Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

Okamura, Takashi; Nakajima, Yasuyo; Katano-Toki, Akiko; Horiguchi, Kazuhiko; Matsumoto, Shunichi; Yoshino, Satoshi; Yamada, Eijiro; Tomaru, Takuya; Ishii, Sumiyasu; Saito, Tsugumichi; Ozawa, Atsushi; Shibusawa, Nobuyuki; Satoh, Tetsurou; Okada, Shuichi; Nagaoka, Rin; Takada, Daisuke; Horiguchi, Jun; Oyama, Tetsunari; Yamada, Masanobu

doi:10.1507/endocrj.ej16-0243

Cited by 27 publications

(18 citation statements)

References 39 publications

(84 reference statements)

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“…Regarding KCNJ5 mutations, we and other groups from Western countries reported that patients with KNCJ5 mutations were younger and had high aldosterone levels [14, 15, 17, 33]. The current study also demonstrated that the mutation rate of the KCNJ5 gene in patients with APAs was 95% for those <50 years old, and this decreased to 67% in those ≥50 years old.…”

Section: Discussionsupporting

confidence: 75%

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Age-Dependent Progression of Renal Dysfunction After Adrenalectomy for Aldosterone-Producing Adenomas in Japan

Yoshioka

Nakajima

Miyamoto

et al. 2018

Journal of the Endocrine Society

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ContextIn patients with aldosterone-producing adenomas (APAs), adrenalectomy causes a rapid decrease in blood pressure and increase in blood potassium levels; however, the effects of these intensive metabolic changes on kidney function with age have not yet been examined in Japan.ObjectiveTo investigate factors related to the progression of kidney dysfunction after adrenalectomy in different age groups.ParticipantsFifty Japanese patients with APAs and 27,572 health checkup patients as controls were examined.Main Outcome MeasuresWe investigated changes in estimated glomerular filtration rate (eGFR) after adrenalectomy and characterized patients who progressed to chronic kidney disease (CKD).ResultsThe postoperative cutoff age of CKD is 50 years and age is a unique factor for the progression of CKD after adrenalectomy. Among preoperative patients, CKD was 6% for those <50 years old and 40% for those ≥50 years old, indicating a higher prevalence of CKD with APAs than in control subjects. Median eGFR <50 mL/min/1.73 m2 did not significantly change after adrenalectomy but decreased from 67 to 42 mL/min/1.73 m2 in those with APAs ≥50 years old. Patients with APAs ≥50 years old who progressed to CKD showed higher preoperative aldosterone/renin ratios, lower potassium and chloride levels, lower body mass index, and a higher incidence of a history of cardiovascular events and KCNJ5 mutation rates.ConclusionAge is the most important predictor of the progression of kidney dysfunction after adrenalectomy in Japanese patients with APAs, particularly those with a history of cardiovascular events and positivity for KCNJ5 mutations.

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Section: Discussionsupporting

confidence: 75%

“…We recently reported a very high frequency (~80%) of somatic mutations in the KCNJ5 gene in Japanese APAs [14–16]. In contrast, the prevalence of KCNJ5 mutations in APAs was found to be ~40% in Western countries [17].…”

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confidence: 99%

Age-Dependent Progression of Renal Dysfunction After Adrenalectomy for Aldosterone-Producing Adenomas in Japan

Yoshioka

Nakajima

Miyamoto

et al. 2018

Journal of the Endocrine Society

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“…The majority of studies documenting the KCNJ5 genotype of APAs reported that patients harboring a KCNJ5 mutant APA were more commonly females, adrenalectomized at a younger age, with a larger tumor size than those harboring a KCNJ5 wild-type APA (18–25, 34, 41). Though, some studies in Oriental cohorts had found no gender bias, as male and female APAs had similar KCNJ5 mutation rates (23, 29–31, 33). In this study, males more commonly harbored a KCNJ5 mutant APA compared to females (39% vs. 23%) and there were no significant differences in age at adrenalectomy or tumor size between patients with a KCNJ5 mutant APA compared to patients with a KCNJ5 wild-type APA.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Histopathological Characteristics of KCNJ5 Mutant Aldosterone-Producing Adenomas in a Multi-Ethnic Malaysian Cohort

et al. 2019

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Studies on excised adrenals from primary aldosteronism patients have found that somatic mutations in KCNJ5 frequently cause excess aldosterone production in the culprit aldosterone-producing adenoma (APA). KCNJ5 mutant APAs were reported to be peculiarly overrepresented among young females and in Oriental cohorts, compared to their older male, or Caucasian counterparts. These larger APAs were also reported to have similarities with the zona fasciculata (ZF) in the adrenal both from the steroid production profile and the morphology of the cell. We therefore aimed to corroborate these findings by characterizing the APAs from a multi-ethnic Malaysian cohort. The prevalence of KCNJ5 mutations was estimated through targeted DNA sequencing of KCNJ5 in 54 APAs. Confirmation of APA sample acquisition was performed by CYP11B2 immunohistochemistry (IHC) staining. The ZF steroid production profile was based on the ZF enzyme CYP17A1 IHC staining, and ZF cell morphology was based on a high cytoplasm to nucleus ratio. Seventeen (31.5%) APAs studied, harbored a KCNJ5 mutation. No female over-representation was seen in this cohort though females were found to have a higher expression of CYP11B2 than males (p = 0.009; Mann-Whitney U test). Age at adrenalectomy correlated negatively with the percentage of ZF-like cells in the APA (p = 0.01; Spearman's rho) but not with the KCNJ5 genotype. KCNJ5 mutant APAs had a high percentage of ZF-like cells (and high CYP17A1 expression) but so did the wild-type APAs. In summary, prevalence of KCNJ5 mutant APAs in this cohort was similar to other Caucasian cohorts, however, over-representation of females did not occur, which is similar to some studies in Oriental cohorts.

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“…Monticone et al [ 8 ] reported that KCNJ5 -mutated APAs in Italy were composed mainly of fasciculata-like cells with higher CYP11B1 and lower CYP11B2 expressions than those in APAs of other causes. Okamura et al [ 9 ] found that KCNJ5 -mutated APAs in Japan had higher CYP11B2 and lower CYP11B1 mRNA levels than those without mutation. The APA in our patient expressed abundant CYP11B2 and scarce CYP11B1.…”

Section: Discussionmentioning

confidence: 99%

A Novel Case of Somatic KCNJ5 Mutation in Pediatric-Onset Aldosterone-Producing Adenoma

Uchida

Amano

Yamaoka

et al. 2017

Journal of the Endocrine Society

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Aldosterone-producing adenoma (APA), a subtype of primary aldosteronism, is a common cause of secondary hypertension in adults. Somatic KCNJ5 mutations have been identified in about 12%–80% of adult-onset APA. In contrast, there has been no previous reported case of pediatric-onset APA in whom a somatic KCNJ5 mutation was confirmed.We report an 11-year-old Japanese girl who had experienced recurrent headaches and nausea for more than 2 years before hypertension was observed (blood pressure, 150/82 mm Hg). Plasma renin activity was <0.1 ng/mL per hour even after a captopril-challenge or upright furosemide-loading test. Plasma aldosterone concentrations (PACs) before and after saline-infusion test were 28.0 and 40.6 ng/dL, respectively. Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were 16.5 pg/mL and 16.7 µg/dL, respectively. The patient was diagnosed with APA in the left adrenal gland on the basis of selective adrenal venous sampling after ACTH stimulation (PAC in the left adrenal vein, 3630 ng/dL) and histopathologic findings of the tumor obtained by laparoscopic left adrenalectomy. Sanger sequencing of KCNJ5 using genomic DNA from peripheral lymphocytes and laser-captured microdissected APA tissues demonstrated the presence of a somatic KCNJ5 mutation p.L168R, previously reported only in adult-onset APA. Immunohistochemistry detected strong immunoreactivity for CYP11B2, but not for CYP11B1 in the APA, consistent with the endocrinologic findings in this patient.Somatic KCNJ5 mutations are also identified in pediatric-onset APA. Further cases are needed to elucidate functional characteristics of pediatric-onset APA with a somatic KCNJ5 mutation.

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Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

Cited by 27 publications

References 39 publications

Age-Dependent Progression of Renal Dysfunction After Adrenalectomy for Aldosterone-Producing Adenomas in Japan

Age-Dependent Progression of Renal Dysfunction After Adrenalectomy for Aldosterone-Producing Adenomas in Japan

Prevalence and Histopathological Characteristics of KCNJ5 Mutant Aldosterone-Producing Adenomas in a Multi-Ethnic Malaysian Cohort

A Novel Case of Somatic KCNJ5 Mutation in Pediatric-Onset Aldosterone-Producing Adenoma

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