The renin-angiotensin-aldosterone system (RAAS) is an important regulator of cardiac, vascular, and renal physiology via the regulation of vascular tone and salt and water homeostasis. However, overactivation of RAAS plays a critical role in various pathophysiological conditions such as hypertension, heart failure, and chronic kidney disease (CKD). Blockade of RAAS overactivation has been shown to improve the outcome in various cardiovascular and renal diseases [1,2]. In the setting of CKD, aldosterone becomes dysregulated. First, the circulating aldosterone level is increased and the aldosterone receptor sensitivity and binding affinity is upregulated [3]. Aldosterone receptor activation in CKD promotes renal fibrosis by stimulating profibrotic pathways via upregulation of plasminogen activator inhibitor, transforming growth factor β1, interleukin-6, monocyte chemoattractant protein-1, and so on, leading to excessive collagen deposition and tissue remodeling, further exacerbating renal damage and promoting kidney disease progression [4]. Therefore, mineralocorticoid receptor antagonists (MRA) further inhibit the RAAS through direct aldosterone antagonism.

Up to now, there are several types of available MRA. Spironolactone and eplerenone are steroidal MRAs that have shown therapeutic benefits in cardiovascular disease, especially in heart failure with reduced ejection fraction [5,6], while finerenone is a selective, nonsteroidal MRA that is effective in reducing albuminuria and in patients with diabetic nephropathy [7].

CKD and cardiovascular disease often coexist and share the same risk factors such as hypertension, diabetes, and atherosclerosis. Therefore, MRA may also improve outcomes in patients with CKD. Previous studies have shown that MRA treatment is beneficial in improving renal inflammation and fibrosis and delaying CKD progression [8]. Nevertheless, MRA has some adverse effects, such as causing electrolyte disturbance, gynecomastia, and gastrointestinal discomfort; indeed, hyperkalemia is a common side effect, especially in the setting of co-administrating RAAS inhibitors in CKD, wherein the risk of hyperkalemia is increased [9]. Meanwhile, hyperkalemia is associated with the discontinuation or reduced dosage of RAAS inhibitors and/or MRA, which in turn worsens clinical prognosis [10,11]. Therefore, it is of great importance to balance the benefit and risk of MRA use in patients with cardiovascular disease or CKD.

In this issue of the Journal, Møller et al.[12] investigated the impact of MRA treatment on the risk of hyperkalemia and death in patients with CKD from nationwide Danish healthcare registers. In this retrospective cohort study, they found that MRA treatment was associated with an increased risk of hyperkalemia across all strata of renal function compared with no MRA therapy. However, MRA treatment was associated with a reduced risk of 30-day mortality across all strata of renal function. The results were consistent in subgroup analyses stratified by age, sex, and specific risk factors. Hence, their study indicates that MRA treatment for patients with CKD benefits mortality despite an increased risk of hyperkalemia.

The strength of the study lies in the large sample size of Danish registers and the nested case--control design, the advantage of which has been clearly addressed [13]. Hyperkalemia associated with MRA use has been widely confirmed [14]; however, a novel finding in this study is hyperkalemia in people receiving a MRA was associated with significantly lower risk of 30-day mortality compared with hyperkalemia in absence of MRA, which was interpreted by different triggering causes of hyperkalemia and their contribution to the death. Hence, this study addresses that the MRA benefits the mortality despite its increased risk of hyperkalemia in patients with CKD.

Another interesting finding from this study is that although MRA treatment was associated with a reduced risk of 30-day mortality across all strata of renal function, renal function was positively correlated with mortality. This finding was unexpected and was perhaps contrary to previous findings [15]. Although the authors explained the phenomenon was partly attributed to a higher percentage of patients suffering from more severe, acute causes of hyperkalemia rather than renal insufficiency or medication, those who had significant impaired renal function were prone to receive closer monitoring and aggressive treatment, which in turn could improve the outcome. Moreover, the authors suggest that some physiological adaption of hyperkalemia in patients with CKD may occur. Indeed, patients with CKD are chronically exposed to hyperkalemia, which is different from an acute increase of serum potassium, whereby the latter is more lethal. Therefore, the impact of hyperkalemia on CKD versus non-CKD may be quite different. Although one previous study indicated the optimal serum potassium concentration in patients with CKD seems to be between 4.0 and 4.5 mmol/l [16], chronic acidosis and kidney potassium excretion dysfunction usually cause chronic potassium retention in patients with CKD. Also, studies have shown that as CKD progresses, patients are more likely to tolerate hyperkalemia [17], indicating the existence of physiological adaption of hyperkalemia in patients with CKD.

Of note, this is not the first study to evaluate the impact of hyperkalemia on the RAAS inhibitors and/or MRA prescription or discontinuation as well as the outcome. In patients with heart failure, the BIOSTAT-CHF cohort demonstrated higher baseline potassium was associated with lower odds of RAAS inhibitors up-titration; however, hyperkalemia itself was not significantly associated with the composite outcome of all-cause death or heart failure hospitalization up to 2 years [18]. Similarly, in the Swedish HF Registry, hyperkalemia per se was not associated with worse outcomes [19]. Taken together, these data suggest that hyperkalemia is not a risk factor but a risk marker leading to suboptimal use of RAAS inhibitors and/or MRA, which in turn results in poorer clinical outcome [20].

Hyperkalemia secondary to MRA use may increase the risk of potentially life-threatening arrhythmias such as cardiac arrest while discontinuation of MRA may adversely affect clinical outcomes. Therefore, a comprehensive assessment of the risk of hyperkalemia versus the benefit of MRA use is warranted.

On the one hand, optimizing the use of RAAS inhibitors and/or MRA is important based on the extent of hyperkalemia. Although current guidelines do not recommend MRA use in patients with serum more than 5.0 mmol/l [21], if possible, nondiscontinuation of RAAS inhibitors and/or MRA could keep the clinical outcome benefits. Indeed, current KDIGO guidelines recommend that hyperkalemia associated with use of RAAS inhibitors can often be managed by measures to reduce the serum potassium rather than decreasing the dose or stopping RAAS inhibitors [22]. This strategy is probably also applicable to the management of hyperkalemia associated with MRA. On the other hand, oral potassium binders such as sodium zirconium cyclosilicate could effectively lower serum potassium and maintain normokalaemia [23]. Monitoring serum potassium and based on the potassium concentration to take the potassium-lowering agents regularly is helpful to maintain potassium concentration within the normal range.

Regularly using oral potassium-lowering agents could safely maintain normokalemia for patients at high risk of developing hyperkalemia [23] and reduce the possibility of discontinuation of RAAS and/or MRA. In addition, sodium-glucose cotransporter 2 inhibitors (SGLT2i), a kind of cardiorenal protective effect agent, when co-administrated with finerenone, has been shown to provide protection from hyperkalemia in patients with CKD and diabetes [24]. A meta-analysis also demonstrated the use of SGLT2i was associated with reduced risk of hyperkalemia possibly due to the diuretic effects of SGLT2i [25]. Thus, this complimentary effect of combination of finerenone with SGLT2i may be a well tolerated option to reduce the risk of hyperkaliemia in patients with CKD. Moreover, whether patients on chronic dialysis could benefit from MRA is not well understood. A recent retrospective cohort study shows that use of MRAs is associated with lower risks of all-cause mortality and cardiovascular disease death in patients with heart failure and undergoing regular dialysis [26]. A going on multicenter randomized controlled trial (ACHIEVE trial) aims to determine whether MRA (spironolactone) reduces cardiac mortality and hospitalizations for heart failure in patients treated with dialysis (https://clinicaltrials.gov/study/NCT03020303). On the basis of the current evidence, MRA should be aggressively used in patients with CKD in the setting of dietary control and novel potassium binder application. Last but not least, given the different pathophysiological status in patients with CKD compared with non-CKD patients, the relatively well tolerated range of serum potassium concentration perhaps needs to be clarified in order to avoid overaggressive treatment of hyperkalemia and/or discontinuation of RAAS inhibitors and/or MRA. All these important aspects need to be put in context in relation to the high prevalence of multimorbidity and polypharmacy evident in patients with cardiovascular disease, which have implications for risk and patient management [27,28].

ACKNOWLEDGEMENTS Conflicts of interest

The authors declare no conflicts of interest.

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