Primary Aldosteronism: Clinical Characteristics of Patients with a Paradoxical Increase in P-Aldosterone in Response to Captopril Challenge Test

Abstract

A proportion of patients with primary aldosteronism (PA) have a paradox increasein plasma-Aldosterone (P-Aldosterone) concentration (PAC) during the Captopril Challenge Test (CCT). This study aimed to investigate if a paradoxical rise in PAC during CCT, was associated with clinical characteristics or outcomes inpatients with PA. We hypothesized that a paradoxical response to CCT is ameasure of disease severity, reflected by a higher baseline aldosterone/renin-ratio (ARR). A retrospective study of patients with PA,confirmed by CCT, who were referred for adrenal venous sampling between May 2011and August 2021 were eligible. Patients with an increase in PAC>10% frombaseline during CCT were classified as cases, while patients with 10 to 30% suppression were classified as controls. Of 167 patients referred, 116 (70%) were eligible for this study. Based on the CCT, 61/116 (53%) were classified as cases while 55/116 (47%) were classified as controls. The baseline ARR was 122 pmol/mIU (IQR: 65 to 223) for cases and 137 pmol/mIU (IQR: 65 to 223) for controls (p=0.66). Cases had lower systolic blood pressure (p=0.02) and higherpotassium levels (p=0.05) compared to controls. Complete clinical remission was obtained in 22 of 31 (71%) of the cases and 13 of 27 (48%) of the controls (p=0.03) after adrenalectomy. In conclusion, a paradoxical response to CCT wasnot associated with ARR. By contrast, patients with a paradoxical response did have lower systolic blood pressure, higher potassium levels, and markedly higher odds of full clinical remission after adrenalectomy.

Keywords

primary aldosteronism - captopril challenge test - paradoxical response - clinical remission

Introduction

Primary aldosteronism (PA) is the most common cause of endocrine hypertension and has a prevalence of 3–30% in patients diagnosed with hypertension [1] [2]. The most frequent causes of PA are bilateral adrenal pathology and unilateral aldosterone-producing adenomas with the former being treated with mineralocorticoid receptor antagonists such as spironolactone and the latter with unilateral adrenalectomy. Diagnosing a patient with PA consists of a measurement of the aldosterone/renin-ratio (ARR) and the use of a confirmatory test is currently recommended [3] [4] [5]. Elevated ARR suggests autonomous aldosterone secretion and current guidelines recommend proceeding with one of the following tests to confirm the diagnosis: oral sodium loading, saline infusion, fludrocortisone-suppression test, suppression or captopril challenge test (CCT) [3]. There is no “gold standard” confirmatory testing [3] [6], however, CCT [7] [8] is the preferred method in the authors’ department.

Captopril is an angiotensin-converting enzyme (ACE) inhibitor and thereby inhibits the conversion of Angiotensin I (ATI) to Angiotensin II (ATII). ATII is a systemic vasoconstrictor that directly stimulates aldosterone secretion via a Gs-coupled receptor. The normal physiological response to an ACE inhibitor is a reduction in aldosterone secretion, and the lack of reduction in aldosterone levels in response to captopril suggests autonomous aldosterone secretion [7].

A subgroup of patients exhibits a paradoxical increase in P-Aldosterone in response to captopril in our experience. However, this phenomenon has not been described in the literature. We therefore propose that a paradoxical increase in aldosterone in response to the captopril challenge test is associated with clinical characteristics in patients with confirmed PA. We specifically hypothesize that patients with a paradoxical aldosterone increase have a more severe form of PA, reflected primarily by higher pre-CCT ARR compared to patients without a paradoxical aldosterone response to a CCT.

Subjects and Methods

Design

This study was a retrospective cohort study of consecutive patients with PA, who had been referred to Rigshospitalet for adrenal venous sampling (AVS). The protocol was approved by the Danish Data Protection Agency (P-2021–289) and the Research Ethics Committee of the Capital Region of Greater Copenhagen (journal-nr.: R-20072913).

Study population

The eligible patients had a confirmed diagnosis of PA by CCT and were referred to Copenhagen University Hospital – Rigshospitalet (RH) for AVS between May 1 2011 and August 31 2021. Patients were diagnosed according to Endocrine Society Clinical Practice Guidelines, including calculation of ARR and confirmatory testing, and classification as unilateral or bilateral disease was obtained by AVS without the use of cosyntropin [3]. The correct placement of catheters was defined as a selectivity index≥2, that is, the ratio between plasma cortisol from adrenal vein and plasma cortisol from a peripheral vein. Lateralization and unilateral disease were defined as a lateralization index≥4, that is, the ratio between the cortisol adjusted aldosterone from dominant adrenal gland and the cortisol adjusted aldosterone levels from the non-dominant adrenal gland. Contralateral suppression was present when the ratio between the cortisol adjusted aldosterone from the non-dominant gland and the cortisol adjusted aldosterone level from a peripheral vein was<1.0. The study population has been described in detail previously [9] [10]. Patients with a paradox response to CCT were classified as cases: a paradoxical response during CCT was defined as an increase in PAC, equal to or greater than 10%, at 60 and/or 120 minutes, compared with baseline values. Patients with a 10 to 30% decrease at 60 and/or 120 minutes in P-Aldosterone compared to baseline, but not a paradoxical increase in one of the samples, were classified as controls. The following patients were excluded from the study: patients diagnosed with other confirmatory tests than CCT and patients with no data available from the CCT. Furthermore, patients with an increase or decrease in PAC between –10% and+10%, at 60 minutes and 120 minutes, were excluded to reduce the risk of including patients with variations in P-Aldosterone due to simple analytical variation of the analyte (P-Aldosterone).

Captopril challenge test (CCT)

In preparation for CCT, correction of potential hypokalemia was attempted and agents affecting the ARR were withdrawn for at least 4 weeks before testing [7]. After 30 minutes of seated rest and baseline blood sampling (renin, aldosterone, potassium), captopril 25 mg was administered orally, and blood was sampled for PAC 60 and 120 minutes after captopril ingestion. PA was confirmed if the CCT did not reduce PAC by more than 30% from the baseline level [7]. PAC was measured using the IDS-ISYS assay, which is the recommended method of analysis and standard throughout Denmark, with the maximum coefficient of variation (CV) estimated to be 10% at 200 pmol/l and 20% at 1000 pmol/l [11]. P-Renin (PRC) was measured using the IDS-ISYS assay, the maximum coefficient of variation (CV) is estimated to be 20% at 10 mIU/l and 8% at 100 mIU/l [11].

Outcomes

The primary outcome was the difference in baseline (pre-CCT) ARR in patients with versus without a paradoxical increase in PAC during CCT. ARR was calculated by dividing the measured P-Aldosterone by the measured P-Renin. Secondary outcomes included nadir of potassium levels before referral, number of anti-hypertensives, potassium supplementation, and potassium level, kidney function (estimated glomerular filtration rate, eGFR), systolic blood pressure, and diastolic blood pressure before CCT, that is, after removal and/or substitution of interfering anti-hypertensive medications that may interfere with assessment of aldosterone or renin. Other secondary outcomes were the proportion of patients with contralateral suppression (CLS) and lateralization index of≥4 at adrenal venous sampling as well as the proportion of patients who obtained clinical or biochemical remission according to the PASO criteria [12] after unilateral adrenalectomy.

Clinical remission following unilateral adrenalectomy was categorized as either complete, partial, or absent according to the PASO criteria [12]. PASO outcomes were evaluated 6 months following surgery, or as close to this date as possible. Complete clinical remission was obtained if blood pressure (BP) had normalized (<140/90 mmHg) with no need for antihypertensive medications. Due to a lack of data on post-operative aldosterone and renin levels, we used a modified version of complete biochemical remission which we defined as p-potassium within the normal range (3.6 to 4.4 mmol/l), without the use of potassium supplements [10].

Data extraction

Data were extracted from electronic patient files, including age, sex, current weight, height, blood pressure, anti-hypertensive medicine, hypertension duration, and treatment selection. Data from the AVS procedure were used to detect lateralization and CLS, the lateralization index (LI) and the CLS index (CLSI) as previously described [10] [13].

Confounders

Our analysis regarding the association between a paradox response and remission for patients who were treated by adrenalectomy, age, gender, and number of anti-hypertensives were included as potential influential variables, as these factors have previously been shown to have an impact on the risk of remission in this cohort [10].

Statistical analysis

Demographical data and outcomes were compared between cases and controls by either t-tests or Mann–Whitney U-tests in parametric or non-parametric data describing variation in data using standard deviation (SD) or interquartile range (IQR) as the 25th and 75th percentile. Dichotomous data were described by proportions (%) and were compared using chi-square tests. One of the secondary outcomes, full clinical remission, was compared by multiple regression including confounding variables with a univariate association to full clinical remission of a p-value>0.2. We also conducted a sensitivity analysis with cases defined as an increase in aldosterone of≥20% at both sample times. Development in aldosterone levels during CCT within groups was assessed by the Wilcoxon signed rank test due to the non-parametric nature of data. Statistical analysis was performed using SPSS IBM version 28 and p-values≤0.05 were considered significant.

Results

Patient characteristics

From May 1 2011 to August 31 2021, 167 patients with PA were referred, and as shown in supplementary Fig. S1, 116/167 (69.5%) patients were included. The main reason for exclusion was that CCT was not performed or lacked data regarding response to CCT. Twelve patients were excluded from the analysis due to an increase in PAC between –10 and+10% at both sample times during CCT. Based on their response to captopril, 61/116 (52.6%) patients had a paradoxical increase in aldosterone and were defined as cases, and the remaining 55/116 (47.4%) were defined as controls. As shown in Fig. S2, the majority (49%) of cases were classified as such due to a≥10% increase in PAC solely in the 120-minute sample. According to [Fig. 1], PAC levels increased from baseline to 60 minutes and from 60 to 120 minutes during the CCT in patients with a paradoxical response while the controls had a decrease in aldosterone from baseline. In the included sample, the mean age was 55 years (SD 12), 67/116 (58%) were male and there were no differences in duration of hypertension or total antihypertensive dose ([Table 1]).

Fig. 1 Aldosterone response to captopril challenge test in PA-patients with paradox response and in patients with aldosterone suppression. Cases:≥10% increase in P-Aldosterone at 60 and/or 120 minutes during CCT. Controls:≥10% suppression in P-Aldosterone at 60 and/or 120 minutes during CCT. *p-Values are based on Wilcoxon signed rank test, paired sampled test for non-parametric data.

Table 1 Baseline characteristics of included patients; cases are PA patients with a paradox increase in P-Aldosterone in response to captopril challenge test (CCT), while controls have a suppression of P-Aldosterone.

	Cases (n=61)	Controls (n=55)	p-Value
Age, years, mean (SD)	54.8 (11.4)	55.8 (12.1)	0.63
Men, n (%)	35 (57)	32 (58)	0.93
BMI; mean (SD)	30.1 (5.7)	29.4 (5.7)	0.53
Hypertension duration, years; median (IQR)	10.5 (7.6)	11.4 (9.4)	0.70
Total DDD mg; median (IQR)	69.5 (6.3 to 237.5)	70 (7.5 to 190.0)	0.51

Cases:≥10% increase in P-Aldosterone at 60 and/or 120 minutes during CCT. Controls:≥10% suppression in P-Aldosterone at 60 and/or 120 minutes during CCT. BMI: Body mass index; BP: Blood pressure; DDD: Defined daily dose of antihypertensive medication; IQR: Interquartile range (25th to 75th percentile).

Primary outcome: ARR estimated at baseline of captopril challenge test

As shown in [Fig. 2], the median ARR in cases was 122.2 pmol/mIU (65.0 to 223.0) compared with 136.5 pmol/mIU (65.1 to 223.0) in controls, p=0.66. As shown in [Table 2], the median PAC was 608 pmol/l (IQR 475 to 1014) in cases compared to 715 pmol/l (IQR 446 to 937) in controls (p=0.27), and there were no significant differences in levels of renin.

Fig. 2 Aldosterone/renin ratio in PA patients with a paradoxical response to CCT versus controls. PA patients with an increase in P-Aldosterone of≥10% during CCT were defined as cases. PA patients with suppression of P-Aldosterone (≥10–30%) were defined as controls. Data is shown as median with interquartile range. PA: Primary aldosteronism; CCT: Captopril challenge test; ARR: Aldosterone/renin ratio.

Table 2 Primary and secondary outcomes comparing PA patients with a paradoxical increase in P-Aldosterone to PA patients with suppression of P-Aldosterone during CCT.

	Cases n=61	Controls n=55	p-Value
At CCT
P-Aldosterone, pmol/l, median (IQR)	608 (475 to 1014)	715 (446 to 937)	0.27
Renin, IU/L, median (IQR)	5.0 (2.3 to 8.1)	5.0 (3.1 to 11.3)	0.93
ARR, pmol/mIU, median (IQR)	122 (65 to 223)	137 (65 to 223)	0.66
P-potassium, mmol/l, mean (SD)	3.8 (0.4)	3.6 (0.5)	0.05*
Potassium supplement, mmol/day, median (IQR)	40 (20 to 55)	40 (10 to 60)	0.62
P-Potassium – nadir, mmol/l, mean (SD)	2.7 (0.3)	2.8 (0.4)	0.59
No. of anti-hypertensives, mean (SD)	2.2 (1.2)	2.2 (1.4)	0.88
Systolic BP, mmHg, mean (SD)	146 (21)	158 (23)	0.02*
Diastolic BP, mmHg, mean (SD)	91 (14)	92 (14)	0.65
eGFR, ml/min/1.73 m2	80 (17)	76 (14)	0.21
After CCT
LI≥4, n (%)	35 (57)	37 (67)	0.38
LI, median (IQR)	6.3 (2.0 to 24.8)	6.3 (2.9 to 23.4)	1.00
CLS, n (%)	24 (39)	24 (44)	0.64
CLSI, median (IQR)	1.8 (0.4 to 6.0)	1.1 (0.4 to 2.8)	0.46
Cortisol, right adrenal gland, nmol/l, median (IQR)a	1820 (634 to 4560)	1990 (802 to 11000)	0.85
Cortisol, left adrenal gland, nmol/l, median (IQR)a	985 (492 to 3530)	1590 (673 to 6330)	0.23
No. of anti-hypertensives 6 months after, mean (SD)	0.9 (1.0)	1.1 (1.1)	0.32
Patients recieving potassium supplement , n (%)	4 (6.6)	4 (7.2)	1.00
Systolic blood pressure 6 months after, mean (SD)	131.2 (15.1)	135.8 (16.8)	0.25
Diastolic blood pressure 6 months after, mean (SD)	85.3 (3.2)	82.3 (10.3)	0.31
Adrenalectomy, n (%)	31 (51)	27 (49)	0.71
Pathology, adenoma, n (%)	28 (90)	22 (82)	0.63
Pathology, hyperplasia, n (%)	2 (7)	2 (7)
Pathology, not classified, n (%)	1(3)	3 (11)
Clinical full remissionb, n (%)	22 (71)	13 (48)	0.03
Clinical full or partial remissionb, n (%)	26 (84)	16 (59)	0.04
Biochemical full remissionb, n (%)	30 (97)	23 (85)	0.12

Cases:≥10% increase in P-Aldosterone at 60 and/or 120 minutes during CCT. Controls:≥10% suppression in P-Aldosterone at 60 and/or 120 minutes during CCT.

^*Adjusting for sex and age did not change the p-value.

^a Sampled during adrenal venous sampling.

^b Clinical and biochemical remission is according to the PASO criteria, i. e., in patients who had adrenalectomy.

BP: Blood pressure; CCT: Captopril challenge test; eGFR: Estimated glomerular filtration rate; IQR: Interquartile range (25th to 75th percentile); P: Plasma; LI: Laterelization index; CLS: Contra lateral suppression; CLSI: Contra lateral suppression index; ARR: Aldosterone renin ratio; AVS: Adrenal venous sampling.

Secondary outcomes

Cases had lower systolic blood pressure compared with controls with a mean difference of 12.2 mmHg (95% CI; 2 to 22, p=0.02) and on average 0.18 mmol/, (95% Cl; 0.0 to 0.4, p=0.05) higher potassium levels compared to controls. As shown in [Table 2], there we no other significant baseline differences between cases and controls at the time of CCT.

After CCT and subsequent adrenal venous sampling 31/61 (51%) cases and 27/55 (49%) controls underwent unilateral adrenalectomy (p=0.71). According to the PASO criteria, cases had a significantly higher chance of ‘clinical full remission’ as well as ‘clinical partial or full remission’ compared with cases ([Fig. 2]), while there were no differences regarding the risk of biochemical remission. As shown in [Table 3] and [Fig. 3], the differences regarding clinical remission remained significant in multivariate analysis for full remission with an 11.3-fold (95% Cl; 1.7 to 75.1; p=0.01) higher odds of remission in patients with paradox response while the risk of ‘partial or full remission’ was reduced to borderline significant.

Fig. 3 The risk of remission after adrenalectomy in PA patients with a paradoxical increase in P-Aldosterone during CCT compared to patients with suppression of P-Aldosterone. Cases:≥10% increase in P-Aldosterone at 60 and/or 120 minutes during CCT. Controls:≥10% suppression in P-Aldosterone at 60 and/or 120 minutes during CCT. Full or partial remission according to the PASO criteria. *In multivariate analysis adjusted for age, sex, no. of antihypertensives. CCT: Captopril challenge test; P: Plasma; PA: Primary aldosteronism.

Table 3 The association between a paradoxical response to CCT and full remission after adrenalectomy in 58 patients with primary aldosteronism.

	OR (95% CI) Univariate	P-value	OR (95% CI) Multi-variate	P-value
Paradoxical response	3.69 (1.1 to 12.0)	0.03	11.32 (1.7 to 75.1)	0.01
Age	0.95 (0.9 to 1.0)	0.06	0.98 (0.9 to 1.1)	0.56
Gender, female	9.14 (2.6 to 32.3)	<0.001	6.90 (1.3 to 36.0)	0.02
No. antihypertensives	0.33 (0.2 to 0.6)	<0.001	0.31 (0.1 to 0.7)	0.008

Paradox response was defined as≥10% increase in P-Aldosterone at 60- and/or 120-minutes during CCT while controls had≥10% suppression in P-Aldosterone at 60- and/or 120 minutes during CCT. Full remission was defined as normalized blood pressure (<140/90) without the requirement of antihypertensives.

Abbreviations: OR – odds ratio; CI – confidence interval; CCT – captopril challenge test.

Sensitivity analysis

The planned sensitivity analysis including patients with an increase in PAC≥20% at both 60- and 120 minutes included 15 cases and 56 controls. In cases the potassium levels were 3.7 mmol/l (SD) versus 3.6 mmol/l (SD 0.6) in controls (p=0.59), systolic blood pressure was 156.4 (SD 20) in cases versus 157.3 (SD 23) in controls (p=0.90), while 4/6 (67%) cases underwent adrenalectomy obtained full clinical remission, which was the case for 17/25 (68%) among controls (p=0.95). The median ARR was 129.5 (IQR 67 to 287) in cases versus 139.2 (IQR 73 to 267) in controls, p=0.80. Overall, there were no significant differences between cases and controls. Post-hoc we pooled patients with either nadir potassium levels below 2.4 mmol/l or systolic blood pressure above 180 mmHg as a group of patients with severe PA. Using this definition 25/61 (41%) among the cases had a severe form of PA compared to 25/55 (45%) among the controls, p=0.63.

Post-hoc, we compared cortisol levels during adrenal venous sampling and as shown in [Table 2] there were no differences between cases and controls (p>0.23).

Discussion

Our study aimed to investigate whether a paradoxical increase in PAC, as a response to the captopril challenge test, was associated with clinical characteristics in patients with PA. In our patient cohort, approximately half (53%) of the population had a paradoxical aldosterone response to CCT. Patients with a paradoxical response had markedly lower systolic blood pressure and higher potassium levels compared to patients with aldosterone suppression. In addition, patients with a paradoxical response had a significantly higher chance of full clinical remission after adrenalectomy compared to patients with aldosterone suppression during CCT.

To the best of our knowledge, no similar study or data has previously been published. The classification of patients based on their aldosterone response to CCT suggests that a paradox response is present in approximately half of the patients. In our analysis, patients with a paradox response were characterized by substantially lower systolic blood pressure and higher potassium levels suggesting, contrary to our hypothesis, a less severe form of PA than patients with aldosterone suppression in response to CCT. This was supported by a markedly higher chance of full clinical remission in patients with paradoxical response. The sensitivity analysis, including only cases with at least a 20% increase in aldosterone during CCT did not find any significant differences between cases and controls. However, the sensitivity analysis only included 15 cases and results may reflect a type II error.

The division of patients into two more or less identical halves suggests that the division of patients merely reflects simple measurement error. The CV_max for PAC at 200 pmol/l and 1000 pmol/l is 10% and 20% in our assay and the majority of values in the current study are between these values and our cut-off at 10% increase for the definition of a paradox response may be too small to avoid measurement error. However, the distribution of paradoxical aldosterone increase during CCT did not appear completely random with the majority of increase in aldosterone levels observed at 120 minutes, which is supported by a significant increase in PAC from 60 to 120 minutes in cases. In controls, the levels of PAC remained the same in the 60 and 120-minute samples, which has been shown elsewhere [14]. The lower systolic blood pressure and higher potassium levels in paradox responders may suggest a less severe form of PA, however, while median values for PAC were approximately 100 pmol/l lower in the group of paradoxical responders this finding was insignificant nor were there any differences on levels of renin. In patients without autonomous aldosterone secretion ACE-inhibitors like Captopril reduce aldosterone levels, while this effect is less pronounced or abolished in patients with partly autonomous aldosterone secretion, that is, PA. Also, to support our findings we would expect an even greater difference regarding systolic blood pressure potassium levels when examining more extreme cases in our sensitivity analysis including cases with≥20% increase in aldosterone levels, however, this was not the case suggesting that our main findings were not robust and potentially spurious. Should one speculate on the reason for the observed paradoxical increase in PAC in a subgroup of patients may be due to an increased sensitivity to fall in blood pressure in response to captopril, and that the associated increase in renin overrules the captopril induced drop in conversion of Angiotensin I to Angiotensin II and suggest a less autonomous disease. The higher risk of remission suggests a less severe disease form in patients with a paradoxical response and may be the result of less systemic consequences of hyperaldosteronism despite the same duration of hypertension. This is also supported by the lower systolic blood pressure and higher potassium levels observed in this subgroup of patients.

This study was a retrospective study with inherent limitations of data quality. Assessment of biochemical remission after adrenalectomy was assessed solely on correction of hypokalemia as data for ARR in the postoperative period were missing for more than half of the participants. Only 15 cases were available for sensitivity analysis regarding patients with a 20% increase in aldosterone, which was insufficient to confirm our main study findings. The lack of a convincing hypothesis regarding our findings does not support our key findings, that is, that patients with a paradoxical increase in aldosterone represent a subgroup of patients. It could also be hypothesized that the increase in aldosterone in approximately half of the population may be due to stress induced ACTH stimulated aldosterone secretion [15] [16]. We post-hoc tested this hypothesis using cortisol samples during adrenal venous sampling, which is likely to be perceived as more stressful than CCT, however, there were no significant differences between cases and controls. While current guidelines suggest the use of confirmatory testing [3], new studies have demonstrated the inconsistency in the performance of traditional confirmatory tests, including the CCT, and suggested that these are not generally helpful for establishing a diagnosis of PA [4] [5]. However, the purpose of the current study was not to assess the value of CCT, rather it was based on the unexpected biochemical response to CCT, which may represent a sub-group of patients.

We have observed an unexpected increase in aldosterone in response to CCT in patients with PA. Based on the current findings we propose that patients who respond with a paradox increase in aldosterone levels when challenged with captopril may represent a subgroup of PA-patients characterized by lower systolic blood pressure and higher potassium levels. This would suggest a milder or different form of PA reflected in the markedly higher odds of complete clinical remission observed in this subgroup. With the lack of any convincing mechanistic explanation for these findings, the current study should be perceived as hypothesis-generating and tested in other cohorts.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 23 October 2024

Accepted after revision: 23 January 2025

Article published online:
06 March 2025