Background: According to the Centers for Disease Control and Prevention (CDC), diabetes affects approximately 37.3 million individuals in the USA, with another estimated 96 million people having a prediabetic state. Furthermore, one or two out of three adult Americans exhibit metabolic syndrome or an insulin-resistant state, depending on their age group. Summary: Chronic kidney disease (CKD) represents a complication often associated with type II diabetes or the insulin-resistant condition, typically identifiable through proteinuria. Proteinuria serves as both a marker and a contributing factor to kidney damage, and it significantly heightens the risk of cardiovascular (CV) events, including atherosclerosis, heart attacks, and strokes. Renin-angiotensin-aldosterone system inhibitors (RAASis) have demonstrated clinical efficacy in lowering blood pressure, reducing proteinuria, and slowing CKD progression. However, hyperkalemia is a common and serious adverse effect associated with using RAASi. Key Messages: It is imperative to establish personalized management strategies to enable patients to continue RAASi therapy while effectively addressing hyperkalemia risk. Healthcare professionals must be careful not to inadvertently create a low renal perfusion state, which can reduce distal nephron luminal flow or luminal sodium concentration while using RAASi. Nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), such as finerenone, are demonstrated to delay CKD progression and reduce CV complications, all while mitigating the risk of hyperkalemia. Additionally, maintaining a routine monitoring regimen for serum potassium levels among at-risk patients, making dietary adjustments, and considering the adoption of newer potassium-binding agents hold promise for optimizing RAASi therapy and achieving more effective hyperkalemia management.

Diabetes is a major health problem worldwide. Many adults in the USA have either prediabetes or type II diabetes (T2D), encompassing >50% of adult US population. Chronic kidney disease (CKD) is a common complication that comes with T2D and is often associated with a higher chance of heart problems. When caring for CKD patients with T2D, certain medicines, such as renin-angiotensin-aldosterone system inhibitors (RAASis), are important because they have beneficial effects in delaying CKD progression and decreasing blood pressure. However, healthcare professionals should be careful in maintaining satisfactory kidney blood flow and glomerular pressure (a specific part of the kidneys) while using these medicines. These medicines can also cause high potassium levels in the blood (hyperkalemia), which is dangerous. In the early stages of kidney disease, a medicine like finerenone could help slow kidney disease progression and reduce heart problems while having a relatively low risk of triggering high potassium compared to other RAASi. To ensure patients can keep taking kidney-boosting medicines without major problems, it is crucial to regularly check their potassium levels and make a personalized plan for each person. This article will describe the prerequisites and strategies to keep CKD patients with T2D on RAASi therapy. These approaches might include checking patients’ baseline characteristics and medical history, changes in their diet, and trying new medicines that can help control potassium levels. Overall, these steps can ensure that the kidney medicines work well and prevent the severe problem of high potassium.

Approximately 537 million people have diabetes worldwide, with an additional 352 million people having a prediabetic state [1]. According to the Centers for Disease Control and Prevention (CDC), 37.3 million people in the USA have diabetes, 90–95% of them have type II diabetes (T2D), and among the adult population, 96 million have prediabetes in the USA [2]. Furthermore, one or two out of three adult Americans exhibit metabolic syndrome or an insulin-resistant state, depending on their age group. The resultant hyperinsulinemia favors de novo lipogenesis and ectopic adiposity in visceral organs [3]. Since visceral adipose tissue is an endocrine organ that produces many hormones and cytokines, e.g., aldosterone, cortisol, cytokines-like TNF alpha, IL-6, individuals with an insulin-resistant state or hyperinsulinemia suffer from obesity, prediabetes, T2D, dyslipidemia, fluid retention tendency, hypertension, and many other inflammatory conditions (Fig. 1) [4, 5]. Chronic kidney disease (CKD) is one of the complications of T2D or insulin-resistant state, characteristically manifested by proteinuria. The presence of protein in urine is more than just a marker of glomerular injury; it may cause further tubulointerstitial injury. Large amounts of protein in the tubular lumen may play a direct role in kidney injury through inflammation and oxidative stress that contribute to renal injury and the development of interstitial fibrosis, further facilitated by the presence of a high aldosterone environment in active renin-angiotensin-aldosterone system (RAAS) (Fig. 1) [5, 6]. Therefore, proteinuria is a marker as well as a cause of kidney damage and a powerful predictor of cardiovascular (CV) events with an increased risk of developing atherosclerosis, heart attack, and stroke [7]. CKD is most commonly assessed by the estimated glomerular filtration rate (eGFR) [8]. However, the urine albumin to creatinine ratio (UACR) shows more sensitivity and specificity in detecting early kidney damage. The UACR is not widely implemented as recommended by Kidney Disease: Improving Global Outcomes (KDIGO) due to under-awareness of its validity in early kidney disease detection [9]. RAAS inhibitors (RAASis) are a group of medications that have clinical effectiveness in reducing blood pressure (BP) and proteinuria and delaying the progression of CKD [10]. However, hyperkalemia (serum potassium concentration of ≥5.5 mEq/L) is one of the most common adverse effects of using RAASi [11, 12]. Also, people experiencing hyporeninemic hypoaldosteronism are at an increased risk of developing hyperkalemia due to diminished release of renin from cells in the juxtaglomerular apparatus and reduced secretion of aldosterone from the adrenal gland. These effects result from injury to the juxtaglomerular apparatus (Fig. 2) [13]. The prevalence of hyperkalemia (≥5.0 mEq/L) in CKD (stage 3–5), diabetes, and HF patients is 11.5%, 8.3%, and 9.1%, respectively. The patients who had the three conditions CKD, diabetes, and HF showed a hyperkalemia prevalence of 13.1% [14]. This review article will discuss the strategies to be followed by healthcare professionals (HCPs) in managing hyperkalemia risk in CKD patients with T2D on RAASi.

Fig. 1.

Mechanism of aldosterone-activated inflammatory and fibrotic effect in mineralocorticoid-responsive cells. Referenced and modified from Brem et al. [5] (2011).

Fig. 1.

Mechanism of aldosterone-activated inflammatory and fibrotic effect in mineralocorticoid-responsive cells. Referenced and modified from Brem et al. [5] (2011).

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Fig. 2.

Site of action of renin-angiotensin-aldosterone and renal potassium homeostasis. Referenced and modified from Sousa et al. [13] (2016) and Palmer and Clegg [15] (2022).

Fig. 2.

Site of action of renin-angiotensin-aldosterone and renal potassium homeostasis. Referenced and modified from Sousa et al. [13] (2016) and Palmer and Clegg [15] (2022).

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The kidney is the primary organ responsible for maintaining total body potassium content [15, 16]. Approximately 98% of body potassium is stored within the cells, most of which reside in skeletal muscle [12]. The kidney excretes an estimated 90% of dietary potassium (Fig. 3) [15‒17]. Potassium secretion by the distal nephron, primarily by the principal cells in the cortical collecting tubule, plays the ultimate crucial regulatory role in potassium excretion from the body. The process of potassium secretion by the distal convoluted tubule (DCT) cells is a passive process that follows an electrochemical potential gradient (Fig. 2.) [12, 15].

Fig. 3.

Factors involved in potassium homeostasis in the human body.

Fig. 3.

Factors involved in potassium homeostasis in the human body.

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The gastrointestinal tract and sweat excrete the remaining 10% of potassium (Fig. 3.). The role of the colon in the excretion of potassium may become increasingly important when kidney function declines [15, 18]. Under normal circumstances, insulin and beta-adrenergic stimulation primarily regulate potassium distribution between the intracellular and extracellular space, whereas the amount of potassium excreted is regulated by various factors, including the hormone aldosterone (Fig. 1) [5, 15, 16].

As mentioned above, potassium secretion by the principal cells in the distal nephron follows an electrochemical potential gradient. Three factors can modulate this electrochemical potential gradient, either accelerating or reducing renal potassium secretion, leading to hypokalemia or hyperkalemia, respectively. The first factor is the luminal flow in the distal nephron, as increased luminal flow in the presence of adequate, effective circulating volume, BP, and renal perfusion pressure leads to a favorable gradient facilitating potassium secretion (Fig. 4) [16, 19]. The second factor is luminal sodium concentration; an increased luminal sodium concentration in the presence of adequate, effective circulating volume, BP, and renal perfusion pressure facilitates potassium secretion (Fig. 4) [19, 20]. While the third factor is the epithelial sodium channel (ENaC) activity in the presence of aldosterone. Aldosterone increases the number and efficacy of ENaC in the luminal membrane of principal cells of DCT, facilitating potassium secretion (Fig. 4) [12, 19, 20]. MRA counters the third factor here in renal potassium secretion; therefore, maintaining the first two factors would become particularly important in mitigating hyperkalemia while using MRA.

Fig. 4.

Role of epithelial sodium channel (ENaC) activity of the principal cell in potassium secretion. Referenced and modified from Sørensen et al. [19] (2019).

Fig. 4.

Role of epithelial sodium channel (ENaC) activity of the principal cell in potassium secretion. Referenced and modified from Sørensen et al. [19] (2019).

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The discussion above clarifies that during RAASi administration, HCPs must be careful not to inadvertently create a low renal perfusion state, which can reduce distal nephron luminal flow or luminal sodium concentration while using RAASi. When utilizing RAASi, it is crucial to recognize vulnerable populations, including patients with low renal perfusion state (for example, those with pronounced renovascular disease or decompensated congestive heart failure [CHF]), individuals with a decreased nephron count (such as elderly patients with CKD or those with advanced CKD), and patients prescribed medications that inhibit the renin-angiotensin-aldosterone axis, including β-blockers, heparin, specific antibiotics (i.e., trimethoprim), and potassium-sparing diuretics.

Activation of the RAAS results in vasoconstriction, increased sodium reabsorption, and enhanced release of noradrenaline, aldosterone, and antidiuretic hormones (Fig. 2) [10, 21]. RAASis counteract the improper activation of the RAAS, thereby mitigating hypertension and other harmful effects on the CV and renal systems. RAASi are a group of medications that include angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor-neprilysin inhibitors [10]. RAASi improves outcomes in CKD patients with or without proteinuria and heart failure with reduced ejection fraction by reducing mortality, improving the symptoms, and preventing disease progression [22]. RAASi are also beneficial in obesity-related diastolic CHF, CKD with T2D, and essentially all insulin-resistant states. It is relevant to mention here that it has been repeatedly reported in medical literature that hypokalemia in CHF and CKD is associated with poor outcomes and high CV mortality risk. The poor outcome is rooted in those patients’ underlying high renin-angiotensin-aldosterone state not being treated adequately. Here, hypokalemia is the association (manifestation of highly active RAAS), not the cause, of poor prognosis; although hypokalemia can impair the renal tubular ability to excrete sodium load to some extent and can raise BP slightly, that is not the principal cause (Fig. 4) [19]. The principal cause is stemming from the unopposed RAAS as the underlying cause of high mortality risk [12, 16]. The KDIGO 2021 clinical practice guidelines for managing BP in CKD patients and KDIGO 2022 guidelines for diabetes management in CKD patients recommend RAASi be used at the highest approved doses that are tolerated, given the CV and kidney benefits [17, 21‒23]. A clear understanding of potassium homeostasis is crucial in mitigating the risk of hyperkalemia while maximizing the extended outcome benefits of RAASi.

Prerequisite Kidney Function Assessment

The comprehensive definition of CKD considers both structural and functional aspects of kidney health (Fig. 5). It emphasizes the importance of assessing kidney function by recognizing various indicators of kidney damage, including imaging studies such as renal ultrasound (and sometimes, but less commonly, CT scan or MRI) along with laboratory markers (eGFR and UACR). Both imaging studies and lab markers should be used to assess kidney function better, considering conditions that sometimes overestimate eGFR (glomerular hyperfiltration resulting from glomerular hypertension in the setting of hypertension and/or hyperglycemia) [6]. In addition, information on cortical thinning, ultrasound echogenicity, and kidney size facilitate HCP’s understanding of the full assessment of the severity of CKD and also risk for hyperkalemia. A patient with very low eGFR or significant bilateral renovascular disease as evident in ultrasound as bilateral renal cortical thinning or asymmetric kidneys may not tolerate two different RAASi at the same time (Fig. 1).

Fig. 5.

Guidelines for hyperkalemia prevention and management strategies in CKD patients.

Fig. 5.

Guidelines for hyperkalemia prevention and management strategies in CKD patients.

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CKD is considered when eGFR <60 mL/min/1.73 m2 and/or albuminuria (urinary albumin excretion rate ≥30 mg per 24 h or UACR ≥30 mg/gCr for over 3 months) [9, 11]. UACR that ranges from ≥30 to <300 mg/gCr suggests the presence of early onset of kidney damage. UACR ≥300 mg/gCr indicates significant kidney damage according to KDIGO guidelines and requires additional testing and medication to control the underlying causes [9, 11]. KDIGO CKD heat map staging is a recommended color-coded tool that includes the two tests, eGFR and UACR, to determine the kidney damage stage early and guide HCPs as they develop the treatment plan.

Prerequisite Reviewing the Patient Medication Profile

HCPs might decide to discontinue or lower the dosage of any medications that interfere with the RAASi. They may even consider transiently lowering or discontinuing one RAASi while another RAASi is being used, which may favorably affect the serum potassium level. However, patients might lose the extended beneficial outcomes of RAASi [24]. It is crucial to identify the risk of medication combinations that can lead to glomerular ischemia leading to low distal luminal flow and sodium concentration, i.e., NSAID combined with ACEi/ARB.

Ensuring Adequate Renal Perfusion Pressure

HPCs should be mindful of the target BP while using RAASi and not lower BP beyond that margin where renal perfusion pressure is compromised, reducing distal luminal flow and Na+ in DCT, thereby increasing the risk of hyperkalemia (Fig. 4) [19]. This very important point is often overlooked in both inpatient and outpatient clinical practices, resulting in hyperkalemia, where low renal perfusion pressure is the sole cause of hyperkalemia; this seems to be the most common iatrogenic cause of treatment failure and discontinuation of RAASi. Low renal perfusion pressure can lead to hyperkalemia even when a patient is not on RAASi, but of course, it would happen relatively easily in the presence of RAASi. On the other hand, we can mitigate the risk of hyperkalemia while using RAASi if we are mindful of ensuring adequate renal perfusion pressure.

In cases where the patient has mild hyperkalemia levels (5.0–5.5 mEq/L), but remains stable, a suitable approach may involve down-titrating the RAASi medication that still provides the desired therapeutic benefits [25‒27]. In cases with severe hyperkalemia (>5.9 mEq/L) or when the patient exhibits clinical signs/symptoms associated with elevated potassium levels, temporary discontinuation of the RAASi medication may become necessary. Following the down-titration or temporary interruption of RAASi, diligent monitoring of the patient's potassium levels and clinical status is essential. HCPs should repeat serum potassium tests to determine whether further modifications or reintroduction (re-challenging) of RAASi is necessary while readdressing the target BP goal [27].

Addressing Diet as Certain Foods Contain Increased Amounts of Potassium

Educating patients on the impact of their diet is vital, particularly considering the fact that the majority of cardiac and renal patients’ conditions are rooted in insulin-resistant state. Certain foods are enriched in potassium, and curtailing those foods might also have beneficial effects, i.e., fruit juice, vegetable juice, soda, and highly processed food [26]. However, by restricting potassium-enriched foods, one might also be restricting foods that could be heart and CKD healthy as they may help prevent high BP and hyperinsulinemia, i.e., food with high fiber content [28, 29]. It is important to review basic principles – they should be aware of fruit with relatively low fiber, i.e., watermelon, ripe banana, mango, and also try to avoid root vegetables that are not rich in fiber, like potatoes, sweet potatoes, yam, radishes, beets. Boiling those root vegetables or skinning and soaking them in water can reduce their potassium content by demineralization [30]. Of note, too stringent dietary potassium restriction (particularly in the setting of GI or renal potassium loss), if leads to mild to moderate hypokalemia, can impair the kidney’s sodium load excretion ability by increasing sodium reabsorption (because of intracellular acidosis) in PCT and DCT, leading to slight positive sodium balance and resulting in slightly high BP, which is why sometimes potassium-rich food is recommended in patient with hypertension. On the other hand, high dietary potassium consumption, particularly in the setting of CKD, leads to hyperkalemia; not only does it pose a cardiac arrest risk in severe cases of hyperkalemia, but chronic mild to moderate hyperkalemia can also lead to a high aldosterone state (Fig. 2). Aldosterone is a pro-inflammatory and pro-fibrotic hormone that can rapidly progress CKD (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) (Fig 3; [5, 31]).

Dietary recommendations for CKD and cardiac patients should not exclude plant-based foods entirely since those are excellent sources of fiber (both soluble and insoluble), vitamins, minerals, other bioactive compounds, antioxidants, etc. Keeping the above-mentioned basic principles in mind may prevent hyperkalemia and enable our high-risk patients to utilize the benefits of RAASi.

Diuretics May Help Attenuate Hyperkalemia

Utilizing loop and thiazide diuretics promotes potassium urinary excretion by increasing the luminal flow, and delivery of sodium to the distal collecting tubule facilitates potassium secretion by the principal cells [32]. On the other hand, it is crucial to note that high doses or unnecessarily prolonged use of those diuretics, if it leads to volume depletion or low BP, can paradoxically precipitate hyperkalemia as a result of creating a low renal perfusion state. Paradoxical hyperkalemia of diuretics usage mainly occurs in patients with bilateral renovascular disease, critical aortic stenosis (because of preload dependence of cardiac output), or while a patient is on a high dose of ACEi/ARB. For example, a high dose of loop diuretic may be warranted in CKD patients with T2D having CHF exacerbation, and to avoid the risk of developing paradoxical hyperkalemia, MRAs can briefly replace ACEi/ARB until CHF is resolved. Once the patient comes out of CHF and does not require aggressive diuresis, the patient should go back to ACEi/ARB, which is how hyperkalemia (as well as azotemia) can be prevented efficiently without discontinuing RAASi [32].

Correct Acidosis if Present

It is also essential to understand the conditions with the potential for a transcellular shift of potassium leading to hyperkalemia, i.e., patients with acidosis, muscle injury, or severe hyperglycemia [25]. HCPs should correct those conditions prior to using RAASi. Acidosis causes a significant extracellular shift of intracellular potassium in exchange for protons, leading to hyperkalemia. Type IV renal tubular acidosis is a significant factor contributing to hyperkalemia in CKD patients with T2D [33]. Type IV renal tubular acidosis arises when the collecting duct cannot effectively eliminate protons and potassium due to diminished aldosterone function, impacting the ENaC activity and impeding the potassium secretion facilitation process. KDIGO CKD guidelines suggest treatment with oral bicarbonate supplementation when patients with CKD have serum bicarbonate concentrations below the normal range [34].

Considering Sodium Glucose Cotransporter-2 Inhibitors

The ADA standards of care suggest initiating sodium glucose cotransporter-2 (SGLT-2) inhibitor treatment for patients with T2D and CKD who have UACR ≥200 mg/gCr [35]. SGLT-2i is a glucose-lowering medication that has shown efficacy in mitigating the risk of kidney disease progression and CV events [36]. CONFIDENCE is the first phase 2 study currently investigating the efficacy and safety of combination treatment of SGLT-2i and finerenone compared to one medication used in CKD patients with T2D [37]. The study’s primary objective is to demonstrate whether initiating this dual therapy strategy is superior in reducing UACR and lowering hyperkalemia compared to treatment with either empagliflozin or finerenone alone. SGLT-2i decreases the frequency of hyperkalemia in patients treated with RAASi and, at the same time, is uncommonly associated with hypokalemia [38]. Even in this case, paradoxical hyperkalemia is expected if the volume depletion and hypotension occur after initiation of SGLT-2i; HCPs should be aware of that, too.

Consider Potassium Binders to Avoid Discontinuation of ACEi and ARB

Elevated serum potassium levels are associated with an increased rate of RAASi treatment discontinuation [39, 40]. Luo et al. [39] reported a statistically significant (p < 0.001) increase in the rate of discontinuation for patients with hyperkalemia of ≥6.0 mmol/L with an incidence rate ratio (IRR) of 1.81 (95% CI: 1.45–2.26) in patients with an eGFR <30 mL/min/1.73 m2. Furuland et al. [40] also reported that patients with serum potassium ≥6.0 mmol/L required RAASi discontinuation 2.79 times higher than patients with normokalemia. Another study by Epstein et al. reported that patients with CKD, HF, T2D, and hypertension who received the maximum RAASi dose found that 47% discontinued RAASi at hyperkalemia of ≥5.5 mmol/L [41]. For patients receiving RAASi treatment at a sub-maximal dose, 27% discontinued at hyperkalemia of ≥5.5 mmol/L.

The development of hyperkalemia can often be managed by strategies other than decreasing or stopping RAASi. In CKD patients on RAASi who develop hyperkalemia, newer oral potassium-binding drugs can allow continued use of RAASi [42‒44]. Promising developments have been observed with the introduction of these potassium binders, such as patiromer sorbitex calcium and sodium zirconium cyclosilicate (SZC), which have demonstrated efficacy in clinical trials and have received approval for use in the USA and Europe [44, 45]. Recently, the National Institute for Health and Care Excellence has issued guidelines recommending using SZC and patiromer to treat acute life-threatening hyperkalemia, suggesting that these medications could be considered supplementary options to standard care [44]. Furthermore, the European Society of Cardiology advises using potassium binders, patiromer, and SZC to manage hyperkalemia associated with RAASi treatment [46].

Benefits of the Early Introduction of the Nonsteroidal Mineralocorticoid Receptor Antagonist (Finerenone)

Finerenone, as a selective nonsteroidal mineralocorticoid receptor antagonist (nsMRA), has demonstrated higher potency in its anti-inflammatory and antifibrotic effects. In the FIDELIO-DKD trial, individuals were required to be on the maximum tolerated dose of ACEi/ARB for at least 4 weeks before the screening visit. At the same time, their serum potassium levels were also required to remain below 4.8 mmol/L [47, 48]. Studies have shown that finerenone effectively delays the progression of CKD and reduces CV events in CKD patients receiving treatment with RAASi [49]. The risk of hyperkalemia appears to be less as compared to steroidal MRAs. One of the key distinguishing characteristics of finerenone, compared to steroidal MRAs, is its enhanced selectivity for the mineralocorticoid receptor, leading to fewer off-target effects and reducing the anti-androgenic effects [50, 51]. Moreover, nsMRAs have a notably shorter half-life than traditional MRAs, which helps mitigate the risk of hyperkalemia. The risk of hyperkalemia with nsMRAs also exhibits an inverse relationship with the eGFR [51‒53].

Regular monitoring of serum potassium levels in patients at higher risk of hyperkalemia, alongside dietary adjustments and adopting newer potassium binder agents, offers the potential for enhancing RAASi therapy optimization and more efficient hyperkalemia management [54]. Before initiating hyperkalemia treatment, it is essential to differentiate true hyperkalemia from potential artifacts, such as pseudohyperkalemia hemolysis, delayed specimen processing, and other relevant factors [55]. Clinical guidelines suggest measuring serum potassium levels in high-risk individuals before starting medications that can cause hyperkalemia. The KDIGO CKD guidelines recommend serum potassium measurement within 1 week of initiating or increasing the dosage of RAASi in patients with CKD [17]. The patient’s clinical characteristics and the associated comorbidities determine the monitoring frequency of hyperkalemia. The frequency of lab monitoring may have to be increased in patients with CKD, diabetes, HF, or a history of hyperkalemia [56].

Diabetes, or more accurately, insulin-resistant state, poses a significant global health concern, with a high prevalence worldwide. A substantial portion of the US adult population is affected by prediabetes or T2D. CKD is a common complication of T2D or insulin-resistant state, often accompanied by proteinuria and an increased risk of CV events. In managing CKD patients with T2D, RAASi is critical in reducing BP and proteinuria and delaying the progression of CKD. However, hyperkalemia is a severe adverse effect of RAASi in these patients. Early intervention with nsMRA, such as finerenone, holds potential benefits in delaying CKD progression and reducing CV complications while lowering the risk of hyperkalemia. Implementing individualized management strategies is crucial to effectively maintaining patients on RAASi therapy while managing hyperkalemia. Furthermore, ensuring regular monitoring of serum potassium levels in patients at higher risk of hyperkalemia, along with dietary adjustments and the adoption of newer potassium-binding agents, offers the potential for optimizing RAASi therapy and achieving more efficient management of hyperkalemia.

The authors would like to acknowledge the medical writing assistance provided by Mahmoud Azqul, MBBCH, MPH, MMSc, of ILM Consulting Services, LLC, which was funded by Bayer US, LLC. The authors would also like to acknowledge the editorial support, visualizations, and graphical abstract development provided by Aqsa Dar, ScM, of ILM Consulting Services, LLC, which was also funded by Bayer US, LLC. ILM’s services complied with the international guidelines for Good Publication Practice (GPP 2023).

The authors, Humaira A. Mahmud and Biff F. Palmer, have no conflicts of interest to declare in relation to this review article.

Bayer US, LLC funded the article processing charges for this article. Bayer US, LLC also funded ILM Consulting Services, LLC for medical writing support and publication management.

All authors contributed to the writing and/or reviewing of each draft and reviewed and approved the final draft for submission. H.A.M. and B.F.P.: conceptualization and writing – review and editing.

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