Elevated Potassium: Let's rethink Kayexalate and other Potassium Binding Agent

Melissa Staley, MS4

Case Presentation:

· 51 yo M with a PMH of ESRD on MWF iHD, anuric at baseline, presents to the emergency department with 2 days of exertional dyspnea, nausea, and fatigue following his Friday dialysis session.

· Labs were significant for a K+ of 7.0 mEq/L

. EKG demonstrated peaked T waves.

· Patient was given calcium gluconate, started on an albuterol nebulizer, and given insulin with 2 amps of D50. Nephrology was consulted and emergent dialysis was planned.

· The potassium binding agent, sodium zirconium cyclosilicate (SZC), was considered but ultimately held after K+ reduced to 5.4 mEq/L with albuterol and insulin alone.

Question: What role do potassium binding agents play in the acute management of hyperkalemia? Should they still be part of standard of care in these patients and, if so, which agents should be used?

Summary of Evidence:

Potassium binding agents have been part of the mainstay of the management of hyperkalemia for decades. In a hyperkalemic patient with EKG changes, students are commonly taught to stabilize the cardiac membrane with calcium, shift potassium into the cells, and employ agents to promote K+ excretion while waiting for definitive treatment with hemodialysis. Potassium binding agents can be employed to promote fecal excretion of K+ and include sodium polystyrene sulfonate, patiromer, and the newly approved sodium zirconium cyclosilicate.

Sodium Polystyrene Sulfonate (Kayexalate)

Approved for use by the FDA in 1958, sodium polystyrene sulfonate or SPS is a nonspecific cation exchange resin that binds K+ and other cations in the GI tract, allowing for fecal elimination. Despite its long history of use, the clinical data demonstrating its efficacy is sparse. In brief:

· Original studies conducted in 1961 supporting the use of SPS were very small with less than 32 subjects and included heterogenous groups of inpatients with varying degrees of renal function and hyperkalemia (1,2).

· A Cochrane review in 2005 of studies since that time concluded, “though resins are widely used clinically, there was no randomized evidence for their efficacy in an emergency setting” (3). The one RCT included in that review study showed no benefit to SPS use when studied over the first 12 hours after administration (4).

· To date, there are no large RCTs examining the efficacy of SPS in patients with acute hyperkalemia.

Further, SPS use is not without risk. Administration of SPS has been associated with GI disturbances, significant electrolyte abnormalities and, when given alone or with cathartics, bowel necrosis. The risk of bowel necrosis, in particular, is higher in hemodialysis dependent patients (5).

Sodium Zirconium Cyclosilicate (Lokelma)

Sodium zirconium cyclosilicate (SZC) is a relatively new agent that acts by selectively binding K+ ions as it travels through the GI tract. Clinical trials, overall, have demonstrated modest effects in short term K+ reduction. Four hours after the administration of 10g of SZC, studies have shown:

· Ash et al. showed an average drop of 0.25 mEq/L in K+ with SZC (n = 24) compared to a drop of 0.16 mEq/L in the placebo group (n = 30) (6).

· Kosiborod et al. (Harmonize) showed an average drop of ~ 0.4-0.5 mEq/L in K+ with SZC (n = 258) (7).

· Packham et al. showed an average drop of ~0.4 mEq/L in K+ with SZC (n = 143) compared to a drop of ~ 0.2 mEq/L in the placebo group (n = 158) (8).

· Peacock et al. showedan average drop of 0.41 mEq/L in K+ with SZC (n = 143) compared to a drop of 0.29 mEq/L in the placebo group (n = 37) (9).

From these clinical trials, it appears that, at most, SZC is responsible for a 0.5 mEq/L in drop in K+ at 4 hours. Even this is likely to be inflated, given that the Harmonize trial did not include a placebo group and every trial with placebo listed above demonstrated some degree of K+ reduction within their placebo group. The Packham trial, which did use placebo, shows the effect is likely closer to a 0.2 mEq/L drop. All of these studies, however, are limited by small sample sizes.

Short term efficacy aside, SZC has been shown to be safe, with no adverse outcomes reported. SZC can cause mild GI disturbances, including diarrhea, constipation, nausea and vomiting.

Patiromer (Valtessa)

Patiromer is a polymer that acts similarly to SPS, exchanging calcium for potassium in the GI tract.

· To date, patiromer has largely been studied in the outpatient setting, focusing on long term trends in K+ reduction over the span of several weeks (10, 11, 12).

· One small scale RCT showed a 0.61 mEq/L reduction in serum K+ in patients treated with patiromer plus standard of care compared to standard of care alone at 2 hours (13). No significant difference in K+, however, was found between groups at 6 hours.

· Ultimately, further data is needed to assess the efficacy of patiromer in the treatment of acute hyperkalemia to really say whether it has clinical utility in this setting.

Like SZC, patiromer has been proven to be safe but can cause increased calcium load and hypomagnesemia in addition to GI disturbances.

Recommendations:

· In acute hyperkalemia with EKG changes, patients should receive calcium gluconate and the potassium shifting agents, albuterol and insulin. Emergent hemodialysis should be prioritized in these patients.

· SPS should not be used in the acute treatment of hyperkalemia.

· In patients with mild to moderate hyperkalemia, SZC can be considered. Its use is safe and may produce a modest reduction in K+ beyond that caused by potassium shifting agents.

· In patients with severe hyperkalemia, SZC is unlikely to make a clinically significant enough change in serum K+ beyond that caused by potassium shifting agents to avoid dialysis.

· Not enough data exists to support the use of patiromer in acute hyperkalemia management.

References:

1. Scherr, L., Ogden, D. A., Mead, A. W., Spritz, N., & Rubin, A. L. Management of hyperkalemia with a cation-exchange resin. N Engl J Med. 1961;264,115-119. doi:10.1056/NEJM196101192640303

2. Flinn, R. B., Merrill, J. P., & Welzant, W. R. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med. 1961;264,111–115. https://doi.org/10.1056/NEJM196101192640302

3. Mahoney BA, Smith WAD, Lo D, Tsoi K, Tonelli M, Clase C. Emergency interventions for hyperkalaemia. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003235. DOI: 10.1002/14651858.CD003235.pub2. Accessed 04 June 2021.

4. Gruy-Kapral C, Emmett M, Santa Ana CA, et al. Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease. J Am Soc Nephrol. 1998;9:1924–1930.

5. Harel Z, Harel S, Shah PS, et al. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med 2013;126:264:e9–e24.

6. Ash S, Singh B, Lavin P, Stavros F, Rasmussen H. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015;88(2):404-411. doi:10.1038/ki.2014.382

7. Kosiborod M, Rasmussen H, Lavin P, 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):2223-2233. doi:10.1001/jama.2014.15688

8. Packham D, Rasmussen H, Lavin P, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222-231. doi:10.1056/NEJMoa1411487

9. Peacock W, Rafique Z, Vishnevskiy K, et al. Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double-blind, Placebo-controlled Study (ENERGIZE). Acad Emerg Med. Published online March 9, 2020. doi:10.1111/acem.13954

10. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a doubleblind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF trial). Eur Heart J. 2011;32:820–228.

11. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015;372:211–221. 49.

12. Bakris GL, Pitt B, Weir M, 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;314:151–161.

13. Rafique, Z., Liu, M., Staggers, K. A., Minard, C. G., & Peacock, W. F. Patiromer for Treatment of Hyperkalemia in the Emergency Department: A Pilot Study. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine. 2020;27(1),54–60.