Primary Aldosteronism (PA) represents a significant clinical syndrome predominantly characterized by hypertension, which may occur alongside hypokalemia. This condition arises from the adrenal cortex’s autonomous overproduction of aldosterone, leading to consequential effects including sodium retention, potassium excretion, increased blood volume, and diminished activity of the renin-angiotensin system (1, 2). As the foremost cause of secondary hypertension, PA’s recognition has been heightened through improved risk awareness and the implementation of standardized screening protocols, resulting in a notable increase in its detection rates. Recent epidemiological data from China have demonstrated that PA’s prevalence among individuals newly diagnosed with hypertension surpasses 4.0% (3). PA comprises six subtypes: APA, IHA, unilateral adrenal hyperplasia (UAH), familial hyperaldosteronism (FH), aldosterone-producing carcinoma, and ectopic aldosterone-secreting neoplasms (4). APA and IHA constitute the most prevalent forms, collectively accounting for approximately 95% of PA cases (4). Comparative analyses have further established that PA patients are at an elevated risk of renal target organ damage compared to those with Essential Hypertension (EH) (4–6). The extent of renal impairment in PA patients can vary significantly, influenced by factors such as the clinical subtype of PA, exposure to plasma aldosterone concentration (PAC), and the severity of electrolyte imbalances (7). Despite this knowledge, limited clinical literature exists on the differential clinical and renal damage characteristics between PA patients with or without hypokalemia. Furthermore, the phenotypic differences in clinical manifestations and renal injury patterns across etiological subtypes of primary aldosteronism (PA) remain understudied. This study seeks to delineate the clinical features and renal damage observed in PA patients, including subgroup analyses, to identify potential risk factors for renal impairment, enhance the understanding of PA’s clinical and renal damage profiles, and underscore the importance of early diagnosis, treatment, and prevention of renal damage in PA patients.

Primary Aldosteronism (PA) is a leading cause of secondary hypertension and presents a notable health concern due to its association with an increased risk of hypertension-induced renal damage compared to Essential Hypertension (EH) (17–19). This elevated risk emphasizes the importance of identifying clinical characteristics and understanding renal damage in PA patients to enable early diagnosis and timely intervention. Such measures are crucial for reducing the risk of renal complications and improving long-term patient outcomes.

Clinically, PA manifests through several distinct markers: elevated plasma aldosterone concentration (PAC), suppressed plasma renin activity, hypertension, and a dysregulated sodium and potassium balance (20). The presence of hypokalemia in PA patients, while variable, is particularly concerning as it not only indicates altered potassium homeostasis but also serves as a significant risk factor for renal impairment. Despite the variability in hypokalemia among PA patients, the condition necessitates vigilant screening for PA among all hypertensive individuals, irrespective of their potassium levels (21, 22).

Patients with PA often have elevated PAC, which significantly affects renal ion transporters and potassium homeostasis, especially key ion transporters for sodium and potassium handling, such as the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK). Studies have shown that PAC regulates the activity of ENaC through various mechanisms, thereby affecting sodium reabsorption (23). Specifically, PAC can increase the expression and activity of ENaC, mainly by promoting the membrane insertion of ENaC subunits and reducing their degradation (24).For example, PAC can activate protein kinase B (Akt) and serum glucocorticoid kinase 1 (SGK1), inhibit the activity of Nedd4-2, and thus reduce the ubiquitination and degradation of ENaC. This regulatory effect is crucial for maintaining sodium balance and blood pressure stability (25).

The ROMK channel plays a key role in renal potassium secretion. Elevated PAC levels can affect the activity of ROMK through various pathways. On the one hand, aldosterone can increase the expression of ROMK, promoting potassium secretion; on the other hand, aldosterone can also indirectly affect the function of ROMK by regulating the activity of other ion transporters (such as the sodium-chloride cotransporter NCC). This regulatory mechanism helps maintain potassium homeostasis, but in PA patients, the high PAC level may lead to excessive potassium secretion, thereby causing hypokalemia (26).

Moreover, PA patients have chronic elevated PAC, which has a profound impact on cellular processes, especially through various mechanisms triggering inflammation, oxidative stress, and fibrosis (27).These cellular processes not only affect the kidneys but also involve multiple organs such as the heart and blood vessels, leading to severe tissue damage and functional disorders. These mechanisms involve not only the activation of the mineralocorticoid receptor by aldosterone but also its regulation of oxidative stress and inflammatory signaling pathways (28). Therefore, interventions targeting aldosterone and its downstream signaling pathways, such as aldosterone synthase inhibitors and mineralocorticoid receptor antagonists, are expected to become effective strategies for treating PA-related organ damage (29).

Recent studies have reinforced the link between PA and renal damage (30–32). The results of this study showed elevated urinary microalbumin excretion in PA patients, especially those with hypokalemia, highlight the severity of renal impairment associated with this condition. Studies have shown that in the early stages of primary aldosteronism (PA), the degree of renal function impairment may be masked by glomerular hyperfiltration. Elevated plasma aldosterone concentration (PAC) helps maintain the glomerular filtration rate, making early renal damage less detectable (33). In fact, the increase in urinary microalbumin is a sensitive indicator of early renal damage (34). In this study, all PA patients included were in the early stage of the disease, thus only showing increased urinary microalbumin excretion, while the estimated glomerular filtration rate (eGFR) and serum creatinine levels remained within normal ranges.

Hypokalemia leads to renal damage through various mechanisms, including renal tubular dysfunction, reduced renal blood flow and GFR, changes in renal morphology, inflammation and fibrosis, as well as oxidative stress. These mechanisms interact with each other, ultimately resulting in progressive renal dysfunction (35). These indicators are corroborated by a growing body of literature (36–39) that identifies hypokalemia and 24-hour urinary potassium excretion as significant predictors of renal damage in these patients. For instance, research by Rossi et al (40, 41) demonstrated that hypokalemia in PA is strongly linked with increased renal fibrosis and reduced glomerular filtration rate, underscoring the critical impact of electrolyte disturbances on renal health in these individuals.

PA is predominantly classified into APA and IHA, with APA patients typically exhibiting unilateral adrenal adenomas and more severe renal injury (29)—a pathology directly linked to hyperaldosteronism-induced tubulointerstitial fibrosis, glomerulosclerosis, and mineralocorticoid receptor (MR)-mediated dysregulation of tubular sodium-potassium exchange, culminating in hypokalemia and tubular dysfunction. Williams et al. recently proposed a subtyping criterion for unilateral PA (16): Based on postoperative histology, lesions are categorized as classic or non-classic unilateral disease; Solitary nodules exhibiting characteristic adenoma features on CT—even without CYP11B2 immunohistochemical staining—are classified as classic APA. Notably, unilateral PA represents the most common surgically curable hypertension, with AVS remaining the diagnostic gold standard (4). Controversy persists regarding optimal LI thresholds: while most centers use unstimulated LI cutoffs of 2.0-4.0 and Rossi et al. advocate LI≥2 for optimal diagnosis (42), Kobayashi et al. demonstrate comparable validity for LI≥4 without ACTH stimulation (15). Applying this LI≥4 threshold, our study confirmed significantly elevated PAC in APA versus IHA, alongside greater hypokalemia prevalence and exacerbated renal impairment in classic APA subgroups—findings concordant with established evidence.

Furthermore, this study observed no statistically significant correlation between renal impairment and hypertension duration across patient subgroups. Notably, in the primary aldosteronism (PA) patients, neither the duration of hypokalemia nor hypertension duration showed significant associations with renal damage (P > 0.05). These negative findings may reflect the early disease stage of the cohort (mean disease duration <5 years), during which clinically evident renal damage and electrolyte disturbances (e.g., hypokalemia) have not yet manifested. Therefore, early diagnostic confirmation and timely therapeutic intervention are critical for mitigating renal functional decline and improving long-term renal outcomes. Particularly during the compensatory hyperfiltration phase, targeted treatment may halt the progression of nephropathy.

In summary, compared to patients with EH, those with PA exhibit more severe renal impairment, particularly in the aldosterone-producing adenoma (APA) subtype, which can be significantly exacerbated by hypokalemia. Furthermore, both hypokalemia and elevated 24-hour urinary potassium excretion serve as important predictive factors for renal impairment in PA patients. The identification and management of PA at early stages are thus imperative to prevent the progression of renal damage and other complications. However, although this study provides valuable insights into the renal impact of primary aldosteronism (PA), its retrospective design precluded serial monitoring of renal injury markers, limiting assessment of pre- to post-treatment changes in renal parameters and the effects of hypokalemia correction on kidney function. Furthermore, due to the unavailability of CYP11B2 immunohistochemical (IHC) staining, we employed an integrated CT-AVS approach for the further subclassification of the unilateral hypersecretion group. The presence of CT-occult microadenomas may lead to under-detection of atypical cases.

These limitations underscore the need for further prospective studies that can offer a more comprehensive understanding of PA’s progression, treatment efficacy, and outcomes. Such studies should aim to longitudinally assess the impact of targeted interventions, such as adrenalectomy or mineralocorticoid receptor antagonists, on renal function and potassium levels in PA patients. By expanding our knowledge and refining management strategies, we can better address the significant burden of renal complications associated with PA and improve the overall prognosis for these patients.