Predictive model for persistent hypertension after surgical intervention of primary aldosteronism

doi:10.21203/rs.3.rs-1977306/v1

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Predictive model for persistent hypertension after surgical intervention of primary aldosteronism

https://doi.org/10.21203/rs.3.rs-1977306/v1

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Background: Primary aldosteronism (PA) is one of the most common causes of secondary hypertension and is potentially curable. However, a large number of patients still undergo persistent hypertension (PHT) after unilateral adrenal surgery. This research retrospectively studied the factors associated with this clinical difficulty and established a prediction model for the postoperative PHT;

Methods: 353 patients from 2014 to 2021 with PA undergoing unilateral adrenal surgery were enrolled in this study. Clinical and biochemical characteristics were reviewed and the associating factors were examined using univariate and multivariate analysis. A nomogram-based prediction model was established correspondingly;

results: 46.2% (163/190) of patients had post-surgical PHT. Multivariate analysis suggested that BMI≥25, diabetes, duration of hypertension, male gender, and ARR were independent predictors of PHT after surgery. The prediction model based on the nomogram showed good discrimination ability (the C index of the training group and the validation group were 0.783 and 0.769, respectively), and the calibration curves were good as well. Clinical usefulness was quantified using the decision curve analysis (DCA);

Conclusion: This nomogram is an integration of the clinical and biochemical data of patients before surgery, and is a reliable tool with high accuracy for predicting the postoperative PHT in patients with PA.

primary aldosteronism

nomogram

clinical outcome

adrenalectomy

persistent hypertension

Primary aldosteronism (PA) is an abnormally high secretion of aldosterone of the adrenal cortex, leading to the increase of plasma aldosterone concentration, the inhibition of renin activity, and hence a syndrome, namely Conn syndrome, manifested with hypertension, hypokalemia, and metabolic alkalosis. PA is a common cause of secondary hypertension, often resulting in resistant hypertension (RH). Many previous reports have reported that when blood pressure is matched, patients with PA are more likely to suffer cardiovascular and cerebrovascular events and target organ damages due to the abnormal increased plasma aldosterone. In China, the prevalence of PA in hypertensive population is at least 4% [1].

The main types of PA include: 1) idiopathic hyperaldosteronism (bilateral adrenal hyperplasia); 2) aldosterone-producing adenomas, APA; 3) unilateral adrenal hyperplasia, UNAH; 4) familial hyperaldosteronism, FH; 5) pure aldosterone-producing adrenocortical carcinoma, ACC [2]. Surgical removal of the tumor or the whole gland is generally employed in patients with APA or UNAH in hope that the associating clinical symptoms relieves along with the decrease of abnormally elevated aldosterone in plasma. Previous studies indicate that the most of patients with PA can achieve biochemical cure (83%-100%) after surgery. However, the clinical cure rate is generally low (17%-72%) in all studies [3,4,5]. Thus, it is of great importance to identify those potential patients who are not likely to benefit from the surgery. This could help the clinicians to better assess the postoperative clinical results and to strengthen the follow-up of the target population.

Patient collection

This retrospective study was approved by local institutional ethics committee. Because there was no patient interest or privacy, informed consent was waived after careful review by the ethics committee. A total of 1277 underwent adrenal operation at the Department of Urology, The First Affiliated Hospital of Chongqing Medical University, between January 2014 to June 2021. The criterion for inclusion were: 1) preoperative diagnosis of PA according to Endocrine Society guidelines; 2) preoperative diagnosis of hypertension (with or without hypokalemia); 3) perform unilateral adrenal surgery. Patient were excluded with any of following conditions: 1) those failed to achieve complete biochemical success after surgery; 2) suffering from other known diseases that can cause secondary hypertension; 3) those with incomplete clinical data or with a follow-up shorter than 6 months after discharge. A total of 353 eligible patients were ultimately included in this study. (Figure 1)

Diagnosis and subtyping of PA

The diagnosis of PA is based on the Endocrine Society guidelines. Antihypertensive drugs interfering with detection should be withdrawn for at least two weeks before aldosterone/renin ratio (ARR) detection testing. Diuretics should be stopped at least four weeks (including mineralocorticoid receptor antagonist). The cut-off for detection test is a ARR higher than 20 pg·mL^-1/uIU·mL^-1. Patients with suspected PA must use at least one confirmatory test (captopril challenge test, saline infusion test, fludrocortisone suppression test) [2]. Patients with confirmed PA underwent computed tomography (CT) and adrenal venous samples (AVS) to locate the corresponding lesions. In our study, 235 patients underwent AVS and another 118 patients underwent CT, and all the patients were diagnosed with unilateral PA. (Supplementary materials)

Definition of HHD, diabetes, and RH

The hypertensive heart disease (HHD) is diagnosed with the history of hypertension and the heart dysfunction showed in cardiac color Doppler ultrasound examination. According to the 2015 American Diabetes Association, diabetes mellitus is defined as fasting blood glucose greater than 7.0mmol/L or blood glucose greater than 11.1mmol/L two hours after the OGTT experiment [6]. Resistant hypertension (RH) is defined as the inability to reduce blood pressure (BP) to the normal range with at least three or more antihypertensive drugs (including diuretics) [7].

Surgical procedure

Spironolactone (200-400mg/d), irbesartan, nifedipine and other routine antihypertensive agents were used to lower BP during preoperative period (under 140/90 mmHg or 150/90 mmHg in routine patients or RH patients respectively). Oral or intravenous potassium supplementation was used to correct hypokalemia (if present), and to maintain serum potassium greater than 4.0mmol/L before surgery. All patients underwent retroperitoneal laparoscopic surgery. ALL surgeries were performed by surgeons of equal seniority. Adrenal tumors or nodules were removed in surgery. However, when there was no obvious tumor or multiple tumors existed in adrenal gland, a total adrenalectomy was performed.

Definition of postoperative outcome

We reviewed the complete medical records of all patients with PA undergoing adrenal surgery at the First Affiliated Hospital of Chongqing Medical University. According to PASO criteria，BP is assessed at 6 to 12 months after surgery. Patients were categorized as PHT if they had partial or absent clinical success, which means they still underwent hypertension or continued need antihypertensive medications to control BP. Normal BP postoperatively (complete clinical success) is defined as BP in the normal range (SBP＜140mmHg and DBP＜90mmHg）without taking any antihypertensive drugs. The detail methods of blood pressure measurement are described in supplementary materials.

Statistical analysis

Date distributions were analyzed by Kolmogorov-Smirnov test. Normally distributed variables were expressed as mean ± SD and were analyzed by the student t test. Otherwise, it was expressed as median (quartile range), and Mann-Whitney U test was used for it. Logarithmic transformation was used for skewed distribution data to make it normal. Chi-square test or Fisher's exact test was used to compare categorical variables. On the basis of univariate logistic regression, multicollinearity diagnostic method was carried out to eliminate variables with common causes and obvious intermediary variables. In R software, the sample.split function in the caTools of R package was used to divide the data set. All patients were divided into the training set (70%) or the validation set (30%). A nomogram predicting post-surgical PHT was established based on the results of univariate and multivariate analyses. Receiver operating characteristic (ROC) curve, concordance index (C-index) and calibration plot were used to measure the predictive ability of the nomogram. In order to evaluate the clinical usefulness of the nomogram, decision curve analysis (DCA) was used to calculate the net benefits at different threshold probabilities. SPSS 26.0 was used in all analyses, and graphs were generated using R software. In these analyses, P<0.05 was considered statically significant different.

Patient characteristics

A total of 353 patients were included in the analysis (142 males and 211 females). Among them, a total of 163 patients (46.2%) had postoperative PHT, and the mean age at surgery was about 44 years. PHT occurred more frequently in men (52.1% vs 30.0%, P＜0.001), and in patients with advanced ages (43.0 [43.0-55.5] vs 45.0 [35.0-54.8], P=0.001). In addition, compared with those patients who had normal BP (complete clinical success) after surgery, patients with PHT generally had higher systolic blood pressure (184 [175-200] vs 180 [166-190], P＜0.001), hyper BMI values (BMI≥25, 49.1% vs 26.8%, P＜0.001), longer duration of hypertension (8.0 [3.0-10.0] vs 3.0 [0.81-7.0], P＜0.001), more frequent presence of diabetes mellitus (27.0% vs 5.8%, P <0.001), HHD (34.4% vs 16.8% , P＜0.001) and RH (39.9% vs 23.2%, P=0.001), higher DDD of antihypertensive medications (3.6 [2.6-4.4] vs 3.0 [2.5-4.0], P=0.003), lower preoperative ARR (270 [110-541] vs 404 [154-674], P=0.002), lower PAC (293 [192-459] vs 351 [255-533], P=0.006), higher DRC(1.09 [0.50-2.34] vs 0.79 [0.50-1.79], P=0.045), and lower eGFR (96.0 [75.6-109.2] vs 107.2 [91.3-119.5], P＜0.001), higher serum potassium nadir (2.70 [2.40-3.00] vs 2.60 [2.16-2.90], P=0.016), and smaller diameter of nodules (1.4 [1.0-1.7] vs 1.5 [1.0-2.0], P=0.017). (table1)

Table1 Preoperative clinical and biochemical characteristics of all patients（training + validation group）

Characteristics	Total	Persistent hypertension（n=163）	Normal blood pressure（n=190）	P
Age，y	44.0（38.0-55.0）	43.0（43.0-55.5）	45.0（35.0-54.8）	0.001
Sex，M/F	142/211（38.1%）	85/78（52.1%）	57/133（30.0%）	＜0.001
SBP，mmHg	180（170-200）	184（175-200）	180（166-190）	＜0.001
DBP，mmHg	110（100-120）	110（100-120）	110（100-120）	0.011
BMI≥25，yes/no	131/222（37.1%）	80/83（49.1%）	51/139（26.8%）	＜0.001
Duration of HT，y	5.0（1.0-10.0）	8.0（3.0-10.0）	3.0（0.81-7.0）	＜0.001
Family history of HT，yes/no	121/232（34.3%）	63/100（38.7%）	58/132（30.5%）	0.136
Diabetes，yes/no	55/298（21.8%）	44/119（27.0%）	11/179（5.8%）	＜0.001
HHD，yes/no	88/265（24.9%）	56/107（34.4%）	32/158（16.8%）	＜0.001
RH，yes/no	109/244（30.9%）	65/98（39.9%）	44/146（23.2%）	0.001
DDD of antihypertensive medication	3.6（2.6-4.4）	3.6（2.6-4.4）	3.0（2.5-4.0）	0.003
ARR，pg·mL^-1/uIU·mL^-1	340（135-618）	270（110-541）	404（154-674）	0.002
PAC，pg/mL	326（214-503）	293（192-459）	351（255-533）	0.006
DRC，uIU/mL	0.96（0.50-2.10）	1.09（0.50-2.34）	0.79（0.50-1.79）	0.045
Lowest serum K⁺，mmol/L	2.68（2.20-300）	2.70（2.40-3.00）	2.60（2.16-2.90）	0.016
eGFR，（mL/min/1.73m²）	101.2（82.9-114.4）	96.0（75.6-109.2）	107.2（91.3-119.5）	＜0.001
TC，mmol/L	4.03±0.83	4.08±0.90	3.99±0.76	0.297
TG，mmol/L	1.15（0.80-1.63）	1.33（0.98-1.89）	0.98（0.73-1.40）	＜0.001
Diameter of noduler，cm	1.5（1.0-2.0）	1.4（1.0-1.7）	1.5（1.0-2.0）	0.017
Surgical side, L/R	208/145（58.9%）	98/65（60.1%）	110/80（57.9%）	0.752
Total adrenalectomy, yes/no	204/149（52.0%）	97/66（59.5%）	107/83（56.3%）	0.619

SBP, systolic blood pressure; DBP, diastolic blood pressure; HT, hypertension; HHD, hypertensive heart disease; RH, resistant hypertension; DDD, defined daily dose; ARR, aldosterone/renin ratio; PAC, plasma aldosterone concentration; DRC, direct renin concentration; Lowest serum K⁺, lowest serum potassium in history; eGFR, estimated glomerular filtration; TC, total cholesterol; TG, triglyceride

Validation group characteristics

There were no significant differences between the training group and the validation group in terms of age, gender, DBP, BMI, duration of hypertension, family history of hypertension, presence of diabetes mellitus, presence of HHD, presence of RH, DDD of antihypertensive medication, ARR, PAC, DRC, lowest serum potassium, eGFR, TC, TG, tumor diameter, and surgical side. (Supplementary table1)

Prediction model

Univariate and multivariate logistic regression analysis were used to determine the predictors of postoperative PHT. Univariate analysis showed that age, gender, SBP, DBP, BMI≥25, duration of HT, presence of diabetes mellitus, HHD, DDD of antihypertensive medication, ARR, PAC, lowest serum potassium, eGFR, and diameter of nodules were all related to PHT after surgery (table2). On the basis of univariate logistic regression analysis, we employed collinearity analysis to eliminate some variables (Supplementary figure). In the multivariate analysis (table3), five variables (BMI≥25, male, diabetes, ARR, duration of hypertension) were all independent risk factors of the PHT.

Table 2 Univariate logistic regression analysis of predictors of hypertension persistence after operation in training group

Variable	OR（95% CI）	P
Age	1.03（1.0-1.06）	0.013
Male	2.60（1.53-4.40）	<0.001
SBP	1.02（1.01-1.04）	<0.001
DBP	1.02（1.01-1.04）	0.005
BMI≥25	3.16（1.84-5.42）	<0.001
Duration of HT	1.13（1.07-1.19）	<0.001
Diabetes	6.89（2.74-17.34）	<0.001
HHD	2.42（1.33-4.43）	0.004
RH	2.13（1.24-3.66）	0.060
DDD of antihypertensive medication	1.33（1.12-1.73）	0.002
ARR	0.42（0.23-0.75）	0.004
PAC	0.13（0.04-0.40）	<0.001
DRC	1.06（0.94-1.20）	0.347
Lowest serum K^＋	1.62（1.05-2.50）	0.030
eGFR	0.98（0.97-0.99）	<0.001
TG	1.14（0.94-1.39）	0.178
Diameter of nodule	0.66（0.46-0.94）	0.022

Data are expressed as odds ratio (OR)(95% CI). SBP, systolic blood pressure; DBP, diastolic blood pressure; HT, hypertension; HHD, hypertensive heart disease; RH, resistant hypertension; DDD, defined daily dose; ARR, aldosterone/renin ratio; PAC, plasma aldosterone concentration; DRC, direct renin concentration; Lowest serum K⁺, lowest serum potassium in history; eGFR, estimated glomerular filtration; TG, triglyceride

Table3 Multivariate logistics regression analysis of predictors of hypertension persistence after operation in training group

Variable	OR（95% CI）	P
BMI≥25	2.07（1.12-3.81）	0.020
Male	2.33（1.27-4.25）	0.006
Diabetes	3.97（1.44-10.92）	0.008
ARR	0.46（0.23-0.92）	0.027
Duration of hypertension	1.12（1.06-1.19）	＜0.001

Data are expressed as odds ratio (OR)(95% CI). ARR, aldosterone/renin ratio

Finally, these five important variables were included to establish a nomogram (Figure 2). The nomogram showed the score of each variable on each scale. The probability of postoperative PHT was determined by the total score of all variables. According to the model, the ROC curve of the training group and the validation group were drawn. The area under the curve (AUC) of the training group was 0.78 (95%CI 0.72-0.84), and the validation group was 0.77 (95%CI 0.68-0.86) (Figure 3). The C index of the training group and the validation group were 0.783 and 0.769, respectively.

The calibration plot revealed excellent agreement between the probability of PHT estimated by the nomogram and the actual status of PHT (Figure 3). These results showed that the nomogram is efficient in predicting PHT after surgery. DCA was performed in the validation group, and the results showed that when the threshold probability was about 10% to 80%, the nomogram produced a greater net benefit than a treat-all or treat-none strategy, indicating that the nomogram had good clinical value (Figure 4).

Our study found that BMI≥25, male gender, history of diabetes mellitus, ARR, and duration of hypertension were reliable predictors for the PHT postoperatively, and the nomogram based clinical prediction model was useful to predict the PHT postoperatively in patients and identify high-risk patients in order to develop a postoperative follow-up plan.

Reported proportions of patients achieving clinical success vary widely between studies (17%-72%) [3,4,5]. The results of our study suggested that 190 patients (53.8%) achieved complete clinical success through surgical treatment, and 163 patients (46.2%) had PHT, which was consistent with previous research reports.

Efforts have been made to establish a predictive model in complete clinical success among PA patients[8,9]. ARS and PASO score both had a high accuracy in predicting the likelihood of hypertension remission after surgery. However, the models for predicting the postoperative PHT are lacking. In addition, ARS score failed to contain several recently reported predictors of surgical outcome, such as ARR. The variable of number of antihypertensive medications which included in ARS can be a robust predictor, whereas DDD of antihypertensive drugs can be a better indicator, because it can better reflect the total consumption[10]. In terms of PASO score, although it included target organ damage into their model, not all patients in hypertension centers underwent microalbuminuria measurements. These may be limitations of these two classical models. Nevertheless, we have established a high accurate prediction model of PHT after surgery, and all the variables are easily obtained preoperatively.

Long-lasting excessive aldosterone in plasma of PA patients can lead to vascular remodeling, ventricular hypertrophy, and myocardial damage [11,12,13,14]. Vascular remodeling may lead to the persistence of hypertension, even if the plasma aldosterone level is normalized by surgery, and the outcome cannot be reversed [15]. We found that the duration of hypertension was an independent risk factor for PHT, and it obtained the highest score in the nomogram. Therefore, early diagnosis and treatment of PA is critical to maximize the benefits of surgery.

Previous studies have shown that higher ARR is related to hypertension remission, but this association was not shown in multivariate analysis. Our study found that lower preoperative ARR was closely associated with postoperative PHT and was a reliable predictor of postoperative hypertension. Patients with lower preoperative serum potassium and higher ARR are more likely to obtain better clinical outcomes. We speculate that it may be related to the early appearance of clinical symptoms.

PA is closely related to metabolic syndrome [16,17,18]. Excessive aldosterone or concomitant hypokalemia increases the risk of diabetes. High aldosterone concentration causes impairment of pancreatic islets β cell function and decreases in sensitivity of target organs to insulin [19,20,21]. The prevalence of PA is at least 19% in patients with new-onset diabetes, which is higher than that in essential hypertension and in general population. The high prevalence of PA in diabetic patients suggests that PA patients are more likely to develop diabetes. In addition, some studies suggested that PA and glucose metabolism may influence with each other [22]. Diabetes complicating PA can increase the progression of cardiovascular events and renal complications [23]. The risk of new-onset diabetes in PA patients undergoing surgery is lower than the matched essential hypertension [19]. We found that high BMI (≥25) and history of diabetes both are independent predictors of the persistence of postoperative hypertension.

Our study aims at identifying patients with PHT, instead of identifying those with postoperative hypertension remission as most models do. This is because these very population (PHT) constitute the majority of the study target (the rate of PHT is 43.2% in this study), but a useful model is lacking. In conclusion, we first established a prediction model for the postoperative PHT. Clinicians could use this nomogram to predict PHT based on clinical and biochemical characteristics, and to strengthen follow-up for high-risk population. Because our present study was a single-center retrospective study, selection deviation is inevitable. In addition, the lack of external validation is a limitation, and relevant prospective multi-center clinical studies should be performed in the future to evaluate the accuracy of the proposed model.

PHT, persistent hypertension; PA, primary aldosteronism; HT, hypertension; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HHD, hypertensive heart disease; RH, resistant hypertension; ARR, aldosterone/renin ratio; PAC, plasma aldosterone concentration; DRC, direct renin concentration; eGFR, estimated glomerular filtration; TC, total cholesterol; TG, triglyceride; SIT, saline infusion test; DCA, decision curve analysis; APA, aldosterone-producing adenomas; UNAH, unilateral adrenal hyperplasia; FH, familial hyperaldosteronism; ACC, pure aldosterone-producing adrenocortical carcinoma; CT, computed tomography; AVS, adrenal venous samples; OGTT, oral glucose tolerance test.

Ethics approval and consent to participate: The studies involving human participants were reviewed and approved by Ethics Committee of the First Affifiliated Hospital of Chongqing Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: None.

Authors' contributions: ZYL, XHW and ZQ designed this study. ZYL, YFH, YZ, GC, YBZ, and YG collected the data, ZYL analyzed the data. All authors contributed to the article and approved the submission version.

Acknowledgements: The authors appreciate all of the staff involved in the preparation of the study.

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No competing interests reported.

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Predictive model for persistent hypertension after surgical intervention of primary aldosteronism

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