Elimination of potassium from the body
Potassium binding agents. Table 2 includes a detailed comparison of existing potassium binding agents.
Sodium polystyrene sulfonate (SPS)
With higher affinity for potassium than sodium or calcium, cation-exchange resins including SPS, work by competitively exchanging cations for secreted potassium in the colon, where the most potassium excretion takes place. [52] Each gram of resin binds approximately 0.65 mmol of potassium in vivo . [53] In patients with CKD and mild hyperkalemia (5.0–5.9 mmol/L), the results of a double-blind randomized controlled trial showed that 30 g daily of SPS for 7 days was superior to placebo in reducing serum potassium concentration.[54] This study reported an absolute reduction of serum potassium concentration of 1.25 mmol/L (p<0.001) with SPS. More subjects in the SPS group achieved normokalemia, although the difference was not statistically significant (p=0.07). Common adverse reactions of SPS include diarrhea, abdominal bloating and cramps, vomiting, and electrolyte imbalance.[54 55] SPS can cause serious adverse gastrointestinal (GI) events including bowel necrosis and consequent death. In a systematic review, SPS use was associated with 58 cases of bowel necrosis and 33% mortality. [56] SPS occasionally is mixed with sorbitol, a polyalcohol sugar, to induce faster passage through the digestive system. Sorbitol is thought to be the reason for these serious GI adverse events, but the findings of 2 recent large observational studies refuted that notion. Serious adverse GI events were twice as high among those treated with SPS (without sorbitol) compared to the non-SPS groups. [57 58] It should be noted that SPS should be avoided in patients who are not having consistent bowl movements as well as in KT recipients in the immediate post-operative phase. The use of SPS in clinical practice is controversial due to its unestablished safety and efficacy profiles.[59 60] In the acute setting, SPS utilization should be limited to patients with mild to moderate hyperkalemia without electrocardiography (EKG) changes as the onset of action may take up to 3 days. [55 61] Nevertheless, SPS continues to be routinely used due to its accessibility and lower cost. [18] Limited data in using SPS in the management of hyperkalemia in kidney transplant recipients.
Patiromer
Patiromer is an organic, non-absorbable potassium-binding polymer. It is formulated with calcium as the exchange ion, leading to less excessive sodium absorption and potentially less volume overload compared to SPS. The drug is active throughout the GI tract but mostly in the colon with an onset of action ranging from 4 – 7 hours. [62] PEARL-HF was a double-blinded, placebo-controlled study evaluating the role of patiromer in heart failure patients with CKD.[63] The patiromer group (15g twice daily) had a mean potassium reduction of –0.22 mmol/L from baseline to week 4 compared to an increase of 0.23 mmol/L in the placebo group (mean difference –0.45 mmol/L, p <0.0001). The proportion of patients with potassium > 5.5 mmol/L at any time during the study was 7% in the patiromer group vs 25% in the placebo group (p=0.015). The use of patiromer allowed the dose of spironolactone to be increased from 25 mg/day to 50 mg/day in 91% of patiromer patients compared to 74% of placebo patients (p=0.019). Patiromer was also evaluated in patients with CKD on RAAS inhibitors. (Weir, 2015) Patiromer was dosed based on serum potassium as 4.2g twice daily (serum K+ 5.1 – 5.4 mmol/L) or 8.4g twice daily (serum K+ level 5.5 – 6.4 mmol/L). Mean change in serum potassium concentration at week 4 (phase 1) was −1.01 ± 0.03 mmol/L (P<0.001). After 8 weeks, more patients in the patiromer group (94% vs. 44%) were maintained on RAAS inhibitors. The AMETHYST-DN study was designed to establish the safety, efficacy, and optimal dosing of patiromer in patients with hyperkalemia and diabetic nephropathy. [64] Patiromer dose varied from 4.2g – 16.8g twice daily. In the maintenance phase, the proportion of patients with normal potassium at each visit through week 52 was 83.1%–92.7% in the mild-hyperkalemia group (5.1-5.5 mmol/L) and 77.4%–95.1% in the moderate-hyperkalemia group (5.6-5.9 mmol/L). The lowest starting dose was selected to be 8.4 g/day for mild hyperkalemia and 16.8 g/day for moderate hyperkalemia. PEARL-HF Extension study was an 8-week open-label follow-up study to the PEARL-HF trial to determine the effectiveness of patiromer 8.4 g twice daily. In 90.5% of patients, serum potassium concentrations between 3.5 – 5.5 mmol/L were reached with mean potassium reduction -0.13 mmol/L at the end of study. [65]
Patiromer is generally well tolerated with common adverse effects including constipation and hypomagnesemia.[62 66 67] Patiromer was shown to bind to half of tested oral medications in vitro. When tested in humans, patiromer did not impact the bioavailability of 14 drugs when administration was separated by 3 hours, however, the bioavailability of ciprofloxacin was decreased (90% CI) for maximum concentration 83%–133.8%, exceeding the 80%–125% limit. [62] Hypercalcemia, though uncommon, has been reported in patients receiving patiromer as a result of systemic absorption of calcium released from the patiromer polymer. [68] Patients with more advanced CKD are thought to be more prone to this adverse effect. [69]
In KT recipients, there is limited data regarding the safety and efficacy of patiromer when taken with anti-rejection medications. In a retrospective study of 19 KT recipients, patiromer, when administered 3 hours apart from tacrolimus, was shown to be effective in reducing serum potassium concentration without having a significant impact on tacrolimus trough concentrations. [70 71] A pharmacokinetic study is currently underway to evaluate the significance of the drug-drug interaction between patiromer and tacrolimus or mycophenolate mofetil. [72] With the limited available evidence, spacing out patiromer 3 hours from anti-rejection medications should be considered. Patiromer has become a valuable treatment option for chronic hyperkalemia as it has demonstrated a better safety and efficacy profile when compared to SPS. While chronic patiromer use can be costly (a 30 day supply of patiromer 8.4 g is $850), it was associated with a reduction in hospitalization costs related to hyperkalemia in heart failure patients. [73]
Sodium zirconium cyclosilicate (ZS9)
ZS9 is the newest potassium binder that received an initial FDA approval for the treatment of hyperkalemia in 2018. ZS9 is a non-absorbable potassium binder that exchanges hydrogen and sodium for potassium and ammonium ions throughout the entire GI tract with an onset of action within 1 hour after ingestion. [74] Unlike patiromer, ZS9 does not affect magnesium levels, but does increase bicarbonate levels, which is an advantage in the context of hyperkalemia. In a multicenter randomized, double-blind, placebo-controlled clinical trial, patients with mean serum potassium concentration 5.3 mmol/L were randomized to receive ZS9 (1.25g – 10g by mouth 3 times daily) or placebo for 48 hours.[75] A significant dose-dependent reduction in serum potassium concentration was observed in the ZS9 groups. Following the initial 48 hour phase, patients who received a maintenance dose of ZS9 (5 or 10 g daily) remained normokalemic for 12 days. Similar outcomes were seen when the maintenance phase was extended to 28 days and 12 months. [76 77] It important to note that KT recipients were excluded from all of the previous studies, except in the study by Spinowitz et al. where only 1% of included patients were KT recipients (n=9). [77]
In a recent retrospective study of 35 transplant patients (16 kidney recipients), the effect of ZS9 on both hyperkalemia and immunosuppression concentrations was evaluated. The mean decrease in serum potassium concentration from day 0 to day 7 was -1.3 mmol/L (p= <0.001) without a significant impact on tacrolimus drug pharmacokinetics (the mean change in tacrolimus concentrations was -0.54 ng/mL). [78] ZS9 is generally well tolerated when compared to SPS. The most common adverse effects are hypokalemia and edema. [74]
The drug-drug interaction profile of ZS9 has not been established, however, it is reasonable to separate ZS9 from other medications to prevent chelation and decreased absorption. Due to its relatively fast onset of action, ZS9 is the only potassium binder shown to be effective in the setting of acute hyperkalemia. Cost may be a barrier in the US, a 30 day supply of ZS9 can cost $656 USD. The cost-effectiveness of ZS9 is questionable when compared to the other potassium binders. [79]
Fludrocortisone
The role of fludrocortisone in the management of hyperkalemia is due to its mineralocorticoid properties as well as its ability to enhance potassium secretion in the GI tract. [80] Fludrocortisone, when given for 3 months to patients with CKD on dialysis showed no benefit in decreasing serum potassium concentrations. [81] In kidney transplant, most data are from case reports. Marfo et al. reported 3 cases of successful hyperkalemia management when fludrocortisone 0.1 mg/day was used in the setting of acute and chronic hyperkalemia. [82] Its role was also described in tacrolimus-induced aldosterone resistance. [13] In 2 case reports, normokalemia was achieved in 2 days when fludrocortisone 0.1 mg/day was initiated in KT recipients.[83 84] Signs and symptoms of fluid retention need to be monitored in patients receiving fludrocortisone.
Diuretics
Loop and thiazide diuretics enhance potassium excretion by increasing delivery of sodium to the collecting ducts. [10 85] Loop diuretics are the most common diuretic class used in hyperkalemia because they promote urinary potassium excretion even in patients with moderate renal impairment. There are no data in using loop diuretics in acute hyperkalemia. Loop diuretics can be considered in the setting of mild chronic hyperkalemia in patients with CKD and volume overload. [10] Generally, the use of thiazides should be avoided in kidney transplant recipients due to increase the risk of developing potassium disturbances. [86] The role of diuretics in acute hyperkalemia is uncertain, but in patients with chronic hyperkalemia who are normovolemic or hypervolemic, diuretic therapy can be considered. [28]
Dialysis
Dialysis is the ultimate treatment for severe hyperkalemia (serum potassium concentration ≥ 6.0 mmol/L with EKG changes or ≥ 6.5 mmol/L) in patients with ESRD. [23] Potassium removal can be effected by dialysate concentrations of potassium and bicarbonate, as well as a dialyzer blood flow. Using a low potassium and glucose dialysate can enhance potassium removal, however, it may reduce the efficiency of urea clearance and aggravate ventricular arrhythmias. [87-89] The use of high bicarbonate dialysate can also accelerate the drop in the serum potassium concentration. [90] However, the safety of this approach has not been established. Lastly, potassium clearance can be enhanced by increasing the dialysis blood flow resulting in maximizing the potassium gradient between the blood and the dialysate. [91]