Masataka Kudo

Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism.

Adrenal vein sampling (AVS) is fundamental for subtype diagnosis in patients with primary aldosteronism. AVS protocols vary between centers, especially for diagnostic indices and for use of adrenocorticotropic hormone (ACTH) stimulation. We investigated the role of both continuous ACTH infusion and bolus on the performance and interpretation of AVS in a sample of 76 patients with confirmed primary aldosteronism. In 36 primary aldosteronism patients, AVS was performed both under basal conditions and after continuous ACTH infusion, and in 40 primary aldosteronism patients, AVS was performed both under basal conditions and after ACTH IV bolus. Both ACTH protocols determined an increase in the rate of successful cannulation of the adrenal veins. Both ACTH infusion and bolus determined a significant increase in selectivity index for the right adrenal vein and ACTH bolus for the left adrenal vein. Lateralization index was not significantly different after continuous ACTH infusion and IV bolus. In 88% and 78% of the patients, the diagnosis obtained was the same before and after ACTH infusion and IV bolus, respectively. However, the reproducibility of the diagnosis was reduced using less stringent criteria for successful cannulation of the adrenal veins. This study shows that ACTH use during AVS may be of help for centers with lower success rates, because a successful adrenal cannulation is more easily obtained with this protocol; moreover, this technique performs at least as well as the unstimulated strategy and in some cases may be even better. Stringent criteria for cannulation should be used to have a high consistency of the diagnosis.

18-Oxocortisol Measurement in Adrenal Vein Sampling as a Biomarker for Subclassifying Primary Aldosteronism

CONTEXTn18-Oxocortisol (18-oxoF) is a derivative of cortisol (F) that is produced by aldosterone synthase (CYP11B2). The potential for this steroid as a biomarker for differentiating patients with aldosterone-producing adenoma (APA) from those with idiopathic hyperaldosteronism (IHA) has not been examined.nnnOBJECTIVESnWe measured 18-oxoF, aldosterone, and F in plasma from adrenal vein sampling (AVS) of patients with primary aldosteronism. We compared 18-oxoF levels and 18-oxoF/F ratios for their potential to differentiate APA from IHA.nnnDESIGN, SETTING, AND SUBJECTSnThis study measured 18-oxoF, F, and aldosterone in AVS obtained from patients with unilateral APA (14 cases) or bilateral IHA (seven cases, 14 samples total) using liquid chromatography-tandem mass spectrometry and RIA analyses.nnnRESULTSnThe levels of 18-oxoF and the ratios of 18-oxoF/F, before and after ACTH stimulation, were significantly higher in blood-draining APA than in those from the contralateral adrenal glands and from adrenal glands with IHA.nnnCONCLUSIONSnThe 18-oxoF levels and ratios of 18-oxoF/F in AVS samples can be a clinically useful biomarker for differentiating APA from IHA and for determining the localization or lateralization of APA in patients with primary aldosteronism.

Predictors of decreasing glomerular filtration rate and prevalence of chronic kidney disease after treatment of primary aldosteronism: renal outcome of 213 cases.

CONTEXTnIn primary aldosteronism (PA), glomerular hyperfiltration due to excessive aldosterone is considered to underestimate actual renal damage.nnnOBJECTIVEnOur objectives were to determine the prevalence of chronic kidney disease (CKD) in PA and identify the predictors of decreasing estimated glomerular filtration rate (eGFR) after treatment.nnnDESIGN AND SETTINGnThis was a 12-month prospective study of patients with PA treated at Tohoku University Hospital.nnnPATIENTS AND INTERVENTIONSnAll patients were treated according to the results of adrenal venous sampling; 102 patients with aldosterone-producing adenoma underwent adrenalectomy, and 111 with bilateral hyperaldosteronism were treated with mineralocorticoid receptor antagonists.nnnMAIN OUTCOME MEASURESnElectrolytes, blood pressure, and indicators of renal function were determined at 1 and 12 months after intervention.nnnRESULTSnBlood pressure, urinary albumin excretion (UAE), and eGFR, which significantly decreased at 1 month after treatment of PA, did not further decrease at 12 months. Prevalence of CKD, which was 15.7% in aldosterone-producing adenoma and 8.1% in bilateral hyperaldosteronism at the first visit, increased to 37.1% and 28.3%, respectively, at the end of study (P < .0001). Multivariate regression analysis revealed that higher UAE and lower serum potassium levels were found to be independent predictors of decreasing eGFR after intervention.nnnCONCLUSIONSnThis large cohort study shows that the prevalence of CKD in PA was increased after treatment and that higher UAE and lower serum potassium levels at the first visit were predictors of decreasing eGFR after treatment of PA. To prevent a large decrease of eGFR after intervention, PA patients should be diagnosed before evolution to severe albuminuria and hypokalemia.

Aldosterone Suppression on Contralateral Adrenal During Adrenal Vein Sampling Does Not Predict Blood Pressure Response After Adrenalectomy

CONTEXTnAdrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers.nnnOBJECTIVEnThe objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA.nnnSETTINGnThe study was carried out in eight different referral centers in Italy, Germany, and Japan.nnnPATIENTSnFrom 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses.nnnRESULTSnOverall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy.nnnCONCLUSIONSnFor patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

Different Expression of 11β-Hydroxylase and Aldosterone Synthase Between Aldosterone-Producing Microadenomas and Macroadenomas

Aldosterone-producing adenoma is a major subtype of primary aldosteronism. The number of cases of these adenomas, which are below the detection limit of computed tomography but diagnosed by adrenal venous sampling, has recently been increasing. However, the pathophysiology of these adenomas, especially those manifesting clinically overt hyperaldosteronism despite their small size, remains unknown. Therefore, we examined the correlation between tumor size and the status of intratumoral steroidogenic enzymes involved in aldosterone biosynthesis using immunohistochemistry. Forty patients with surgically proven aldosterone-producing adenomas were retrospectively studied. Multidetector computed tomography, adrenal venous sampling, and laparoscopic adrenalectomy were performed in all of the patients studied. The tumor area at the maximum diameter of the sections was precisely measured by ImageJ software. The status of the steroidogenic enzymes was immunohistochemically analyzed, and the findings were evaluated according to the H-score system, based on both the number of immunopositive cells and relative immunointensity. Adrenal masses were not detected by computed tomography in 20 patients. Blood pressure, plasma aldosterone concentration, urinary aldosterone excretion, and the number of antihypertensive agents also decreased significantly after the surgery in these patients, as well as in the patients with adenomas detectable by computed tomography. Maximum tumor area obtained in the specimens was significantly correlated with preoperative plasma aldosterone concentration, urinary aldosterone excretion, and the H score of 11&bgr;-hydroxylase and was inversely correlated with the H score of aldosterone synthase. These results demonstrated that small adenomas could produce sufficient aldosterone to cause clinically overt primary aldosteronism because of the significantly higher aldosterone synthase expression per tumor area.

Measurement of Peripheral Plasma 18-Oxocortisol Can Discriminate Unilateral Adenoma From Bilateral Diseases in Patients With Primary Aldosteronism

Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral diseases in primary aldosteronism. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol (18oxoF) and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism in 234 patients with primary aldosteronism, including computed tomography (CT)–detectable aldosteronoma (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected and the accuracy of diagnosis was clinically and histopathologically confirmed. 18oxoF and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. Receiver operating characteristic analysis of 18oxoF discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cut-off value of 4.7 ng/dL, compared with that based on 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18oxoF levels above 6.1 ng/dL or of aldosterone >32.7 ng/dL were found in 95 of 113 patients with aldosteronoma (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18oxoF levels below 1.2 ng/dL, the lowest in aldosteronoma, were found 52 of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that 8 of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of 18oxoF and aldosterone were 4.8 and 24.5 ng/dL, respectively, both below their cut-off levels indicated above. The peripheral plasma 18oxoF concentrations served not only to differentiate aldosteronoma but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma.

Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism

OBJECTIVE AND DESIGNnAdrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS)--that is, the collection of effluents from bilateral adrenal central veins (CV)--sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA.nnnMETHODSnWe performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens.nnnRESULTSnS-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV.nnnCONCLUSIONSnCompared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.

Intra-adrenal Aldosterone Secretion: Segmental Adrenal Venous Sampling for Localization

PURPOSEnTo use segmental adrenal venous sampling (AVS) (S-AVS) of effluent tributaries (a version of AVS that, in addition to helping identify aldosterone hypersecretion, also enables the evaluation of intra-adrenal hormone distribution) to detect and localize intra-adrenal aldosterone secretion.nnnMATERIALS AND METHODSnThe institutional review board approved this study, and all patients provided informed consent. S-AVS was performed in 65 patients with primary aldosteronism (34 men; mean age, 50.9 years ± 11 [standard deviation]). A microcatheter was inserted in first-degree tributary veins. Unilateral aldosterone hypersecretion at the adrenal central vein was determined according to the lateralization index after cosyntropin stimulation. Excess aldosterone secretion at the adrenal tributary vein was considered to be present when the aldosterone/cortisol ratio from this vein exceeded that from the external iliac vein; suppressed secretion was indicated by the opposite pattern. Categoric variables were expressed as numbers and percentages; continuous variables were expressed as means ± standard errors of the mean.nnnRESULTSnThe AVS success rate, indicated by a selectivity index of 5 or greater, was 98% (64 of 65). The mean numbers of sampled tributaries on the left and right sides were 2.11 and 1.02, respectively. The following diagnoses were made on the basis of S-AVS results: unilateral aldosterone hypersecretion in 30 patients, bilateral hypersecretion without suppressed segments in 22 patients, and bilateral hypersecretion with at least one suppressed segment in 12 patients. None of the patients experienced severe complications.nnnCONCLUSIONnS-AVS could be used to identify heterogeneous intra-adrenal aldosterone secretion. Patients who have bilateral aldosterone-producing adenomas can be treated with adrenal-sparing surgery or other minimally invasive local therapies if any suppressed segment is identified at S-AVS.

Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression.

Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing’s disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXRα. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing’s disease.

Effects of PPARγ Agonists against Vascular and Renal Dysfunction

Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear hormone receptor, is activated by its agonists including anti-diabetic thiazolidinediones, and has recently been reported to exert beneficial effects in the vasculature independently of its anti-diabetic effects. We here discuss our recent findings on the beneficial pleiotropic effects of PPARγ agonists. PPARγ agonists have been shown to lower blood pressure in both animals and humans, which may possibly be mediated via the PPARγ agonist-mediated inhibition of the renin-angiotensin-aldosterone system (RAAS) including the suppression of angiotensin (Ang) II type 1 receptor expression/Ang II-mediated signaling pathways and Ang II-induced adrenal aldosterone synthesis/secretion. PPARγ agonists also inhibited the progression of atherosclerosis in both animals and humans. PPARγ agonist-mediated inhibition of the RAAS and the thromboxane A2 system as well as endothelial protection may possibly be involved in the inhibitory effects on blood pressure and atherosclerosis. Furthermore, PPARγ agonists were demonstrated to have reno-protective effects, especially in reducing proteinuria in diabetic nephropathy in both animals and humans. The reno-protective effects of PPARγ agonists were also observed in non-diabetic renal dysfunctions. The effects may possibly be mediated via the PPARγ agonist-mediated blood pressure lowering, endothelial protection, and vasodilation of the glomerular efferent arterioles.. Additionally, anti-neoplastic effects of PPARγ agonists have recently received much attention. PPARγ agonists, may therefore, be useful and effective against lifestyle-related diseases.