Abstract

Context:

The plasma aldosterone concentration (PAC) is less than 5 ng/dL after saline infusion test (SIT) in essential hypertension (EH) and healthy people. It is unclear if the same standard is applicable for Chinese subjects.

Objective and Design:

We assessed the serum aldosterone response after SIT in subjects with primary aldosteronism (PA), EH, and healthy volunteers (normal control, NC), and to investigate the optimal aldosterone level of post-SIT for the diagnosis of PA.

Subjects and Setting:

The study included 120 hypertensive patients who conform to the PA screening criteria and 21 healthy volunteers.

Intervention:

All subjects underwent SIT.

Main Outcome Measures:

PAC was measured in all subjects before and after SIT. The total sodium intake was estimated from 2 timed 24-hour urinary excretion.

Results:

The area under the receiver-operator characteristic curves was higher than under the diagonal (0.967, 95% confidence interval [CI]: 0.94–0.993). The best cutoff value for PAC after SIT for diagnosis of PA was 11.45 ng/dL, with sensitivity and specificity of 88.2% and 95.4%, respectively. The PAC of post-SIT was more than 10 ng/dL in most PA patients, whereas it was greater than 5 ng/dL in both EH and NC except for 1 at 4.93 ng/dL. Serum aldosterone level was unrelated to dietary salt intake.

Conclusions:

The optimal post-SIT aldosterone cutoff value for identifying PA was 11.45 ng/dL in Chinese patients. However, the PAC higher than 5 ng/dL after SIT was found in a majority of EH and healthy subjects. The cutoff value of aldosterone post-SIT is higher than the current clinical recommendations and practice guidelines of The Endocrine Society. We found no relationship between high salt intake and lower responses of renin aldosterone system to high loading with saline infusion.

Primary aldosteronism (PA) has emerged as the most frequent form of secondary hypertension. Compared with patients with essential hypertension (EH), patients with PA show high frequency and concomitant risks of cardiovascular and kidney disease (1, 2). Therefore, early diagnosis and treatment are very important for patients with PA. The aldosterone to renin ratio (ARR) is currently the most recommended screening test for PA (35). Patients with a positive case detection test are required to undergo confirmation via functional testing (6, 7). The Endocrine Society's clinical practice guidelines recommend 4 confirmatory tests: saline infusion test (SIT), oral sodium loading, fludrocortisone suppression, and captopril challenge test (4). The guidelines recommend that a plasma aldosterone concentration (PAC) of less than 5 ng/dL after SIT usually rules out PA, whereas more than 10 ng/dL usually confirms PA (4). However, in our clinical works, we found that the PAC was still more than 5 ng/dL after SIT in many patients with EH (8). This finding suggested that the aldosterone response after saline loading was lower in Chinese subjects. Whether this low response is associated with high-salt diet in Chinese patients is unknown. To the best of our knowledge, no study investigated the optimal aldosterone cutoff value after SIT for identifying PA in Chinese patients. The relationship between aldosterone values and dietary salt intake is also unknown in Chinese. Therefore, in this study, we evaluated the serum aldosterone suppression with iv 2-L normal saline infusion among PA, EH, and healthy volunteers, and investigated the optimal aldosterone cutoff value in post-SIT for PA diagnosis in Chinese subjects. The correlation between estimated sodium intake and serum aldosterone level was also assessed.

Subjects and Methods

Subjects

The present study was conducted in the West China Hospital, Sichuan University. The study protocol was approved by the ethics committee of West China Hospital Sichuan University. The subjects provided informed consent. All subjects were hospitalized during the investigation.

Hypertensive patients

The diagnosis of hypertension was confirmed by established criteria based on consulting room blood pressure (BP) measurement by mercury sphygmomanometer. According to the recommended The Endocrine Society's clinical practice guidelines (4), hypertensive patients who were perceived at a higher risk of hyperaldosteronism participated in the study from January 2011 to July 2014. Screening is recommended for patients with hypertension accompanied by drug-resistant hypertension, or unexplained spontaneous or diuretic-induced hypokalemia, or adrenal incidentaloma, or family history of early-onset hypertension or cerebrovascular accident at a young age (<40 y). Resistant hypertension was defined as failure to achieve target BP despite appropriate intervention using 3 different antihypertensive drugs at the maximal tolerated dosage. Potassium-wasting or -sparing diuretics and products derived from liquorice root were discontinued at least 4 weeks before testing. Other drugs, including β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, were withdrawn for at least 2 weeks before PAC and plasma rennin activity (PRA) measurements. Patients with severe hypertension were prescribed α1-blockers, and long-acting calcium channel blockers if necessary, to control BP less than 160/100 mm Hg before SIT. Dietary sodium intake was unrestricted. The screening test was considered positive when ARR was higher than 30 ng/dL:ng/mL · h together with supine PAC higher than 15 ng/dL (4).

Healthy volunteers

A total of 21 healthy volunteers with a BP below 130/80 mm Hg, no history or family history of hypertension, and not receiving any medication, participated in the study. During SIT, their BP was also less than 130/80 mm Hg.

Serum biochemical analysis was performed in 76 patients with confirmed PA, 44 patients with EH and 21 healthy volunteers. Total sodium intake was calculated from 2 timed 24-hour urinary excretion (1 mEq of sodium = 58.5 mg of NaCl). Patients with hypokalemia were given adequate oral or iv potassium supplements before SIT to maintain the serum potassium levels higher than 3.0 mmol/L.

SIT was performed in the morning and 2-L 0.9% NaCl solution was infused iv from 8 am to 12 pm after overnight recumbency. Subjects still remained in supine position during infusion and blood samples for PRA and serum aldosterone were drawn before and after infusion (4). All hypertensive patients underwent an enhanced adrenal computed tomography (CT) scan with fine cuts (5 mm). Bilateral adrenal venous sampling (AVS) was performed and the criteria for lateralization of aldosterone secretion were established according to previous recommendations (4, 9).

Biochemical measurements

Sodium and potassium levels in blood and urine were measured using fully automated instrumentation. Hypokalemia was defined as serum K+ less than 3.5 mmol/L. PRA was measured by RIA using a commercial kit (Atomic Hi-Tech Co, LTD). The intra- and interassay coefficients of variations for PRA were less than 10% and less than 15%, respectively. The assay for PAC was performed with a commercial kit (Jiuding Medical Biological Engineering Co, LTD). The intra- and interassay coefficients of variation for PAC were 7.3% and 9.6%, respectively.

Diagnostic criteria

Normal BP was defined as a systolic BP ranged from 90 to 130 mm Hg, and diastolic BP ranged from 60 to 80 mm Hg without any antihypertensive medications.

EH was defined as a systolic and diastolic BP more than or equal to 140/90 mm Hg according to the established criteria, excluding secondary hypertension.

Identification of aldosterone-producing adenoma (APA) was based on the next criteria: 1) evidence of autonomous excessive aldosterone production, which was defined as an ARR more than or equal to 30 at baseline plus aldosterone more than or equal to 15 ng/dL; 2) PAC of post-SIT more than or equal to 10 ng/dL; 3) unilateral or bilateral adrenal nodule was confirmed by CT; and 4) inappropriate lateralization of aldosterone secretion at AVS, and/or surgery, and pathologically confirmed adenoma.

Identification of idiopathic hyperaldosteronism (IHA) was based on the next criteria: 1) evidence of autonomous excess aldosterone production, which was defined as an ARR more than or equal to 30 at baseline plus aldosterone more than or equal to 15 ng/dL; 2) PAC of post-SIT more than or equal to 5 ng/dL; 3) bilateral adrenal limb thickening or nodule was confirmed by CT; 4) inappropriate lateralization of aldosterone secretion at AVS; and 5) demonstration of normokalemia and improvement of hypertension (defined as a systolic and diastolic BP less than 140/90 mm Hg) after treatment with mineralocorticoid receptor antagonists.

Statistical analysis

Statistical analysis was performed using the statistical software package SPSS 18.0 for Microsoft Windows (SPSS Inc). All evaluated parameters are expressed as mean ± SD or median (interquartile range) where appropriate. The normal distribution of the parameters between the groups was performed using the Student's t test. Abnormal distribution of the data was compared by rank-sum test between groups. The area under receiver operator characteristics (ROC) curve was used to assess the accuracy of SIT for identifying PA, and the best combination of sensitivity and specificity was provided. P < .05 was considered statistically significant.

Results

Clinical characteristics of each group are summarized in Table 1. Age, body mass index (BMI), BP, and serum sodium in group APA were in accordance with group IHA (P > .05). In group EH, BMI, systolic pressure and serum sodium were significantly different when compared with group APA (P < .05). There was no significant difference between groups IHA and EH for age, BMI, BP, and serum sodium (P > .05). However, compared with both groups EH and normal control (NC), serum potassium was much lower in group PA, in which serum potassium was even lower in group APA when compared with group IHA (P < .05). The prevalence of hypokalemia was 86.3% in group APA and 45.5% in group IHA. In PA patients, the proportion of potassium values less than 3 mmol/L was 39.7%, 93.1% of whom were diagnosed with APA. In IHA patients, there were 90.1% subjects with potassium values more than 3 mmol/L.

Table 1.

Clinical Characteristics of Healthy Volunteers and the Patients Studied

APA (n = 51)IHA (n = 25)EH (n = 44)NC (n = 21)
Sex (F/M)16/3510/1516/289/12
Age (y)44.5 ± 10.547.2 ± 12.846.5 ± 13.228.7 ± 5.1a,c,e
BMI (kg/m2)23.3 ± 3.323.5 ± 4.324.9 ± 4.3a22.0 ± 2.2f
SBP (mm Hg)162.7 ± 21.2157.7 ± 24.4152.0 ± 18.8b110.8 ± 9.6a,c,e
DBP (mm Hg)98.8 ± 13.198.2 ± 14.995.5 ± 13.767.9 ± 8.5a,c,e
Serum Na (mmol/L)143.8 ± 3.0142.6 ± 2.8142.2 ± 2.7b143.3 ± 2.9
Serum K (mmol/L)2.86 ± 0.593.52 ± 0.44a3.81 ± 0.37a,d4.20 ± 0.35a,c,e
Prevalence of hypokalemia (%)86.3%45.5%
PAC (ng/dL)32.1 ± 11.022.7 ± 8.2a12.6 ± 3.5a,c13.3 ± 3.3a,c
PRA (ng/mL · h)0.15 (0.09–0.23)0.32 (0.16–0.47)a0.45 (0.30–0.67)a,c0.81 (0.51–1.01)a,c,e
ARR (ng/dL: ng/mL · h)202 (106–345)67.1 (39.8–130)a27.9 (17.7–37.4)a,c14.9 (11.3–35.6)a,c,e
APA (n = 51)IHA (n = 25)EH (n = 44)NC (n = 21)
Sex (F/M)16/3510/1516/289/12
Age (y)44.5 ± 10.547.2 ± 12.846.5 ± 13.228.7 ± 5.1a,c,e
BMI (kg/m2)23.3 ± 3.323.5 ± 4.324.9 ± 4.3a22.0 ± 2.2f
SBP (mm Hg)162.7 ± 21.2157.7 ± 24.4152.0 ± 18.8b110.8 ± 9.6a,c,e
DBP (mm Hg)98.8 ± 13.198.2 ± 14.995.5 ± 13.767.9 ± 8.5a,c,e
Serum Na (mmol/L)143.8 ± 3.0142.6 ± 2.8142.2 ± 2.7b143.3 ± 2.9
Serum K (mmol/L)2.86 ± 0.593.52 ± 0.44a3.81 ± 0.37a,d4.20 ± 0.35a,c,e
Prevalence of hypokalemia (%)86.3%45.5%
PAC (ng/dL)32.1 ± 11.022.7 ± 8.2a12.6 ± 3.5a,c13.3 ± 3.3a,c
PRA (ng/mL · h)0.15 (0.09–0.23)0.32 (0.16–0.47)a0.45 (0.30–0.67)a,c0.81 (0.51–1.01)a,c,e
ARR (ng/dL: ng/mL · h)202 (106–345)67.1 (39.8–130)a27.9 (17.7–37.4)a,c14.9 (11.3–35.6)a,c,e

Data are expressed as mean ± SD or median (25th–75th percentiles). SBP, systolic BP; DBP, diastolic BP.

a

P < .01, vs APA.

b

P < .05, vs APA.

c

P < .01, vs IHA.

d

P < .05, vs IHA.

e

P < .01, vs EH.

f

P < .05, vs EH.

Table 1.

Clinical Characteristics of Healthy Volunteers and the Patients Studied

APA (n = 51)IHA (n = 25)EH (n = 44)NC (n = 21)
Sex (F/M)16/3510/1516/289/12
Age (y)44.5 ± 10.547.2 ± 12.846.5 ± 13.228.7 ± 5.1a,c,e
BMI (kg/m2)23.3 ± 3.323.5 ± 4.324.9 ± 4.3a22.0 ± 2.2f
SBP (mm Hg)162.7 ± 21.2157.7 ± 24.4152.0 ± 18.8b110.8 ± 9.6a,c,e
DBP (mm Hg)98.8 ± 13.198.2 ± 14.995.5 ± 13.767.9 ± 8.5a,c,e
Serum Na (mmol/L)143.8 ± 3.0142.6 ± 2.8142.2 ± 2.7b143.3 ± 2.9
Serum K (mmol/L)2.86 ± 0.593.52 ± 0.44a3.81 ± 0.37a,d4.20 ± 0.35a,c,e
Prevalence of hypokalemia (%)86.3%45.5%
PAC (ng/dL)32.1 ± 11.022.7 ± 8.2a12.6 ± 3.5a,c13.3 ± 3.3a,c
PRA (ng/mL · h)0.15 (0.09–0.23)0.32 (0.16–0.47)a0.45 (0.30–0.67)a,c0.81 (0.51–1.01)a,c,e
ARR (ng/dL: ng/mL · h)202 (106–345)67.1 (39.8–130)a27.9 (17.7–37.4)a,c14.9 (11.3–35.6)a,c,e
APA (n = 51)IHA (n = 25)EH (n = 44)NC (n = 21)
Sex (F/M)16/3510/1516/289/12
Age (y)44.5 ± 10.547.2 ± 12.846.5 ± 13.228.7 ± 5.1a,c,e
BMI (kg/m2)23.3 ± 3.323.5 ± 4.324.9 ± 4.3a22.0 ± 2.2f
SBP (mm Hg)162.7 ± 21.2157.7 ± 24.4152.0 ± 18.8b110.8 ± 9.6a,c,e
DBP (mm Hg)98.8 ± 13.198.2 ± 14.995.5 ± 13.767.9 ± 8.5a,c,e
Serum Na (mmol/L)143.8 ± 3.0142.6 ± 2.8142.2 ± 2.7b143.3 ± 2.9
Serum K (mmol/L)2.86 ± 0.593.52 ± 0.44a3.81 ± 0.37a,d4.20 ± 0.35a,c,e
Prevalence of hypokalemia (%)86.3%45.5%
PAC (ng/dL)32.1 ± 11.022.7 ± 8.2a12.6 ± 3.5a,c13.3 ± 3.3a,c
PRA (ng/mL · h)0.15 (0.09–0.23)0.32 (0.16–0.47)a0.45 (0.30–0.67)a,c0.81 (0.51–1.01)a,c,e
ARR (ng/dL: ng/mL · h)202 (106–345)67.1 (39.8–130)a27.9 (17.7–37.4)a,c14.9 (11.3–35.6)a,c,e

Data are expressed as mean ± SD or median (25th–75th percentiles). SBP, systolic BP; DBP, diastolic BP.

a

P < .01, vs APA.

b

P < .05, vs APA.

c

P < .01, vs IHA.

d

P < .05, vs IHA.

e

P < .01, vs EH.

f

P < .05, vs EH.

PAC was markedly elevated and PRA was significantly reduced in group PA when compared with both EH and NC groups (P < .01), and PAC was even higher in group APA than in group IHA (P < .01). Therefore, ARR was much higher in group PA than in both groups EH and NC (P < .01). There was no significant difference of PAC between groups EH and NC.

Increased BP was occasionally seen with SIT, but no adverse effects occurred (Table 2). The PAC of post-SIT was significantly higher in group PA than in both groups EH and NC (P < .01), which was even higher in group APA than in group IHA (P < .01). By contrast, there was no significant difference of PAC between groups EH and NC. We found that the PAC post-SIT was higher than 10 ng/dL in group PA, except in 2 cases with 7.84 and 9.48 ng/dL, respectively. In both groups EH and NC, the PAC post-SIT was still higher than 5 ng/dL, except one with 4.93 ng/dL.

Table 2.

Biochemical Characteristics of Healthy Volunteers and Patients Studied During Saline Infusion

Before Saline InfusionAfter Saline Infusion
PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)
APA (n = 51)30.9 ± 11.40.14 (0.08–0.23)195 (116–454)24.6 ± 9.90.12 (0.08–0.20)175 (101–338)
IHA (n = 25)20.7 ± 6.3a0.26 (0.10–0.46)73.7 (45.7–227)b14.9 ± 6.2a0.15 (0.08–0.26)80.9 (45.4–263)b
EH (n = 44)12.1 ± 3.1a,c0.44 (0.26–0.85)a,c26.4 (16.5–48.4)a,c8.7 ± 2.3a,c0.28 (0.16–0.44)a,c31.5 (18.1–56.1)a,c
NC (n = 21)13.3 ± 3.3a,c0.81 (0.51–1.01)a,c,e14.9 (11.3–35.6)a,c,f8.3 ± 1.8a,c0.44 (0.25–0.62)a,c21.9 (12.2–29.3)a,c
Before Saline InfusionAfter Saline Infusion
PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)
APA (n = 51)30.9 ± 11.40.14 (0.08–0.23)195 (116–454)24.6 ± 9.90.12 (0.08–0.20)175 (101–338)
IHA (n = 25)20.7 ± 6.3a0.26 (0.10–0.46)73.7 (45.7–227)b14.9 ± 6.2a0.15 (0.08–0.26)80.9 (45.4–263)b
EH (n = 44)12.1 ± 3.1a,c0.44 (0.26–0.85)a,c26.4 (16.5–48.4)a,c8.7 ± 2.3a,c0.28 (0.16–0.44)a,c31.5 (18.1–56.1)a,c
NC (n = 21)13.3 ± 3.3a,c0.81 (0.51–1.01)a,c,e14.9 (11.3–35.6)a,c,f8.3 ± 1.8a,c0.44 (0.25–0.62)a,c21.9 (12.2–29.3)a,c

Data are expressed mean ± SD or median (25th–75th percentiles).

a

P < .01, vs APA.

b

P < .05, vs APA.

c

P < .01, vs IHA.

e

P < .01, vs EH.

f

P < .05, vs EH.

Table 2.

Biochemical Characteristics of Healthy Volunteers and Patients Studied During Saline Infusion

Before Saline InfusionAfter Saline Infusion
PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)
APA (n = 51)30.9 ± 11.40.14 (0.08–0.23)195 (116–454)24.6 ± 9.90.12 (0.08–0.20)175 (101–338)
IHA (n = 25)20.7 ± 6.3a0.26 (0.10–0.46)73.7 (45.7–227)b14.9 ± 6.2a0.15 (0.08–0.26)80.9 (45.4–263)b
EH (n = 44)12.1 ± 3.1a,c0.44 (0.26–0.85)a,c26.4 (16.5–48.4)a,c8.7 ± 2.3a,c0.28 (0.16–0.44)a,c31.5 (18.1–56.1)a,c
NC (n = 21)13.3 ± 3.3a,c0.81 (0.51–1.01)a,c,e14.9 (11.3–35.6)a,c,f8.3 ± 1.8a,c0.44 (0.25–0.62)a,c21.9 (12.2–29.3)a,c
Before Saline InfusionAfter Saline Infusion
PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)PAC (ng/dL)PRA (ng/mL · h)ARR (ng/dL: ng/mL · h)
APA (n = 51)30.9 ± 11.40.14 (0.08–0.23)195 (116–454)24.6 ± 9.90.12 (0.08–0.20)175 (101–338)
IHA (n = 25)20.7 ± 6.3a0.26 (0.10–0.46)73.7 (45.7–227)b14.9 ± 6.2a0.15 (0.08–0.26)80.9 (45.4–263)b
EH (n = 44)12.1 ± 3.1a,c0.44 (0.26–0.85)a,c26.4 (16.5–48.4)a,c8.7 ± 2.3a,c0.28 (0.16–0.44)a,c31.5 (18.1–56.1)a,c
NC (n = 21)13.3 ± 3.3a,c0.81 (0.51–1.01)a,c,e14.9 (11.3–35.6)a,c,f8.3 ± 1.8a,c0.44 (0.25–0.62)a,c21.9 (12.2–29.3)a,c

Data are expressed mean ± SD or median (25th–75th percentiles).

a

P < .01, vs APA.

b

P < .05, vs APA.

c

P < .01, vs IHA.

e

P < .01, vs EH.

f

P < .05, vs EH.

ROC curve analysis was performed to determine the optimal cutoff value for PA diagnosis (Figure 1). A PAC of 11.45 ng/dL after SIT represented the optimal cutoff value for PA diagnosis, resulting in 88.2% sensitivity and 95.4% specificity with a positive predictive value (PPV) of 95.7% and a negative predictive value (NPV) of 87.3%. Meanwhile, false positive rate and false negative rate were 4.6% and 11.8%, respectively.

ROC curve analysis of PAC after SIT.
Figure 1.

ROC curve analysis of PAC after SIT.

AUC, area under the receiver-operator characteristic curves.

Because the cutoff values for PAC after SIT varied, we assessed the effect of different post-SIT PAC cutoff values on the diagnosis of PA by ROC curve analysis. A sensitivity of 100% was obtained with a PAC cutoff of 7.78 ng/dL after SIT with a specificity of 36.9%, accompanied by 65% PPV and 100% NPV, and a false positive rate of up to 63.1%. A specificity of 100% was observed with a PAC limit of 17.95 ng/dL after SIT with a sensitivity of 52.6%, accompanied by 100% PPV and 64.4% NPV, and a false negative rate of up to 47.4%. A PAC value of 10.0 ng/dL after SIT showed a sensitivity of 97.4% and specificity of 80%, with a false positive rate of 20% and a false negative rate of 2.6%.

The effects of sodium intake on SIT performance are shown in Table 3. Based on 6 g of daily sodium intake, the subjects were divided into normal sodium intake and high-sodium intake groups. Between the 2 groups, the PAC and PRA values, whether pre-SIT or post-SIT, had no significant differences in PA, EH patients, and healthy subjects.

Table 3.

Results of SIT According to an Na+ Intake Below or Above 6 g/d

APA and IHAEH and NC
<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 46)<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 36)
Urine sodium (mmol/24 h)80.8 (66.75–86.7)167.0 (153.1–219.9)a72.6 (72.6–117.8)162.4 (136.1–206.1)a
Pre-SIT PAC (ng/dL)28.1 ± 10.829.9 ± 12.012.6 ± 3.412.5 ± 3.4
Pre-SIT PRA (ng/mL · h)0.10 (0.065–0.22)0.15 (0.095–0.265)0.51 (0.363–1.068)0.495 (0.31–0.955)
Post-SIT PAC (ng/dL)22.5 ± 10.923.4 ± 10.48.2 ± 1.39.1 ± 2.5
Post-SIT PRA (ng/mL · h)0.12 (0.098–0.195)0.12 (0.07–0.22)0.25 (0.16–0.385)0.42 (0.25–0.55)
APA and IHAEH and NC
<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 46)<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 36)
Urine sodium (mmol/24 h)80.8 (66.75–86.7)167.0 (153.1–219.9)a72.6 (72.6–117.8)162.4 (136.1–206.1)a
Pre-SIT PAC (ng/dL)28.1 ± 10.829.9 ± 12.012.6 ± 3.412.5 ± 3.4
Pre-SIT PRA (ng/mL · h)0.10 (0.065–0.22)0.15 (0.095–0.265)0.51 (0.363–1.068)0.495 (0.31–0.955)
Post-SIT PAC (ng/dL)22.5 ± 10.923.4 ± 10.48.2 ± 1.39.1 ± 2.5
Post-SIT PRA (ng/mL · h)0.12 (0.098–0.195)0.12 (0.07–0.22)0.25 (0.16–0.385)0.42 (0.25–0.55)

Data are expressed mean ± SD or median (25th–75th percentiles).

a

P < .01 vs below 6 g/d.

Table 3.

Results of SIT According to an Na+ Intake Below or Above 6 g/d

APA and IHAEH and NC
<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 46)<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 36)
Urine sodium (mmol/24 h)80.8 (66.75–86.7)167.0 (153.1–219.9)a72.6 (72.6–117.8)162.4 (136.1–206.1)a
Pre-SIT PAC (ng/dL)28.1 ± 10.829.9 ± 12.012.6 ± 3.412.5 ± 3.4
Pre-SIT PRA (ng/mL · h)0.10 (0.065–0.22)0.15 (0.095–0.265)0.51 (0.363–1.068)0.495 (0.31–0.955)
Post-SIT PAC (ng/dL)22.5 ± 10.923.4 ± 10.48.2 ± 1.39.1 ± 2.5
Post-SIT PRA (ng/mL · h)0.12 (0.098–0.195)0.12 (0.07–0.22)0.25 (0.16–0.385)0.42 (0.25–0.55)
APA and IHAEH and NC
<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 46)<102.6 mmol/24 h (n = 11)>102.6 mmol/24 h (n = 36)
Urine sodium (mmol/24 h)80.8 (66.75–86.7)167.0 (153.1–219.9)a72.6 (72.6–117.8)162.4 (136.1–206.1)a
Pre-SIT PAC (ng/dL)28.1 ± 10.829.9 ± 12.012.6 ± 3.412.5 ± 3.4
Pre-SIT PRA (ng/mL · h)0.10 (0.065–0.22)0.15 (0.095–0.265)0.51 (0.363–1.068)0.495 (0.31–0.955)
Post-SIT PAC (ng/dL)22.5 ± 10.923.4 ± 10.48.2 ± 1.39.1 ± 2.5
Post-SIT PRA (ng/mL · h)0.12 (0.098–0.195)0.12 (0.07–0.22)0.25 (0.16–0.385)0.42 (0.25–0.55)

Data are expressed mean ± SD or median (25th–75th percentiles).

a

P < .01 vs below 6 g/d.

Discussion

Over the past decade, many studies found that PA was the most common cause of endocrine hypertension. Because the widespread use of ARR as a case detection test for hypertensive patients, the prevalence of PA dramatically increased from less than 1% of the population with hypertension to about 10%, which is higher in resistant hypertension (1014). In addition, patients with PA exhibit a higher rate of cardiovascular and cerebrovascular complications, and target organ damage compared with EH (1518). However, patients with PA were successfully treated for hypertension with appropriate interventions such as surgery or treatment with mineralocorticoid receptor antagonists (1, 2). Therefore, it is imperative that hypertensive patients with high risk of PA are screened for early diagnosis.

Representative PA is characterized by hypertension, hypokalemia, and autonomous production of aldosterone, accompanied by suppressed renin activity. Hypokalemia was previously considered as a determinant for PA diagnosis although a recent study reported contrary findings (19). It is now generally recognized that PA in several patients is not accompanied by hypokalemia (19). Our results showed that APA prevailed in 93.1% of PA patients with potassium values less than 3 mmol/L, whereas a great majority of IHA patients showed potassium levels more than 3 mmo/L. Thus, a lower potassium (<3 mmol/L) might be used as an extra confirmation of APA.

A positive screening test is not an independent diagnostic tool for PA, due to the low specificity of ARR (7, 20). Therefore, confirmatory tests should always be performed to verify any inappropriate autonomous hypersecretion of aldosterone to establish the diagnosis (6, 21, 22). SIT has been considered as one of the most widely used functional tests to confirm or exclude the diagnosis of PA (4, 2325). Giacchetti et al (26) used such a design in 61 PA patients, including APA in 26, and EH in 96 patients. In this context, a postsodium infusion test with a cutoff value for PAC of 7 ng/dL with an upright ARR of 40 showed 100% specificity and PPV (26). Additionally, a study suggested that the PAC after SIT was almost always suppressed below 5 ng/dL in normal subjects and patients with EH (27). In contrast, patients with APA only rarely show plasma aldosterone level below 10 ng/dL, whereas patients with IHA frequently have plasma aldosterone level suppression after saline infusion to between 5 and 10 ng/dL (27). The 2008 The Endocrine Society clinical practice guidelines state that post-SIT plasma aldosterone levels below 5 ng/dL are not diagnostic of PA, and levels above 10 ng/dL are a very probable sign of PA, whereas values between 5 and 10 ng/dL are indeterminate (4). However, whether the recommendation was appropriate for Chinese subjects was unknown.

In the current study, the results suggested that the supine PAC, among patients with PA, EH, and healthy volunteers, was in accordance with the previous studies (25, 28, 29). We presume that it was appropriate for Chinese subjects to establish a PAC of 15 ng/dL as a cutoff value in the screening test. Nevertheless, a great discrepancy of PAC after SIT was found between the present study and other previous studies. Some studies reported that PAC limit of 5–7 ng/dL after SIT showed higher sensitivity and specificity for diagnosis of PA. In the prospective Primary Aldosteronism Prevalence in Italy study (30), patients undergoing SIT had an optimal aldosterone cutoff of 6.75 ng/dL for the diagnosis of APA, resulting in 82.6% sensitivity and 75.1% specificity because of overlap between patients with and without APA. Giacchetti et al proposed that a PAC of 7 ng/dL with saline infusion was a satisfactory cutoff value to confirm PA diagnosis (26). Another study demonstrated that the best cutoff for PAC after SIT was 5 ng/dL, with 88.0% sensitivity and 88.0% specificity for PA diagnosis (25). Additionally, many studies reported that the PAC of post-SIT for IHA diagnosis was almost within the range of 5–10 ng/dL (27, 30). The results of the current study, based on ROC curve analysis, revealed that a PAC of 11.45 ng/dL after SIT was the optimal cutoff value, which was inconsistent with previous studies. Diagnosis based on SIT was accurate in most cases (96.7%), with a high PPV (95.7%), high sensitivity and specificity (88.2% and 95.4%, respectively). In our present study, we found that the PAC after SIT in PA patients was more than 10 ng/dL except for 2 cases with 7.84 and 9.48 ng/dL, respectively, which was higher than in the Western populations. Based on a PAC of 10 ng/dL, SIT for PA diagnosis showed 97.4% sensitivity and 80% specificity, with a false negative rate of 20%. Additionally, a hypothetical choice of PAC of 7.78 ng/dL after SIT as a cutoff value, showed no false-negative diagnosis of PA (0 of 76), but an increase in false-positive diagnosis of EH (28 of 44). Therefore, according to the present study, the reactivity for high volume loading with saline infusion was lower in Chinese patients. Further, we found that the PAC was still higher than 10 ng/dL after saline infusion in a great majority of patients with PA, rather than above 5 ng/dL. Notably, a PAC of less than 5 ng/dL after SIT confirmed the diagnosis of EH in hypertensive patients with a positive PA screening test (27, 31). Similarly, PAC was also suppressed in normotensive subjects without any antihypertensive drugs, which was verified by previous studies (27, 31). The Endocrine Society Guidelines recommend a post-SIT aldosterone level below 5 ng/dL as the cutoff value for excluding PA diagnosis (4). However, in our present study, the post-SIT aldosterone levels were above 5 ng/dL in all EH subjects and healthy volunteers except one, which was inconsistent with the previous studies. A PAC of 5 ng/dL after SIT as a cutoff value, showed 100% sensitivity, but only 1.5% specificity, for PA diagnosis. Based on these results, we conclude that the post-SIT aldosterone levels in Chinese essential hypertensive and healthy subjects were obviously higher than in the Western population (25, 27, 29, 30). Therefore, our findings provide evidence that aldosterone reactivity to high volume loading after saline infusion was lower in Chinese EH and healthy subjects. We found that a great majority of Chinese had a PAC after SIT higher than 5 ng/dL. Thus, we conclude that it was inappropriate for Chinese subjects to use the PAC of less than 5 ng/dL after SIT to exclude the diagnosis of PA.

A multicenter epidemiologic study in 11 provinces of China performed by Sang et al revealed that the median (interquartile) of aldosterone after saline infusion was 18.6 (12.3–32.0) ng/dL in Chinese PA patients (32). However, they had not analyzed the optimal cutoff value for PAC after SIT for PA diagnosis based on their own data. In the present study, the median (interquartile) of aldosterone after saline infusion was 19.1 (13.8–27.8) ng/dL, which was almost consistent with Sang's results (32). Both the Chinese studies demonstrated that aldosterone responses to SIT were lower in Chinese people when compared with Western data.

Sodium intake is associated with the renin-angiotensin system, which is normally suppressed by a high-salt diet. It has been postulated that a high salt intake inhibits the renin-angiotensin system activity and therefore, alters the results of the SIT. Plasma renin activity and plasma aldosterone were inversely related to dietary sodium intake (33). However, a Japanese study showed a negative correlation between salt excretion and PAC, but not PRA level (34). Rossi et al showed that although the accuracy of the SIT for the diagnosis of APA was unaffected by Na+ intake, the optimal aldosterone cutoff values for SIT was elevated (30). On the basis of the median daily urinary Na+ excretion, at a sodium intake less than 7.6 g/d, the best cutoff value for PAC after SIT was 6.61 ng/dL. However, when sodium intake was more than 7.6 g/d, the optimal cutoff value for PAC after SIT was 11.3 ng/dL. Chinese diet is high in sodium, which might cause low reactivity for high loading with saline infusion. However, in the present study, by dividing the subjects based on 6 g of daily sodium intake into normal and high intake groups, we found that plasma aldosterone and PRA values were unaffected. We found no evidence that the lower response of renin-angiotensin system to high loading with saline infusion was related to high-salt intake. However, it is quite possible that long-term high-salt diet might inhibit the renin-angiotensin system activity and lead to a lower response to SIT in Chinese subjects.

In summary, this study indicates that it is appropriate for Chinese patients to use a baseline PAC of 15 ng/dL as a cutoff in the screening test. SIT is a reliable functional test to confirm the diagnosis of PA in patients with a positive case detection but the optimal post-SIT aldosterone cutoff value for identifying PA was 11.45 ng/dL in Chinese patients, which was higher than the recommendations of the current clinical practice guidelines of The Endocrine Society. The PAC after SIT was still higher than 5 ng/dL in a great majority of Chinese EH and healthy subjects. No relationship between high salt intake and lower responses of renin aldosterone system to high loading with saline infusion was found in this study but it is logical to speculate that long-term high-salt diet might be 1 of the factors for higher PAC cutoff value after SIT in Chinese subjects. Additional large-scale studies are needed to establish the optimal aldosterone cutoff value after SIT in Chinese and the factors underlying the variation between Chinese and Western populations.

Acknowledgments

Disclosure Summary: The authors have nothing to disclose.

Abbreviations

     
  • APA

    aldosterone-producing adenoma

  •  
  • ARR

    aldosterone to renin ratio

  •  
  • AVS

    adrenal venous sampling

  •  
  • BMI

    body mass index

  •  
  • BP

    blood pressure

  •  
  • CT

    computed tomography

  •  
  • EH

    essential hypertension

  •  
  • IHA

    idiopathic hyperaldosteronism

  •  
  • NC

    normal control

  •  
  • NPV

    negative predictive value

  •  
  • PA

    primary aldosteronism

  •  
  • PAC

    plasma aldosterone concentration

  •  
  • PPV

    positive predictive value

  •  
  • PRA

    plasma rennin activity

  •  
  • ROC

    receiver operator characteristics

  •  
  • SIT

    saline infusion test.

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