Abstract
Background
Primary aldosteronism can arise from one or both adrenal glands. Adrenal vein sampling (AVS) is the standard of care for identifying patients with lateralized primary aldosteronism who would benefit from surgery. Variability in AVS lateralization has been primarily attributed to cosyntropin use and lateralization index thresholds. Data regarding intraprotocol variability are lacking.
Purpose
To assess the rates of intraprotocol lateralization inconsistency during simultaneous AVS.
Materials and Methods
This retrospective cross-sectional study assessed patients with primary aldosteronism who underwent simultaneous AVS at a single tertiary referral center between January 2015 and December 2023. Six sets of adrenal vein and peripheral vein samples were obtained: three baseline samples obtained after cannulation, 5 minutes apart; and three samples obtained between 5 and 30 minutes after cosyntropin stimulation. Patients with successful cannulation and valid hormonal data at all six time points were included. A lateralization index (computed as the aldosterone-to-cortisol ratio between the two adrenal veins, with the highest number as numerator) of at least 4 was considered indicative of lateralized primary aldosteronism. The proportions of baseline and stimulated AVS sets within which one of three lateralization indexes provided different subtype results were assessed. Linear mixed-effects models were used to estimate the between- and within-patient hormonal and lateralization index variances.
Results
Of 402 patients (median age, 53 years; IQR, 45–63 years; 233 male) included, 129 patients (32.1%) had at least one lateralization index inconsistency. Of these 402 patients, 89 patients (22.1%) had lateralization inconsistencies within the baseline sets, 53 patients (13.2%) within cosyntropin-stimulated sets, and 13 patients (3.2%) in both baseline and cosyntropin-stimulated sets. The highest outlier prevalence occurred in the first (42 patients; 10.4%) and third (33 patients; 8.2%) baseline samples, with roughly twofold-lower rates in the first (23 patients; 5.7%) and last postcosyntropin stimulation samples (4.2%; 17 patients). The absolute change in baseline and cosyntropin-stimulated lateralization index (maximum-minimum lateralization index within a triplicate) was as high as 152.9 and 327.4, respectively. The highest hormonal variability was noted in the adrenal vein producing less aldosterone.
Conclusion
Almost a third of patients undergoing AVS in triplicate, both before and after cosyntropin stimulation, had intraprotocol discrepancies in lateralization results, with the highest variability occurring within samples obtained without cosyntropin stimulation.
© RSNA, 2025
See also the editorial by Georgiades in this issue.
Summary
Almost a third of patients with primary aldosteronism had intraprotocol inconsistencies in subtyping during simultaneous adrenal vein sampling; thus, obtaining multiple sample sets may reduce erroneous surgical recommendations.
Key Results
■ This retrospective cross-sectional study assessed 402 patients with primary aldosteronism who underwent simultaneous adrenal vein sampling to identify lateralization; intraprotocol lateralization inconsistency was assessed using triplicate serum samples obtained from the left and right adrenal veins both before and 5–30 minutes after cosyntropin stimulation.
■ Subtyping inconsistencies occurred in 129 of 402 (32.1%) patients, including 89 (22.1%) within baseline sets, 53 (13.2%) within cosyntropin-stimulated sets, and 13 (3.2%) within both protocols.
■ Absolute change in baseline and cosyntropin-stimulated lateralization index (aldosterone-to-cortisol ratio between the two adrenal veins) was as high as 152.9 and 327.4, respectively.
Introduction
Primary aldosteronism is a common cause of secondary hypertension, affecting 5%–10% of individuals with hypertension and up to 25% of those with treatment-resistant hypertension (1,2). Primary aldosteronism is associated with a disproportionate risk of cardiovascular and renal complications (3–6). Primary aldosteronism is broadly subtyped into unilateral and bilateral forms. The role of cross-sectional imaging in identifying the sources of aldosterone excess is limited due to subcentimeter primary aldosteronism sources, as well as to coexisting nonfunctional adrenal nodules (7,8). Therefore, adrenal vein sampling (AVS) is the current standard of care for identifying lateralized primary aldosteronism and for guiding treatment decisions. Unilateral or AVS-lateralized primary aldosteronism is often cured with surgery, whereas bilateral primary aldosteronism requires life-long targeted medical therapy (9). Unilateral adrenalectomy is superior to medical therapy for blood pressure control and improving quality of life, and it is associated with lower all-cause mortality and major adverse cardiovascular outcomes (10,11). Furthermore, unilateral adrenalectomy is more cost-effective compared with long-term medical therapy (5,6,12–14). Thus, accurate identification of lateralized primary aldosteronism is important for individualized therapy.
AVS is invasive, costly, and scarcely available due to its reliance on highly specialized interventional radiologists. Considering these limitations, along with the therapy decision implications, the importance of accurate AVS results cannot be overstated. Although AVS has been performed for decades, the procedure protocols and data interpretation remain highly heterogeneous across centers (15,16). Variability in AVS results has been primarily attributed to cosyntropin use and to criteria implemented to ascertain lateralization. Numerous other factors might contribute to inconsistent AVS results, such as the time of day, sedatives (17,18), cosyntropin administration protocols (bolus vs continuous infusion, time from cosyntropin administration to catheterization and/or sampling initiation), and assay inaccuracies, particularly when they require dilution. Many centers obtain a single set of samples during AVS, and data concerning intraprotocol variability are lacking. Thus, this study aimed to assess the rates of intraprotocol lateralization inconsistency during simultaneous AVS.
Materials and Methods
Study Design and Patients
This retrospective study reviewed all consecutive patients with confirmed primary aldosteronism who underwent AVS at a single tertiary referral center (University of Michigan) between January 2015 and December 2023. Inclusion criteria consisted of patients who had successful adrenal vein catheterization and valid data at six time points. Exclusion criteria consisted of either unsuccessful catheterization or data from fewer than six time points. Primary aldosteronism diagnosis was made in accordance with standing Endocrine Society guidelines (9,19). In addition to relevant clinical data, demographic information (including age, sex, and self-reported ethnicity/race) was collected from electronic health records because these have been associated with differences in primary aldosteronism pathogenesis and phenotype (20–22). This study was conducted with University of Michigan Institutional Review Board approval and followed the Health Insurance Portability and Accountability Act Privacy Rule. All patients signed informed consent for AVS. A waiver of informed consent was granted for the retrospective data collection (HUM00055821).
AVS Procedure
During the studied period, AVS was performed primarily by a single experienced interventional radiologist (J.S., with 45 years of experience). Simultaneous AVS was performed both before and after cosyntropin stimulation, as previously described (23). Briefly, a catheter was inserted through a femoral vein and positioned in the infrarenal inferior vena cava. Two separate catheters were then used to cannulate the right and left adrenal veins, the locations of which were visually confirmed using adrenal venography and occasional adjunctive cone-beam CT (Fig 1). The catheters remained in place for the duration of the procedure, with intermittent injections to confirm stability of catheterization. In total, six sets of samples were obtained from the adrenal and peripheral veins: three after cannulation, 5 minutes apart as baseline assays; and three between 5 and 30 minutes from the initiation of cosyntropin. Cosyntropin was administered as a 0.125-mg bolus, followed by continuous infusion at 0.125 mg per hour for the duration of the procedure.
Figure 1:
Images show adrenal vein sampling. (A) Schematic representation shows anatomy of the adrenal veins (created with BioRender.com). (B, C) Venograms obtained during the procedure show (B) right adrenal vein and (C) left adrenal vein. Two separate catheters were used to cannulate the right and left adrenal veins. The vein locations were visually confirmed using adrenal venography and occasional adjunctive cone-beam CT.
AVS Data Interpretation
The selectivity index was calculated (L.M.M. and A.F.T., with 16 and 12 years of experience, respectively) as the ratio of cortisol concentration in the adrenal vein to that in the inferior vena cava at each time point. Successful adrenal vein catheterization was confirmed on the basis of a selectivity index of at least 2 and at least 5 before and after cosyntropin administration, respectively. Similarly, a time point–specific lateralization index was computed between the two adrenal veins, with the highest (dominant adrenal vein) as the numerator and the lowest (nondominant adrenal vein) as the denominator. Based on at least two concordant datasets within each protocol, AVS subtyping was classified as lateralized if lateralization index was at least 4 or bilateral if lateralization index was less than 4. Inconsistent AVS lateralization within baseline and cosyntropin-stimulated samples was defined as the proportion of sets in which one of three lateralization indexes provided subtyping results that were different than the other two.
Hormonal Assays
Serum aldosterone was measured using competitive chemiluminescent immunoassay on an analyzer (Liaison XL; DiaSorin); the coefficients of variation, (ie, ratio of SD to the mean) of multilevel quality control material are less than 10%. Serum cortisol was measured using competitive chemiluminescent immunoassay on analyzers (Advia Centaur XP or Atellica IM; Siemens Healthineers), with coefficients of variation of multilevel quality control material less than 10%. Aldosterone and/or cortisol concentrations greater than that of the analytical measurement range of the respective assay were diluted with a specific manufacturer diluent until a result was obtained. Plasma renin activity was measured as previously reported (23). Direct renin concentration was measured after February 2018 with a competitive chemiluminescent immunoassay (Liaison; DiaSorin) with a coefficient of variation of less than 10%. For data analysis, a conversion factor of eight to one was used to convert direct renin concentration to plasma renin activity; this factor was derived following rigorous in-house analysis of both assays over a 9-month transition period. Renin was considered suppressed when plasma renin activity was less than 1.0 ng/mL per hour.
Statistical Analysis
Categorical parameters were compared between groups using the χ2 and Fisher exact tests, as appropriate. Comparisons of continuous parameters between the two groups were evaluated using the Student t test (for normally distributed variables) and Mann-Whitney U test (for variables with skewed distribution). The percent difference for triplicate lateralization index within each set was calculated as the difference between the highest and lowest lateralization index values within the triplicate for each patient divided by the average lateralization index value and multiplied by 100.
We used linear mixed-effects models (with patient as random) to estimate the between- and within-patient hormonal and lateralization index variances. For these calculations, hormonal and lateralization index values were first log-transformed to account for their right-skewed distribution. The intraclass correlation coefficients (ICCs) were subsequently calculated on the basis of the two variance estimates. The 95% CI for ICC was calculated using bootstrapping. An ICC of 1 indicated perfect agreement between values and an ICC of 0 indicated no agreement or reliability (random variation).
Univariable and multivariable logistic regression analysis was performed to assess the association between inconsistent AVS results as an independent variable and demographic and clinical parameters as potential confounding variables. Data are shown as odds ratios and 95% CIs, with regression coefficients and their standard errors. Adjusted logistic regression was based on clinical relevance, collinearity, and interactions of variables. Statistical significance was indicated at two-tailed P < .05. Statistical analysis and data interpretation were performed by three authors (L.M.M.; L.Z., with 19 years of experience; and A.F.T.). Statistical analysis was performed using software (Prism, version 10.4.1, GraphPad; and SAS, version 9.4, SAS Institute).
Results
Patient Characteristics
Between January 2015 and December 2023, AVS was performed in 471 patients with primary aldosteronism at our institution. Of these, 69 patients were excluded due to either unsuccessful catheterization (n = 11) or data from fewer than six time points (three per each protocol) (n = 58). A single complication was recorded, in a 45-year-old man with diabetes, who reported postprocedural right flank pain. The patient was found to have a right adrenal hematoma, which was fully resorbed at the 3-month imaging follow-up. In total, 402 patients (median age, 53 years; IQR, 45–63 years; 233 male and 169 female; 11 Asian patients, 96 Black patients, and 273 White patients; Table 1) with successful AVS and six valid datasets were included for analysis (Fig 2).
Table 1:
Demographic and Clinical Characteristics of Patients Undergoing AVS
Figure 2:
Study flow and proportion of intraprocedural lateralization inconsistencies. A total of 69 patients were excluded due to either unsuccessful catheterization or less than six adrenal vein sampling (AVS) sets (three per each protocol) obtained.
Intraprotocol Lateralization Variability
In total, 129 of 402 patients (32.1%) had a lateralization index inconsistency (indicating different primary aldosteronism subtyping) within at least one of the two protocols (Fig 2), including 89 patients (22.1%) with a discrepant lateralization index within the baseline sets, 53 patients (13.2%) within the cosyntropin-stimulated sets, and 13 patients (3.2%) in both baseline and cosyntropin-stimulated sets. Patients with AVS inconsistencies were slightly older (median age, 55 years [IQR, 48–64 years] vs 52 years [43–62 years], respectively; P = .009) and had a higher serum creatinine concentration (1.0 mg/dL [IQR, 0.9–1.3 mg/dL] vs 0.9 mg/dL [IQR, 0.8–1.1 mg/dL], respectively; P = .003) (Table 1). Adjusted logistic regression showed that inconsistent AVS results were associated with older age (odds ratio, 1.06; IQR, 1.03, 1.08) and with lower serum potassium concentration (odds ratio, 0.62; IQR, 0.38, 0.99) (Table 2).
Table 2:
Adjusted Associations between Patient Demographics and Clinical Data and Intraprotocol Adrenal Vein Sampling Data Consistency
Across the 402 patients, the highest outlier proportion was observed in the first basal sample (42 patients; 10.4%) and third basal sample (33 patients; 8.2%), followed by the first postcosyntropin sample (23 patients; 5.7%) and the last postcosyntropin sample (17 patients; 4.2%). As expected, the lateralization index ICC was lower in patients with conflicting AVS results compared with those with consistent data (lateralized or bilateral) within both protocols (baseline and cosyntropin-stimulated AVS, Table 3). The absolute change in baseline and stimulated lateralization index (with maximum-minimum lateralization index within a triplicate) was as high as 152.9 (184.1–31.1) and 327.4 (415.6–88.3), respectively, corresponding to percent changes of 271% and 255% in baseline and stimulated lateralization index, respectively (Fig 3). Aldosterone and cortisol ICCs within each sampling location are shown in Table 4. Hormonal fluctuations were highest in the nondominant adrenal vein (aldosterone ICC, 0.42 [95% CI: 0.38, 0.46] at baseline and 0.27 [95% CI: 0.25, 0.30] after cosyntropin stimulation; Table 4).
Table 3:
ICCs for Log-transformed Lateralization Indexes in Baseline and Cosyntropin-stimulated AVS Stratified by Results
Figure 3:
Plots show (A) baseline and (B) cosyntropin-stimulated lateralization indexes in patients with inconsistent adrenal vein sampling (AVS) results. Each patient had six AVS sets (three obtained before and three obtained after cosyntropin stimulation). Paired lateralization indexes are shown for each patient (baseline = ■, cosyntropin stimulation = ●). Lateralization indexes were computed as the aldosterone-to-cortisol ratio between the two adrenal veins, with the highest (dominant adrenal vein) as the numerator and the lowest (nondominant adrenal vein) as the denominator. The gray zone marks lateralization indexes less than 4, which indicate bilateral primary aldosteronism (PA). Lateralization indexes of at least 4 indicate lateralized primary aldosteronism. Patients are ordered ascendingly based on the lowest lateralization index. Of 402 patients, 102 had conflicting AVS data within baseline sets (A) and 66 had conflicting AVS data within cosyntropin-stimulated sets (B).
Table 4:
ICCs for Log-transformed Aldosterone and Cortisol Measurements during Baseline and Cosyntropin-stimulated AVS at Each Sampling Location
Discussion
Adrenal vein sampling (AVS) is the standard of care for identifying lateralized primary aldosteronism in most patients who consider adrenalectomy (9). Differences in primary aldosteronism subtyping with AVS have been primarily attributed to cosyntropin use and lateralization index thresholds (9,24,25). Yet, data on intraprotocol variability in AVS lateralization are lacking. In this study, we illustrate that, despite simultaneous cannulation, AVS results might indicate conflicting subtyping results both within baseline and cosyntropin-stimulated protocols. Overall, almost a third of included patients (129 of 402; 32.1%) had intraprotocol AVS data discrepancies, underscoring the importance of obtaining multiple sample sets during the procedure to accurately guide primary aldosteronism treatment. Of the 402 patients included, AVS inconsistencies were displayed in 89 (22.1%) patients within the baseline sets and 53 (13.2%) patients in cosyntropin-stimulated sets. In 13 of 402 patients (3.2%), discrepant lateralization occurred within both baseline and stimulated sets.
Expectedly, AVS data inconsistencies were highest within baseline samples, likely mediated by acute adrenocorticotropic hormone fluctuations during the procedure. Indeed, the inconsistent results were most common within the first baseline samples sets. During baseline AVS, hormonal excursions were highest within the right adrenal vein sets, possibly reflecting variable contamination with peripheral blood, because a slanted catheter is typically placed at the junction of the right adrenal vein with the inferior vena cava. These hormonal excursions also question the utility of lateralization index calculations based on averaged hormonal data, as previously proposed (26).
For aldosterone, the highest variability was observed within samples obtained from the nondominant adrenal vein. This variability might reflect a higher vulnerability of normal glomerulosa cells versus primary aldosteronism foci to intrinsic adrenocorticotropic hormone fluctuations. Additionally, it could reflect variable reserves of normal zona glomerulosa, which tends to diminish with aging, renin suppression, and a high-salt diet (27). Physiologic aldosterone production responds acutely to even lower adrenocorticotropic hormone stimuli than cortisol does (28).
Incongruent responses of aldosterone and cortisol to cosyntropin stimulation, differences in their protein binding and half-lives, as well as assay variability could contribute to inconsistencies in lateralization during cosyntropin-stimulated AVS. Cosyntropin stimulation enhances the selectivity index and the rates of successful adrenal vein cannulation by amplifying the adrenal cortisol output (29). The effect of adrenocorticotropic hormone on aldosterone-producing adenoma and normal glomerulosa cell–derived aldosterone is variable, and it is largely driven by differences in the expression of the melanocortin 2 receptor, the adrenocorticotropic hormone receptor, in aldosterone-producing adenoma and adjacent tissue. We have shown that the degree of melanocortin 2 receptor expression in aldosterone-producing adenoma differs with the underlying aldosterone-driver mutation (24). Correspondingly, the lateralization index response to cosyntropin clusters across the major aldosterone-driver mutations, with an enhancement of lateralization index seen in patients harboring ATP1A1 or ATP2B3 mutations and a decline of lateralization index for aldosterone-producing adenomas harboring KNCJ5 mutations (24). Taken together, these data explain the occasional hormonal inconsistencies even during pharmacologic cosyntropin stimulation, albeit these occur less frequently than under baseline conditions.
Our study had limitations. First, its retrospective study design may have made it less generalizable to real-world practice. Second, the study did not address potential contributing factors to the observed hormonal variability, such as assay imprecisions or intrinsic intraindividual biologic factors.
In summary, almost a third of patients undergoing adrenal vein sampling (AVS) in triplicate, both before and after the administration of cosyntropin, had intraprotocol discrepancies in lateralization results, with the highest variability occurring within samples obtained without cosyntropin stimulation. These results offer opportunities for evaluating the reliability of AVS data. They suggest that stress-induced responses of aldosterone and cortisol are not synchronized, and they emphasize the value of obtaining multiple datasets to best inform an adequate treatment decision. Further prospective studies are necessary to address the AVS intraprotocol variability and the potential contributing factors to these observed hormonal fluctuations.
Acknowledgments
Acknowledgments
We thank the University of Michigan adrenal team members who participated in the care of patients with primary aldosteronis, the interventional radiology staff who assisted with adrenal venous sampling protocols, and all study participants.
Funding: L.M.M. was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant 2023/00196-4). A.F.T. was supported by the Doris Duke Foundation (grant number 2019087) and the National Heart, Lung, and Blood Institute (grant number 1R01HL15583401).
Disclosures of conflicts of interest: L.M.M. No relevant relationships. L.Z. No relevant relationships. C.L. No relevant relationships. Z.S. No relevant relationships. D.M.M. No relevant relationships. J.S. No relevant relationships. A.F.T. Payments made to author’s institution from CinCor Pharma.
Abbreviations:
- AVS
- adrenal vein sampling
- ICC
- intraclass correlation coefficient
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