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Clinical Challenges: Managing Chronic Hyperkalemia

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A blue-gloved hand holds a test tube of blood labeled Potassium-Test

As explained by the National Kidney Foundation, the goal of management of chronic hyperkalemia — i.e., high levels of potassium in the blood — is to prevent the development or recurrence of the condition by correcting the underlying disturbances in potassium balance.

However, the use of the term “chronic” may actually be a misnomer in the case of hyperkalemia, noted Csaba P. Kovesdy, MD, director of the Clinical Outcomes and Clinical Trials Program, Division of Nephrology, at the University of Tennessee Health Science Center in Memphis.

“When we think of the term chronic, we think of a condition or state that is persistent. It is very rare that people walk around with potassium levels that are always elevated. For hyperkalemia, by ‘chronic’ we really mean recurrent. For a variety of reasons potassium levels will fluctuate,” he said.

Still, there are groups of patients who are at risk for chronic/recurrent hyperkalemia. Those who are at particularly high risk are patients with chronic kidney disease (CKD) — especially those with advanced disease and those on dialysis — as well as patients with congestive heart failure.

Other major risk factors include diabetes and medications that can disrupt potassium levels, such as antihypertensive drugs.

A high-potassium diet can contribute to chronic hyperkalemia as well, but only in cases where the patient has a reduced ability to excrete potassium, said Kamyar Kalantar-Zadeh, MD, MPH, PhD, chief of the Division of Nephrology, Hypertension, and Kidney Transplantation at the University of California Irvine School of Medicine.

“It’s highly unlikely that diet alone will cause hyperkalemia,” he noted. “I could give you 10 times more potassium than the normal human being consumes and it is unlikely you would have even borderline hyperkalemia. Kidneys are that resilient.”

Whatever the cause of hyperkalemia, a sudden surge in potassium levels can be life threatening. “The problem with hyperkalemia is that patients are also more susceptible to having worsening surges,” Kalantar-Zadeh said. “Once your baseline is high, you can easily go very high and that poses the danger of developing cardiac arrhythmia.”

Thus the importance of preventing the surges in the first place.

The first step in managing chronic/recurrent hyperkalemia is to identify and eliminate any potential causes that are modifiable, including diet. As he told MedPage Today previously, this can be problematic and involves a therapeutic tradeoff since eliminating potassium from the diet is the antithesis of a heart-healthy diet.

Other steps could include elimination of medications, such as nonsteroidal anti-inflammatory drugs and certain antibiotics that can be safely removed from a patient’s regimen.

“The next step would be to see if we can somehow fend off the hyperkalemia by implementing certain treatments,” Kalantar-Zadeh continued. “For example, diuretics have the side effect of inducing potassium wasting in urine. So, If you have a patient who is hypertensive, the addition of a diuretic to their regimen could help prevent future events of hyperkalemia.”

“Where we end up with therapeutic compromises is with clearly beneficial medications like renin-angiotensin-aldosterone system [RAAS] inhibitors,” Kovesdy noted. “The groups at highest risk of hyperkalemia — those with chronic kidney disease and congestive heart failure — are the groups that benefit most from these drugs. Yet this is a class that clearly induces hyperkalemia.”

“So we are faced with the situation where when we do everything else and the patient is still hyperkalemic and you end up having to discontinue these medications or lower their doses, despite the fact that data suggests it may not be beneficial,” Kovesdy said.

For example, researchers have found that reducing RAAS doses in order to prevent hyperkalemia results in an increased risk of mortality and major adverse cardiovascular events (MACE) in patients with CKD and heart failure.

Specifically, the researchers found that among patients with CKD, mortality occurred at a rate of 57.7 deaths per 1,000 patient‐years for those on a suboptimal RAAS inhibitor dose (i.e., less than 50% of the guideline‐recommended dose) compared with 7.2 deaths per 1,000 patient‐years for those prescribed at least 50% of the dose. The corresponding rates of MACE were 130.0 and 73.0 events per 1,000 patient‐years, respectively.

Among patients with heart failure, the differences were even more pronounced, Kovesdy noted. The mortality rate for patients on a suboptimal dose of an RAAS inhibitor was 141 deaths per 1,000 patient-years compared with 12 deaths per 1,000 patient‐years for patients on an optimal dose. MACE rates were 290.4 vs 148.5 events per 1,000 patient‐years, respectively.

“That’s why the advent of these new potassium binders — patiromer [Veltassa] and sodium zirconium cyclosilicate [Lokelma] — has brought on a new perspective on this issue,” he said, noting that there is now the thought that RAAS inhibitors could be used to treat hyperkalemia with a binder that can be applied chronically, rather than as a one-time intervention, but in effect as a preventive means, “could allow us to continue the use of these medications without the risk of the associated hyperkalemia.”

Long-term management of hyperkalemia has for many years relied on another binder — sodium polystyrene sulfonate (SPS) — a cationic exchange resin that exchanges potassium for sodium in the colon.

There are problems with SPS, however. One study, for example, found that SPS is associated with a higher risk of hospitalization for serious adverse gastrointestinal events, such as intestinal necrosis. Tolerability is also an issue: common side effects include loss of appetite, stomach discomfort, nausea, vomiting, and constipation.

In addition, Kovesdy said, SPS has never been studied as a chronic intervention — i.e., as a drug that should be applied long-term to prevent hyperkalemia.

Clinical trials, such as this one in 2015, have shown that the use of patiromer for hyperkalemia significantly reduced the concentration of serum potassium, is well tolerated in CKD patients, including those with diabetic nephropathy and heart failure, as well as patients taking renin-angiotensin-aldosterone inhibitors.

Sodium zirconium cyclosilicate was approved by the FDA in 2018 based on clinical trials that found it lowers potassium levels to within normal ranges within 48 hours, maintains those levels up to 12 months across all patient subgroups (e.g., those with CKD, diabetes, heart failure, and those with concomitant use of RAAS inhibitors), and is well tolerated.

“I have to emphasize that these are biochemical endpoints,” said Kovesdy. “We know [these potassium binders] can lower potassium and maintain potassium in the normal range, and they have been shown to do that in the context of treatment with RAAS inhibitors, so they are effective enabling medications, if we can use that term.”

“Their long-term effects in terms of clinical benefit is still an open question,” he added. “Preventing hyperkalemia is one thing, but the risks associated with hyperkalemia come exclusively from observational studies. We know persons with higher potassium have higher mortality rates and higher cardiovascular event rates, but we don’t have data to show that if we correct those high potassium levels that we can prevent those poor outcomes. Those would require randomized clinical trials where we randomize people to an intervention or no intervention and show there is a difference — and that has never been done.”

Disclosures

Kovesdy reported financial relationships with AstraZeneca and Relypsa.

Kalantar-Zadeh reported financial relationships with Abbott, AbbVie, Alexion, Amgen, AstraZeneca, Aveo, Chugai, DaVita, Fresenius, Genentech, Haymarket Media, Hospira, Kabi, Keryx, Novartis, Pfizer, Relypsa, Resverlogix, Sandoz, Sanofi, Shire, Vifor, UpToDate, and ZS-Pharma.

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