Key words
renin-aldosterone relationship - primary aldosteronism - APA - adrenalectomy
Introduction
Primary aldosteronism (PA), characterized by high plasma aldosterone and suppressed
plasma renin, has been recognized as one of the most common causes of secondary
hypertension [1]. However, it is still
unrecognized by physicians [2] and has high
heterogeneity among centers worldwide [3]. The
PA prevalence has been increasing since its first description six decades ago [4]
[5]
ranging from 5–10% in the general hypertensive population to
15–26% in resistant hypertension patients [2]
[6].
Unilateral aldosterone-producing adenoma (APA) and idiopathic bilateral adrenal
hyperplasia are the most common causes of the autonomous aldosterone hypersecretion.
Various genetic abnormalities have been identified in APA and in familial forms of
the disease [7]. Clinical practice guidelines
have established PA diagnosis recommendations for clinical detection, screening and
confirmatory tests, adrenal Computed Tomography (CT) scan, and bilateral adrenal
vein sampling (AVS) to differentiate unilateral from bilateral forms of PA [8]
[9]
[10]. APA has been primarily
treated by laparoscopic adrenalectomy while the bilateral form of PA mostly treated
by mineralocorticoid receptor antagonists [1]
[9].
Recently, the Primary Aldosteronism Surgical Outcome (PASO) study established
international criteria for clinical and biochemical treatment success in APA
patients [11]
[12] and a numerical PASO score has been used for the prediction of
patient clinical outcome after APA adrenalectomy [13]
[14]. The aldosterone excess in
patients with unilateral APA chronically suppresses renal renin release and
decreases aldosterone secretion from the zona glomerulosa (ZG) of the contralateral
adrenal gland [15]
[16]
[17]
leading to the ZG insufficiency. Consequently, these patients present low plasma
aldosterone after unilateral adrenalectomy and some isolated recent case reports
have presented post-operative hyperkalemia as an indicator of post-operative
hypoaldosteronism [12]
[17]
[18]
[19]
[20]
[21]
[22]
[23].
The importance of the post-operative hypoaldosteronism recovery had surfaced since
the 1960s [24]
[25]
[26]
[27]. However, there has been limited
comprehension on renin and aldosterone relationship after APA adrenalectomy since
most of the previous studies were retrospective reviews and none evaluated their
recoveries using concurrent and consecutive samples at short- and long-term
observation periods after adrenalectomy in patients presenting APA. Therefore, we
designed the current study to clarify the relationship of serum aldosterone and
renin levels at immediate and long-term follow-up, using a prospective and
longitudinal protocol, in a cohort of patients with APA who underwent unilateral
adrenalectomy in a single tertiary medical center. The second aim was to evaluate
the time to reestablish the renin and aldosterone normal secretion after
adrenalectomy in APA patients.
Patients and Methods
Patients
We prospectively studied forty-three patients with confirmed PA consecutively
referred from September 2016 to February 2020 to the Division of Endocrinology,
University Hospital at Ribeirao Preto Medical School, University of Sao Paulo, a
Brazilian tertiary center for adrenal diseases. We adopted the protocol for PA
clinical diagnosis and etiology differentiation according to The Endocrine
Society guideline [9]
[10]. The diagnostic differentiation between
unilateral and bilateral PA forms was performed using a dedicated adrenal CT
scan protocol in all 43 patients. In 26 out of 43 patients, the AVS protocol
with continuous cosyntropin infusion was also performed. Cortisol concentrations
from the adrenal and peripheral veins were used to confirm successful
catheterization, adopting as selectivity index the adrenal:peripheral vein
cortisol ratio of 5:1 [9]. To characterize
lateralization, we used the cortisol-corrected aldosterone ratio from high-side
to low-side of 4:1 [9]. In the setting of
failed cannulation of the right adrenal vein, the aldosterone:cortisol ratio of
the left adrenal vein compared with the inferior vena cava (LAV/IVC) was
used based on Pasternak et al. [28]. We
considered as suppression index, the cutoff values ratios of≥5.5
and≤0.5, which predicted left- and right-sided disease,
respectively.
Nineteen patients had confirmed APA diagnosis and were enrolled in this study
([Fig. 1]). At the time of the
diagnosis, APA patients underwent systematic assessment for aldosterone and
cortisol co-secretion [29] by
well-established tests for hypercortisolism diagnosis [30]. There were no shift workers among
patients. The study was approved by the Ethical Committee of the Ribeirao Preto
Medical School, University of Sao Paulo.
Fig. 1 Flow chart of the prospective and longitudinal study in
patients with primary aldosteronism. *These patients
were analyzed separately.
Patient blood samples were collected for baseline serum aldosterone and direct
renin between 09:00 to 10:00 h, after 2 hours in the upright
position followed by 10 minutes seated. Patients had normal sodium
intake diet and hypokalemia, if present, was corrected. Drugs affecting
aldosterone and DRC were withdrawn for at least 4 weeks. PA detection cut-off
levels were serum aldosterone of>15 ng/dl associated with a
suppressed renin concentration of<5 mIU/l. Diagnosis of PA was
confirmed by intravenous saline suppression test using an aldosterone cut-off
of>10 ng/dl. Confirmatory tests were not performed in patients
with suppressed direct renin concentration (DRC), plasma aldosterone
concentration of>20 ng/dl, and spontaneous hypokalemia [9].
Study design: post-adrenalectomy prospective longitudinal protocol
Nineteen patients submitted to unilateral adrenalectomy were followed by a
prospective longitudinal study protocol. Briefly, serum aldosterone and DRC were
measured in the morning before and 1, 3, 5, 7, 15, 30, 60, 90, 120, 180, 270,
and 360 days after adrenalectomy. Potassium, creatinine, cortisol, and ACTH
levels were also determined. There was a rigorous control of pre-analytical and
samples storage phases. Additionally, at the same time points, blood pressure
measurement and antihypertensive treatment requirement were obtained.
Antihypertensive medications were expressed as defined daily doses (DDD). In
addition, prior to the blood collection during the longitudinal protocol,
patients were on unrestricted salt intake diet and, when necessary, potassium
replacement was prescribed. Subsequently, six patients were excluded due to the
following reasons: progressive severity of chronic kidney disease (n=2),
persistent PA (n=1), loss to follow-up (n=1), and aldosterone
and cortisol co-secretion (n=2, [Fig.
1]). The descriptive data of aldosterone and cortisol co-secretion
patients were presented separately. Clinical evaluation and the prospective
protocol were under supervision of the same endocrinologists (LMM, PCLE, ACM).
The same surgeons (CAFM, STJ) performed the unilateral video laparoscopic
adrenalectomy.
Assays and laboratory methods
Serum aldosterone and plasma DRC were determined by chemiluminescence
immunoassays using DiaSorin kits (Liaison, Stillwater, MN, USA). The limits of
detection (LoD) and quantitation (LoQ) at 20% coefficient of variation
(CV) of aldosterone immunoassay were 2.2 and 3.0 ng/dl,
respectively [31]. The limit of detection
of DRC was 2.3 mIU/l at 11% CV. The intra- and
inter-assay CVs were 4.8 and 6.7% for aldosterone and 5.8 and
12.8% for DRC. In our laboratory, the median (5th and 95th percentiles)
values for healthy subjects in the upright position are, respectively, 12.5 (4.5
and 30) ng/dl for serum aldosterone and 16.9 (4.2 and 40) mIU/l
for DRC. To convert aldosterone from ng/dl to nmol/l multiply by
0.027.
Serum cortisol and plasma ACTH levels were determined using standard immunoassays
[30]. To convert cortisol from
µg/dL to nmol/l multiply by 27.59 and ACTH from
pg/ml to pmol/l multiply by 0.2202. The cut
of≤2 μg/dl of serum cortisol levels after the
overnight 1 mg dexamethasone test excluded endogenous hypercortisolism.
Serum potassium and creatinine were measured using Atellica CH Analyzer (Siemens
Healthcare Diagnostics Inc. Tarrytown, NY, USA). All assays were determined at
the Endocrinology and Clinical Chemistry Laboratories at the University
Hospital.
Definitions of criteria for postoperative outcomes
Complete biochemical surgical success was defined when plasma aldosterone levels
were<5 ng/dl, according to PASO study consensus [11]. The PASO criteria for clinical and
biochemical surgical success can be classified as complete, partial, or absent.
We evaluated these criteria at 1, 3, 6, and 12 months after surgery [11]
[12]
[13].
For biochemical criteria, we defined serum aldosterone levels (ng/dl)
lower than 2.2 as undetectable, between 2.2 and 3 as very low, and between 3 and
4.9 as low, based on our laboratory reference values. We arbitrarily considered
post-operative aldosterone and renin recoveries when serum aldosterone level and
DRC were>3 ng/dl and≥5 mU/l,
respectively. These values should be observed on two subsequent blood
collections and remained throughout the study. Hypokalemia and hyperkalemia were
defined as serum potassium of≤3.5
and≥5.5 mmol/l, respectively [11]
[17].
Statistical analysis
Data were analyzed for descriptive statistics and expressed as the
mean±SEM or median and the 25th to 75th percentiles (interquartile
range) when appropriated. Results below the LoD of the assay were considered as
the value of the limit of detection.
Two independent investigators (LMM and ACM) reviewed the data looking at
post-operative recovery days of serum aldosterone and renin for each patient,
with concordant observations. The difference (days) between the recoveries of
DRC and serum aldosterone for each patient was also calculated.
The paired samples for each patient were analyzed by non-parametric paired
Wilcoxon signed-rank test. Categorical variables were compared using
Fisher’s exact test. Data analyses were carried out with the statistical
package GraphPad PRISM 8 (GraphPad Software, 2020, La Jolla, CA, USA).
Significance was assumed when p<0.05.
Results
Nineteen patients diagnosed with APA (11 M/8 F, age
48±14 years) underwent unilateral adrenalectomy were initially included in
the prospective protocol. Among them, nine patients were young (median age 26 years
– range: 17 to 37 years) with spontaneous hypokalemia, marked aldosterone
excess (median 68 ng/dl), and unequivocal radiological features of
unilateral cortical adenoma on adrenal CT scan. Therefore, according to the current
guidelines, they did not require AVS before proceeding to unilateral adrenalectomy
[9]. APA patients who underwent AVS had a
median lateralization index of 44 (range: 8.3–119) while in the bilateral PA
group, the median lateralization index was 1.7 (range: 1–2.6). APA patients
presented the aldosterone:cortisol ratio of the left adrenal vein compared with the
inferior vena cava of 9.1 (range: 6–34) and 0.4 (range: 0.7–0.4) for
left and right lateralization, respectively. Among the PA bilateral group, the
median suppression index was 1.6 (range: 1–4.7).
After exclusion of the six patients, 13 APA patients
(9 M/4 F) were fully analyzed. They had mean body mass index
of 31±9.8 kg/m2. Hypertension had been diagnosed
at the median age of 31 years (interquartile range 17–37 years) in these
patients. However, PA diagnosis were performed later at the median age of 47 years
(interquartile range 34–63 years). PA diagnosis occurred with a mean delay
of 15.2 years (7.5–24.5). The huge variation in the time of PA diagnosis
reflects the delay in the diagnosis of PA. Indeed, at diagnosis, ten patients had
been previously treated with various antihypertensive drugs, including
spironolactone, by nonspecialized medical services, which delayed the PA screening
and diagnosis. Only years later, patients were admitted to the university hospital
to properly proceed to PA investigation after withdrawal of interfering medications,
such as diuretics and spironolactone for at least four weeks. At diagnosis, the
median aldosterone levels were 54.8 (24.0–103) ng/dl while DRC were
2.3 (2.3–2.3) mU/l. The mean adrenal nodule size at pathology
evaluation was 1.5±0.8 cm. One-year post-adrenalectomy, mean
systolic and diastolic blood pressure decreased from 146±31 to
131±11 mmHg (p=0.09) and from 91±17 to
81±13 mmHg (p=0.1), respectively. The antihypertensive daily
requirement was also reduced from DDD 6.1±2.5 to 1.7±1.4
(p=0.001) being 30.7% normotensive with no medications.
In pre-operatory period, 7 out of 13 patients have not been treated with
spironolactone. In one patient spironolactone withdrawal occurred four weeks before
surgery while in five patients, the drug withdrawal occurred 2 days before surgery.
The majority of patients (84%) had hypokalemia at diagnosis, with potassium
levels of 2.5±0.5 that increased progressively, achieving levels of
4.8±0.6 mmol/l (p=0.0002) one year after
adrenalectomy. Hyperkalemia was observed post-operatively in 38% of patients
fifteen days after surgery and decreased progressively to normal values. Two
patients received fludrocortisone post-operatively (patients 7 and 8). All patients
were followed for at least 12 months. In patients who were still hypertensives after
the surgery, antihypertensives that did not interfere with the assessment of renin
and aldosterone were prescribed, such as amlodipine, hydralazine, clonidine, or
diltiazem. Thus, post-operatively no patients were on spironolactone and diuretics
on post-operative period.
[Figure 2] and [Table 1] show the longitudinal mean
(±SEM) values of serum aldosterone ([Fig.
2A]) and DRC ([Fig. 2B]) of the 13
APA patients obtained before (day 0) and 1, 3, 5, 7, 15, 30, 60, 90, 120, 180, 270,
and 360 days post-adrenalectomy. High preoperative serum aldosterone levels rapidly
decreased to undetectable levels between the first and seventh postoperative days.
All patients attained aldosterone levels<5 ng/dl at the
immediate postoperative period, characterizing the complete biochemical surgical
success. The lowest mean aldosterone levels were observed between the fifth to
seventh days, when 85% of patients presented undetectable
(<2.2 ng/dl) or very low
(<3.0 ng/dl) levels. From 15th to 90th postoperative days
aldosterone levels were between 4 and 5 ng/dl (low normal range).
Three months from on, serum aldosterone levels gradually increased to the normal
range. The median postoperative recovery time was 60 days (interquartile range
15–225).
Fig. 2 Prospective and longitudinal levels of serum aldosterone
(a) plasma renin (b), serum cortisol (c), and
plasma ACTH (d) obtained in the morning before (day 0) and 1, 3, 5,
7, 15, 30, 60, 90, 120, 180, 270, and 360 days after adrenalectomy in
thirteen APA patients. Data are presented as mean (±SEM). The
horizontal dotted lines represent the limits of detection for serum
aldosterone (2.2 ng/dl) and plasma renin (2.3 m IU/l)
levels. The grey area represents the laboratory normal morning levels
(5th–95th percentiles) for each hormone.
Table 1 Prospective and longitudinal follow up of aldosterone,
renin, cortisol, ACTH, potassium, and creatinine levels in thirteen
patients with aldosterone-producing adenomas before (pre-op) and 1, 3,
5, 7, 15, 30, 60, 90, 120, 180, and 360 days after unilateral
adrenalectomy.
|
Days
|
Aldosterone ng/dl
|
Renin mIU/l
|
Cortisol μg/dl
|
ACTH pg/ml
|
Potassium mmol/l
|
Creatinine mg/dl
|
|
Pre-op
|
74.5±17.7
|
2.3±0.1
|
11.5±2.2
|
13.5±2
|
3.7±0.2
|
1.1±0.1
|
|
1
|
14.1±6.5
|
3.6±0.8
|
9.2±2.6
|
29.5±16.3
|
3.8±0.1
|
1.4±0.2
|
|
3
|
4.4±1.9
|
6±2.1
|
19.0±2.7
|
24.1±2.7
|
3.8±0.2
|
1.2±0.2
|
|
5
|
2.7±0.3
|
2.7±0.4
|
14±2.1
|
25.6±4.6
|
4.0±0.2
|
1.1±0.1
|
|
7
|
2.6±0.3
|
6±2.1
|
15.9±3.2
|
31.1±4.1
|
4.5±0.1
|
1.3±0.1
|
|
15
|
4±1.3
|
11.5±2.6
|
14.1±1.1
|
43.6±13
|
5.2±0.2
|
1.5±0.2
|
|
30
|
4.5±0.9
|
12.6±2.3
|
13.2±1.6
|
36.3±4.2
|
5.1±0.2
|
1.4±0.1
|
|
60
|
4.6±1
|
7.5±2.2
|
12.4±1.1
|
34.4±6.4
|
5.2±0.1
|
1.3±0.2
|
|
90
|
4.6±0.7
|
8.8±2.8
|
11.6±1.4
|
46.4±14.9
|
4.9±0.2
|
1.3±0.1
|
|
120
|
6±1.7
|
17.6±5.9
|
13.8±2.7
|
30.7±5.2
|
5.0±0.2
|
1.4±0.2
|
|
180
|
4.3±0.7
|
11±3.4
|
10.3±1.4
|
30.7±4.8
|
4.9±0.1
|
1.5±0.2
|
|
270
|
8±2.5
|
19.7±8.7
|
13.6±1.7
|
27.5±3.5
|
4.8±0.1
|
1.4±0.1
|
|
360
|
7.8±1.7
|
9.3±2.1
|
13.6±1
|
27.0±4.9
|
4.8±0.2
|
1.4±0.1
|
Values represent the mean±SEM.
The suppressed preoperative DRC became rapidly detectable between the 15th and 30th
days after surgery, attaining plasma values≥5 mU/l in
92% of patients (12/13). DRC remained in the normal range for all
subsequent days throughout the study ([Fig.
2B], [Table 1]). The median DRC
postoperative recovery time was 15 days (interquartile range, 5–30) after
surgery. In 77% of the patients, the DRC recovered earlier than aldosterone
levels while both hormones recovered simultaneously in 23%. Thus, the
recovery of aldosterone took longer than renin recovery (60 vs. 15 days;
p<0.002).
There was no association between the recovery of aldosterone and DRC with age at
diagnosis, duration of hypertension, potassium levels, spironolactone or
fludrocortisone treatments. However, patients with aldosterone
levels≥52 ng/dl at diagnosis presented later
renin (>15 days; p=0.02) and aldosterone (>60 days;
p=0.03) recoveries. There was no relationship between the age at PA
diagnosis and the day in which the lowest post-operative serum aldosterone levels
were attained (r=0.2, p=0.5). Moreover, there was no relationship
between the preoperative treatment with spironolactone and the aldosterone
(p=0.16) and DRC (p=0.19) recoveries.
All thirteen APA patients presented complete biochemical success at 1, 3, 6, and 12
months post-adrenalectomy, according to the PASO criteria ([Table 2]). However, complete clinical success
was observed only in 30% of the patients, while 70% presented
partial clinical success at 6 and 12 months after surgery. Complete biochemical and
clinical success at 12 months was observed in 23% (3/13) of the
patients. The PASO performance at 3 months was concordant with 6- and 12-months
evaluation in 92% (12/13) of the patients. However, at one month,
the PASO clinical score presented lower concordance with 3-, 6- and 12-month
evaluation (69, 77, and 77%, respectively).
Table 2 Categorization of degrees of biochemical and clinical
success according to International Consensus Definitions for Cure of
Primary Aldosteronism (PASO) system applied at 1-, 3-, 6- and 12- months
after adrenalectomy.
|
Patients
|
PASO
|
PASO
|
PASO
|
PASO
|
|
1 month
|
3 months
|
6 months
|
12 months
|
|
Clinical
|
Biochemical
|
Clinical
|
Biochemical
|
Clinical
|
Biochemical
|
Clinical
|
Biochemical
|
|
1
|
C
|
C
|
C
|
C
|
C
|
C
|
C
|
C
|
|
2
|
A*
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
3
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
4
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
5
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
6
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
7
|
P*
|
C
|
C
|
C
|
C
|
C
|
C
|
C
|
|
8
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
9
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
10
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
11
|
P
|
C
|
P
|
C
|
P
|
C
|
P
|
C
|
|
12
|
P*
|
C
|
C
|
C
|
C
|
C
|
C
|
C
|
|
13
|
C
|
C
|
P*
|
C
|
C
|
C
|
C
|
nr
|
C: Complete clinical or biochemical responses; P: Partial clinical or
biochemical responses; A: Absent clinical or biochemical responses; NR: Not
reported; * Represents discordant PASO criteria at 1 or 3
months versus 6 and 12 months.
The morning serum cortisol and plasma ACTH levels remained in their normal range
during the whole longitudinal protocol as shown in [Fig. 2C, D] and in [Table 1]. Of
note, two female patients, aging 60 and 61 years-old, presented aldosterone and
cortisol co-secretion but no Cushingoid features. They had preoperative morning
suppressed ACTH levels (<10 pg/ml) and cortisol of 14 and
16 μg/dl, with no suppression after overnight 1 mg
dexamethasone (13 and 3.5 μg/dl, respectively). Serum
cortisol dropped to undetectable levels (<2 μg/dl)
after surgery and recovered (>5 μg/dl) after 60th
and 15th post-operative days. These two patients required hydrocortisone
postoperatively and subsequently prednisone and fludrocortisone replacement. The
pre-operative DRC were 2.9 and 2.3 mIU/l and serum aldosterone
levels were 12 and 38 ng/dl. Serum aldosterone decreased to
undetectable levels from 1st to 5th postoperative day and remained undetectable or
very low even after 360 days. After two years of follow-up, aldosterone and DRC
returned to normal levels. Both patients presented hyperkalemia after
adrenalectomy.
Discussion
This report is the first to perform a prospective and longitudinal protocol with
simultaneous measurement of serum aldosterone and renin levels in patients with APA
at immediate and long-term time course after adrenalectomy. Our original data
reveals that the preoperative suppressed renin levels became rapidly detectable
after surgery and attained normal values from the 15th post-operative days in the
great majority of patients. The current study also demonstrates that DRC recovery
occurs much earlier than aldosterone (median 15 vs. 60 days) after adrenalectomy.
Thus, the borderline persistent hypoaldosteronism remains, even in the presence of
detectable DRC. This finding indicates that renin deficiency does not seem to be the
main cause of sustained post-operative hypoaldosteronism in patients with APA who
underwent surgery.
In the present study, we observed a long delay between the beginning of hypertension
and the PA diagnosis as well as a higher incidence of hypokalemia (84%) at
the diagnosis, suggesting patients with severe hyperaldosteronism. Indeed, the
median aldosterone levels before surgery in our study were higher (54.8;
24–103 ng/dl) than those described in two multicenter (28.2
and 34.9 ng/dl) studies [17]
[23] and in another referral
center (34.8 ng/dl) in Brazil [32]. However, in all these studies, the frequencies of hypokalemia (92,
91.9, and 80%) were similar to ours (84%) and much higher than those
accepted in the last guideline [9], in which
hypokalemia has been described in only one-third of the APA patients. The different
rates of hypokalemia can be due to where the patients are seen, whether a primary
care setting or referral centers [3].
Post-operative studies evaluating the adrenal function in APA have been described for
almost six decades [12]
[17]
[23]
[24]
[25]
[26]
[27] shown the persistency of
low urinary or plasma aldosterone after unilateral adrenalectomy. However, most of
these studies are retrospective [12]
[17]
[23].
Also, in the previous large series, the post-operative renin and aldosterone levels
were assessed from one [17] to three months
following surgery [26]. More comprehensively,
the present study focuses on evaluating these hormones from the immediate first
post-operative days.
Our data on the DRC in APA patients reveal that preoperative suppressed renin
concentrations became rapidly detectable and achieved normal values around the
second postoperative week in the majority of patients. This very early DRC recovery
after removal of APA had not been previously described. In previous reports, the
renin recovery occurred either between one or three months after surgery [17] or persisted high until 24 months
post-operative [26]. These differences may be
ascribed to different methods to measure renin, such as DRC in present study or
other commercial renin assays [17] or plasma
renin activity [26]. However, these
differences may also be attributed to clinical diversity or the severity of the
disease among these studies. We could ask if the spironolactone treatment in the
immediate pre-operatory period in some patients would interfere with the assessment
and the recovery of DRC and aldosterone in post-operative period. Our data on
suppressed renin until 5 days post operatively in all patients, including those who
had been treated with spironolactone before the surgery, clearly demonstrate that
this drug did not interfere either with the assessment of DRC and aldosterone nor
with the time of recovery of these hormones post-operatively.
We also demonstrated that in all APA patients, high preoperative serum aldosterone
levels rapidly decreased to undetectable levels during the first week after
adrenalectomy. Then, aldosterone levels gradually increase but yet at the lower
normal range. This finding agrees with previous long-term studies that showed a
persistent postoperative hypoaldosteronism after surgery [17]
[26].
Our results also show that in three-quarters of the APA patients, aldosterone
recovered later than renin whereas in one-quarter they recovered simultaneously. One
possibility to explain the different aldosterone and DRC recovery times is that
chronic suppression of JGA in the kidney rapidly gains function, allowing the renin
secretion to return to normal, in contrast to the gradual recovery of the adrenal
ZG. This phenomenon can be due to the differences between renin and aldosterone
regulation, although both hormones, besides angiotensin II, are part of the same
endocrine interconnected system [33]. Indeed,
the JGA, the primary source of renin circulation, acts as a sensing device regulated
by multiple factors, such as the blood pressure, the sodium chloride delivery to the
macula, and by the β-adrenergic activation. Also, angiotensin II may exert a
renin inhibition by a short-loop feedback mechanism and by the action of atrial
natriuretic peptide (ANP). Of note, elevated preoperative ANP levels in APA patients
dropped after surgery [26]. Therefore, we
hypothesized that as soon as hypervolemia and blood pressure reduction occur at the
immediate period of adrenalectomy, these multiple factors contribute to the early
recovery of the renin secretion. In contrast, the biosynthesis and secretion of
aldosterone from ZG cells is a tightly-regulated process under the primary control
of Angiotensin II and plasma potassium levels, and partially influenced by other
factors such as ACTH concentrations, which usually acts a potent but transient
aldosterone secretagogue. Biglieri et al. [24]
and Bravo et al. [25] in their seminal studies
demonstrated that, after APA adrenalectomy, urinary aldosterone excretion is reduced
with no increase neither by direct stimulation with angiotensin II or corticotrophin
administration nor by indirect stimulus through sodium intake restriction.
The observed post-operative hypoaldosteronism in the presence of normal renin might
occur due to the ZG incapability of the remaining adrenal gland to produce
aldosterone. Indeed, the enzymes involved in aldosterone synthesis, such as
cholesterol side chain cleavage, 3beta-hydroxysteroid dehydrogenase, and
21-hydroxylase were expressed in the adenoma but were completely absent in the ZG of
the adjacent normal adrenal tissue [15]. The
mechanism involved in aldosterone synthesis suppression seems similar to the
observed after removing of a cortisol secreting adenoma, when insufficient cortisol
production by the contralateral adrenal occurs despite normal ACTH secretion [34]. Moreover, in patients with adrenal
Cushing’s syndrome, the adrenal recovery time was tightly related to the
degree of previous hypercortisolism [35].
Similarly, here, we demonstrate that APA patients with aldosterone levels higher
than 52 ng/dl at the diagnosis needed longer time to achieve renin
and aldosterone recoveries with no association with age at diagnosis and duration of
hypertension.
Our data on normal serum cortisol in APA patients after unilateral adrenalectomy
confirm previous studies using urinary 17-OHCS levels or plasma cortisol measured by
fluorometric assay [24]
[25]. The present study also shows, for the
first time, that plasma ACTH levels remained in the normal range during all the
postoperative periods in APA patients, despite the presence of hypoaldosteronism.
These results are in accordance with the role of ACTH as a mild regulator of
aldosterone secretion when compared with angiotensin II and potassium stimuli.
We also found aldosterone and cortisol co-secreting adenoma in 2 out of 18 patients
(11%), similar to other small series (4 to 16%) [36]. However, the co-secretion seems to be more
frequent by a steroid metabolome analysis [29]. Both patients presented a transitory postoperative hypocortisolism, with
recovery at 15 and 60 days after unilateral adrenalectomy, but aldosterone and renin
levels recovery times were longer than two years.
Regarding the clinical applications of the results, we suggest that to assess
complete biochemical surgical success, plasma aldosterone should be obtained between
the 3rd and 7th days after surgery, whereas serum potassium and creatinine weekly
until one month after surgery. We also suggest repeating renin and aldosterone
measurement at 30th and 60th postoperative days to detect their recoveries. Finally,
our data also indicates that PASO criteria at three months, in opposition to PASO at
one-month, maybe an early indicator of clinical and biochemical success, reflecting
the well-established PASO at 6- and 12-month evaluation after APA adrenalectomy.
The limitations of our study are, at first, the small sample size compared with
retrospective multicenter studies [13]
[17]. Another limitation might be the long delay
between the beginning of hypertension and the PA diagnosis as well as the higher
incidence of hypokalemia at the diagnosis, suggesting patients with severe
hyperaldosteronism. Therefore, the conclusions of the present study should be
restricted to PA patients with severe clinical and biochemical features, which are
not the majority PA patients diagnosed in several specialized centers. Finally, the
arbitrary criterion that we assumed to characterize the postoperative aldosterone
levels recovery has never been described and it might be questioned. One of the most
important strengths of our study is the prospective and longitudinal nature of its
protocol in a single tertiary medical center. Thus, our study originally contributes
to clarify the outcome of APA patients, mainly at the immediate postoperative
period.
In conclusion, our prospective and longitudinal study shows immediate recovery of
plasma renin at median of 15 days while serum aldosterone recovery occurs later at
60 days. The borderline persistent hypoaldosteronism, even in the presence of normal
DRC, indicates that more than renin deficiency, the ZG incapability of the remaining
adrenal gland to produce aldosterone justifies the prolonged post-operative
hypoaldosteronism in APA patients who underwent surgery. This study also shows the
adequate cortisol-ACTH relationship despite the presence of a post-operative
hypoaldosteronism. Taken together, these findings contribute to the comprehension of
conceptual aspects of the aldosterone-renin relationship following complete removal
of aldosterone-producing adenoma.
