Abstract
Objective
Adrenal vein sampling (AVS) is a technically demanding procedure required for the identification of suitable candidates for unilateral adrenalectomy in primary aldosteronism. Recently, somatic KCNJ5 K+-channel mutations in aldosterone-producing adenoma (APA) patients have been shown to influence steroid gradients during AVS. These and other recently identified genetic modifiers (ATP1A1 and ATP2B3) might affect the final diagnosis and treatment of the affected patients.
Design
Fifty-nine patients with APAs who had undergone successful AVS (adrenal vein cortisol:peripheral cortisol ratio ≥2) and had undergone a mutation analysis of their tumor tissue were studied. The mutation status of the APAs was as follows: 19 KCNJ5 mutations, eight ATPase mutations (five ATP1A1 and three ATP2B3), and 32 patients with none of these mutations.
Methods
The lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) and the contralateral suppression index (ratio of aldosterone:cortisol on the contralateral side to aldosterone to cortisol in the periphery) were calculated for the KCNJ5-mutated, ATPase-mutated, and the KCNJ5/ATPase mutation-negative APA patients.
Results
The lateralization indices of the ATPase mutation carriers had a median of 19.9 compared with a median of 16.0 in the KCNJ5 mutation carriers and that of 20.5 in the KCNJ5/ATPase mutation-negative patients. The contralateral suppression indices of the ATPase-mutated patients had a median of 0.1 compared with a median of 0.4 in the KCNJ5 mutation carriers and that of 0.2 in the KCNJ5/ATPase mutation-negative patients. The differences between the genetic groups were not statistically significant.
Conclusions
We did not find evidence for a clinically important impact of mutation status on steroid gradients during AVS.
Introduction
Primary aldosteronism (PA) is the most common cause of secondary arterial hypertension. It has been reported to occur in ∼7% of hypertensive patients in population-based studies and in up to 20% of those with resistant hypertension in specialized centers (1, 2). Cardiovascular and renal morbidities are increased in patients with PA compared with patients with essential hypertension (3, 4, 5). Therefore, early diagnosis and specific therapy are of crucial importance (6). The two main causes of PA are aldosterone-producing adenomas (APAs) and bilateral idiopathic adrenal hyperplasia. While APAs can effectively be cured with unilateral adrenalectomy, bilateral idiopathic adrenal hyperplasia is treated with lifelong therapy with mineralocorticoid receptor antagonists. Subtype differentiation between unilateral adrenal disease and bilateral adrenal disease necessitates adrenal vein sampling (AVS) (7).
Recently, somatic mutations in APA patients have become a focus of research. In 2011, Choi et al. (8) discovered mutations in the KCNJ5 gene, coding for the potassium channel KIR3.4, in 36% of the sporadic APA cases. The detected mutations were localized near the selectivity filter of the channel. Thus, KCNJ5-mutated potassium channels lose their ion selectivity and permit sodium influx, leading to the depolarization of the cell (9). This leads to the opening of voltage-dependent calcium channels and influx of calcium. The enhanced calcium concentration induces aldosterone production via the calcium signaling cascade. In many consecutive studies including our own series, affected patients were demonstrated to be predominantly females (10). We have recently discovered somatic mutations in the Na+, K+-ATPase (ATP1A1) and Ca2+-ATPase (ATP2B3) genes in 5.2 and 1.6% of the APA patients respectively (11). These mutations were localized in the ion-binding pocket. Functional studies of ATP1A1 mutations have demonstrated the loss of function of the pump and depolarization of the cells. Patients affected by these mutations are predominantly males and have a more severe endocrine and cardiovascular phenotype.
AVS is a technically demanding procedure that is required for the identification of suitable candidates for unilateral adrenalectomy in PA. A recent study has shown that steroid gradients during AVS are influenced by the KCNJ5 mutation status of the APA (12). However, the impact of ATPase mutations has not been studied yet. This might have an impact on final diagnosis and treatment.
Subjects and methods
Patient cohort
Patients with APAs were recruited consecutively in three different German centers (Munich, n=50; Berlin, n=8; and Würzburg, n=1) of the German Conn's Registry – Else Kröner-Fresenius Hyperaldosteronismus Registry (www.conn-register.de). Of the 59 patients recruited, 46 were part of the study carried out by Beuschlein et al. (11). Case detection and subtype identification of PA were carried out according to institutional guidelines and in accordance with the Endocrine Society Guidelines (7, 13). The final diagnosis of APAs was based on the following criteria: biochemical diagnosis of hyperaldosteronism, lateralization of aldosterone production during AVS, histological confirmation of adrenocortical adenomas and normalization of hypokalemia, hypertension, and aldosterone-to-renin ratio after adrenalectomy (14, 15). The Ethics Committee of the participating centers approved the protocol of the German Conn's Registry, and all patients provided written informed consent for genetic and clinical investigations.
Adrenal vein sampling
Before AVS, the use of interfering medications such as mineralocorticoid receptor antagonists, diuretics, and β-blockers was stopped. Instead, verapamil (maximum dose of 240 mg twice daily) and doxazosin (maximum dose of 16 mg daily) were used and hypokalemia was corrected. AVS was carried out between 0800 and 1200 h by experienced radiologists. Blood samples were sequentially collected from both adrenal veins without adrenocorticotrophic hormone (ACTH) stimulation. Hydrophilic 4 French catheters with different configurations were used, depending on the anatomy of the adrenal veins. The samples were collected by gravity or gentle suction. Corresponding peripheral samples were collected at the time of AVS of each adrenal vein (n=48) or only once during AVS (n=11). The mean selectivity index of the two groups was similar.
A selectivity index (adrenal vein cortisol to peripheral cortisol) of at least 2 on both sides and a lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) of 4 or above were set for the diagnosis of unilateral aldosterone excess (16). The contralateral suppression index was calculated as the ratio of the cortisol-corrected aldosterone ratio (AC) of the nondominant adrenal gland to the peripheral AC (ACnondominant adrenal/ACperiphery). The decision for adrenalectomy was not based on the contralateral suppression of aldosterone secretion.
Biochemical measurements
Plasma aldosterone concentration was measured using Coat-a-Count RIA (Biermann DPC, Bad Nauheim, Germany). Active renin concentration was measured using the Diasorin assay (Liaison, Saluggia, Italy) in Munich and Würzburg and using the Cisbio assay (Berlin, Germany) in Berlin. In this study, the respective within-assay and between-assay coefficients of variation were below 9 and 12% for aldosterone and below 5.6 and 12.2% for renin respectively. All other biochemical variables were assayed using plasma or serum in our central laboratory using standard methods. Serum potassium concentration was measured using flame photometry (ISE Indirect, Cobas Integra, the Roche platform; Roche).
KCNJ5, ATP1A1, and ATP2B3 sequencing
DNA was extracted from APA tissue using the RNeasy DNA extraction kit (Qiagen) and amplified using intron-spanning primers as described previously (8, 11). Bi-directional Sanger sequencing was carried out using the ABI 3730xl Analyzer.
Statistical analysis
Data were extracted from the German Conn's Registry – Else Kröner-Fresenius Hyperaldosteronismus Registry. If not stated otherwise, group results are reported as medians and interquartile ranges (IQRs). Data of the groups were compared using the Kruskal–Wallis test followed by a two-sided test for pairwise comparison of two groups. Power calculation of the study was based on the data of the study carried out by Seccia et al. (12) and on a conservative assumption of mean lateralization indices of 30 and 15 (s.d.±15) in mutated vs nonmutated APA patients. This estimation required 17 patients in each group to detect a significant difference (P<0.05) with a power of 80%. Statistical analysis was carried out using the standard statistical software (SPSS 21).
Results
To analyze the potential influence of somatic mutations on steroid gradients during AVS, 59 consecutive patients with APAs in three German centers were prospectively studied. Among the patients, 37 were men and 22 were women. All the subjects were diagnosed according to the German Conn's Registry standard. Following genetic analysis of the adenoma tissue, it was found that 19 patients had KCNJ5 mutations (11 G151R and eight L168R) and eight had ATPase mutations (five ATP1A1 and three ATP2B3), while 32 APA patients did not harbor any of these mutations.
The baseline and follow-up characteristics of the cohort are summarized in Table 1. As has been reported previously, patients with KCNJ5 mutations were predominantly females and younger at the time of surgery, whereas patients with ATPase mutations displayed a male predominance and were older.
Clinical characteristics of the patient cohort.
| KCNJ5/ATPase | KCNJ5 | ATPase | All | KCNJ5 vs KCNJ5/ATPase | ATPase vs KCNJ5/ATPase | KCNJ5 vs ATPase | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Median | IQR | n | Median | IQR | n | Median | IQR | Pa | Pb | Pb | Pb | |
| Age at diagnosis (years) | 32 | 54 | 16 | 19 | 40 | 12 | 8 | 56 | 5 | 0.001 | 0.002 | NS | 0.015 |
| Adenoma size (mm) | 32 | 15 | 8 | 19 | 16 | 3 | 8 | 15 | 7 | 0.248 | |||
| Serum potassium concentration (mmol/l) | 32 | 3.2 | 0.6 | 19 | 3.4 | 1.0 | 8 | 2.8 | 0.6 | 0.069 | |||
| Plasma aldosterone concentration (ng/l) | 31 | 285 | 301 | 19 | 228 | 191 | 8 | 611 | 628 | 0.106 | |||
| Plasma renin concentration (mU/l) | 30 | 4.5 | 5.7 | 19 | 2.2 | 8.2 | 8 | 3.5 | 16.2 | 0.270 | |||
| Aldosterone-to-renin ratio (ng/mU) | 30 | 63.0 | 109.1 | 19 | 75.3 | 227.3 | 8 | 127.2 | 617.8 | 0.395 | |||
| Systolic blood pressure (mmHg) | 32 | 146 | 20 | 19 | 142 | 26 | 8 | 168 | 51 | 0.045 | NS | NS | 0.038 |
| Diastolic blood pressure (mmHg) | 32 | 91 | 20 | 19 | 89 | 16 | 8 | 96 | 16 | 0.788 | |||
| No. of antihypertensive agents | 17 | 3.0 | 3.0 | 11 | 2.0 | 2.0 | 8 | 2.0 | 2.0 | 0.074 | |||
| Serum potassium concentration (mmol/l) postoperative | 31 | 4.3 | 0.4 | 18 | 4.2 | 0.5 | 7 | 4.7 | 0.8 | 0.124 | |||
| Plasma aldosterone concentration (ng/l) postoperative | 28 | 44 | 35 | 18 | 56 | 57 | 7 | 35 | 1 | 0.464 | |||
| Plasma rennin concentration (mU/l) postoperative | 28 | 11.3 | 22.9 | 18 | 16.5 | 27.0 | 7 | 23.8 | 54.5 | 0.478 | |||
| Aldosterone-to-rennin ratio (ng/mU) postoperative | 28 | 3.7 | 6.0 | 18 | 4.3 | 5.1 | 7 | 1.5 | 2.6 | 0.185 | |||
| Systolic blood pressure (mmHg) postoperative | 25 | 142 | 18 | 18 | 131 | 33 | 7 | 141 | 12 | 0.187 | |||
| Diastolic blood pressure (mmHg) postoperative | 25 | 86 | 14 | 18 | 82 | 16 | 7 | 90 | 24 | 0.473 | |||
| No. of antihypertensive agents postoperative | 24 | 2 | 2 | 16 | 0.5 | 2 | 7 | 2 | 3 | 0.069 | |||
n, number of subjects for each group; IQR, interquartile range; NS, not significant.
Data of the groups were compared using the Kruskal–Wallis test followed by a two-sided test.
For pairwise comparison of the two groups. Conversion of aldosterone (ng/l) to SI unit (pmol/l) by multiplication by 2.77.
AVS was carried out without ACTH stimulation. The AVS values are summarized in Table 2, and individual values are given in Supplementary Table 1, see section on supplementary data given at the end of this article.
AVS values of the patient cohort.
| KCNJ5/ATPase | KCNJ5 | ATPase | All | KCNJ5 vs KCNJ5/ATPase | ATPase vs KCNJ5/ATPase | KCNJ5 vs ATPase | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Median | IQR | n | Median | IQR | n | Median | IQR | Pa | Pb | Pb | Pb | |
| Aldosterone adenoma (ng/l) | 32 | 8328.5 | 25 953 | 19 | 17 980.0 | 31 200 | 8 | 15 707.5 | 60 389.0 | 0.204 | |||
| Aldosterone contralateral (ng/l) | 32 | 428.0 | 875 | 19 | 466.0 | 879 | 8 | 1184.5 | 2379 | 0.196 | |||
| Cortisol adenoma (μg/dl) | 32 | 55.0 | 111.0 | 19 | 174.8 | 320.7 | 8 | 207.3 | 544.3 | 0.162 | |||
| Cortisol contralateral (μg/dl) | 32 | 112.5 | 275.1 | 19 | 45.4 | 216.9 | 8 | 261.7 | 1548.9 | 0.081 | |||
| AC adenoma | 32 | 123.8 | 216 | 19 | 146.7 | 469.0 | 8 | 120.7 | 127.4 | 0.645 | |||
| AC contralateral | 32 | 4.7 | 8.1 | 19 | 5.0 | 6.7 | 8 | 2.0 | 8.0 | 0.291 | |||
| Aldosterone peripheral (AVS ipsilateral; ng/l) | 32 | 149.6 | 138.0 | 19 | 214.0 | 264.0 | 8 | 402.5 | 697.0 | 0.075 | |||
| Aldosterone peripheral (AVS contralateral; ng/l) | 32 | 125.5 | 109.0 | 19 | 214.0 | 132.0 | 8 | 256.5 | 432.0 | 0.037 | NS | NS | NS |
| Cortisol peripheral (AVS ipsilateral; μg/dl) | 32 | 8.8 | 7.9 | 19 | 12.0 | 8.1 | 8 | 14.1 | 12.4 | 0.382 | |||
| Cortisol peripheral (AVS contralateral; μg/dl) | 32 | 8.6 | 10.3 | 19 | 12.7 | 9.0 | 8 | 13.9 | 12.1 | 0.430 | |||
| AC peripheral (AVS ipsilateral) | 32 | 13.8 | 16.3 | 19 | 19.2 | 20.2 | 8 | 29.8 | 37.7 | 0.230 | |||
| AC peripheral (AVS contralateral) | 32 | 12.5 | 23.5 | 19 | 14.7 | 17.9 | 8 | 19.1 | 35.2 | 0.266 | |||
| Selectivity index (minimal) | 32 | 4.7 | 7.5 | 19 | 3.3 | 6.9 | 8 | 11.7 | 24.0 | 0.250 | |||
n, number of subjects for each group; IQR, interquartile range; NS, not significant; AC, aldosterone:cortisol ratio; AVS ipsilateral and AVS contralateral, time points during AVS when the peripheral sample was withdrawn.
Data of the groups were compared using the Kruskal–Wallis test followed by a two-sided test.
For pairwise comparison of two groups. Conversion of aldosterone (ng/l) to SI unit (pmol/l) by multiplication by 2.77. Conversion of cortisol (μg/dl) to SI unit (nmol/l) by multiplication by 27.59.
To analyze the lateralization of aldosterone production during AVS, the lateralization index was calculated. The lateralization index of the nonmutated and KCNJ5-mutated patients had a median of 20.5 (IQR 30.3) and 16.0 (IQR 41.9) respectively (Fig. 1A). The ATPase mutation carriers had a median lateralization index of 19.9 (IQR 122.3). These differences between the genetic groups were not significant (P=0.959).
(A) Lateralization index. The box and whisker plot (median and 25–75th percentiles) shows the ratio of cortisol-normalized aldosterone on the APA side:cortisol-normalized aldosterone on the contralateral side for KCNJ5/ATPase-nonmutated (w/o) patients and for the KCNJ5- and ATPase-mutated patients. (B) Suppression index. The box and whisker plot (median and 25–75th percentiles) shows the ratio of cortisol-normalized aldosterone on the contralateral side:cortisol-normalized aldosterone in the periphery for the KCNJ5/ATPase-nonmutated (w/o) patients and for the KCNJ5- and ATPase-mutated patients.
Citation: European Journal of Endocrinology 169, 5; 10.1530/EJE-13-0551
(A) Lateralization index. The box and whisker plot (median and 25–75th percentiles) shows the ratio of cortisol-normalized aldosterone on the APA side:cortisol-normalized aldosterone on the contralateral side for KCNJ5/ATPase-nonmutated (w/o) patients and for the KCNJ5- and ATPase-mutated patients. (B) Suppression index. The box and whisker plot (median and 25–75th percentiles) shows the ratio of cortisol-normalized aldosterone on the contralateral side:cortisol-normalized aldosterone in the periphery for the KCNJ5/ATPase-nonmutated (w/o) patients and for the KCNJ5- and ATPase-mutated patients.
Citation: European Journal of Endocrinology 169, 5; 10.1530/EJE-13-0551
(A) Lateralization index. The box and whisker plot (median and 25–75th percentiles) shows the ratio of cortisol-normalized aldosterone on the APA side:cortisol-normalized aldosterone on the contralateral side for KCNJ5/ATPase-nonmutated (w/o) patients and for the KCNJ5- and ATPase-mutated patients. (B) Suppression index. The box and whisker plot (median and 25–75th percentiles) shows the ratio of cortisol-normalized aldosterone on the contralateral side:cortisol-normalized aldosterone in the periphery for the KCNJ5/ATPase-nonmutated (w/o) patients and for the KCNJ5- and ATPase-mutated patients.
Citation: European Journal of Endocrinology 169, 5; 10.1530/EJE-13-0551
Contralateral suppression was most distinct in the ATPase-mutated patients with a median of 0.1 (IQR 0.3) compared with a median of 0.4 (IQR 0.5) in the KCNJ5-mutated patients and that of 0.2 (IQR 0.6) in the nonmutated patients (Fig. 1B), but these differences were not significant (P=0.060).
Discussion
AVS is the recommended procedure for the identification of patients with APAs that can be cured with unilateral adrenalectomy. However, it is unclear whether the mutation status of APAs affects steroid gradients during AVS. Seccia et al. (12) have reported on the impact of KCNJ5 mutations on aldosterone gradients during AVS and have found a more profound lateralization index in their cohort. These data have not been confirmed in independent cohorts, and the newly identified ATPase mutations have not been appreciated in this context yet.
Only patients who had undergone technically successful AVS (selectivity index ≥2.0) exhibiting a lateralization of aldosterone production (lateralization index ≥4.0) were included in this study as these were set as the criteria for unilateral adrenalectomy within the German Conn's Registry. The patient cohort displayed a composition similar to the ones reported previously (17). Among the subjects, 32% had KCNJ5 mutations and 14% had ATPase mutations. Gender distribution and age at diagnosis also resembled published data (10).
In this study, the lateralization indices of the nonmutated and ATPase-mutated patients were nearly equal and were higher than those of the KCNJ5 mutation carriers. This finding is in contrast to the findings of the study of Seccia et al., who demonstrated that KCNJ5-mutated patients have a significantly higher lateralization index than the KCNJ5 mutation-negative patients. This discrepancy might be explained by different inclusion criteria for their patient cohort based on a selectivity index of 2 and a lateralization index of 2, impeding the direct comparison of the two studies (12, 18). A lateralization index of 4, as used in the present study, would have placed 68% of the KCNJ5 mutation-negative patients and 24% of the KCNJ5 mutation-positive cases of the Seccia study in the category of bilateral adrenal hyperplasia. These patients probably would not have been adrenalectomized in our clinical setting. Notably, the KCNJ5-mutated patients in the study carried out by Seccia et al. exhibited a more severe phenotype with higher aldosterone levels and lower potassium levels than our patients. One speculation might be that this cohort was diagnosed later and suffered longer from hyperaldosteronism than our patients. On the other hand, the Italian KCNJ5 mutation-negative patients seemed to exhibit a less severe phenotype with higher potassium levels and lower blood pressure in comparison with our nonmutated patients, despite the fact that within this group an unknown proportion of yet undiagnosed ATPase mutation carriers might have been included. In this context, it is not surprising if this group has high lateralization indices similar to the KCNJ5-mutated patients.
We found contralateral suppression to be most distinct in the ATPase-mutated patients. In general, a low contralateral suppression index indicates a more pronounced inhibition of aldosterone production from the contralateral adrenal gland. In our series, all the ATPase-mutated patients displayed full contralateral suppression (100%), whereas only 84% of the KCNJ5-mutated patients and 78% of the nonmutated patients had suppression indices below 1. In the patient cohort of Seccia et al., 74% of the KCNJ5-mutated APA patients exhibited contralateral suppression compared with 54% of the KCNJ5 mutation-negative APA patients. These findings again support the hypothesis that the nonmutated patients in our cohort are different from the ones of the study of Seccia et al.
In summary, AVS is a clinically accurate method in the presence of APAs with or without KCNJ5 and ATPase mutations. We did not find convincing evidence for a clinically important impact of KCNJ5 and ATPase mutations on steroid gradients during AVS.
Supplementary data
This is linked to the online version of the paper at http://dx.doi.org/10.1530/EJE-13-0551.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was made possible by a grant from the Else Kröner-Fresenius-Stiftung in support of the German Conn's Registry – Else Kröner-Fresenius Hyperaldosteronism Registry (to M Reincke). Further funding was provided by the Deutsche Forschungsgemeinschaft to M Reincke and F Beuschlein (Re 752/17-1).
Acknowledgements
The authors thank the Munich PA team (Susanne Schmid, Friederike Konrad, and Gabriele Breu), without whose support this work would not have been feasible. They are indebted to Brigitte Mauracher for technical assistance.
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