1. LB SAT 66 Combination of aldosterone to renin ratio and plasma aldosterone concentration is useful in detecting unilateral subtype of primary aldosteronism The data from WAVES-J study
Yui Shibayama, MD1, Norio Wada, MD, PhD1, Hironobu Umakoshi, MD2, Takamasa Ichijo, MD, PhD3, Yuichi Fujii, MD, PhD4, Kohei Kamemura, MD, PhD5, Tatsuya Kai, MD, PhD6, Ryuichi Sakamoto, MD, PhD7, Atsushi Ogo, MD, PhD7, Yuichi Matsuda, MD, PhD8 , Tomikazu Fukuoka, MD, PhD9, Mika Tsuiki, MD, PhD2, Tomoko Suzuki, PhD10, Mitsuhide Naruse, MD, PhD2 1Sapporo City General Hospital, 2Kyoto Medical Center, 3Saiseikai Yokohama Tobu Hospital, 4Hiroshima General Hospital of West Japan Railway Company, 5Akashi Medical Center, 6Saiseikai Tondabayashi Hospital, 7Kyushu Medical Center, 8Sanda City Hospital, 9Matsuyama Red Cross Hospital, 10Kitasato University School of Medicine
Analysis: We analyzed the basal PAC as a cut-off value for a screening test of PA. PRA, PAC and ARR were evaluated using the basal values at diagnosis. We divided the patients into the following four groups, PAC≦100pg/ml (Low PAC group), PAC pg/ml (Normal PAC group), PAC pg/ml (High normal PAC group), and PAC>150pg/ml (High PAC group).
Table2. Percentages of the unilateral disease in the four PAC groups 　
Introduction
Discussion
Low
PAC group
Normal
High normal PAC group
High
Before ACTH stimulation
(n=301)
SI>2
n=40
n=22
n=64
n=175
LI>2 (n=196)
19 (48%)
10 (45%)
32 (50%)
135 (77%)*
LI>2, CR<1 (n=104)
8 (20%)
5 (23%)
18 (28%)
73 (42%)
LI>3 (n=161)
16 (40%)
9 (41%)
28 (44%)
108 (62%)
LI>3, CR<1 (n=99)
7 (18%)
15 (23%)
72 (41%)
LI>4 (n=134)
14 (35%)
4 (18%)
21 (33%)
95 (54%)*
LI>4, CR<1 (n=85)
5 (13%)
11 (17%)
65 (37%)
After ACTH stimulation
(n=354)
SI>5
n=41
n=32
n=66
n=215
LI>2 (n=165)
12 (29%)
9 (28%)
18 (27%)
126 (59%)*
LI>2, CR<1 (n=115)
4 (10%)
5 (16%)
95 (44%)*
LI>3 (n=116)
3 (7%)
3 (9%)
99 (46%)*
LI>3, CR<1 (n=89)
0 (0%)
2 (9%)
7 (11%)
80 (37%)*
LI>4 (n=101)
LI>4, CR<1 (n=87)
6 (9%)
90 (42%)*
1 (3%)
5 (8%)
81 (38%)*
In primary aldosteronism (PA), although aldosterone/renin ratio (ARR) has been utilized as the most reliable screening test of PA, the very low plasma renin activity (PRA) could cause a false positive result even if the plasma aldosterone concentration (PAC) is not increased. 1 Previous studies reported patients with the low PAC were rarely diagnosed as aldosterone producing adenoma (APA). Some investigators recommended the basal PAC of 150pg/ml for a screening test of PA. 2 Others indicated 100pg/ml to reduce the risk of missing APA. 3 In this study, we aimed to evaluate the appropriate basal PAC value for detecting unilateral subtype of PA combined with an ARR for a screening test of PA.
The prevalence of the unilateral disease in AVS after ACTH stimulation was significantly higher in the High PAC group, and it was not different among the other groups. Among the three hypothetical cut-off values of PAC, the percentages of detectable patients with the unilateral disease in AVS were not different. In contrast, the higher cut-off value of PAC was adopted, the significantly higher rate of patients showed the basal PAC less than each cut-off value. Therefore we could obtain the higher reduction rate of confirmatory tests and AVS.
In order to emphasize the usefulness of the cut-off value of basal PAC combined with ARR for a screening test of PA, we have to consider a balance of the following two aspects, decreasing the missing of the unilateral disease, and decreasing the confirmatory tests and AVS.
It is recommended that the cut-off value of basal PAC (not exceeding 150pg/ml) be adopted based on the clinical needs and the capacity for confirmatory tests and AVS in each center.
In contrast, the effectiveness of medical treatment for the cases with low PAC value most of whom have the bilateral disease should be discussed.
Results
Figure1. Classification into the four PAC groups
Patients with basal ARR >200
and confirmed as PA (n=449)
Low PAC group (PAC ≦100pg/ml)
(n=54, 12%)
Normal PAC group
(PAC pg/ml)
(n=39, 9%)
High normal PAC group
(PAC pg/ml)
(n=81, 18%)
High PAC group
(PAC >150pg/ml)
(n=275, 61%)
Patients and methods
Data are shown as numbers or percentages of the unilateral disease in each PAC group whose AVS were successfully performed. The frequency of the unilateral disease was compared with the High PAC group. Red bold*: Percentage of the unilateral disease was significantly higher in the High PAC group than the other group, p<0.05. Blue bold: Percentage of the unilateral disease was not significantly different in the High PAC group from the the other group showed in blue bold, p>0.05.
Patients: Nine hospitals participated in the West Japan adrenal vein sampling study (WAVES-J study). The patients with PA who underwent AVS from January 2006 to December 2013 were enrolled in this study. We analyzed the 449 PA patients (198 men, 251women, mean age 54.3 ± 11.1 y) who fulfilled the basal ARR>200 and at least one positive confirmatory test, including the captopril challenge test, the upright furosemide-loading test and the saline loading test.
AVS: Blood samples obtained via AVS were generally collected before and at 30 minutes after ACTH stimulation from both adrenal veins and from the IVC at a point distal to the renal vein. The blood samplings from both adrenal veins were performed sequentially in 8 centers, simultaneously in 1 center. Catheterization was judged to be successful if the selectivity index (SI) was either more than 2 before ACTH stimulation, or more than 5 after ACTH stimulation. The unilateral disease in AVS was determined by the lateralization index (LI) with or without the contralateral ratio (CR). We analyzed by the 12 criteria, LI>2, 3, or 4 with or without the unilateral CR<1, before or after ACTH stimulation. The frequency of the unilateral disease was investigated in the four PAC groups.
SI>2 before ACTH stimulation (n=40)
SI>5 after ACTH stimulation (n=41)
SI>2 before ACTH stimulation (n=22)
SI>5 after ACTH stimulation (n=32)
SI>2 before ACTH stimulation (n=64)
SI>5 after ACTH stimulation (n=66)
SI>2 before ACTH stimulation (n=175)
SI>5 after ACTH stimulation (n=215)
Table3. Percentages of detectable patients of the unilateral disease in each
cut-off value of PAC and the patients with basal PAC less than each cut-off value
PAC 100pg/ml
PAC 120pg/ml
PAC 150pg/ml
Before ACTH stimulation
(n=301)
SI>2
n=261
n=239
n=175
Detectable patients of the unilateral disease in AVS
LI>2 (n=196)
89.8%
84.7%
65.3%
LI>2, CR<1 (n=104)
92.3%
87.5%
70.2%
LI>3 (n=161)
90.1%
84.5%
67.1%
LI>3, CR<1 (n=99)
92.9%
87.9%
72.8%
LI>4 (n=134)
89.6%
86.6%
70.9%
LI>4, CR<1 (n=85)
94.1%
89.4%
76.5%
Patients with basal PAC less than each cut-off value
13.2%
20.6%
41.9%*
After ACTH stimulation
(n=354)
SI>5
n=313
n=281
n=215
LI>2 (n=165)
92.7%
87.3%
76.4%
LI>2, CR<1 (n=115)
96.5%
92.2%
82.7%
LI>3 (n=116)
97.4%
94.8%
85.3%
LI>3, CR<1 (n=89)
100%
97.8%
89.9%
LI>4 (n=101)
LI>4, CR<1 (n=87)
97.0%
95.0%
89.1%
98.9%
93.1%
11.6%
20.6%✝
39.3%*
Table1. Baseline characteristics of the four PAC groups
Low
PAC group
Normal
High normal
High
Age (years)
58.6 a±7.8
59.1 a±8.8
55.3±10.9
52.5±11.6
Sex (men:
women) (%)
16 (30%):
38 (70%) a
17 (44%):
22 (56%)
36 (44%):
45 (56%)
129 (47%):
146 (53%)
Systolic BP (mmHg)
139.8±16.0
147.2±22.8
141.7±19.1
145.6±19.7
Diastolic BP (mmHg)
84.1±11.0
87.7±15.8
83.9±13.4
87.8±14.3
Duration of HT (years)
5.5 b±7.3
9.6±9.1
7.4±7.9
8.8±8.1
Medication score
50 b [25-75]
57 [50-100]
50 [50-100]
100 [50-125]
PRA (ng/ml/h)
0.2 b [ ]
0.3 [ ]
0.3 [ ]
PAC (pg/ml)
90 b [72-95]
110 b [ ]
134 b [ ]
228 [ ]
ARR
358 b [ ]
388 b [ ]
440 b [ ]
807 [ ]
Serum K (mEq/l)
3.9 a±0.3
3.9 a±0.4
3.5±0.6
eGFR (ml/min/1.73m2)
77.6±16.1
73.8±13.7
81.4±17.4
78.5±20.1
Adrenal nodule on CT (%)
27 b (50%)
23 (59%)
43 a (81%)
186 (67%)
Conclusion
In screening for PA, the combination of ARR and basal PAC can not only reduce false positive cases, but also find cases with unilateral subtype in AVS who are possibly cured by an unilateral adrenalectomy efficiently and reduce excessive confirmatory tests and AVS.
References
Funder J et al, JCEM 2016:
Young Jr et al, Clinical Endocrinology 2007:
Stowasser M et al, Hormone and Metabolic Research 2012:
Data are expressed as the mean ± SD, median [interquartile range], or number (percentage). BP: blood pressure, HT: hypertension, PRA: plasma renin activity, PAC: plasma aldosterone concentration,
ARR: aldosterone renin ratio, P value: patients of High PAC group vs. patients of the other groups,
a: significantly higher than High PAC group, b: significantly lower than High PAC group, p<0.05.
✝: significantly higher than PAC 100pg/ml, *: significantly higher than PAC 120pg/ml, p<0.05. Percentages of
detectable patients of the unilateral disease were not significantly different in all the criteria, p>0.05.