For Primary aldosteronism (PA) is one of the most common causes of secondary hypertension and is characterized by inappropriate aldosterone overproduction, leading to a spectrum of clinical manifestations, including hypertension and hypokalemia (1). Excessive and inappropriate aldosterone secretion promotes cardiovascular remodeling and increases the risk of adverse cardiovascular events, such as atrial fibrillation and heart failure, which occur more frequently in patients with primary aldosteronism than in those with essential hypertension (2–4). In recent years, with the increasing understanding of PA, the clinical screening rate has been increasing year by year and is currently around 5% (5). Early screening and diagnosis of primary aldosteronism enable timely individualized treatment and may reduce the risk of disease-related complications.

The renin–angiotensin–aldosterone system (RAAS) plays a central role in maintaining fluid balance, regulating electrolyte homeostasis, and controlling blood pressure. The pathophysiology of PA is characterized by autonomous aldosterone secretion from the adrenal cortex, which leads to feedback suppression of renin release. Consequently, initial screening for PA relies primarily on the aldosterone-to-renin ratio (ARR), which reflects the inappropriate elevation of aldosterone relative to suppressed renin levels (6). This index provides a comprehensive response to the status of the RAAS axis. However, plasma aldosterone levels are susceptible to a wide range of medications and physiological factors (7), and therefore medication adjustments, postural and salt intake control, and other treatments are often required prior to screening. Multiple antihypertensive medications may result in false-positive or false-negative ARR, which in turn affects the judgment of PA (8). Current guidelines recommend that all hypertensive patients be screened for PA at least once. Interfering medications need to be discontinued for 2–4 weeks, but discontinuation may lead to uncontrolled blood pressure and delayed diagnosis, so the necessity of switching medications before screening for ARR remains a controversial issue in clinical practice. Aldosterone secretion has a distinct circadian rhythm. Compared with a single blood sample, 24-h urinary aldosterone (24h-Uald) provides a more complete picture of a complete secretion cycle, while the urine matrix is relatively clean and less disturbed by external factors (9). Previous studies suggest that 24h-Uald has potential clinical value in the diagnosis of PA (10–12).

Based on the above background, the aim of this study was to investigate the value of 24h-Uald and its related indexes in PA screening under the condition of taking drugs that interfere with the reliability of ARR results.

In this study, we evaluated the predictive value of 24-h Uald and UARR for PA screening in patients who had not undergone medication washout. The results showed that 24-h urinary aldosterone alone had limited diagnostic performance in distinguishing PA from EH, whereas UARR demonstrated better discriminative ability.

Whether to switch antihypertensive medications before PA screening has long been a focus of clinical debate. Some patients, due to comorbid cardiovascular diseases or refractory hypertension, are unable or unsuitable to undergo medication adjustment (16). Notably, pivotal studies have demonstrated that the ARR remains a robust and accurate screening tool even in patients maintaining their antihypertensive medications (17, 18). This established reliability of ratio-based assessments provides a strong theoretical foundation for the clinical application of UARR without medication washout. However, despite the robustness of the ratio, plasma aldosterone remains susceptible to various influencing factors such as momentary body position and sodium intake. Under conditions without medication adjustment, these factors may increase the difficulty of interpreting screening results (7). Furthermore, plasma biomarkers are highly sensitive to the patient’s acute state at the moment of sampling. Markou et al. (19) demonstrated that acute psychological or physiological stress can trigger transient aldosterone hypersecretion via the ACTH pathway, potentially leading to fluctuations in the ARR. In contrast, 24-h Uald reflects the integrated secretion over a full day (20), effectively buffering these episodic secretory pulses. In our study population without medication adjustment, both 24-h Uald and UARR levels were higher in the PA group than in the EH group. Notably, UARR demonstrated higher specificity than ARR (0.791 vs. 0.740), further supporting the advantage of urinary markers in reducing stress interference and assessing the true biochemical load. Current guidelines recommend that all hypertensive patients should undergo at least one PA screening. Given its diagnostic stability and ease of implementation, UARR is particularly well-suited for large-scale screening in primary care settings.

After adjusting for age, BMI, renal function, serum potassium and a history of CHD, both 24-h Uald and UARR remained independently associated with PA, suggesting that they may provide supplementary information for PA screening in patients receiving antihypertensive medications. Notably, the prevalence of prior coronary artery disease and diabetes mellitus was higher in the PA group than in the EH group, and a history of CHD remained positively associated with PA in the multivariate analysis. However, the significance of this association was markedly reduced in Model 2. This finding suggests that the interpretation of CHD history should be approached with caution. It is possible that PA had been present for a prolonged period, leading to chronic aldosterone excess. Aldosterone may promote plaque formation through mechanisms such as activation of vascular endothelial cells and facilitation of inflammatory cell migration (21–23), thereby contributing to the development of CHD. However, CHD is often considered a high-risk condition, and patients with coronary artery disease are more likely to undergo PA screening, which may lead to selection bias and contribute to the higher prevalence observed in this study. Therefore, these findings suggest an association between a history of CHD and PA, but the directionality and underlying mechanisms remain difficult to ascertain.

In addition, lower eGFR levels were independently associated with PA, which is consistent with previous studies (24). Since 24-h Uald is an excretory product of renal filtration, its urinary excretion is influenced by glomerular filtration capacity (25). Moreover, chronic aldosterone excess can lead to renal structural and functional damage through proinflammatory and profibrotic mechanisms, resulting in a bidirectional interaction between aldosterone excess and renal impairment (26).Notably, the correlation analysis in this study revealed that while 24-h Uald levels exhibited a clear dependency on serum potassium and renal function, UARR demonstrated a more stable profile. Specifically, UARR showed no significant correlation with serum potassium and only a marginal correlation with eGFR. In model 3, the correlation of eGFR was still statistically significant, but the significance level was substantially reduced. This may be due to the inclusion of renin as the denominator in the UARR index, the level of which not only reflects the suppressed state of the RAAS system, but also to some extent reflects the renal perfusion and reserve function. Consequently, the incorporation of renin into the UARR index functions as a robust correction mechanism, effectively mitigating the diagnostic bias introduced by variations in renal function and electrolyte status.

A similar corrective effect was observed in the analysis of BMI. In model 2, BMI was significantly associated with PA, which is consistent with previous findings showing a positive correlation between BMI and 24-hour urinary aldosterone (27, 28). However, in model 3, after incorporating renin indicators, BMI was no longer an independent correlate of PA. Previous studies have shown that adipocytes promote aldosterone synthesis and secretion through multiple pathways, and that, in addition to traditional RAAS activation, adipokines can directly stimulate the adrenal cortex, leading to increased aldosterone levels (29, 30). Although aldosterone secretion is elevated in obese individuals, this increase is often insufficient to cause the profound renin suppression observed in PA patients; therefore, BMI is not significantly correlated with renin concentration. Consequently, by using renin as the denominator, the UARR metric effectively adjusts for obesity-mediated physiological fluctuations in aldosterone, thereby attenuating the independent predictive contribution of BMI in multivariable analyses.

Multivariable analysis showed that both 24-h Uald and UARR were independently associated with PA, but their diagnostic performance differed substantially in ROC curve analysis. In this study, the AUC of 24-h Uald alone without medication washout was only 0.657, indicating limited efficacy in distinguishing PA from EH. In contrast, the AUC of UARR reached 0.862, which was comparable to that of ARR. This result differs from the findings of You et al. (10), who reported that the AUC of 24-h Uald under the influence of medication could be as high as 0.82. The weaker performance of 24-h Uald in our study (AUC 0.657 overall and 0.688 in the false-negative drug group) may be due to differences in subgroup definitions. You et al. mainly classified drugs based on their direction of interference with renin, whereas the “false-negative group” in the present study included a complex combination of CCBs, ARBs, ACEIs, and diuretics. Although this grouping increases the heterogeneity of interfering factors, it more closely reflects the real-world scenario of multi-drug combination therapy in clinical practice and highlights the limitations of 24-h Uald for PA screening in the context of complex medication use.

UARR introduces plasma renin concentration as the denominator, which effectively mitigates the bias caused by antihypertensive drugs on the RAAS axis. In EH patients, drug-induced increases in aldosterone are usually accompanied by parallel fluctuations in renin, resulting in a relatively stable ratio. In contrast, in PA patients, even when renin-stimulating medications are administered, renin levels remain suppressed due to autonomous aldosterone secretion from the adrenal glands. In further subgroup analyses, we also found that the diagnostic AUC of UARR was higher than that of ARR, with improved specificity in patients taking medications that produce false-negative ARR results, which may further explain this observation. Therefore, UARR more sensitively reflects the underlying imbalance of the RAAS system than simple excretory metrics, and demonstrates greater diagnostic value in clinical settings with complex medication use.

The main limitation of this study is the relatively small sample size. In addition, due to the limited number of patients taking only false-positive drugs, it was difficult to evaluate the diagnostic performance in this specific subgroup. In future studies, we plan to expand the sample size and further refine subgroup classification to more comprehensively assess the clinical diagnostic efficacy of the relevant indicators.

In conclusion, this retrospective study evaluated the screening value of 24-h Uald and UARR for PA under conditions of ongoing medication use. The diagnostic performance of 24-h Uald alone was limited, whereas UARR, which incorporates renin metrics, substantially improved screening specificity. These findings provide useful evidence for PA screening in patients who are unable to discontinue antihypertensive therapy.