Nomogram-Based Preoperative Score for Predicting Clinical Outcome in Unilateral Primary Aldosteronism

Abstract

Context

More than half of patients diagnosed with unilateral primary aldosteronism (UPA) suffer from persisting hypertension after unilateral adrenalectomy.

Objective

The objective of this work is to develop and validate a nomogram-based preoperative score (NBPS) to predict clinical outcomes after unilateral adrenalectomy for UPA.

Design and Setting

The NBPS was developed in an Asian cohort by incorporating predictors independently associated with remission of hypertension after unilateral adrenalectomy for UPA and validated in a Caucasian cohort.

Participants

Participants comprised patients with UPA achieving complete biochemical success after unilateral adrenalectomy.

Main Outcome Measure

Measurements included the predictive performance of the NBPS compared with 2 previously developed outcome prediction scores: aldosteronoma resolution score (ARS) and primary aldosteronism surgical outcome (PASO) score.

Results

Ninety-seven of 150 (64.7%) patients achieved complete clinical success after unilateral adrenalectomy in the training cohort and 57 out of 165 (34.5%) in the validation cohort. A nomogram was established incorporating sex, duration of hypertension, aldosterone-to-renin ratio, and target organ damage. The nomogram showed good C indices and calibration curves both in Asian and Caucasian cohorts. The area under the receiver operating characteristic curve (AUC) of the NBPS for predicting hypertension remission in the training cohort was 0.853 (0.786-0.905), which was superior to the ARS (0.745 [0.667-0.812], P = .019) and PASO score (0.747 [0.670-0.815], P = .012). The AUC of the NBPS in the validation cohort was 0.830 (0.764-0.884), which was higher than the ARS (0.745 [95% CI, 0.672-0.810], P = .045), but not significantly different from the PASO score (0.825 [95% CI, 0.758-0.880], P = .911).

Conclusion

The NBPS is useful in predicting clinical outcome for UPA patients, especially in the Asian population.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension, with a prevalence of nearly 5% to 10% in the general population with hypertension and as high as 20% in patients with resistant hypertension (1-4). The inappropriate elevation of the plasma aldosterone concentration (PAC) predisposes patients with PA to an increased risk of cardiovascular, cerebrovascular, and renal complications compared with age-, sex-, and blood pressure–matched patients with essential hypertension (5, 6). PA is typically classified into unilateral and bilateral subtypes, with unilateral PA (UPA) mainly caused by an aldosterone-producing adenoma. UPA can be biochemically cured, with complete resolution of hyperaldosteronism after unilateral adrenalectomy. In contrast, nearly half of patients with UPA suffer from persisting hypertension after unilateral adrenalectomy (7-9). According to the Primary Aldosteronism Surgical Outcome (PASO) study, only 37% (17%-63%) of patients with UPA achieved complete clinical success after unilateral adrenalectomy, defined as normalization of blood pressure without antihypertensive medication (10). Thus, for clinicians and patients to have realistic expectations of clinical outcomes, it is crucial for them to be aware of predictors of complete clinical success before they undergo surgery.

It has previously been reported that sex, duration of hypertension, and body mass index (BMI) are preoperative predictors of clinical outcome after unilateral adrenalectomy for UPA (11-15). To use these parameters in clinical practice, an aldosteronoma resolution score (ARS) was established (16) that incorporated sex, duration of hypertension, number of preoperative antihypertensive drugs, and BMI in a points system to predict 3 levels (low, medium, and high) of likelihood of complete clinical success. The ARS performed well in an American cohort (17) and a Japanese cohort (18) but not in a French cohort (19). Utsumi et al also used a nomogram to estimate hypertension remission in UPA by incorporating age, female sex, duration of hypertension, and number of antihypertensive drugs (20), although this normogram was tested only in a Japanese cohort. Recently, using clinical data from 8 different international centers, a primary aldosteronism surgical outcome (PASO) score was also developed (21) that additionally employed target organ damage (TOD) and adrenal nodule size on imaging as predictive factors. However, these predictive scores did not use certain pivotal clinical and biochemical predictors of hypertension remission in UPA. It was recently reported that the PAC post–saline infusion test (SIT) (22) and medical history of diabetes (23) can predict hypertension remission in UPA. Additionally, the aldosterone-to-renin ratio (ARR) is also associated with hypertension remission in UPA, although the association existed only in univariate analysis (24).

The present study is an international, multicenter, multiethnic study that comprehensively evaluated potential clinical and biochemical predictors of hypertension remission in UPA by stepwise selection. The selected predictors were incorporated into a novel user-friendly nomogram-based preoperative score (NBPS). We also compared the predictive performance of NBPS with the previously developed ARS and PASO score.

Materials and Methods

Study cohort

Patient data were collected from 3 international hypertension referral centers between April 6, 2014, and February 22, 2020 (Chongqing, China [n = 163]; Munich, Germany [n = 98]; and Torino, Italy [n = 75]). The Chongqing cohort (Chinese) was used as the training cohort and the Munich/Torino cohort (European) are a subset of patients from the PASO study (10) and were used as the validation cohort. Ethics approval was obtained from local ethics committees in all centers and written informed consent was acquired from all participants. The criterion for inclusion were 1) confirmed diagnosis of UPA according to the Endocrine Society guidelines (25) and as described as follows, and 2) postsurgical follow-up for at least 6 months. The criterion for exclusion were 1) patients with UPA who failed to achieve complete biochemical success after unilateral adrenalectomy, and 2) those with a postsurgical follow-up shorter than 6 months.

Diagnosis of primary aldosteronism and unilateral primary aldosteronism

The diagnosis of PA was achieved in accordance with the Endocrine Society guidelines (25), consisting of case detection, confirmatory testing, and subtype classification. All antihypertensive drugs interfering with case detection were stopped at least 2 weeks before screening (at least 4 weeks for diuretics). At least one diagnostic confirmation test of SIT or captopril challenge testing was used according to local protocols. In the training cohort, UPA was identified by 1) adrenal venous sampling in 132 patients, or 2) typical adenoma on computed tomography scanning and age younger than 35 years, as described previously (26-28), in 18 patients. In the validation cohort, UPA was confirmed by adrenal venous sampling in all patients. Criteria for case detection, confirmation tests, and adrenal venous sampling interpretation are described in the Supplementary Materials (29).

Laboratory measurements

In the Chongqing and Munich cohorts, direct renin concentration (DRC, mU/L) and PAC (pg/mL) were measured using an automated chemiluminescence immunoassay (LIAISON; DiaSorin). In the Torino cohort, PAC (pg/mL) was assessed by solid-phase radioimmunoassay (RIA) ALDOCTK-2 (DiaSorin) and plasma renin activity (PRA, ng/ml/h) was assessed using the RENCTK RIA kit (DiaSorin). For the calculation of the ARR, PRA was converted to DRC using the conversion factor of 8.2 (1 ng/mL/h PRA = 8.2 mU/L DRC) based on the Endocrine Society guidelines (25).

Definition of target organ damage, and medical history of diabetes and hypokalemia

TOD was defined according to the guidelines of the European Society of Hypertension (30), namely, the presence of left ventricular hypertrophy (LVH) and/or microalbuminuria. LVH was assessed by echocardiography and was defined as a left ventricular mass index greater than 115 g/m² for men and greater than 95 g/m² for women; microalbuminuria was defined as a 24-hour urinary albumin between 30 and 300 mg or by an albumin-to-creatinine ratio of 30 to 300 mg/g. Medical history of diabetes was defined according to the 2015 American Diabetes Association criteria (31) as a fasting plasma glucose level greater than 7.8 mmol/L and/or a postprandial 2-hour plasma glucose level greater than 11.1 mmol/L. Hypokalemia was defined as a serum concentration of potassium lower than 3.5 mmol/L.

Definition of biochemical outcome and clinical outcome

Biochemical and clinical outcomes were classified as complete, partial, or absent success and were defined according to the PASO criteria (10).

Blood pressure measurements

In both cohorts, office blood pressure was measured according to the European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension (32, 33). Detailed methods have been described previously (26, 34) and are available in the Supplementary Materials (29).

Development and validation of the nomogram and the nomogram-based predictive score

Univariate and multivariate logistic regression analyses were used to identify predictors of hypertension remission in patients with UPA. A nomogram was developed based on the results of multivariate logistic regression analyses and by using the rms and forign package of R, version 3.6.1 (http://www.r-project.org/). The nomogram was established by proportionally converting each regression coefficient in the multivariate logistic regression to a 0- to 100-point scale. The variable with the highest β coefficient (absolute value) was assigned 100 points. The predictive performance of the nomogram was evaluated by concordance index (C index) and calibrated by the bootstrap method; the higher a C index of a nomogram, the better a predictive performance it would achieve (35, 36). An NBPS was established, in which the continuous variables were first categorized into low, medium, or high levels based on data from the entire cohort with the cutoffs of each category determined by tertiles, and each variable was weighted according to its weight in the nomogram.

Statistical analysis

Data distributions were analyzed by Kolmogorov-Smirnov test. Normally distributed variables were expressed as mean ± SD and were analyzed by the student t test. Skewed distributed variables were expressed as median (quartile range) and analyzed after a Z logarithm transformation. Categorical variables (sex and TOD) were expressed as absolute numbers and proportions (percentages, %) and analyzed by chi-square test. All variables significantly associated with hypertension remission were candidates for stepwise multivariate analysis (forward). All analyses were performed using SPSS, version 21.0. Receiver operating characteristic (ROC) curve analysis was used to calculate the predictive performance of the NBPS, ARS, PASO score, and the nomogram established by the Japanese team and were performed using MedCalc software 8.1.1.0. In all analyses, P less than .05 was considered statistically significant.

Results

A total of 315 cases of UPA with postsurgical complete biochemical success were included in the present study, with the training cohort comprising 150 cases and the validation cohort comprising 165 cases (Fig. 1).

Ninety-seven out of 150 cases (64.7%) achieved complete clinical success after unilateral adrenalectomy in the training cohort at 6- to 12-month postsurgical follow-up. In the training cohort, patients with complete clinical success were younger (43.6 ± 12.8 vs 48.9 ± 10.6, P = .011), more frequently female (78.4% vs 43.4%, P < .001), had a shorter duration of hypertension (3.0 [1.0-8.0] vs 8.0 [3.0-13.5], P = .001), and a lower BMI (22.7 ± 2.7 vs 24.8 ± 3.5, P < .001) compared with patients in the partial plus absent clinical success group. Patients with complete clinical success also had a lower systolic blood pressure (153.4 ± 17.6 vs 160.7 ± 17.4, P = .016), a higher preoperative ARR (293.5 [95.8-487.1] vs 89.8 [43.1-195.4], P < .001), a higher PAC post-SIT (288.0 [180.5-465.0] vs 208.0 [133.0-308.0], P = .013), and a lower incidence of medical history of diabetes (8.2% vs 28.3%, P = .002). As for TOD, the prevalence of LVH was lower in those with postsurgical complete clinical success (40.2% vs 77.4%, P < .001), but the incidence of microalbuminuria was not significantly different between the 2 groups (47.9% vs 57.1%, P = .483). The overall prevalence of TOD was lower in those with postsurgical complete clinical success (56.7% vs 86.8%, P < .001). The prevalence of family history of hypertension, the defined daily dose (DDD) of antihypertensive drugs and the largest adrenal nodule size at imaging were not significantly different between the 2 groups (Table 1).

In the validation cohort, 57 of 165 cases (34.5%) achieved complete clinical success after unilateral adrenalectomy at postsurgical follow-up. In line with the training cohort, UPA patients with postsurgical complete clinical success in the validation cohort were also younger (44.9 ± 10.4 vs 52.9 ± 10.3, P < .001), more frequently female (64.9% vs 32.4%, P < .001), and had a shorter duration of hypertension (5.1 [1.3-7.6] vs 8.0 [3.0-13.5], P < .001) and a lower BMI (25.0 ± 4.3 vs 28.3 ± 4.5, P < .001) compared with patients with partial or absent clinical success. Patients with complete clinical success in the validation cohort also had a lower systolic blood pressure (155.2 ± 20.9 vs 164.8 ± 26.2, P = .019) and a higher preoperative ARR (178.3 [84.2-291.0] vs 56.3 [15.0-145.5], P < .001). As for TOD, the prevalence of LVH was lower in those with postsurgical complete clinical success (42.1% vs 71.3%, P < .001) but the incidence of microalbuminuria was not significantly different between the 2 groups (34.0% vs 41.7%, P = .483). The overall prevalence of TOD was lower in those with postsurgical complete clinical success (50.9% vs 81.5%, P < .001). In contrast to the training cohort, patients with complete clinical success in the validation cohort had a lower DDD of antihypertensive drugs (2.1 [1.5-4.2] vs 4.0 [2.0-5.6], P = .001) and larger nodule size at imaging (15.1 [10.0-21.5] vs 14.0 [9.0-16.7], P = .014) compared with the partial plus absent clinical success group (Supplemental Table 1) (29).

We also compared the clinical and biochemical parameters between the training and validation cohorts. Patients in the training cohort were more frequently female (66.0% vs 43.6%, P < .001) and had a higher incidence of complete clinical success (64.7% vs 34.5%, P < .001) and a higher ARR (201.6 [56.6-445.6] vs 87.4 [27.8-219.2], P < .001). In addition, patients in the training cohort were younger (45.5 ± 12.3 vs 50.2 ± 11.0, P < .001) and had a lower duration of hypertension (4.0 [1.0-10.0] vs 7.4 [3.2-14.6], P < .001), lower BMI (23.5 ± 3.2 vs 27.2 ± 4.8, P < .001), lower systolic blood pressure (156.0 ± 17.9 vs 161.5 ± 24.9, P = .026), and a lower DDD of antihypertensive medication (2.0 [1.0-2.7] vs 3.3 [2.0-5.0], P < .001) (Supplemental Table 2) (29).

Univariate and multivariate logistic regression analysis were used to identify predictors of hypertension remission in UPA in the training cohort. Univariate analysis showed that age (odds ratio [OR], 0.964 [95% CI, 0.937-0.992]; P = .012), duration of hypertension (OR, 0.938 [95% CI, 0.891-0.986]; P = .012), female sex (OR, 4.720 [95% CI, 2.282-9.766); P < .001), BMI (OR, 0.794 [95% CI, 0.705-0.895]; P < .001), systolic blood pressure (OR, 0.977 [95% CI, 0.958-0.996]; P = .018], ARR (OR, 1.788 [95% CI, 1.328-2.407]; P < .001], PAC post-SIT (OR, 1.723 [95% CI, 1.154-2.574]; P = .008), absence of medical history of diabetes (OR, 0.228 [95% CI, 0.089-0.582], P = .002), and absence of TOD (OR, 0.199 [95% CI, 0.082-0.486], P < .001) were associated with complete clinical success in UPA (Table 2). All variables significantly associated with hypertension remission (P < .05) in the univariate analysis were candidates for stepwise multivariate analysis (forward). Four variables were independent predictors of complete clinical success in the multivariate analysis (Table 3). Female sex was the strongest independent predictor (OR, 5.374 [95% CI, 2.257-12.792]; P < .001), followed by ARR (OR, 2.183 [95% CI, 1.503-3.169]; P < .001), duration of hypertension (OR, 0.910 [95% CI, 0.854-0.970]; P = .004), and absence of TOD (OR, 0.278 [95% CI, 0.099-0.783]; P = .015).

A nomogram was established by incorporating the 4 significant parameters from the multivariate analysis (sex, ARR, duration of hypertension, and TOD) (Fig. 2A). The nomogram demonstrated a good accuracy in predicting hypertension remission in UPA, with a bootstrap-corrected C-index of 0.842 (95% CI, 0.774-0.897). In addition, calibration plots showed good agreement between the actual status of hypertension remission and the probability of hypertension remission estimated by the nomogram (Fig. 2B). In the validation cohort, the nomogram also displayed a good C-index of 0.833 (95% CI, 0.767-0.886) for the prediction of hypertension remission in UPA and a good agreement in the calibration plots (Fig. 2C).

To facilitate routine clinical use, the NBPS was established. In the NBPS model, 4 predictors were weighted according to their weight in the nomogram. Categorical variables of sex and TOD were weighted 3.5 (for female) and 2.5 (for absence of TOD) points, respectively. The continuous variables ARR and duration of hypertension were categorized into low, medium, or high levels according to the nomogram. In the NBPS, low, medium, or high levels of ARR (pg^.mL^–1/mIU^.L^–1) were defined as 60 or less, 60.1 to 180, or greater than 180 and were weighted 0, 5, and 10 points, respectively. The duration of hypertension (in years) was categorized as 5 or less, 5.1 to 10, and greater than 10 and weighted 6, 3, 0 points, respectively (Table 4).

We then compared the predictive performance of NBPS to the previously established ARS and PASO score in predicting hypertension remission in UPA. The ARS and PASO score of all UPA patients were calculated as previously described (16, 21). In the training cohort, compared with those without complete clinical success (partial plus absent clinical success), patients with complete clinical success had a higher ARS and PASO score (4.0 [3.0-5.0] vs 3.0 [2.0-4.0]; P < .001) and (19.0 [16.0-21.0] vs 15.0 [12.5-17.0]; P < .001), respectively. The NBPS in patients with complete clinical success was also significantly higher than the partial plus absent clinical success group (16.5 [13.5-19.5] vs 8.5 [6.0-12.5]; P < .001). In the validation cohort, those with complete clinical success also had a higher ARS and PASO score compared with those in the partial plus absent complete clinical success group (3.00 [2.00-4.50] vs 1.00 [0.00-2.00]; P < .001) and (18.00 [14.50-21.75] vs 12.00 [9.13, 14.38]; P < .001), respectively. The NBPS in patients with complete clinical success was also significantly higher than the partial plus absent clinical success group (14.5 [10.5-17.0] vs 6.0 [3.5-10.5]; P < .001) (Supplemental Table 3) (29). In the training cohort, ROC curve analysis revealed that NBPS could accurately predict remission of hypertension, with an area under ROC curve (AUC) of 0.853(0.786-0.905), which was superior to that of the ARS (0.745 [95% CI, 0.667-0.812]; P = .019) and PASO score (0.747 [95% CI, 0.670-0.815]; P = .012) (Fig. 3A). In the validation cohort, the AUC of the NBPS was 0.830 (0.764-0.884), which was superior to that of the ARS (0.745 [95% CI, 0.672-0.810]; P = .045) but not significantly different from the PASO score (0.825 [95% CI, 0.758-0.880]; P = .911) (Fig. 3B). We also compared our NBPS to the nomogram established by the Japanese team (20) and found that the AUC of the NBPS is superior in the training cohort (0.853 [0.786-0.905] vs 0.731 [95% CI, 0.653-0.800]; P = .005), although no significant difference was found in the validation cohort (0.830 [0.764-0.884] vs 0.770 [95% CI, 0.698-0.832]; P = .157) (Supplemental Fig. 1) (29).

The optimal cutoff of the NBPS for the prediction of hypertension remission was 11.5 or greater, with a sensitivity of 85.6% (77.0%-91.9%) and a specificity of 71.7% (57.7%-83.2%) in the training cohort and a sensitivity of 68.4% (54.8%-80.1%) and a specificity of 78.7% (69.8%-86.0%) in the validation cohort (Table 5). If we use a cutoff for the NBPS of greater than or equal to 16.5, the specificity of the NBPS increases to 94.3%; whereas using an NBPS cutoff of 8.5 or greater increases the NBPS sensitivity to 95.9% (Supplemental Table 4) (29).

Discussion

In the present study, we found the ARR to be a robust predictor of hypertension remission and established an NBPS for the prediction of clinical outcome for UPA patients in a large international, multiethnic cohort. Our newly developed NBPS was useful to predict remission of hypertension in patients diagnosed with UPA after adrenalectomy, especially in Asian patients.

Efforts have been made to establish an outcome-prediction model (16, 21) in UPA. ARS and PASO score both performed well in predicting the likelihood of hypertension remission following the surgical treatment of UPA. However, these scores did not incorporate several recently reported predictors of hypertension remission (22, 23) whereas the present study comprehensively evaluated all the relevant clinical and biochemical parameters. Consistent with the previously developed ARS and PASO score, our NBPS presented herein also employed female sex, duration of hypertension, and absence of TOD as predictors of hypertension remission in UPA. However, BMI was excluded because its correlation with hypertension remission appeared only in the univariate analysis. Additionally, the preoperative number of antihypertensive drugs (DDD) and adrenal nodule size were also excluded because these variables were not significantly different between those with complete clinical success and those without. The difference in parameters between the NBPS and PASO score could be attributed to the relatively lower predictive performance of BMI and adrenal nodule size, as shown by the borderline OR in the PASO study (21). The DDD of antihypertensive drugs was excluded because its association with hypertension remission may be directly related to the duration of hypertension and ARR.

In addition to the 3 abovementioned clinical characteristics, we also found the ARR to be a robust predictor of hypertension remission in UPA patients. The difference in ARR between training and validation cohorts (201.6 vs 87.4) could be partially attributed to referral bias because there is a lower level of awareness of PA case detection in China compared to Japan and Italy, so the majority of PA patients have a more pronounced hyperaldosteronism in the hypertension referral center in China. The role of the ARR in predicting hypertension remission in UPA has been investigated in several studies. In a Taipei cohort, Chan et al found that the ARR in those with complete clinical success were significantly higher than those without (22). Sawka et al also reported an association of a higher preoperative ARR with hypertension remission in UPA, but the association was found only in univariate analysis (24). Though there were significant differences in the ARR between the training and validation cohorts, our results demonstrated that the ARR in those with complete clinical success was significantly higher than those without in the training and validation cohorts alike. A multivariate analysis also confirmed the ARR as a strong independent predictor of hypertension remission in UPA. We speculate that UPA patients with a higher ARR at the time of screening were more likely to have severe disease (such as higher blood pressure and hypokalemia) and were therefore diagnosed and treated in a timely manner, enabling better clinical outcomes after surgery.

In the present study, by incorporating the selected components of ARS and PASO score in addition to the ARR into the NBPS, we developed a useful clinical outcome prediction tool for UPA patients. Further analyses revealed that the AUC of the NBPS is higher than that of ARS and PASO in the training cohort, and not significantly different from the PASO score in the validation cohort. The NBPS provides additional value to the PASO score in some ways. On the one hand, the NBPS was developed in an Asian cohort, and its AUC is significantly higher than the PASO score (0.85 [0.79-0.91] vs 0.75 [0.67-0.82]; P = .012). The validation of the NBPS was conducted in a Caucasian cohort, and the AUC was similar to the PASO score. It should be noted that the characteristics of UPA (ie, the prevalence of KCNJ5 mutation and tumor size) were different between Caucasian and Asian patients (37). Our analyses indicated that the NBPS is applicable both to Caucasian and Asian patients, with a superior performance in the Asian population. On the other hand, the use of fewer variables (4 in NBPS vs 6 in PASO) and visualized scoring of the nomogram ensures that the NBPS is user-friendly. We also develop an online calculator (38) to allow easier adoption into clinical practice of our nomogram.

Utsumi and colleagues also used a nomogram to estimate hypertension remission in UPA by incorporating age, female sex, duration of hypertension, and number of antihypertensive drugs (20). Our newly developed nomogram, after multiethnic training and validation, excluded parameters of age and the number of antihypertensive drugs and additionally included ARR and TOD. Furthermore, we converted our nomogram into a more user-friendly score, which should facilitate its wide clinical use. A comparison of our NBPS with the nomogram established by the Japanese team (20) revealed that the AUC of the NBPS performed better than the nomogram in the training cohort, although no significant difference was found in the validation cohort. Taken together, our results indicated that the newly developed NBPS offers an improvement over the previously published nomogram.

The incidence of complete clinical success differed between the training and validation cohorts, being much higher in the training cohort (64.7% vs 34.5%). The difference could partially be explained by ethnic differences. According to our unpublished data, the prevalence of somatic KCNJ5 mutations in patients with UPA in the training cohort was 76.7%, which is much higher than the reported 35% in the Caucasian population (37). It is reported that patients with UPA with KCNJ5 mutations have a higher probability of complete clinical success after adrenal surgery (39). The shorter duration of hypertension, higher prevalence of female patients, and younger age in the training cohort could also explain the higher clinical remission rate.

Our study has several strengths. First, we comprehensively evaluated clinical and biochemical predictors of hypertension remission in UPA, and all the parameters enrolled in the NBPS were subjected by stepwise selection. Second, the NBPS was developed and validated in different ethnic cohorts, and our results indicate that the NBPS is applicable to UPA patients with differences in severity and clinical presentation. Furthermore, the present study excluded patients with UPA with partial or absent biochemical success because the lack of complete biochemical success (largely due to wrong judgment of lateralization or incompletely excised aldosterone-producing tissues) would confound the main outcome. Thus, eliminating those patients may increase the reproducibility of our results. A potential limitation of the NBPS is the inability to differentiate patients with partial clinical success from those with absent clinical success. In addition, not all patients with UPA in hypertension referral centers underwent echocardiography and microalbuminuria measurement, and this may be a limiting factor with the present nomogram. However, it is feasible for the majority of PA referral centers to pursue these investigations and fully use our NBPS.

Conclusions

In conclusion, we found the ARR to be a robust predictor of hypertension remission in UPA and established an NBPS for the prediction of clinical outcomes following unilateral adrenalectomy for UPA patients in a large international, multiethnic cohort. The NBPS could accurately predict hypertension remission for UPA patients, especially in the Asian population. Patients with a higher NBPS preoperatively are more likely to achieve complete resolution of their hypertension after unilateral adrenalectomy. In contrast, patients with a lower NBPS were more likely to experience ongoing hypertension and should be closely monitored following surgery with a low threshold for reinitiating antihypertensive therapy.

Novelty and Significance

What is new?

For the prediction of clinical outcomes after surgery for UPA patients, we found the ARR to be a robust predictor. Furthermore, an NBPS was developed and validated on the basis of a large international, multiethnic cohort.

What is relevant?

Our study provides valuable information for clinicians about the pros and cons of adrenal surgery for UPA patients and may help guide their postsurgical follow-up.

Summary

On the basis of a large international, multiethnic cohort, we found the ARR to be a robust predictor of clinical outcome for UPA patients and developed and validated a novel NBPS. The newly developed NBPS was particularly useful in predicting clinical outcomes for UPA patients in the Asian population. These data may provide valuable information for treatment and postsurgical follow-up for UPA patients.

Abbreviations

Abbreviations
 
• ARS

  aldosteronoma resolution score

 
• AUC

  area under receiver operating characteristic curve

 
• BMI

  body mass index

 
• DDD

  defined daily dose

 
• DRC

  direct renin concentration

 
• LVH

  left ventricular hypertrophy

 
• NBPS

  nomogram-based predictive score

 
• PA

  primary aldosteronism

 
• PAC

  plasma aldosterone concentration

 
• PASO

  primary aldosteronism surgical outcome

 
• PRA

  plasma renin activity

 
• SIT

  saline infusion test

 
• TOD

  target organ damage

 
• UPA

  unilateral primary aldosteronism

Acknowledgments

The authors thank the Membership of the Chongqing Primary Aldosteronism Study (CONPASS) Group: Suxin Luo, MD, PhD; Kangla Liao, MD; Yao Zhang, MD, PhD; Yunfeng He, MD, PhD; Yihong He, MD; Ming Xiao, PhD; and Bin Peng, PhD. The authors also thank Laboratory of Endocrine and Laboratory of Lipid and Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University.

Financial Support: This work was supported by the National Natural Science Foundation of China (Grants 81670785, 81800701, 81870567, 81800731 and 81970720); Outstanding Talents Foundation of the First Affiliated Hospital of Chongqing Medical University (Grant 2019-4-22); and Chongqing Outstanding Youth Funds (Grant cstc2019jcyjjq0006).

Clinical Trial Information: ClinicalTrials.gov registration No. NCT03224312 (registered July 29, 2013).

Author Contributions: Conception and design: Q.F. Li, S.M. Yang, J.B. Hu, and Y. Yang; analysis and interpretation of the data: J.B. Hu and Y. Yang; drafting of the article: Y. Yang, J. Yang, S.M. Yang, and K.R. Wang; critical revision of the article for important intellectual content: J.B. Hu, Q.F. Li, J. Burrello, P. Mulatero, T.A. Williams, and M. Reincke; statistical expertise: J.B. Hu and K.R. Wang; obtaining of funding: Q.F. Li, S.M. Yang, Y. Song, and J.B. Hu; administrative, technical, or logistic support: Y. Song, Ting Luo, and W.W. He; collection and assembly of data: W.W. He, Q.F. Cheng, L.Q. Ma, J. Burrello, P. Mulatero, T.A. Williams, and M. Reincke. All authors have read the journal’s authorship agreement and the manuscript has been reviewed by and approved by all named authors.

Additional Information

Current Affiliations: Drs Yi Yang, Jinbo Hu, Ying Song, Wenwen He, Qingfeng Cheng, Linqiang Ma, Ting Luo, Shumin Yang, Qifu Li: Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Drs Jun Yang: Cardiovascular Endocrinology Laboratory, Hudson Institute of Medical Research, Clayton, Vic, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia. Drs Tracy Ann Williams and Martin Reincke: Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany. Drs Jacopo Burrello and Paolo Mulatero: Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Italy.

Disclosure Summary: The authors have nothing to disclosed.

Data Availability

The study protocol and statistical code are available from the corresponding author, and data are available to approved individuals through written agreements with the authors and the data partner.

References

Author notes