Hyperkalemia meets their new K-busters

      Hyperkalemia is a challenge in CKD and ESRD patients. The treatment agents for this complication have been limited to bowel resins, diuretics and dialysis.  There has been some recent interest in novel agents as some evidence suggesting the efficacy of Kayexalate and side effects leading to colonic necrosis in some settings.

Three articles published this week (2 in NEJM and 1 in JAMA) give us trials of using novel K lowering agents in three different settings.

The first trial looked at patiromer use for hyperkalemia in CKD patients on RAAS inhibitors. The active moiety of patiromer for oral suspension is a nonabsorbed polymer that binds potassium in exchange for calcium in the distal colon leading to highest K excretion possible. Patiromer is a dry powder, primarily a spherical bead that is not absorbed and that binds potassium when mixed in small amounts of water. It exchanges potassium for calcium, which would be of some concern if the drug were absorbed. It appears, however, that the drug is not absorbed and that the amount of calcium absorbed is small. In A RCT with placebo, patiromer treatment was associated with a decrease in serum potassium levels and, as compared with placebo, a reduction in the recurrence of hyperkalemia. Mild-to-moderate constipation was the most common adverse event (in 11% of the patients); hypokalemia occurred in 3%.

The second trial looked at zirconium cyclosilicate (ZS-9), a novel selective cation exchanger, could lower serum potassium levels in patients with hyperkalemia. ZS-9 is a compound with a crystalline structure that traps potassium  10 times as much potassium as kayexalate does. It is insoluble and remains in the intestine during transit. This was in a variety of diagnosis leading to hyperkalemia in over 700 patients. There was an initial phase and then a maintenance phase. Patients with hyperkalemia who received ZS-9, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy per their conclusion

The third trial titled HARMONIZE was a phase 3, multicenter, randomized,

double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium_5.1mEq/L) . Among outpatients with hyperkalemia, sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days.

Two accompanying editorials are in NEJM and JAMA as well

Few questions still remain and are a concern:

Since all 3 trials were pharmaceutical company sponsored, placebo was used to compare the agents for efficacy. Why not kayexalate?- it works and it’s cheaper. The authors in one study did state that the agent was not compared to sodium or calcium polystyrene  since prospective studies are lacking in the later and also agents cause bowel necrosis.

But there are significant years of experience and pathophysiology that it works.  Side effects are part and parcel of every agent. The above agents had constipation as side effect, and some might have calcium and magnesium concerns if used long term given how they work. Also all three trials were very short term and long term trials are needed still.  FDA approval is also warranted before any use.

Nevertheless, the patients we have that have CKD and or heart failure and we really want them to be on ACEI, ARB or aldactone but cannot due to K related concerns and or require diuretics with them:- now we may have an alternative option for the situation.