Potassium is the main intracellular cation. Potassemia is regulated by potassium entering and leaving the cell.1 Potassium from the diet is rapidly absorbed passively by the small intestine and accumulates intracellularly before being excreted in urine. Several factors modify its transcellular flux. Insulin and beta-2-adrenergic activity introduce potassium into the cell, reducing potassemia, while exercise, metabolic acidosis, hyperglycemia, hyperosmolarity and tissue destruction release potassium from cells, increasing its serum concentration. Although potassemia is usually maintained in the normal range despite physiological variations related to diet and physical activity, even during prolonged fasting (low insulin levels) or extreme physical exercise, these oscillations could become clinically relevant in patients that develop hypo- or hyperkalemia.2–4 Finally, several drugs interfere with transcellular potassium transfer (Table 1).5,6

The recommended daily intake of potassium is around 3,500 mg (90 mEq), requirements that are easily met with regular intake, given its wide distribution in multiple foods and beverages.7,8

The foods richest in potassium are fruits and vegetables, although it is also present in meat, nuts, legumes, seeds and cocoa (Table 2). Another important source of potassium is potassium salts, used as a substitute for common salt.9,10 The use of these salts may increase after a recent clinical trial demonstrated that their use decreases cardiovascular events and death from any cause in hypertensive patients with a history of stroke or age 60 years or older.11 Plant sources of potassium are also a source of dietary alkalis, which can reduce metabolic acidosis in CKD by helping to maintain potassium within the cell.

Potassium leaves the body in a regulated manner in urine and in an unregulated manner in feces, vomit or sweat. Urinary potassium excretion is regulated at the level of the distal nephron.6,7 Aldosterone promotes potassium secretion by the principal cells of the connecting segment and cortical collecting tube, which exchange it for sodium reabsorption from the tubular lumen. This process can be inhibited, even in the presence of hyperkalemia, by drugs that decrease the levels or block the action of aldosterone, by a decrease in the sodium available in the lumen of the distal nephron, or by the inability of the principal cells to reabsorb sodium (Table 3). Conversely, increased sodium availability in the distal nephron (e.g., by diuretics that inhibit sodium reabsorption in more proximal segments of the nephron) favors sodium reabsorption in exchange for potassium, which is secreted into the urine, even in the presence of hypokalemia. Polyuria interferes with the kidney's ability to retain potassium, since there is a reduced urinary potassium concentration, and the high urine volume is accompanied by increased urinary potassium loss (Table 3). Excessive unregulated loss of potassium in digestive secretions or sweat may promote hypokalemia.

There is no universally accepted definition of hyperkalemia. Laboratories provide a range of normality based on the distribution of potassemia in the general population, but it would be desirable to evolve to a definition of hyperkalemia based on health risk. The recent Kidney Disease Improving Global Outcomes (KDIGO) conference defined hyperkalemia as potassemia above normal, taking into account that serum levels of potassium are 0.1−0.7 mEq/L higher than tha plasma levels, so laboratories should indicate in which fluid it was measured and what the normality values are for each fluid.12 Serum is usually used n routine analyses, whereas plasma is commonly used in emergency department analyses because of the faster sample preparation time. In any case, KDIGO suggests classifying acute hyperkalemia as mild, moderate or severe depending on potassium levels and electrocardiographic impact, using the respective cut-off points at 5.0 mEq/L (or the upper limit of laboratory normal), 6.0 mEq/L and 6.5 mEq/L (Table 4). Acute hyperkalemia is considered when it was not previously known, but there is no consensus on the magnitude, duration and frequency of elevated potassium values that define chronic hyperkalemia.

In clinical laboratories, the prevalence of hyperkalemia, defined as potassemia greater than 5.0 mEq/L, is around 3−4% in unselected populations, but increases greatly in populations with predisposing factors. The highest prevalence is observed in hemodialysis patients. A recent study in patients with CKD and glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 illustrates the natural history of hyperkalemia as a recurrent phenomenon, with progressively increasing risk of recurrence and progressively shorter time to recurrence (Fig. 1).13 The incidence of hyperkalemia with potassemia above 5.0 mEq/L was 9, 18, 31 and 42% in one year, in people with GFR of 45–59, 30–44, 15–29 and <15 mL/min/1.73 m2, respectively.13 In this regard, the inability of the kidney to adequately eliminate potassium from the diet is the main predisposing factor, either because there is CKD or other conditions that limit renal excretion of potassium, or because of taking drugs that interfere with its renal elimination, of which the main ones are renin-angiotensin system (RAS) blockers, potassium-sparing diuretics and mineralocorticoid receptor antagonists (MRA) (Table 5). Hyperkalemia is especially frequent if several of these factors are combined.

Fig. 1.

Incidence of first episode of hyperkalemia and recurrence of hyperkalemia in patients with CKD (adapted from Thomsen RW, et al.13).

(0.39MB).

Hyperkalemia is associated with poorer health outcomes. Severe acute hyperkalemia can be lethal, and hyperkalemia is associated with an increased risk of hospitalizations (including increased cardiac events, ventricular arrhythmias, cardiac arrest, and intensive care) and death over the next six months, ranging from two to five times that observed in controls, even in populations in which one would assume a higher tolerance to hyperkalemia, such as patients with CKD.12 The association between hyperkalemia and events could have several causes, including causality by itself (for example, malignant ventricular arrhythmias), or related causes such as suboptimal use of drugs with recognized cardiovascular and renal benefits, such as RAS blockers or MRAs, the conjunction of comorbidities or even the prescription of potassium-poor diets that are not very heart-healthy.

Treatment aims to avoid the acute lethality of hyperkalemia and to decrease potassemia by three types of maneuvers15: (1) antagonizing the effects of potassium on the cell membrane; (2) bringing potassium into the cells; (3) taking potassium out of the body (Box 1Table 6). Only the last two reduce potassemia.

Calcium antagonizes the effect of potassium on the cardiac cell membrane. The onset of action of calcium is a few minutes, but lasts only 30–60 min, which makes it necessary to use it in combination with other strategies. It is available in two preparations: calcium gluconate and calcium chloride. Calcium gluconate 1,000 mg i.v. administered in two to three minutes with cardiac monitoring is preferred for convenience of use and less damaging effect on the veins if it is misplaced. If the emergency persists, calcium administration can be repeated every 30−60 min if there is no increase in calcemia.

The administration of insulin and/or beta-2-adrenergic agonists and/or sodium bicarbonate (the latter only if there is metabolic acidosis) favors the entry of potassium into the cell.

Insulin activates the sodium-potassium-ATPase (Na/K-ATPase) exchange pump in the cell membrane, especially in the muscle cell. It is the most effective measure. Its effect starts in 10−20 min and lasts up to six hours. Insulin is generally administered with glucose to prevent hypoglycemia or alone if blood glucose is greater than 250 mg/dL. One of the most widespread guidelines is the intravenous administration of 10 units of insulin in 500 mL of 10% glucose saline over one hour. The aim is to maintain the effect of the insulin and avoid the onset of hypoglycemia.

Beta-2-adrenergic agonists also activate the Na/K-ATPase pump. They are effective both inhaled and intravenously and are indicated as an adjunct to insulin administration. Salbutamol is usually used, 10−20 mg in 10 min if inhaled (a much higher dose than that administered in the treatment of bronchospasm), or 0.5 mg in 100 mL of 5% glucose in 15 min if intravenous. Its action starts in 10 min if inhaled and 15 min if intravenous, lasting three hours. It can produce tachycardia. The combination of insulin and beta-2-adrenergic agonists has an additive effect on the reduction of potassemia, making it more effective than their separate use.

Sodium bicarbonate is added to the previous measures only if there is metabolic acidosis. It is not considered a fundamental measure as it has much less effect, and more delayed, than the other maneuvers.

It can be achieved in three ways: increased urinary elimination, increased digestive elimination or by dialysis.

• •

  Increase the urinary excretion. Only loop diuretics have an onset and magnitude of action that allows them to be useful in the acute treatment of hyperkalemia in patients with normal or slightly impaired renal function, but they may not be effective if renal insufficiency is severe. Concomitant administration of loop or thiazide diuretics could have an adjuvant effect, especially in patients with hypervolemia.21

• •

  Increase gastrointestinal elimination. There are three options:

  • 1

    Ion exchange resins such as sodium or calcium polystyrene sulfonate. Their use in situations of acute hyperkalemia is limited, given their slow onset of action and the absence of clinical trials that have demonstrated efficacy. In a placebo-controlled clinical trial, the association of resinsodium with cathartics did not reduce potassemia more than placebo in the following 12 h.22

  • 2

    Patiromer. It is a non-absorbable polymer containing a calcium-sorbitol complex. It binds potassium in the colon in exchange for calcium, having also the capacity to bind magnesium. It thus reduces the concentration of free potassium in the intestinal lumen and increases its fecal excretion. There are three authorized presentations in the form of 8.4, 16.8 and 25.2 g powder for oral suspension. REDUCE was a single-center, open-label pilot study, which randomized 43 hemodialysis patients with potassemia ≥6.0 mEq/L to treatment as usual with or without (non-placebo control group) the addition of 25.2 g patiromer, with 30 patients being finally evaluated23 (NCT02933450). The primary endpoint was potassemia at 6 h, with no differences between groups: patiromer 5.8 mEq/L (95% confidence interval [95% CI] 5.4–6.1 mEq/L) and control 6.3 mEq/L (95% CI, 6.0–6.6 mEq/L). However, at 2 h, potassemia was lower in the patiromer group than in the control group: 5.9 mEq/L (95% CI, 5.6–6.1 mEq/L) vs. 6.5 mEq/L (95% CI, 6.2–6.7 mEq/L), the baseline potassium concentration being 6.4 ± 0.5 and 6.7 ± 0.5 mEq/L, respectively. The poor efficacy of "treatment as usual" is explained by the fact that it only consisted of insulin (33% of patients) or beta-adrenergics before 2 h in less than half of the patients, whereas in that period the patients randomized to patiromer had also received insulin (40%) or beta-adrenergics. That is, at 2 h patiromer was compared with no intervention in more than half of the patients.

  • 3

    Sodium zirconium cyclosilicate (SZC). It is a crystalline, non-polymeric, non-absorbable potassium binder. The ENERGIZE study (NCT03337477)24 was a multicenter, double-blind, placebo-controlled, Phase 2 clinical trial evaluating the efficacy of SZC in the emergency treatment of hyperkalemia, added to glucose and insulin, with the primary endpoint being the change in potassemia at 4 h. Patients aged ≥18 years admitted to an Emergency Department and with a potassemia ≥5.8 mEq/L measured using an i-STAT rapid analyzer (Abbott Point of Care, Inc. Chicago, IL, USA), confirmed by a simultaneous determination of serum potassium in a central laboratory, were included. Although a sample size of 132 participants was estimated to achieve adequate statistical power, only 70 patients were randomized to receive 10 g SZC (repeatable at 4 and 10 h) or placebo. Overall, 30.3% (10/33) and 43.2% (16/37) of patients randomized to SZC and placebo, respectively, discontinued treatment. The treatment completion rate was 57.6% in the SZC group and 45.9% in the placebo group. At 4 h, there was no significant difference in serum potassium reduction between the two groups: mean (least squares) covariate-adjusted change of -0.41 ± 0.11 vs. −0.27 ± 0.10 mEq/L, in SZC and placebo, respectively (difference −0.13 mEq/L; 95% CI, −0.44 to 0.17). Approximately half of the patients receiving treatment in each group (57.6% in the SZC group and 45.9% in the placebo group) did not have a central measurement of serum potassium at 4 h, using the value obtained with the i-STAT adjusted to correct the difference between the two methods. Six patients in the SZC group (18.2%) and 10 (27%) in the placebo group lacked serum potassium determination by both methods, the data being imputed using the last determination made up to and including 4 h. The authors recognize as an additional limitation the potential differences in therapeutic strategies between the different centers in relation to the use of rescue therapies. In the assessment of potassium level, at 2 h there was a greater reduction in potassemia in patients randomized to SZC compared to placebo: −0.72 ± 0.12 vs. −0.36 ± 0.11 mEq/L (difference −0.35 mEq/L; 95% CI, −0.68 to −0.02). Finally, in relation to safety aspects, a similar proportion of patients experienced adverse effects in both groups in the first 24 h, being thereafter more frequent in those who received SZC (24.1 vs. 9.1%). There were no differences in terms of severe adverse effects. To summarize this section, SZC is the only intervention to increase the G.I. elimination of potassium that has been evaluated in a placebo-controlled clinical trial in the acute treatment of hyperkalemia as an added strategy to those usually used to introduce potassium into the cells, demonstrating a greater decrease in potassemia at early times (two hours) than placebo (Box 2). The PLATINUM study is currently underway, a multicenter, randomized, placebo-controlled clinical trial evaluating aspects related to the use of Patiromer in the context of hyperkalemia in emergency services.

    Box 2.

    New developments in acute treatment of severe hyperkalemia.

    1) To the classical measures available for antagonizing the effects of potassium on the cell membrane, getting potassium into the cells and getting potassium out of the body (Table 11Box 1), we must add the new oral potassium binders, which can accelerate the removal of potassium from the body in the acute treatment of hyperkalemia by a non-renal route, an advantage in patients with limited urinary potassium excretion due to anuria, oliguria, renal insufficiency or sustained activity of mineralocorticoid receptor antagonists.

    2) Specifically, in patients with hyperkalemia, sodium zirconium cyclosilicate (SZC) decreased potassemia at 2 h more when added to glucose and insulin than placebo, with glucose and insulin in a multicenter, double-blind, placebo-controlled clinical trial.

• •

  Hemodialysis. In a hyperkalemic emergency, especially in patients on chronic dialysis programs, hemodialysis is the treatment of choice,25 since it is the fastest and most efficient strategy to reduce potassemia, and should be applied as soon as possible, although the use of hemodialysis does not exclude the application of the previously mentioned measures. In patients with advanced CKD who are not yet in dialysis programs, hemodialysis should be considered, for which it will be necessary to have an adequate vascular access for dialysis. In general, and depending on the baseline potassemia concentration, the alterations associated with hyperkalemia are resolved within the first 30−60 min of hemodialysis.

Except when there is a clear transient and isolated cause that triggers the episode of hyperkalemia; in general, patients with severe hyperkalemia are at a high risk of recurrent hyperkalemia, this is due to the chronicity of the usual predisposing factors (CKD, heart failure, diabetes and their treatments) and it requires chronic intervention. There have been recent developments in this field (Box 3) that have changed the therapeutic approach to this complication (Box 4).

Reducing the potassium content of the diet is a virtually universal measure in the management of hyperkalemia, although most clinical practice guideline recommendations for the dietary management of hyperkalemia are based on expert opinion, given the limited evidence and biases of the available studies.26 A recent meta-analysis revealed that dietary potassium restriction with the aim of reducing potassemia presents very low quality evidence, and it cannot be concluded that it decreases the risk of death or slow down the progression of CKD.27

Reducing dietary potassium load should be integrated with the other nutritional goals of the CKD patient (adequate protein intake, high fiber intake and healthy cardiovascular dietary pattern) through the following strategies28:

Nutritional education to learn about the foods with the highest potassium content, recommendations on the diet required to maintain a good nutritional status in CKD, and indications on the classification of foods according to the amount of potassium in relation to fiber. In this sense, patients should be trained to learn how to interpret the nutritional cards and food labeling, so that they can choose the most appropriate foods for their clinical situation.

Use of appropriate culinary techniques for food preparation that result in lower potassium content, such as cooking in water, pressure cooker or microwave for all foods, and prolonged soaking in water of root, tuber, leafy and cruciferous vegetables.29

Detection of hidden sources of potassium, such as low-sodium salt substitutes (no evidence in patients at risk of hyperkalemia), and certain food additives, used in up to 40% of processed products (mainly meat products, breaded products, soft drinks, ready-to-eat products and cereal products).30 The most frequently used food additives containing potassium are E202, E252, E340, E450, E452, E508 and E950.31 It is important that the patient identifies them by inspection of the nutrition labeling and restricts their consumption.

Potassium-rich foods that should generally be avoided to reduce the risk of hyperkalemia are listed in Table 2, which also includes some examples of low-potassium alternatives, duly indicated.

Compliance with a low potassium diet is not easy, given barriers such as fragmented dietary advice, contraindication to healthy eating patterns, and potential changes in appetite and taste.32 Patient-centered education strategies, motivation for transplantation or delayed dialysis, and visualization of accommodation to restrictions often facilitate adaptation to these dietary guidelines.33

Under physiological conditions, the factors that most increase potassium uptake by cells, as they stimulate Na-K-ATPase, are insulin, beta-adrenergic stimulation and, to a lesser extent, aldosterone34–37 (Table 1). On a chronic basis, adequate control of diabetes and correction of metabolic acidosis can help treat hyperkalemia, especially in CKD, which is characterized by the development of metabolic acidosis.38,39 The KDIGO guidelines suggest treatment with oral sodium bicarbonate supplementation unless contraindicated, when serum bicarbonate concentration is less than 22 mEq/L, to maintain serum bicarbonate in the normal range, regardless of potassemia.40 This approach prevents metabolic acidosis from releasing potassium from inside the cell to the extracellular space, which favors its urinary elimination.41 In a recent multicenter observational study of more than 500 non-dialysis CKD patients (66.7% with category G3b-G5), patients with incident or persistent hyperkalemia over 12 months were characterized by lower serum bicarbonate concentration, while the prescription of sodium bicarbonate was associated with a reduction in potassemia.42 Likewise, clinical trial results show that SZC corrects metabolic acidosis in CKD patients, decreasing the percentage of patients with a serum bicarbonate <22 mEq/L after 29 days of treatment from 39.4% to 17.2%.43 However, there are no clinical trials specifically designed to evaluate the effect of sodium bicarbonate on serum potassium levels or on the incidence of hyperkalemia, the existing information being derived from secondary or exploratory objectives44–50 (Table 7).

Thiazides and loop diuretics increase urinary potassium excretion and can cause hypokalemia when used for other indications. They are not usually used for the sole purpose of treating chronic hyperkalemia, as they can cause volume depletion that can even lead to acute renal failure and also water and electrolyte disturbances (e.g., thiazides can cause hyponatremia). However, they can be used in cases of chronic hyperkalemia when an additional benefit is expected from their use, such as better control of arterial hypertension, heart failure and even a greater decrease in albuminuria, especially in patients with these comorbidities in whom the combination of diuretics with RAS blockade or MRA allows treatment with the latter to be maintained.51–54

Sodium-glucose cotransporter type 2 (iSGLT2) inhibitors also protect against hyperkalemia in patients with RAS blockade, in addition to improving renal and cardiovascular prognosis.55 In a recent meta-analysis of six clinical trials involving 49,875 patients with type 2 diabetes and high cardiovascular risk or CKD, iSGLT2s decreased the risk of severe hyperkalemia (potassemia ≥6.0 mEq/L) by16% without increasing the risk of hypokalemia, with a consistent effect in all subgroups, including patients treated with MRA.54,56 The mechanism is not completely clarified, but probably depends, at least in part, on increased sodium delivery to the distal nephron lumen, where it is reabsorbed in an exchange for potassium, which is eliminated in urine. It would therefore be a mechanism shared with thiazides and loop diuretics.

The use of drugs that bind potassium, limiting its intestinal absorption and favoring its elimination in the feces, is a key strategy in the management of chronic hyperkalemia.

Three options are currently available:

Cation exchange resins (sodium or calcium polystyrene sulfonate). They capture potassium in the intestinal lumen in exchange for the release of sodium and calcium, respectively. Although there is ample clinical experience supporting their efficacy, the scientific evidence from placebo-controlled clinical trials is very limited, as is the number of patients included in these studies and the follow-up period, especially with the concomitant use of RAS inhibitors and MRAs57–60 (Table 8), so the safety profile has not been sufficiently evaluated in prolonged treatments of more than three weeks, which limits their use for the chronic treatment of hyperkalemia in contemporary clinical practice.61 Its G.I. tolerance is poor. Frequent G.I. side effects include constipation and nausea, which limits therapeutic compliance. Other frequent side effects are hypercalcemia (calcium polystyrene sulfonate) and hypokalemia, as a consequence of the mechanism of action. Much more rarely, cases of gastrointestinal ischemia, ischemic colitis, ulceration or necrosis of the gastrointestinal tract that may lead to intestinal perforation have been reported.61,62

In Spain there are two preparations of calcium polystyrene sulfonate. In one of them, Resincalcio®, the recommended dose is 15 g three or four times a day, which should be suspended in case of constipation and is contraindicated in "renal insufficiency associated with diseases such as hyperparathyroidism, multiple myeloma, sarcoidosis or metastatic carcinoma". Sorbitol (oral or rectal) is contraindicated as a laxative, since concomitant use with calcium polystyrene sulfonate may cause colon necrosis.61,63 In the other preparation, Sorbisterit®, the dosage is 20 g, one to three times a day mixed in about 150 mL of liquid (i.e. 150−450 mL/day), at least three hours before or after oral administration of other medications or up to six hours in case of gastroparesis, as may occur in diabetes.63

The poor tolerance and poor compliance observed clinically by the authors of the present mnucript in their clinical practice were recently confirmed in a crossover clinical trial versus patheromer; although at the doses tested (15 g three times daily for resinsodium and 16.8 g once daily for patiromer, both on non-dialysis days), resinsodium lowered potassemia more than patiromer in hemodialysis patients over four weeks, but tolerance of resinsodium was lower and noncompliance four times higher, raising questions about longer-term compliance (e.g., years).64

Patiromer. An initial dose of 8.4 g/day is recommended. Patiromer begins to reduce the serum potassium several hours after ingestion, with the effect being maintained for 12−24 h.65 Patiromer is generally well tolerated, with the most frequently reported adverse effects being gastrointestinal (constipation, diarrhea, flatulence and abdominal pain) and hypomagnesemia.65,66

In clinical trials, patiromer reduced potassemia in different patient profiles (Table 9).

• none-

  Heart failure. The PEARL-HF study67 evaluated the effect on potassemia in patients with chronic heart failure who initiated treatment with spironolactone, and observed a decrease in potassemia in the patiromer group, with a difference with respect to placebo of -0.45 mEq/L (p < 0.001) and a lower incidence of hyperkalemia (7.3% vs. 24.5%, p = 0.01). The decrease in potassemia with respect to placebo was more marked (-0.52 mEq/L, p < 0.05) in patients with CKD (n = 66), that is, in the group with the highest risk of hyperkalemia, in which the incidence of hyperkalemia was 6.7 and 38.5% (p < 0.05) with patiromer and placebo, respectively. The DIAMOND study demonstrated the usefulness of this agent in potassium reduction, adverse events related to hyperkalemia, and a higher proportion of patients treated with optimal doses of antialdosterone drugs in patients with heart failure with reduced ejection fraction and a history or current episode of hyperkalemia.68

• none-

  CKD. Patiromer has been studied in three settings: diabetic kidney disease, resistant arterial hypertension, and CKD in general. The AMETHYST-DN study69 evaluated the effect of patiromer in patients with type 2 diabetes, diabetic kidney disease (CKD G3-G4: eGFR between 15 and 60 mL/min/1.73 m2) on treatment with RAS blockers, who had mild hyperkalemia (serum K 5.1–5.9 mEq/L) and who were randomized to patiromer at increasing doses (from 4.2 to 16.8 g twice daily). Potassemia decreased from 0.35 to 0.97 mEq/L, proportional to the initial degree of hyperkalemia and patiromer dose, and the decrease was statistically significant at the first determination (at approximately 48 h) after drug initiation. The proportion of patients achieving the target range of potassemia was greater than 83% in mild hyperkalemia (serum K+ 5.1–5.5 mEq/L) and greater than 77% in moderate hyperkalemia (serum K+ 5.6–5.9 mEq/L).

AMBER70 patients with resistant arterial hypertension and CKD G3b-G4 (eGFR 25−45 mL/min), in whom spironolactone therapy was initiated, were randomized to patiromer or placebo. The primary endpoint was the proportion of patients who were still on spironolactone at 12 weeks, which occurred in 98/166 (66%) placebo patients and 126/147 (86%) patiromer patients (between-group difference: 19.5%, p < 0.0001).

OPAL-HK71 was a phase 3 clinical trial that randomized patients with G3-G4 CKD treated with stable doses of RAS blockers and hyperkalemia to patiromer or placebo. An initial, open-label phase treated 237 patients with patiromer, in whom potassemia decreased by a mean of −1.01 mEq/L (p < 0.001) at four weeks. In the second phase, 107 patients who had reached potassium levels in the target range (3.8–5.1 mEq/L) were randomized to continue with patiromer or switch to placebo for another four weeks. At the end of this second phase, the mean increase in potassemia was greater in the placebo group (p < 0.001) and the recurrence of hyperkalemia (60%) was more frequent than in the patiromer group (15%, p < 0.001).

Sodium zirconium cyclosilicate. SZC has also demonstrated its efficacy in the chronic treatment of hyperkalemia in a wide range of patients. The presentations authorized in Spain are 5 and 10 g. It rapidly (from the first hour) reduces serum potassium, with a mean time of 2.2 h to reach normal potassemia, and with 98% of patients reaching normalization of potassemia in the first 48 h.72 The most frequently reported adverse reactions are hypokalemia (4.1%) and edema (5.7%). The latter has been related to the sodium content of the molecule (each 5 g of SZC contains approximately 400 mg of sodium), which is exchanged with potassium, being mainly observed with the 15 g/day presentation, which is not authorized in Spain.72,73

The main clinical trials with SZC are listed in Table 10.

HARMONIZE74 studied adults with persistent hyperkalemia seen as outpatients in cardiology, nephrology and research services, who received 10 g of SZC three times daily during an initial 48-h open-label phase; 92% of patients normalized potassemia and were then randomized to 5, 10 or 15 g daily of SZC or placebo for four weeks. Mean potassemia at 29 days was significantly lower with the different doses of SZC than with placebo (p < 0.001). The proportion of patients with normal serum potassium levels was higher with SZC (71, 76, and 85% for the 5 g, 10 g, and 15 g daily dose, respectively, vs. 48% in the placebo group), a statistically significant difference for each dose of SZC vs. placebo.

Another phase 3 clinical trial with 754 patients (74.5% with CKD, 66.7% on RAS blockers, 59.9% with diabetes and 39.8% with a history of heart failure) confirmed the significant reduction of potassemia in 48 h with different doses of SZC compared to placebo and the maintenance of the result up to 14 days.75

DIALIZE76 was a phase 3b clinical trial involving 196 hemodialysis patients with persistent hyperkalemia despite adequate dialysis. The primary efficacy endpoint was the proportion of patients with predialysis potassemia between 4.0 and 5.0 mEq/L without rescue therapy, which was achieved in 41% of SZC patients and 1% of those in the placebo group (p < 0.001).

In a long-term phase 3 study, potassemia was normalized in more than 99% of patients within the first two to three days and these normal levels of serum potassium (K+ ≤ 5.1 mmol/L) was maintained in 87% of participants at the end of a 12-month follow-up.72

In addition to limiting the intestinal absorption of potassium, SZC provides benefits against metabolic acidosis, as indicated in the corresponding section.43

Patiromer and SZC have better tolerance, efficacy and safety than cationic resins, favoring the use of RAS and MRA inhibitors in pathologies where their benefit has been demonstrated, such as arterial hypertension, CKD and heart failure.77,78

There are no clinical trials that have directly compared patiromer and SZC, and differences in the design and setting of clinical trials with each drug make comparison difficult. A meta-analysis of six studies and 1,756 patients (654 on patiromer and 1,102 on SZC) compared the efficacy and safety of patiromer and SZC in the treatment of hyperkalemia.78 No baseline differences were observed in patient age, eGFR or potassemia, although there was a lower proportion of patients with CKD, heart failure and diabetes, and receiving RAS blocker therapy in the SZC trials. With patiromer, the mean decrease in potassemia at 3 days of treatment was 0.36 mEq/L, and with SZC it was 0.67 mEq/L at 48 h; 7.6% of patiromer patients had constipation and 7.1% hypomagnesemia, while in those receiving SZC, 1.6% had diarrhea and 0.9% had edema.79 In a more recent meta-analysis, patiromer showed lower rates of hyperkalemia with respect to standard treatment, with no differences in terms of adverse effects or discontinuation of treatment due to these effects. In relation to SZC, there were no differences in the occurrence of hyperkalemia or in the overall rate of adverse effects, although there was a higher frequency of edema in the SZC group.80

There is no good evidence on the impact of patiromer and SZC on postprandial hyperkalemia after high potassium intake, despite normalizing basal potassemia levels.81

Both patiromer and SZC have been shown to be effective in solid organ transplant patients.82