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. Author manuscript; available in PMC: 2026 Mar 26.
Published in final edited form as: Hypertension. 2025 Aug 4;82(10):1687–1695. doi: 10.1161/HYPERTENSIONAHA.125.24999

Cosyntropin-Stimulated Aldosterone Reserve of the Nondominant Adrenal Predicts Surgical Outcomes in Primary Aldosteronism

Peeradon Vibhatavata 1,2, James J Shields 3, Juilee Rege 4, Aaron M Udager 5, William E Rainey 6,7, Adina F Turcu 8
PMCID: PMC13014288  NIHMSID: NIHMS2147687  PMID: 40755305

Abstract

BACKGROUND:

Adrenal vein sampling (AVS) is commonly used to direct therapy of primary aldosteronism (PA). We hypothesized that cosyntropin stimulation during AVS exposes the reserve of aldosterone-producing cells in the nondominant adrenal gland and might predict postoperative outcomes.

METHODS:

Patients with PA who underwent successful AVS before and after cosyntropin stimulation between January 2015 and December 2024 in a tertiary-referral center were included. The nondominant adrenal aldosterone reserve was assessed with (1) contralateral aldosterone reserve ratio (=aldosterone postcosyntropin-to-baseline ratio in the nondominant adrenal vein) and (2) lateralization index (LI) ratio (=LIpost-cosyntropin/LIbaseline). Lateralization was based on LI ≥4.

RESULTS:

Four hundred thirty-four patients (57% men; mean age, 53±12 years) were included. AVS lateralized only at baseline in 52 (12%) patients, only after cosyntropin in 46 (11%), and in both protocols in 166 (38%); 170 (39%) patients had bilateral PA. PA severity decreased from cases lateralized in both protocols, to postcosyntropin only, baseline only, and consistently bilateral; conversely, the contralateral aldosterone reserve increased across these groups. The contralateral aldosterone reserve ratio was higher in patients without PA cure and bilateral PA (median [interquartile range], 11.2 [5.0–23.5] and 17.8 [9.1–32.0], respectively, versus 4.9 [2.5–9.4] in those cured; P<0.01) and in Black individuals, those aged ≥45 years, and with CACNA1D mutations. Contralateral aldosterone reserve and postcosyntropin lateralization and contralateral suppression were predictive of residual PA, while baseline parameters were not.

CONCLUSIONS:

Cosyntropin stimulation during AVS unveils the aldosterone reserve of the nondominant adrenal gland, exposing the risk of residual disease after adrenalectomy.

Keywords: adrenal glands, adrenalectomy, aldosterone, hyperaldosteronism, hypertension

Primary aldosteronism (PA) is a leading cause of secondary hypertension,1,2 and it is associated with increased cardiovascular and renal morbidity and mortality.3,4 Accurate subtyping of PA is essential for guiding appropriate treatment and improving clinical outcomes. Unilateral PA, commonly caused by an aldosterone-producing adenoma, can be cured with adrenalectomy, which mitigates the excessive cardiovascular and renal risks.5–7 In contrast, patients with bilateral PA require long-term medical management.

The Endocrine Society clinical practice guideline endorses adrenal vein sampling (AVS) as the standard test for PA subtyping.8 While AVS protocols and interpretations vary across centers, a lateralization index (LI; defined as a ratio of aldosterone/cortisol between the 2 adrenal veins [AVs], with the highest as the numerator) ≥2 to 4 is considered indicative of unilateral PA. However, residual PA is not uncommon after unilateral adrenalectomy guided by such thresholds,9–12 reflecting that LI does not convey the potential aldosterone reserve in the nondominant adrenal gland.

Cosyntropin, a synthetic adrenocorticotropic hormone, is used to stimulate cortisol secretion during AVS and, hence, to increase the confidence of successful AV catheterization.13 Cosyntropin is also used to circumvent intraprocedural hormonal fluctuations.14 Some studies report that cosyntropin has the potential to decrease LI and to mask aldosterone lateralization, although such studies often used lower LI thresholds at baseline than after cosyntropin stimulation.15–18 The effect of cosyntropin on aldosterone lateralization is, in fact, variable,19,20 and it may reflect differences in MC2R (melanocortin 2 receptor) expression in normal zona glomerulosa cells and pathological aldosterone-producing lesions.21–24 We hypothesized that cosyntropin stimulation during AVS unveils the aldosterone reserve in the nondominant adrenal gland, exposing the risk of residual disease after adrenalectomy.

METHODS

Data Availability

We will consider sharing deidentified, individual participant-level data that underlie the results reported in this article upon receipt of a request detailing the study hypothesis and statistical analysis plan. All requests should be sent to the corresponding author. The corresponding author and lead investigators of this study will discuss all requests and make decisions about whether data sharing is appropriate based on the scientific rigor of the proposal. All applicants will be asked to sign a data access agreement.

We retrospectively reviewed all patients with confirmed PA who underwent AVS at the University of Michigan between January 2015 and December 2024. Patient demographics, antihypertensive medication dosages (calculated using the World Health Organization’s anatomic therapeutic chemical to daily defined dose [total daily dose of antihypertensive agents] index), biochemical data, imaging findings, AVS results, pathological data, follow-up records, and postadrenalectomy outcomes were collected.

Plasma aldosterone concentration, plasma renin activity, plasma renin concentration, and serum cortisol concentration were measured by Clinical Laboratory Improvement Amendments–certified immunoassays, as previously reported.25 The diagnosis of PA was established in accordance with the Endocrine Society guidelines.8,26

Simultaneous AVS was performed both after catheter insertion (baseline) and 5 to 30 minutes after cosyntropin stimulation, as previously described.25 Catheterization success was determined using the selectivity index, defined as the ratio of AV cortisol to peripheral serum cortisol, with a selectivity index >2 at baseline and >5 postcosyntropin stimulation. Patients with unsuccessful cannulation either at baseline or postcosyntropin were excluded. LI was used to classify PA as lateralized (LI ≥4) or bilateral (LI <4) both at baseline and postcosyntropin stimulation. The contralateral index (CI), calculated as the aldosterone-to-cortisol ratio between the nondominant AV and peripheral serum, was considered indicative of contralateral suppression when <1.

The dominant AV was defined as the AV with the highest aldosterone:cortisol ratio. The contralateral aldosterone reserve ratio (CARR) was defined as the ratio of aldosterone concentration measured after cosyntropin stimulation to baseline aldosterone concentration in the nondominant AV (CARR= [aldosteronepostcosyntropin/aldosteronebaseline] nondominant AV). The LI ratio (LIR) was defined as the ratio of LI after cosyntropin stimulation to baseline LI (LIR=LIpostcosyntropin/LIbaseline).

Clinical and biochemical outcomes following unilateral adrenalectomy were evaluated according to the International Primary Aldosteronism Surgical Outcome consensus.11 Biochemical cure was defined as normalization of the aldosterone:renin ratio and correction of hypokalemia if previously present. Clinical cure was defined as normalization of blood pressure without the need for antihypertensive medications. For this study, patients were classified as either cured or not cured (having partial or absent improvement) for both biochemical and clinical outcomes.

For patients who underwent adrenalectomy within our institution and provided informed consent for the use of formalin-fixed paraffin-embedded adrenal tissue, CYP11B2 (aldosterone synthase) immunohistochemistry was performed to identify areas of aldosterone production. DNA was subsequently extracted from the CYP11B2-expressing areas and analyzed for aldosterone-driver mutations using next-generation sequencing, as previously reported.27

These studies were approved by the institutional review board. A waiver of informed consent was granted for the retrospective review of electronic health records (HUM00249403), while pathological studies, immunohistochemistry, and genetic testing were conducted with informed consent obtained from all patients (HUM00055821 and HUM00106809).

Statistical Analysis

Proportions between groups were compared using the χ2 test or the Fisher exact test. Continuous variables were analyzed using the Mann-Whitney U test and the Kruskal-Wallis test for 2-group and multiple-group comparisons, respectively. Receiver operating characteristic analysis was performed to evaluate the diagnostic performance of CARR, LIR, LI, and CI in predicting persistent hypertension and residual PA after unilateral adrenalectomy. The area under the curve was calculated, and optimal cutoff values were determined. Univariable and multivariable logistic regressions were conducted to assess associations between AVS parameters (LI, CI, and CARR) and postoperative outcomes. Data analysis was conducted using GraphPad Prism, version 10.2.3 (GraphPad Software, Inc, Boston, MA). A 2-tailed P<0.05 was considered statistically significant.

RESULTS

Demographic and Clinical Characteristics of Participants

Of 458 patients with PA who underwent AVS during the study period, 24 (5.2%) were excluded due to failed AV catheterization (23 at baseline and 1 at both baseline and postcosyntropin; Figure 1). Of 434 patients included, 247 (57%) were men, with a mean age of 53±12 years. Most patients self-identified as White (66%), and 25% identified as Black, with the remaining unreported or other categories.

Figure 1. Study flow.

Figure 1.

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Adrenal venous sampling (AVS) results were classified as bilateral (B) or lateralized (L) based on lateralization indices, with ≥4 categorized as lateralized and <4 as bilateral. The first letter represents baseline results, while the second letter reflects postcosyntropin results.

AVS showed bilateral PA both at baseline and after cosyntropin stimulation (BB) in 170 (39%) patients; lateralization was observed only at baseline (LB) in 52 (12%) patients, only postcosyntropin (BL) in 46 (11%) patients, and in both protocols (LL) in 166 (38%) patients (Table 1). Age was comparable across all 4 groups. The proportion of men was the highest in patients who lateralized only after cosyntropin (72% compared with 50% in those lateralized only at baseline or in both protocols and 62% in the consistently lateralized group). PA severity was the highest in patients with consistent lateralization, followed closely by those who lateralized only after stimulation, which displayed higher aldosterone concentration and lower serum potassium levels (Table 1). Conversely, patients who lateralized only at baseline displayed clinical features resembling more closely with those with consistent bilateral AVS results. Adrenal nodules were observed more frequently in patients with cosyntropin-stimulated (84%) and consistent lateralization (78%) compared with those with consistently bilateral and baseline lateralization (53% and 61%, respectively; Table 1).

Table 1.

Demographics and Clinical Characteristics of Study Participants

Clinical parameter Total (N=434) BB (n=170; 39%) LB (n=52; 12%) BL (n=46; 11%) LL (n=166; 38%) P value
Age, y 53 (45–62) 55 (45–63) 54 (45–61) 54 (47–63) 53 (44–62) 0.78
Men, N (%) 247 (57%) 85 (50%) 26 (50%) 33 (72%) 103 (62%) 0.02
Race, N (%) 0.10
 White 287 (66%) 104 (61%) 31 (59%) 31 (67%) 121 (73%)
 Black 110 (25%) 50 (29%) 17 (33%) 8 (18%) 35 (21%)
 Other/unknown 37 (9%) 16 (9%) 4 (8%) 7 (15%) 10 (6%)
ATC/DDD index 4.3 (2.2–6.7) 3.3 (1.8–5.9) 4.6 (2.0–6.7) 4.6 (2.7–75) 5.2 (2.7–73) <0.01
Serum potassium, mmol/L 3.7 (3.3–4.1) 3.9 (3.5–4.3) 3.9 (3.6–4.1) 3.7 (3.3–4.1) 3.5 (3.2–4.0) <0.01
PAC, ng/dL 25.0 (18.4–37.6) 21.4 (17.2–28.2) 24.0 (16.7–30.6) 29.8 (20.5–42.0) 30.2 (22.2–48.5) <0.01
PRA, ng/mL/h 0.6 (0.2–0.6) 0.6 (0.2–0.8) 0.6 (0.2–0.6) 0.6 (0.2–0.7) 0.6 (0.2–0.6) 0.44
PRC, pg/mL 2.1 (2.1–3.2) 2.1 (2.1–4.3) 2.1 (2.1–4.6) 2.1 (2.1–2.5) 2.1 (2.1–2.7) 0.10
Adrenal nodule, N (%) 281/416 (68%) 85/159 (53%) 30/49 (61%) 38/45 (84%) 128/163 (78%) <0.01
LI, baseline 4.1 (1.7–11.5) 1.5 (1.2–2.4) 7.6 (5.1–11.0) 2.1 (1.5–2.6) 14.2 (7.4–31.4) <0.01
LI, postcosyntropin 3.7 (1.6–18.9) 1.5 (1.2–2.3) 2.2 (1.5–3.1) 10.1 (7.2–18.4) 24.2 (11.2–53.2) <0.01
CI, baseline 0.79 (0.37–1.64) 1.48 (0.79–2.90) 0.96 (0.42–1.64) 0.69 (0.44–1.41) 0.40 (0.19–0.69) <0.01
CI, postcosyntropin 0.52 (0.16–1.31) 1.24 (0.72–1.86) 1.24 (0.59–1.89) 0.30 (0.13–0.50) 0.14 (0.07–0.34) <0.01
Unilateral adrenalectomy, N (%) 169 (39%) 6 (4%) 18 (35%) 33 (72%) 112 (67%) <0.01
Postoperative hypertension remission, N (%) 37/167 (22%) 0/6 (0%) 2/18 (11%) 8/32 (25%) 27/111 (24%) 0.44
Postoperative PA cure, N (%) 123/145 (85%) 3/5 (60%) 9/14 (64%) 25/28 (89%) 86/98 (88%) 0.04
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Data are expressed as a number (percent) or median (interquartile range). ATC/DDD indicates total daily dose of antihypertensive agents; B, bilateral; CI, contralateral index; L, lateralized; LI, lateralization index; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity; and PRC, plasma renin concentration.

Of the 434 patients, 169 (39%) underwent unilateral adrenalectomy (Table S1). Postoperative clinical outcome data were available for 167 patients, followed for a median (interquartile range [IQR]) of 294 (178–388) days. Of these 167 patients, 37 (22%) experienced complete clinical success, defined as hypertension remission. Of 145 patients with postoperative biochemical follow-up available, 123 (85%) achieved complete biochemical success, while 22 (15%) had residual PA.

Cosyntropin-Stimulated Aldosterone Reserve in the Nondominant AV

Aldosterone response to cosyntropin in the nondominant AV was the highest in patients with consistently bilateral AVS (CARR, 17.8 [IQR, 9.0–32.5]), and it progressively decreased in patients with LB (15.3 [IQR, 9.0–27.5]), BL (6.1 [IQR, 2.8–13.4]), and LL groups (4.8 [IQR, 2.6–9.7]; P<0.01; Figure 2). CARR was significantly higher in individuals older versus younger than 45 years (10.4 versus 6.1; P=0.02) and in Black patients compared with White patients (11.6 versus 8.7; P=0.03) but was similar in men and women (Figure S1).

Figure 2. Contralateral aldosterone reserve ratio and lateralization index ratio across adrenal venous sampling (AVS) results.

Figure 2.

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Violin plots displaying the contralateral aldosterone reserve ratio (A) and lateralization index ratio (B) stratified by AVS results (BB, LB, BL, and LL). Median values (interquartile ranges) are indicated for each group. B indicates bilateral; and L, lateralized.

Patients with postoperative hypertension remission had the lowest median CARR (4.1 [IQR, 2.5–5.9]) followed by those with persistent hypertension (6.4 [IQR, 3.0–14.1]) and those with bilateral PA (17.8 [IQR, 9.1–32.0]; P<0.01; Figure 3). Conversely, LIR was the highest in the hypertension remission group (1.6 [IQR, 1.0–5.5]), and it decreased in those with persistent hypertension (1.4 [IQR, 0.7–3.2]) and those with bilateral PA (1.0 [IQR, 0.7–1.3]).

Figure 3. Contralateral aldosterone reserve ratio and lateralization index ratio across postoperative outcomes vs bilateral primary aldosteronism (PA).

Figure 3.

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The contralateral aldosterone reserve ratio and the lateralization index ratio were assessed for biochemical (A and B) and clinical (C and D) outcomes in the surgical and bilateral PA groups using violin plots. Median values (interquartile ranges) are indicated for each subgroup. HT indicates hypertension.

The contralateral aldosterone reserve was also lower in patients with postoperative biochemical cure (CARR, 4.9 [IQR, 2.5–9.4]) than in patients with residual PA (11.2 [IQR, 5.0–23.5]) and those with bilateral PA (17.8 [IQR, 9.1–32.0]). In contrast, the LIR followed an inverse trend across these groups (Figure 3). Baseline LI and CI were similar between patients with clinical or biochemical cure and those without cure, respectively. Conversely, postcosyntropin LI was higher and CI was lower in patients with clinical or biochemical cure versus those without cure (Table 2).

Table 2.

LI and CI Stratified by Postoperative Outcomes

Clinical outcomes Hypertension remission (n=37) Persistent hypertension (n=130) P value
LI baseline 13.6 (4.1–23.7) 8.3 (4.7–16.6) 0.25
LI postcosyntropin 26.8 (13.2–61.9) 14.4 (72–29.7) <0.01
CI baseline 0.44 (0.22–0.62) 0.44 (0.22–0.82) 0.48
CI postcosyntropin 0.11 (0.06–0.32) 0.20 (0.09–0.51) 0.03
Biochemical outcomes PA cure (n=123) Residual PA (n=22) P value
LI baseline 10.7 (4.6–22.0) 5.9 (4.6–9.6) 0.08
LI postcosyntropin 19.0 (9.4–39.3) 79 (3.7–174) <0.01
CI baseline 0.42 (0.24–0.73) 0.66 (0.16–0.91) 0.21
CI postcosyntropin 0.13 (0.07–0.34) 0.48 (0.31–0.79) <0.01
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Data are expressed as median (interquartile range). CI indicates contralateral index; LI, lateralization index; and PA, primary aldosteronism.

CYP11B2 immunohistochemistry–guided next-generation sequencing was performed on 114 patients, and it identified 50 (44%) patients with CACNA1D mutations, 29 (25%) with ATP1A1, 24 (21%) with KCNJ5, 6 (5%) with ATP2B3, 2 (2%) with CACNA1H, and 1 each with CLCN2, CADM1, and SLC30A1 mutations. Aldosterone reserve was the highest in patients harboring CAC-NA1D mutations (CARR, 10.6 [IQR, 5.4–21.0]), followed by the ATP1A1 group (5.5 [IQR, 2.2–11.1]), the KCNJ5 group (3.3 [IQR, 2.5–4.8]), and the ATP2B3 group (1.6 [IQR, 1.3–2.3]; Figure 4).

Figure 4. The contralateral aldosterone reserve ratio and the lateralization index ratio across aldosterone-driver somatic mutations.

Figure 4.

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The contralateral aldosterone reserve ratio (A) and the lateralization index ratio (B) were evaluated across somatic mutations in aldosterone-producing adenomas using violin plots. Median values (interquartile ranges) are presented for each subgroup.

CARR and postcosyntropin, but not baseline LI and CI, predicted residual PA post-adrenalectomy (area under the curve, of 0.73–0.76; P<0.001 for all; Figures S2 through S4). All 3 parameters were weak predictors of persistent hypertension (area under the curve, 0.66; P<0.01 for CARR and stimulated LI; area under the curve, 0.62; P=0.03 for stimulated CI; Figures S2 through S4). Using the highest Youden index, CARR >11 predicted residual PA with 54% sensitivity and 82% specificity, and CARR >6 predicted persistent hypertension with 54% sensitivity and 81% specificity. LIR and baseline LI and CI were not predictive of postoperative outcomes. In adjusted logistic regression models incorporating CARR along with cosyntropin-stimulated LI and CI, only CARR remained predictive of biochemical and clinical postoperative outcomes (Tables S2 and S3).

DISCUSSION

This study illustrates that in patients with PA, the aldosterone response to cosyntropin stimulation from the nondominant adrenal gland predicts the likelihood of cure following AVS-guided adrenalectomy. The cosyntropin-stimulated aldosterone reserve index in the nondominant adrenal gland was lowest in patients with biochemical and clinical cure, and it increased progressively in those without clinical or biochemical cure and further in those with bilateral PA.

We and others have previously shown that even robust AVS lateralization does not always indicate unilateral PA.12,28,29 Instead, some patients with AVS lateralization might have asymmetrical bilateral PA. Such cases often display multiple sources of autonomous aldosterone production within the removed adrenal gland, and these frequently harbor CACNA1D aldosterone-driver mutations.12,29 In line with this PA pathogenesis, we found that the cosyntropin-stimulated aldosterone reserve in the nondominant AV was the highest in patients with documented CACNA1D mutations versus other aldosterone-driver mutations. CACNA1D mutations were also identified in patients with bilateral PA who underwent surgery aiming to reduce disease burden,30 suggesting that CACNA1D-mutated PA foci might be distributed symmetrically or asymmetrically in patients with bilateral PA.

The nondominant adrenal aldosterone reserve augmented by cosyntropin stimulation during AVS aligns well with other indicators of bilateral PA, such as older age and Black race. An accumulation of CYP11B2-expressing aldosterone-producing cell clusters has been reported in aging adrenal glands.31 CACNA1D mutations were frequently observed in older patients32,33 and in Black individuals with PA,34 who also have a higher prevalence of residual PA after adrenalectomy.12 In line with these reports, we found that CARR was higher in Black versus White people and those aged ≥45 years, with no notable differences between men and women.

LI is the primary index of AVS lateralization, and it is broadly used to distinguish unilateral from bilateral PA. LI thresholds were initially derived from small studies, with short-term clinical follow-up.35,36 Following the development of Primary Aldosteronism Surgical Outcome criteria,11 several studies have reported persistent hypertension rates of up to 72% and residual PA in 20% of cases following AVS-guided adrenalectomy.9,12,37,38 The dual classification of PA in our study indicates a spectrum of PA severity across the 4 subtypes, flanked by the mildest PA phenotype in consistently bilateral cases, and the most severe PA in those with consistent lateralization, who have higher aldosterone concentrations, higher total daily dose of antihypertensive agents index, and lower serum potassium and contralateral aldosterone reserve. Among patients with discordant AVS results, those who lateralized only at baseline displayed clinical features and postoperative outcomes comparable to the consistently bilateral cases, including high contralateral aldosterone reserve. Conversely, patients who lateralized only after cosyntropin exhibited clinical phenotype, contralateral aldosterone reserve, and postoperative outcomes similar to those with consistent lateralization. These transitional PA subtypes also feature distinct steroid fingerprints in AVs and peripheral circulation.39 Importantly, postoperative biochemical cure occurred less often in patients with AVS lateralization only at baseline (64%) than in patients with AVS lateralization only after cosyntropin stimulation (89%) or in both protocols (88%). These results further suggest that a relatively low aldosterone response to cosyntropin from the nondominant adrenal compared with the dominant gland indicates a limited reserve of aldosterone-producing cells and a low likelihood of residual or recurrent PA following AVS-guided adrenalectomy.

Reports on the postoperative prediction value of contralateral aldosterone suppression40–42 and LI,43–45 either alone or in combination, have been inconsistent. In part, this variability could be related to the AVS protocol used. In our study, only cosyntropin-stimulated LI and CI differed significantly between patients with and without clinical or biochemical cure. In addition, only cosyntropin-stimulated, but not baseline LI and CI, was predictive of postoperative biochemical outcomes. Similarly, in a European study that conducted postoperative cosyntropin stimulation tests in 100 patients with PA, a higher stimulated aldosterone was linked with a lack of biochemical cure.46

This study was conducted in a single high-volume referral center, providing a large cohort of patients who underwent the same AVS protocol, both without and with cosyntropin stimulation. However, considering the retrospective design of our study and the low number of patients with residual PA following AVS-guided adrenalectomy, we cannot immediately endorse specific cutoffs for any AVS parameters to accurately predict postoperative outcomes. To validate our findings in diverse populations, with varying genetic backgrounds, multicenter studies are needed. Furthermore, prospective designs would allow for uniform decision-making, applying standardized criteria for surgery versus medical therapy.

PERSPECTIVES

In patients with PA, cosyntropin stimulation during AVS maximizes the aldosterone response from the nondominant adrenal gland, and it uncovers the potential for residual or recurrent disease postoperatively. Cosyntropin-augmented aldosterone reserve in the nondominant adrenal gland is higher in patients harboring aldosterone-driver CACNA1D mutations, in Black individuals, and in older individuals. All these factors have been previously associated with bilateral and multifocal PAs. AVS without and with cosyntropin unravels a more granular PA subtyping: patients who lateralize at baseline but lose lateralization after cosyntropin stimulation have a milder PA phenotype and are more likely to have asymmetrical bilateral disease. Conversely, patients in whom lateralization is amplified by cosyntropin stimulation have a more severe phenotype, a lower contralateral aldosterone reserve, and a higher rate of postsurgical cure, resembling more closely to cases with consistent lateralization.

Supplementary Material

Suppl data

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.125.24999.

Tables S1–S3

Figures S1–S4

NOVELTY AND RELEVANCE.

What Is New?

We assessed the cosyntropin-augmented contralateral aldosterone reserve ratio in patients with primary aldosteronism.

A higher contralateral aldosterone reserve ratio was associated with lower rates of clinical and biochemical cure after adrenalectomy.

What Is Relevant?

Adrenal vein sampling without and with cosyntropin stratifies primary aldosteronism subtypes and postoperative outcomes.

Patients who lateralize only at baseline have milder primary aldosteronism phenotypes and are more likely to have asymmetrical bilateral disease.

Conversely, patients in whom lateralization is amplified by cosyntropin stimulation have more severe phenotypes, lower contralateral aldosterone reserve, and higher rates of postsurgical cure.

Clinical/Pathophysiological Implications?

Postoperative follow-up should be emphasized in patients with high contralateral aldosterone reserve ratios, particularly Black individuals and those with documented CACNA1D mutations, who are at higher risk of residual or recurrent primary aldosteronism.

Acknowledgments

The authors thank the University of Michigan research and clinical adrenal team members, the clinical laboratory team, and all study participants. The authors also thank Lili Zhao, PhD, Professor of Biostatistics at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, for statistical consultation.

Sources of Funding

A.F. Turcu was supported by grants 2019087 from the Doris Duke Foundation, R01HL155834 from the National Heart, Lung, and Blood Institute, and 1R01AG080516 from the National Institute on Aging. W.E. Rainey was supported by the grant R01DK106618 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Nonstandard Abbreviations and Acronyms

AV

adrenal vein

AVS

adrenal vein sampling

BB

adrenal vein sampling showing bilateral disease both at baseline and after cosyntropin stimulation

BL

adrenal vein sampling showing bilateral disease at baseline and lateralized disease after cosyntropin-stimulation

CARR

contralateral aldosterone reserve ratio

CI

contralateral index

CYP11B2

aldosterone synthase

IQR

interquartile range

LB

adrenal vein sampling showing lateralized disease at baseline and bilateral disease after cosyntropin stimulation

LI

lateralization index

LIR

lateralization index ratio

LL

adrenal vein sampling showing lateralized disease both at baseline and after cosyntropin stimulation

MC2R

melanocortin 2 receptor

PA

primary aldosteronism

Footnotes

Disclosures

A.F. Turcu served as a local investigator for a clinical study conducted by Astra-Zeneca and reports consulting fees from AstraZeneca. The other authors report no conflicts.

Contributor Information

Peeradon Vibhatavata, Faculty of Medicine, Division of Endocrinology and Metabolism, Thammasat University, Pathum Thani, Thailand; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor..

James J. Shields, Department of Radiology, University of Michigan, Ann Arbor.

Juilee Rege, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor..

Aaron M. Udager, Department of Pathology, University of Michigan, Ann Arbor.

William E. Rainey, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor.

Adina F. Turcu, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Suppl data
NIHMS2147687-supplement-Suppl_data.docx (545KB, docx)

Data Availability Statement

We will consider sharing deidentified, individual participant-level data that underlie the results reported in this article upon receipt of a request detailing the study hypothesis and statistical analysis plan. All requests should be sent to the corresponding author. The corresponding author and lead investigators of this study will discuss all requests and make decisions about whether data sharing is appropriate based on the scientific rigor of the proposal. All applicants will be asked to sign a data access agreement.

We retrospectively reviewed all patients with confirmed PA who underwent AVS at the University of Michigan between January 2015 and December 2024. Patient demographics, antihypertensive medication dosages (calculated using the World Health Organization’s anatomic therapeutic chemical to daily defined dose [total daily dose of antihypertensive agents] index), biochemical data, imaging findings, AVS results, pathological data, follow-up records, and postadrenalectomy outcomes were collected.

Plasma aldosterone concentration, plasma renin activity, plasma renin concentration, and serum cortisol concentration were measured by Clinical Laboratory Improvement Amendments–certified immunoassays, as previously reported.25 The diagnosis of PA was established in accordance with the Endocrine Society guidelines.8,26

Simultaneous AVS was performed both after catheter insertion (baseline) and 5 to 30 minutes after cosyntropin stimulation, as previously described.25 Catheterization success was determined using the selectivity index, defined as the ratio of AV cortisol to peripheral serum cortisol, with a selectivity index >2 at baseline and >5 postcosyntropin stimulation. Patients with unsuccessful cannulation either at baseline or postcosyntropin were excluded. LI was used to classify PA as lateralized (LI ≥4) or bilateral (LI <4) both at baseline and postcosyntropin stimulation. The contralateral index (CI), calculated as the aldosterone-to-cortisol ratio between the nondominant AV and peripheral serum, was considered indicative of contralateral suppression when <1.

The dominant AV was defined as the AV with the highest aldosterone:cortisol ratio. The contralateral aldosterone reserve ratio (CARR) was defined as the ratio of aldosterone concentration measured after cosyntropin stimulation to baseline aldosterone concentration in the nondominant AV (CARR= [aldosteronepostcosyntropin/aldosteronebaseline] nondominant AV). The LI ratio (LIR) was defined as the ratio of LI after cosyntropin stimulation to baseline LI (LIR=LIpostcosyntropin/LIbaseline).

Clinical and biochemical outcomes following unilateral adrenalectomy were evaluated according to the International Primary Aldosteronism Surgical Outcome consensus.11 Biochemical cure was defined as normalization of the aldosterone:renin ratio and correction of hypokalemia if previously present. Clinical cure was defined as normalization of blood pressure without the need for antihypertensive medications. For this study, patients were classified as either cured or not cured (having partial or absent improvement) for both biochemical and clinical outcomes.

For patients who underwent adrenalectomy within our institution and provided informed consent for the use of formalin-fixed paraffin-embedded adrenal tissue, CYP11B2 (aldosterone synthase) immunohistochemistry was performed to identify areas of aldosterone production. DNA was subsequently extracted from the CYP11B2-expressing areas and analyzed for aldosterone-driver mutations using next-generation sequencing, as previously reported.27

These studies were approved by the institutional review board. A waiver of informed consent was granted for the retrospective review of electronic health records (HUM00249403), while pathological studies, immunohistochemistry, and genetic testing were conducted with informed consent obtained from all patients (HUM00055821 and HUM00106809).

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