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]