# Potassium management and heart failure: a nephrologist's perspective

Denis Fouque, Carmine Zoccali, Francesco Pesce

► To cite this version:

Denis Fouque, Carmine Zoccali, Francesco Pesce. Potassium management and heart failure: a nephrologist's perspective. Clinical Kidney Journal, 2025, 18 (2), pp.sfae424. 10.1093/ckj/sfae424. inserm-05344924

HAL Id: inserm-05344924

https://inserm.hal.science/inserm-05344924v1

Submitted on 3 Nov 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
EDITORIAL COMMENT

# Potassium management and heart failure: a nephrologist's perspective

Denis Fouque ID¹, Carmine Zoccali² and Francesco Pesce³

¹dept of nephrology, Lyon Sud hospital, Hospices Civils de Lyon, Carmen Inserm U1060 and University Claude Bernard Lyon1, Pierre Benite, France, ²Renal Research Institute, NY, USA; BIOGEM, Ariano Irpino, Italy; Associazione Ipertensione Nefrologia Trapianto Renal (IPNET), C/O Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy and ³Division of Renal Medicine, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy

Correspondence to: Denis Fouque; E-mail: denis.fouque@gmail.com

Potassium serum concentration is tightly and promptly regulated to allow adequate cell functioning, especially for cardiac rhythm control. Beside absorption/release linked to digestive fluid metabolism, potassium behavior depends on multiple regulatory mechanisms, involving the kidney, the skin and the intra-/extracellular exchanges. Various hormones impact on these regulatory loops, among them aldosterone, corticosteroids, catecholamines, insulin, and IGF-1. Likewise, several drugs also alter serum potassium levels, including diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, steroidal and non-steroidal mineraloreceptor antagonists (MRA), sodium-glucose co-transporter 2 (SGLT2) inhibitors, potassium binders and substances that alter the acid-base balance, such as sodium bicarbonate, sodium citrate, etc. Dietary intake of potassium comes from different sources and is variable, generally ranging from 1 to 4 g per day. It is increased in diets that are rich in fruits and vegetables, such as the PLADO (plant-dominant low protein) and the Mediterranean diets and generally reduced in western-type diets. A high intake of potassium is associated with a reduction in systemic blood pressure. Interestingly, there has been numerous recent research data showing a much weaker (if any) relationship between dietary potassium intake and kalemia than previously thought. This counterintuitive observation is mostly explained by the difference in potassium intake through either a single chemical compound administered during experimental research (K chloride or K phosphate) which is readily absorbed and quickly enters the bloodstream, and dietary

potassium which comes with fibers (legumes), carbohydrates (fruit) and low PRAL (potential renal acid load) brought by most vegetarian diets, all combinations that can neutralize the rise in serum potassium [1]. However, in people with advanced chronic kidney disease (CKD) a relationship may still exist between seasonal substantial potassium intake and kalemia, or obvious dietary error, such as excessive potato, meat or milk portions and potassium additives, which should be assessed by the dietitian. Otherwise, until today there is no proven relationship that reducing dietary potassium can therapeutically improve hyperkalemia [2]. Indeed, in a recent review, a healthy diet including fruits, vegetables and wholegrains was associated with a lower serum potassium [2].

Recently, a debate took place regarding the optimal kalemia and risks of hyperkalemia in patients with cardiac disease taking medications that alter potassium metabolism. Indeed, up to 73% of heart failure patients with CKD may present with hyperkalemia during the first year of follow-up [3-6]. Of note, the level of kalemia and the treatment adjustments differ according to guidelines and publications [7]. New potassium binders have been shown to prevent the recurrence of hyperkalemic episodes under spironolactone treatment, but it is unclear if these binders allow continuation of MRA and improve outcomes [8]. There is a gap in evidence whether these binders should be given preventively in heart failure patients with normokalaemia (<5 mmol/l) as they may induce hypokalemia [8].

Indeed, hypokalemia is also frequently observed in heart failure patients, up to 50% [9], and has been reported to be
<caption>Table 1: Serum potassium range and corrective maneuvers*†.</caption>

<3.5 mmol/l: reduce thiazides and loop diuretics, give orange juice and bananas, give potassium supplements
3.5–4.9 mmol/l: maintain treatments
4.9–5.5 mmol/l: maintain treatments, measure serum K more frequently
>5.5 mmol/l: reduce/stop MRA-ACEi-ARA2, increase thiazides and loop diuretics

<figure><img src="image_2.png" /><figcaption>**Figure 1:** Combined death or kidney replacement therapy start (dotted lines, 95% CIs) related to time-dependent serum potassium in 1714 incident participants in the European Quality study on treatment of older people with advanced CKD during 8 years of follow-up (adjusted for age, sex, current smoking, history of diabetes mellitus, history of cardiovascular disease, estimated glomerular filtration rate, subjective global assessment score, and renin-angiotensin-aldosterone system inhibitor use). From De Rooij et al., ref. 13, with permission.</figcaption></figure>

associated with increased mortality even for mild hypokalemia just below 4 mmol/l [10]. The authors recommend maintaining serum potassium between 4 and 5 mmol/l. Thus, a long-standing relevant clinical question is: what are the goals in serum potassium management, and when and how should we control serum potassium?

The serum potassium target in heart failure and CKD patients should be 3.5–5.5 mmol/l (Table 1) and corrective maneuvers are not recommended within this range. More frequent serum potassium monitoring can be advised when serum potassium ranges between 4.9 and 5.5 mmol/l [11]. Indeed, we learned long ago from electrophysiology that plasma potassium associated with a normal EKG signal is close to 5.0 mmol/l [12]. Above and

below this value, there are slight but abnormal EKG modifications that will be aggravated for values outrunning this threshold. Interestingly, 40 years later, data from the European Quality (EQUAL) study in 1700 CKD stage 4–5 non-dialysis patients concur to the same observation, that a value of 4.9 mmol/l was associated with the lowest mortality [13] (Fig. 1). It is also important to remember that in the presence of elevated potassium, there are numerous reasons for factitious or pseudohyperkalemia, among them a difficult venous puncture, a time lag before actual measurement, hot climate temperature when blood is drawn home and then transported to the laboratory, and test tube hemolysis. In addition, there is a noticeable difference between plasma and serum potassium concentration,

<footnote>* Verify laboratory normal potassium range, blood drawing with no tourniquet, no hemolysis present and measure K rapidly after draw; † adapted from KDIGO guideline [11].</footnote>
<table><caption>Table 2: The sequential choice in the lowering serum potassium armentarium [15].</caption><tr><td>1. Increasing urinary potassium excretion (diuretics—SGLT2i)</td></tr><tr><td>2. Fighting constipation (dietary fibers—laxatives)</td></tr><tr><td>3. Controlling acidosis better (bicarbonate supplement)</td></tr><tr><td>4. Binding digestive potassium (oral potassium binders)/correcting dietary potassium excess</td></tr></table>

serum potassium being greater than plasma potassium by a magnitude of 0.35 mmol/l [14], an important information which has been underlined in the recent KDIGO guideline recommendation 3-11-1-1 [11]. Also, the normal range for serum potassium measurement in biology laboratories/facilities reports is between 3.5 and 5.5 mmol/l. Consequently, one should not take a decision for starting/changing treatment based only on a single potassium measurement. The several confounding parameters should therefore be considered and a double check is often warranted. In our experience, pseudohyperkalemia occurs in 20–30% of elevated kalemia and appears to be normal after a second test. When true hyperkalemia is present, a therapeutic intervention is due, based on the above physiopathology (Table 1) [11].

Moreover, a number of conditions may induce hyperkalemia and should be corrected in the first place (Table 2) [15]. For instance, abnormal glycemia resulting from insulin deficit or insulin resistance during a septic episode will increase serum potassium; also, acidotic episodes with a serum bicarbonate below 23 mmol/l, as in the case of diabetic patients or in those with advanced CKD [16]. More recently, constipation, which allows an unremitting colic potassium reabsorption, has been shown to be associated with altered potassium metabolism. Consequently, patients using chronic laxatives are less prone to develop hyperkalemic episodes [17].

An additional key question would be: is there a particular potassium profile in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF)? Indeed, the current therapeutic tools for these patients comprise angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and SGLT2 inhibitors, most of which can alter potassium metabolism; likewise, the use of RAAS inhibitors (RAASi) is recommended in HF with mildly reduced ejection fraction (EF; HFmrEF). Notably, a major issue concerning the use of RAASi is the occurrence of hyperkalemia [18], which complicates the choice of an optimal treatment, particularly in patients with an impaired renal function [19]. Thus, in clinical practice we often find RAASi doses below the maximum target dose in patients with HF [20, 21] and CKD [22–24]. On top of that, the use of diuretics, often hampered by resistance, influences the outcome of such patients. An analysis of the ESC-HFA-EORP Heart Failure Long-Term Registry [25] performed on HF outpatients (60.6% with HFrEF), showed that, when adjusting for RAASi discontinuation, hyperkalemia was no longer associated with mortality, suggesting that the adverse effects of hyperkalemia might be explained by RAASi discontinuation, and that hyperkalemia might be considered as a risk marker for a suboptimal HF treatment.

Potassium binders might give an edge in patients affected by HF with hyperkalemia allowing to maintain a greater proportion of patients on RAASi therapy [18], but this occurrence has been challenged by the DIAMOND trial [26, 27]. The recently published REALIZE-K study aimed at evaluating sodium zirconium cyclosilicate (SZC) to optimize MRA therapy (spironolactone) over 6 months in adult patients with HFrEF and hyperkalemia

[28]. The study showed that at 6 months, 71% of patients who received SZC achieved the primary endpoint of normokalemia on spironolactone ≥25 mg/daily without rescue therapy for hyperkalemia compared with 36% in the placebo group (P < .001). However, even though overall there were no imbalance in adverse events or serious adverse events, the composite of cardiovascular death or worsening HF occurred more frequently in the SZC (11%) versus the placebo (3%) group. The authors discuss that a few differences in baseline characteristics, such as more advanced heart failure in the SZC group, older age, lower estimated glomerular filtration rate (eGFR), more loop diuretic use, and higher N terminal pro brain natriuretic peptide (NTproBNP) levels, may have potentially contributed to this observation, but nonetheless they conclude that this should be factored into the clinical decision-making.

The treatment with finerenone has proven effective in modifying the CKD-associated composite cardiovascular risk in patients with type 2 diabetes [29]. Finerenone can raise potassium levels as CKD progresses, so monitoring is important. If this happens, the use of diuretics and SGLT-2 inhibitors might be a safe strategy to reduce the risk of hyperkalemia [30]. As for GLP-1r agonists, they typically do not affect potassium levels significantly, although it has been suggested that the risk of heart failure hospitalization may increase in patients with left ventricular ejection fraction (LVEF) < 40% [31]. Therefore, the balance and choice of diuretics remains pivotal, particularly when taking into account the presence or absence of congestion. In fact, both the type of diuretics and the adequacy of dosing are equally important to strike a perfect balance for the heart and the kidney, keeping potassium levels safe while tackling the congestion without the renal function deteriorating.

Finally, how should we manage medications based on serum potassium? The recent KDIGO guidelines in patients with CKD [11] have suggested various interventions to correct serum potassium to its optimal value. The threshold to reduce/stop MRA-ACEi-ARA2 is 5.5 mmol/l, and below this value, no treatment change is required (Table 1). Regular potassium measurements may appear cumbersome; however, they will allow maintenance of cardioprotective medications without adding unnecessary dietary restrictions that may alter patients' quality of life. Potassium binders, which includes drugs used for decades (sodium polystyrene sulfonate) and others more recently marketed (sodium zirconate and patiromer), are efficient in case of confirmed hyperkalemia episodes (Tables 1–2); however, there is no evidence that a preventive administration may benefit the patients.

It can be argued that with regards to all such clinical questions, what seems to be key is a strict and timed interaction between cardiologists and nephrologists to promptly adjust the relative balance between the cardiac symptoms and the underpinning decline of renal function.

## CONFLICT OF INTEREST STATEMENT

The authors have nothing to declare.
REFERENCES

1. St-Jules DE, Fouque D. Etiology-based dietary approach for managing hyperkalemia in people with chronic kidney disease. *Nutr Rev* 2022;80:2198-205. https://doi.org/10.1093/nutrit/nuac026

2. MacLaughlin HL, McAuley E, Fry J et al. Re-thinking hyperkalaemia management in chronic kidney disease—beyond food tables and nutrition myths: an evidence-based practice review. *Nutrients* 2023;16:3. https://doi.org/10.3390/nu16010003

3. Linde C, Qin L, Bakhai A et al. Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK. *Heart Fail* 2019;6:280-90.

4. Cooper LB, Benson L, Mentz RJ et al. Association between potassium level and outcomes in heart failure with reduced ejection fraction: a cohort study from the Swedish Heart Failure Registry. *Eur J Heart Fail* 2020;22:1390-8. https://doi.org/10.1002/ejhf.1757

5. Desai AS, Liu J, Pfeffer MA et al. Incident hyperkalemia, hypokalemia, and clinical outcomes during spironolactone treatment of heart failure with preserved ejection fraction: analysis of the TOPCAT trial. *J Card Fail* 2018;24:313-20. https://doi.org/10.1016/j.cardfail.2018.03.002

6. McDonagh T, Metra M, Adamo M et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. *Eur Heart J* 2021;42:3599-726. https://doi.org/10.1093/eurheartj/ehab368

7. Beldhuis IE, Lam CSP, Testani JM et al. Evidence-based medical therapy in patients with heart failure with reduced ejection fraction and chronic kidney disease. *Circulation* 2022;145:693-712. https://doi.org/10.1161/CIRCULATIONAHA.121.052792

8. Heidenreich PA, Bozkurt B, Aguilar D et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. *Circulation* 2022;145: e895-e1032.

9. Ahmed A, Zannad F, Love TE et al. A propensity-matched study of the association of low serum potassium levels and mortality in chronic heart failure. *Eur Heart J* 2007;28:1334-43. https://doi.org/10.1093/eurheartj/ehm091

10. Bowling CB, Pitt B, Ahmed MI et al. Hypokalemia and outcomes in patients with chronic heart failure and chronic kidney disease: findings from propensity-matched studies. *Circ Heart Fail* 2010;3:253-60. https://doi.org/10.1161/CIRCHEARTFAILURE.109.899526

11. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. *Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group*. *Kidney Int* 2024;105:S117-314.

12. Barker L, Burton J, Zieve P eds. *Principles of Ambulatory Medicine*. Baltimore, USA: Williams & Wilkins, 1982; ISBN, 0683004352, 9780683004359.

13. De Rooij ENM, de Fijter JW, Le Cessie S et al. Serum potassium and risk of death or kidney replacement therapy in older people with CKD stages 4-5: eight-year follow-up. *Am J Kidney Dis* 2023;82:257-66. https://doi.org/10.1053/j.ajkd.2023.03.008

14. Stickle DF, Koob KR, McCudden CR. Characterizing ability of serum potassium (K) and the serum K reference interval to

flag hypokalemia or hyperkalemia as observed in plasma: a simulation study. *Clin Biochem* 2023;118:110606. https://doi.org/10.1016/j.clinbiochem.2023.110606

15. Gabai P, Fouque D. SGLT2 inhibitors: new kids on the block to control hyperkalemia. *Nephrol Dial Transplant* 2023;38:1345-8. https://doi.org/10.1093/ndt/gfad026

16. Moranne O, Froissart M, Rossert J et al. Timing of onset of CKD-related metabolic complications. *J Am Soc Nephrol* 2009;20:164-71. https://doi.org/10.1681/ASN.2008020159

17. Sumida K, Dashputre AA, Potukuchi PK et al. Laxative use and risk of dyskalemia in patients with advanced CKD transitioning to dialysis. *J Am Soc Nephrol* 2021;32:950-9. https://doi.org/10.1681/ASN.2020081120

18. Paolillo S, Basile C, Dell'Aversana S et al. Novel potassium binders to optimize RAASi therapy in heart failure: a systematic review and meta-analysis. *Eur J Intern Med* 2024;119:109-17. https://doi.org/10.1016/j.ejim.2023.08.022

19. Thomsen RW, Nicolaisen SK, Hasvold P et al. Elevated potassium levels in patients with congestive heart failure: occurrence, risk factors, and clinical outcomes: a Danish population-based Cohort Study. *J Am Heart Assoc* 2018;7:e008912. https://doi.org/10.1161/JAHA.118.008912

20. Ouwerkerk W, Voors AA, Anker SD et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. *Eur Heart J* 2017;38:1883-90. https://doi.org/10.1093/eurheartj/ehx026

21. Epstein M, Reaven NL, Funk SE et al. Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors. *Am J Manag Care* 2015;21:S212-S20.

22. Kashihara N, Kohsaka S, Kanda E et al. Hyperkalemia in real world patients under continuous medical care in Japan. *Kidney Int Rep* 2019;4:1248-60. https://doi.org/10.1016/j.ekir.2019.05.018

23. Jackevicius CA, Wong J, Aroustamian I et al. Rates and predictors of ACE inhibitor discontinuation subsequent to elevated serum creatinine: a retrospective cohort study. *BMJ Open* 2014;4:e005181. https://doi.org/10.1136/bmjopen-2014-005181

24. Pecoits-Filho R, Fliser D, Tu C et al. Prescription of renin-angiotensin-aldosterone system inhibitors (RAASi) and its determinants in patients with advanced CKD under nephrologist care. *J Clin Hypertens (Greenwich)* 2019;21:991-1001. https://doi.org/10.1111/jch.13563

25. Rossignol P, Lainscak M, Crespo-Leiro MG et al. Unravelling the interplay between hyperkalaemia, renin-angiotensin-aldosterone inhibitor use and clinical outcomes. Data from 9222 chronic heart failure patients of the ESC-HFA-EORP Heart Failure Long-Term Registry. *Eur J Heart Fail* 2020;22:1378-89. https://doi.org/10.1002/ejhf.1793

26. Butler J, Anker S, Lund L et al. Piaturomer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial. *Eur Heart J* 2022;43:4362-73. https://doi.org/10.1093/eurheartj/ehac401

27. Packer M. Potassium binders for patients with heart failure? The real enlightenment of the DIAMOND trial. *Eur Heart J* 2022;43:4374-77. https://doi.org/10.1093/eurheartj/ehac399

28. Kosiborod MN, Cherney DZI, Desai AS et al. Sodium zirconium cyclosilicate for management of hyperkalemia during spironolactone optimization in patients with heart failure. *J Am Coll Cardiol* 2024; S0735-1097(24)10430-5. https://doi.org/10.1016/j.jacc.2024.11.014
29. Agarwal R, Pitt B, Rossing P *et al*. Modifiability of composite cardiovascular risk associated with chronic kidney disease in type 2 diabetes with finerenone. JAMA Cardiol 2023;8:732–41. https://doi.org/10.1001/jamacardio.2023.1505

30. Agarwal R, Joseph A, Anker SD *et al*.; FIDELIO-DKD investigators. Hyperkalemia risk with finerenone: results from the

FIDELIO-DKD trial. J Am Soc Nephrol 2022;33:225–37. https://doi.org/10.1681/ASN.2021070942

31. Neves JS, Packer M, Ferreira JP. Increased risk of heart failure hospitalization with GLP-1 receptor agonists in patients with reduced ejection fraction: a meta-analysis of the EXSCEL and FIGHT trials. J Card Fail 2023;29:1107–9. https://doi.org/10.1016/j.cardfail.2023.03.017