Hyperkalemia (HK) is defined as a serum potassium concentration above the normal limit (approximately 5 mmol/L), although levels above 5.5 mmol/L are considered clinically relevant. HK is a serious disorder since it can cause potentially fatal arrhythmias1 and is especially common in patients with chronic kidney disease (CKD) and/or heart failure (HF). It is estimated that approximately 28% of patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 present with HK during follow-up.2

The treatments recommended for patients with HF and/or CKD include inhibitors of the renin-angiotensin-aldosterone system (RAASi), as well as, in certain cases, mineralocorticoid receptor antagonists (MRAs). These therapies have been shown to reduce cardiovascular morbidity, slow the progression of kidney disease and improve overall survival in these patients.3,4 However, their use is associated with an increased risk of HK,2 therefore, despite their nephroprotective and cardioprotective benefits, long-term maintenance therapies are not always possible, especially in patients with severe renal dysfunction or advanced comorbidities that increase the risk of HK.5

Historically, the only treatments available for the chronic management of HK were cation exchange resins, such as sodium or calcium polystyrene sulfonate. However, their use has important clinical side effects, such as frequent gastrointestinal effects, especially constipation, and the risk of severe intestinal necrosis and hypokalemia; moreover, there is a lack of controlled trials and robust data on the efficacy and long-term safety of these treatments.6,7

Clearly, there is an unmet clinical need for HK treatment, especially for patients who cannot receive or be maintained on optimal doses of RAASis or MRAs. A reduction in or interruption of these drugs due to the risk of HK is associated with a significant increase in cardiovascular and renal morbidity and mortality.8 In recent years, new therapeutic alternatives, including sodium zirconium cyclosilicate (Lokelma®) and patiromer (Veltassa®), have emerged. Patiromer is a non-absorbable polymer that exchanges calcium for potassium in the colon, facilitating the elimination of potassium and effectively reducing its serum levels. This compound has shown sustained efficacy and a favorable safety profile in clinical studies and in real practice, allowing the optimization of treatment with RAASis with adequate control of serum potassium. In this context, we propose evaluating the use of the patiromer complex in patients with HK under conditions of routine clinical practice in our study population, with the aim of characterizing its effectiveness, safety and impact on treatment with RAASi and MRAs.9,10 To achieve this, a real-life study was conducted to analyze the change in serum potassium levels during the months after the start of patiromer as the primary objective. As secondary objectives, we considered 1) baseline patient characteristics, 2) modifications in treatment with RAASi and MRAs, and 3) side effects related to patiromer use.

This retrospective multicenter study, conducted under routine clinical practice conditions in the Valencian community, demonstrated that the use of patiromer in patients with CKD is associated with a significant, sustained and clinically relevant reduction in serum potassium with a favorable safety profile. In addition, most patients were able to stay on maintenance treatment with therapies such as RAASi and MRAs, with good treatment tolerance and little need for dose modification or discontinuation.

Our work provides additional evidence on the usefulness of patiromer in routine clinical practice in Spain for outpatient medicine and for patients with clear indications for RAAS blockade and/or MRA treatment and a high risk of progression of renal disease or cardiovascular events. In this context, published data on the actual use of this drug are scarce. Aside from clinical trials, only two studies have analyzed real-life data concerning the use of patiromer in patients with CKD, with specific data on the efficacy of potassium reduction and the assessment of adverse effects. One study was on a population of patients with CKD and not on dialysis, similar to ours,17 while the other was on a population on hemodialysis18; notably, both involved the U.S. Veteran’s database.

In both our study and the other two real-life studies, the use of patiromer was associated with a significant reduction in serum potassium levels at the first follow-up visit (−1 mmol/L in the study by Kovesdy et al.,17 −1.03 mmol/L in the study by Pinnell et al.18 and −0.55 to −0.71 mmol/L in our study). These potassium reductions with respect to baseline are consistent with those observed in the AMETHYST-DN12 and OPAL-HK10 studies.

This effect was achieved in most cases with a standard initial dosage of 8.4 g/day, without frequent adjustments, which reinforces its clinical utility. In the study by Kovesdy et al.,17 96% of the participants received a dosage of 8.4 g/day, and 4% received 16.8 g/day. In our study, 86.4% of the participants received 8.4 g/day, 10.2% received 16.8 g/day, and 3.4% received 25.2 g/day. In the study by Pinnel et al., which involved hemodialysis patients, the dosages were more variable, but only 15.3% received more than 8.4 g/day. A total of 69% of the patients received 8.4 g/day, and the remaining patients received lower doses every other day.

The data on the percentage of comorbidities among the patients in the three studies were very similar, but our study was performed on an older population (73.8 years in our study vs. 70 and 66 years on average in the other two real-life studies). This distinction reinforces the applicability of our results to real care scenarios.

Notably, in our study, therapy with RAASi and MRAs was maintained in 94.9% and 98.3% of patients, respectively. These data represent an improvement relative to retrospective series, such as that of Trevisan, who analyzed 36,011 patients with CKD stages 3–5, where HK contributed to the suspension of blockade treatment in more than 30% of cases.19

Both our study and that of Kovesdy et al.17 demonstrate a low rate of discontinuation of patiromer treatment (13.5% and 20%, respectively), which contrasts with the high rate of discontinuation in the study that analyzed patients on hemodialysis, which reached 50% despite a mean sustained reduction in potassium level of 1 mmol/L. The latter may be related to the substantial changes in potassium levels in patients on hemodialysis, many of which are influenced by, among other factors, the dose of dialysis, which rapidly normalizes potassium levels and may even result in hypokalemia. The inclusion criterion of at least three months of patiromer use in our study may have excluded patients who discontinued treatment early. The contribution of patiromer to the maintenance of basic nephroprotective therapies is especially relevant in this context, where the suppression of RAASi/MRA treatment is a frequent cause of kidney disease progression.16,19

Safety is highly important in treatments with chelators or potassium exchangers, where the side effects, especially gastrointestinal effects, have limited the use of cardio- and nephroprotective drugs. This also has implications for morbidity, mortality and renal progression in patients with CKD,20 for whom the use of calcium or sodium polystyrene sulfonate is limited because of its limited effectiveness and safety issues.21 The main side effects described in pivotal studies with patiromer (AMETHYST-DN12 and OPAL-HK10) include constipation (4.6%–11%), diarrhea (2.7%–5%), hypomagnesemia (up to 7.2%) and other minor gastrointestinal side effects, such as nausea and abdominal pain (2%–4%). In our study, the presence of gastrointestinal side effects was lower than that described in the pivotal trials, which may be related to the retrospective nature of the analysis. No cases of hypomagnesemia were detected, despite the monitoring of magnesium levels in the majority of patients during nephrology follow-up.

The identification of two patients with hypercalcemia is noteworthy, which, although mild, led to the suspension of patiromer. Although hypercalcemia was not identified in pivotal trials of patiromer, some isolated clinical cases with this complication have been described, especially among patients with advanced CKD.22–24

The proposed mechanism for this hypercalcemia is based on the ion exchange properties of the drug itself: patiromer (also known as calcium patiromer) releases calcium by binding to potassium in the intestinal lumen, which can increase the systemic absorption of calcium in susceptible patients, especially those with a reduced glomerular filtration rate, in whom the urinary excretion of calcium is compromised, resulting in its accumulation. Other factors, such as the use of thiazide diuretics, secondary hyperparathyroidism, and vitamin D supplementation, may increase calcium absorption. In the published cases, hypercalcemia was resolved by discontinuing patiromer treatment and recurred when patiromer was reintroduced. Although infrequent, this adverse effect should be considered when determining whether to administer patiromer, and serum calcium should be monitored during prolonged treatments.22–24

It is also notable that the majority of treatment discontinuations were not due to side effects per se but to other situations, such as renal deterioration with the start of dialysis, lack of compliance by the patient or suspension by the doctor due to the presence of normokalemia. These findings indicate that the real prevalence of patiromer discontinuation due to adverse side effects may actually be lower than that reported, with most of the side effects being mild and not causing discontinuation of treatment, reinforcing patient tolerance of the drug.

Our study has several limitations. One of them is inherent to its retrospective and observational design, which prevents the establishment of strong, causal relationships between the use of patiromer and the changes observed in serum potassium level or in the continuity of treatment with RAASi/MRA, as well as the possible omission of any adverse effects, especially mild ones, as they were not reported in the clinical history. Second, the relatively limited sample size (59 patients) could restrict the generalization of the findings compared with that of previous studies with larger populations, such as those of Kovesdy et al.17 (n. = 288) or Pinnell et al.18 (n. = 458). Nevertheless, ours is a representative cohort of outpatient nephrology patients with advanced CKD, which provides clinical value and applicability to the findings. Another limitation is the absence of a control group, which also prevents the establishment of direct causal relationships between treatment with patiromer and the change in potassium levels. Although significant and sustained reductions in serum potassium were observed, the influence of other concomitant factors, such as dietary adjustments, changes in medication or spontaneous clinical variability—which may have contributed to the observed effect—cannot be ruled out.

Despite these limitations, the study presents several relevant strengths. First, it offers a detailed evaluation of the safety of patiromer under routine clinical practice conditions, including the adverse effects experienced by the patients. In addition, prolonged follow-up, with a median of 12 months, allows us to assess not only the initial efficacy but also the therapeutic persistence and stability of potassium control in the long term, providing useful information for clinical decision-making.

Finally, this is one of the first studies conducted in Europe in outpatients with CKD and cardiorenal syndrome treated with patiromer, which contributes to expanding the available evidence and supports the implementation of this drug in nephrology practice in our environment.

We would like to emphasize that most of the participating centers were parts of cardiorenal units, where there is a more integrated approach aligned with clinical guidelines. From a clinical perspective, the results reinforce the usefulness of patiromer as a tool to facilitate a comprehensive approach to treating cardiorenal disease. Its use can avoid forced therapeutic decisions, such as a reduction or suppression of renin‒angiotensin axis blockade, in patients who could benefit from these treatments, especially those in advanced stages of CKD where the therapeutic margin is limited. This strategy is in line with the current recommendations of the KDIGO and HF guidelines, which emphasize the importance of maintaining optimized treatment whenever possible,4,25,26 in this case through the use of patiromer. In addition to the recommendations of the guidelines, the use of patiromer in patients with HK and CKD or HF has been associated with a reduction in costs, generating annual savings between € 3127 and € 3466 per patient.27

It should be noted that funding does not always correspond to clinical indications. In Spain, the cost of patiromer is reimbursed only for patients with advanced CKD and grade III–IV HF with mild–moderate HK (5.5–6.4 mmol/L), for those treated with RAASi whose continuation is essential, and those for whom ion exchange resins failed or produced intolerance. Since financing criteria differ across countries and health systems, the generalizability of our results may be limited.

We believe that the new potassium exchangers, such as patiromer, could play a preventive role in the stabilization of potassium and facilitate the maintenance of cardiorenal drugs, even before episodes of severe HK.

In conclusion, this study provides real evidence of the efficacy, safety and usefulness of patiromer in patients with CKD and HK treated under routine conditions. Its ability to reduce and stabilize serum potassium levels in the long term, along with its good tolerance profile and its contribution to the maintenance of treatment with RAASi and MRAs, make it a valuable tool in nephroprotection. Prospective studies designed specifically to evaluate the clinical impact of this strategy would be desirable.

This study was initiated by the researchers and is sponsored by an unrestricted grant from CSL VIFOR FARMA. Support for the study was provided by the INCLIVA Research Institute of the University Clinical Hospital of Valencia. The study design was carried out by the authors. CSL VIFOR has not intervened in the design of the study or in the preparation of the manuscript.