How Should you manage hyperkalemia from RAAS inhibitors in patients with cardiorenal dysfunction?

November 5, 2021

Clinical Questions 8 min read

By Logan Groneck

Peer Reviewed

Your next patient is very familiar. The management of her chronic diseases–heart failure (HF) and chronic kidney disease (CKD)—has been optimized. Like the 6.2 million other Americans with HF1 and the 37 million Americans with CKD,2 practice guidelines have recommended several medications to minimize the risk of disease progression.

In the practice of medicine, much time is spent persuading patients that the new medication being prescribed is vital for continued good health or future survival. For a patient with HF and CKD, there is perhaps no class of medication where this argument is truer than the renin-angiotensin-aldosterone system (RAAS) inhibitors. These medications–angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA)–have been established as particularly important for patients with heart failure with reduced left ventricular ejection fraction (HFrEF), with numerous studies demonstrating their efficacy in reducing hospitalization and mortality.3-9

But perhaps the endorsement of the American College of Cardiology and American Heart Association regarding the cardioprotective, blood pressure lowering benefits of these medications is not a compelling enough selling point for your medication-averse patient. You can confidently tell your patient that this prescription is handling two birds with one stone: a RAAS inhibitor just so happens to be a frontline medication for slowing the progression of their declining kidney function.10-18

Having reminded yourself and the patient of the importance of these medications, you find yourself suddenly given pause while reviewing recent laboratory results: a potassium level of 5.5 mEq/L. On the backfoot now, you are considering a difficult question: For your patient with HF and/or CKD, how can we balance the many benefits of RAAS inhibitors against their risk of exacerbating hyperkalemia?

Hyperkalemia frequently complicates adherence to guideline-recommended RAAS inhibition for patients with HFrEF and CKD.19-22 RAAS inhibitors elevate potassium levels by suppressing aldosterone secretion by the adrenal glands, downstream from renin secretion. Aldosterone normally promotes the activity of epithelial sodium channels (ENaC) in the renal collecting tubules, which promotes potassium wasting through an increased electrochemical gradient, driving potassium out through renal outer medullary potassium (ROMK) channels.23 In patients controlled on RAAS inhibitors, the risk of hyperkalemia must be weighed against the risk of undertreated disease. Hyperkalemia, particularly when resulting from acute elevations, can manifest as severe muscle weakness/paralysis,24 cardiac conduction abnormalities/arrhythmias,25 and metabolic acidosis via impaired renal ammonium excretion.26 Due to concern for these potentially fatal complications, advanced kidney disease with refractory hyperkalemia is an indication for initiating kidney replacement therapy (KRT).27 A nationwide Swedish observational study of over 10,000 individuals suggested that continuation of RAAS inhibitors in the setting of end-stage kidney disease (ESKD) was associated with an increased absolute risk of KRT.28 Analysis of Danish National registries also revealed an association between elevated all-cause mortality and potassium levels over 5.0 mEq/L.29

None of this is to say that the decision to reduce or discontinue these medications in the setting of hyperkalemia is a completely satisfactory solution. Stopping RAAS medications following incident hyperkalemia has been associated with an increased mortality risk in patients admitted for acute heart failure,30 and subgroup analysis of the EMPHASIS-HF study examining patients at high risk for hyperkalemia on the aldosterone antagonist eplerenone has demonstrated preservation of mortality benefit.31 Further support for the lifesaving cardioprotective effects of these medications has been seen in two large observational studies showing decreased 5-year cardiac event and mortality rates in CKD patients maintained on RAAS inhibitors in advanced kidney disease compared to those in whom the medication was withdrawn.28,32

With this delicate balance of risk and benefit in mind, the standard approach to minimize the risk of hyperkalemia has historically been fourfold:

  1. Reduction of dietary potassium to <2-3 g/day; sources include fruits, vegetables, meats, nuts, and cereals.33
  2. Use of potassium-wasting thiazide and loop diuretics.33 Potassium-wasting         diuretics are appropriate for management of blood pressure in CKD; higher doses are likely to be required.
  3. Addition of alkali, which may increase K excretion and slow the progression of CKD when metabolic acidosis is present.34
  4. Reduction in therapeutic RAAS inhibition, as follows: Reduce the dose if K >5.5 mEq/L, stop if K >6.0 mEq/L, until K ≤5.0 mEq/L.35

When facing the unsatisfactory decision to reduce or limit uptitration of effective therapy, there is reason to consider adding instead of subtracting medications and starting one of the promising new potassium-binding agents to boost gastrointestinal potassium excretion.

While the first potassium-binding agent, sodium polystyrene sulfonate (Kayexalate®, Concordia Pharmaceutical, St. Michael, Barbados), was approved in 1958 for the emergent treatment of hyperkalemia through cation exchange for sodium in the GI tract, its tolerability has been limited by this resin’s propensity for volume expansion following water absorption, with risk for bowel obstruction and colonic necrosis.36 Fortunately, newer medications including patiromer (Veltassa®, Vifor Pharma, Zurich, Switzerland; $50.37/8.4g unit, FDA-approved 2015) and sodium zirconium cyclosilicate (SZC, Lokelma®, AstraZeneca, Cambridge, UK; $28.33/5g unit, FDA-approved 2018) have demonstrated promise as cation exchangers with favorable side effect profiles.

Patiromer effectively exchanges potassium in the distal colon for calcium as a means of increasing gastrointestinal potassium excretion, without evidence of volume expansion predisposing to obstruction.37 Patiromer has demonstrated efficacy in reducing the incidence of hyperkalemia (7.3% vs 24.5% placebo), as well as allowing more successful uptitration of spironolactone during four-week treatment in patients with a history of hyperkalemia prompting discontinuation of RAAS inhibitors or CKD with GFR <60 mL/min.38

SZC utilizes sodium exchange for potassium throughout the GI tract. The HARMONIZE clinical trial data revealed a low side-effect burden with 29 days of use, and a return to normokalemia within 48 hours for 98% of participants with a mean potassium of 5.6 mEq/L.39

Given the tolerability and efficacy suggested by these studies, providers caring for HF and CKD patients who are benefiting from RAAS inhibitor therapy should follow further study of these drugs closely, as they represent a promising new solution to an all-too-common high-stakes clinical dilemma.36,40-42 Barriers to widespread adoption of these agents include high cost, a lack of studies demonstrating mortality benefit, and that they come as powders that need to be dissolved in water.

Logan Groneck is a 2nd year medical student at NYU Grossman School of Medicine

Reviewed by David Goldfarb, MD, Professor, Department of Medicine, Neuroscience and Physiology, NYU Grossman School of Medicine, Chief Nephrology, NY Harbor VA Medical Center

Image courtesy of Wikimedia Commons, source:[File:Renal corpuscle-en.svg|Renal_corpuscle-en],  Author-Shypoetess                                   

References

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