.
References
1 Lambers Heerspink HJ et al. The effect of ramipril and telmisartan on serum potassium and its association with cardiovascular and renal events: Results from the ONTARGET trial. Eur J Prev Cardiol 2014;21(3):299–309.
2 Mann JFE et al. Serum potassium, cardiovascular risk, and effects of an ACE inhibitor: results of the HOPE study. Clin Nephrol 2005;63(3):181–7.
3 Miao Y et al. Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. Diabetologia 2011;54(1):44–50.
4 Scherr L et al. Management of hyperkalemia with a cation-exchange resin. N Engl J Med 1961;264(3):115–19.
5 Flinn RB, Merrill JP, Welzant WR. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol. N Engl J Med 1961;264(3):111–15.
6 Lepage L et al. Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD. Clin J Am Soc Nephrol 2015;10(12):2136–42.
7 Li L et al. Mechanism of action and pharmacology of patiromer, a nonabsorbed cross-linked polymer that lowers serum potassium concentration in patients with hyperkalemia. J Cardiovasc Pharmacol Ther 2016;21(5):456–65.
8 Stavros F et al. Characterisation of structure and function of ZS-9, a K+ selective ion trap. PLoS One 2014;9(12):e114686.
9 Weir MR et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;372(3):211–21.
10 Bakris GL et al. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN randomized clinical trial. JAMA 2015;314(2):151–61.
11 Kosiborod M et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA 2014;312(21):2223–33.
12 Packham DK et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015;372(3):222–31.
13 European Medicines Agency. Lokelma.
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004… (accessed March 2017).
