Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) debuted in the early 1970s; they were first used as antihypertensive agents [1]. The indications have been gradually expanded to hypertensive heart failure, acute myocardial infarction, diabetic nephropathy, and non-diabetic nephropathy [2]. These interventions have demonstrated protective effects on cardiac and kidney function [3, 4]. ACEI or ARB monotherapies may fail to control proteinuria and blood pressure, which could be partly ascribed to the “aldosterone breakthrough” phenomenon [5]. To maximize the efficacy of the renin-angiotensin system (RAS) blockade, the dose of monotherapy was increased, or the combination of ACEI and ARB was applied; however such issues remained debatable [6, 7, 8]. ACEI, combined with ARB, is superior in reducing urine protein excretion [9, 10]. Although RAS inhibitors (RASI) benefits patients with hypertension, diabetes, heart failure, and chronic kidney diseases, they may increase the risk of hyperkalemia and acute kidney injury (AKI) [6, 11, 12, 13, 14].

Based on the Kidney Disease: Improving Global Outcomes 2021 (KDIGO 2021 guideline), RASI can be prescribed for hypertension, chronic kidney disease (CKD), and mild-to-moderate diabetes [15]. For patients prescribed with RASI, the incidence of AKI and hyperkalemia have been reported to vary in different diseases [8, 12, 16]. Moreover, the prescription of RASI could increase AKI incidence by 12% compared to patients without ACEI or ARB [17]. Hyperkalemia is more common in RASI-related adverse events (AEs), especially in patients taking the combination of ACEI and ARB, with an incidence rate of 10–20% [8]. Due to such AEs, the dual therapy of ACEI or ARB remained controversial. The Regulators in the United States (US), clinical guidelines, and some randomized controlled trials (RCTs) have suggested against the combination of ACEI and ARB therapies, especially in patients with diabetic nephropathy and CKD [7, 15, 18, 19, 20, 21]. However, clinical guidelines are inconsistent with real-world procedures; doctors still prescribe combination therapies when they encounter some cases such as refractory hypertension. We hope to apply real-world data to verify the risks of AKI and hyperkalemia when prescribing RASI combination therapies.

The Food and Drug Administration’s Adverse Event Reporting System (FAERS) is a database, which collects spontaneously reported drug AEs. The data volume herein is large, and the data type is diverse. Meanwhile, it is open to the public and often employed for signal mining AEs. Based on the FAERS system, we analyzed the RASI-related AKI and hyperkalemia in the real world.

Regarding the FAERS database, we summarized to date the largest real-world epidemiological characteristics and the risk factors for RASI-related AKI or hyperkalemia. We found that: (1) AKI is more commonly reported in ARB receivers than in patients with ACEI, whereas hyperkalemia is more often reported in ACEI receivers. (2) Patients indicated with RASI for heart failure demonstrated a higher death risk when AEs occurred. (3) ACEI combined with ARB may increase the risk of hyperkalemia and AKI, making it critical to manage a personalized approach in patient management.

The efficacy and safety issues of RASI were tested among large-scale RCTs [25, 26, 27]. Such RCTs could be very helpful; however, it was difficult to comprehensively evaluate the RASI AEs due to the relatively short study time, the lack of participants who were either too old or too young, the lack of endpoint event-judgment methods, and the multiple different factors of underlying diseases [28]. Our study is based on the FAERS’s extensive data analysis, which can effectively compensate for such defects as the small sample size and relatively short observation period in clinical trials.

RASI has intraglomerular effects, which can affect renal efferent arterioles and decrease the renal filtration pressure [29]. Our results indicated no noticeable difference in the risk signal intensity of AKI between ACEI and ARB, while the combination of both significantly increased the risk. A previous study showed that old age, deteriorated baseline renal functions, simultaneous loop diuretic treatment, and cardiac failure had been associated with AKI incidence during ACEI or ARB administration [30].

Previous studies have demonstrated that patients with a 30% increase in creatinine after RASI management were mainly middle-aged and elderly adults with cardio-renal comorbidity [31]. We also indicated that the factors of advanced age and heart diseases might associate with death induced by RASI-associated AKI or hyperkalemia. Therefore, it is suggested that RASI should be used cautiously and that creatinine levels should be closely monitored, especially in elderly patients with cardiovascular complications. Furthermore, our findings also indicated that hospitalization could reduce the death risk in AKI or hyperkalemia cases. Timely hospitalization could help such AE patients to recover better.

Hyperkalemia is another common complication of ACEI/ARB [32]. RASI causes hyperkalemia by affecting aldosterone production triggered by several major regulatory factors [29]. The renin-angiotensin-aldosterone system (RAAS) is a well-known regulator of blood pressure (BP); it also controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and kidneys [33]. ACEI inhibits the transformation of angiotensin I (Ang I) into angiotensin II (Ang II). ARB only works on the AT1 receptor of Ang II, while Ang II is required to bind to the angiotensin II type 1 (AT1) receptor in blood vessels. When ARB is used, Ang II levels are elevated; while ACEI is used, Ang II is not secreted, which causes insufficient secretion of adrenal aldosterone [34]. We also found that hyperkalemia was more common in ACEI, which was consistent with such a mechanism. Researchers from the US reviewed electronic medical records, demonstrating that ACEI treatment was associated with a higher incidence and greater degree of hyperkalemia than ARB treatment, especially in CKD patients [33]. Interestingly, although hyperkalemia is common in hospitalized patients with acute heart failure, patients who maintained the dose of ACEI or ARBs during hospitalization had better 6-month survival after careful adjustment [16]. Another study also showed that the continuation of RASI might not associate with higher mortality in RASI-associated hyperkalemia after careful management [35]. Therefore, despite the risks, RASI can benefit certain patients if monitored appropriately.

Recently, double RAAS blockers are not recommended for patients with potential AEs, including renal dysfunction, hyperkalemia, and hypotension [18, 19, 36]. During clinical practice, clinicians may prescribe combination therapy when they encounter uncontrolled hypertension and heart failure. We also found that combination therapies increased the AKI signals by nearly two-fold, compared with ACEI or ARB monotherapies. However, there was no significant increase in mortality, which was consistent with the previous studies [37]. A meta-analysis revealed that dual therapy of ACEI and ARB further reduced urine protein excretion, and controlled blood pressure better [38]. Although the combination therapies may cause hypotension or hyperkalemia, individualized management, and proper potassium binders usage may extend such management in CKD patients [38]. We found that RASI increased the risk of death from AKI or hyperkalemia in patients with heart failure compared with hypertensive therapy (OR = 2.55). However, there was no increased death risk (OR = 0.58) in CKD patients compared to hypertensive patients who received RASI. Strategies to maintain RASI treatment after the onset of hyperkalemia may improve clinical outcomes in the CKD population [35]. We also observed the relationship between RASI-associated AEs and regional incidence. The results showed that North America had a higher incidence but a lower mortality rate, while Africa had the highest mortality rate. This bias could be ascribed to the difference in registered data from different countries. But it could not be very objective because such data was collected chiefly from America. The difference may be related to climate, customs, regional economic development, and medical conditions. In addition, we indicated that older patients, out-of-hospital treatment, and a shorter time to AEs onset after the prescription were related to increasing RASI-related mortality in this study.

Although this study managed the advantages of practical research and data mining technology, we admitted some limitations. First, in the data mining process, the database had incomplete information, such as the inputs being incorrect and the reports being preliminary, which could lead to a deviation from the analysis. Second, the available data in the database only involved patients with AEs. As there was no data on the total number of patients who received RASI and their baseline creatinine, we could not calculate the specific incidence of renal AEs after RASI or describe the severity of RASI-associated AKI.

We need to be alert for AKI and hyperkalemia when RASI is managed. AKI was more commonly reported in patients with ARB while hyperkalemia cases were more widely reported among ACEI users. Patients with heart failure had a significantly increased death risk from hyperkalemia or AKI after RASI use. The combination of ACEI and ARB increased the possibilities of hyperkalemia and AKI based on signals identified through the FAERS database. Therefore, careful and individualized management is necessary for such cases. We hope to further observe the risks and benefits of RASI combination therapies in real-world patients with CKD at different stages in the future.

RAAS, renin-angiotensin-aldosterone system; RASI, Renin-angiotensin-aldosterone system inhibitor; ACEI, Angiotensin-converting enzyme inhibitors; ARB, Angiotensin II receptor blockers; AKI, Acute Kidney Injury; AEs, Adverse events; RCTs, Randomized Controlled Trials.

The data sets and resources analyzed during the current study are available from the corresponding author upon reasonable request.

GC is the corresponding author. GC and YW jointly designed the study. GC analyzed the data. YW drafted the manuscript. YW, QR, BZ, HL and XL collected and viewed the data in the FAERS database. All authors revised the article. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The Institutional Review Board in Peking Union Medical College Hospital certificated the waiver of ethics approval and Patient’s informed consent (ID: I-23ZM0004), since the data was obtained from a public database.

Not applicable.

This work was supported by the Sansheng Yeehong TCP Research Foundation (G.C), Bethune Charitable Foundation (J202103E006) (G.C.) and National High Level Hospital Clinical Research Funding [2022-PUMCH-B-021].

The authors declare no conflict of interest.