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Correlation between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism

Correlation between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in... Correlation between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism Hironobu Umakoshi, Mika Tsuiki, Maki Yokomoto-Umakoshi, Yoshiyu Takeda, Yoneda Takashi, Isao Kurihara, Hiroshi Itoh, Takuyuki Katabami, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Kenji Ashida, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Yuichi Fujii, Koichi Yamamto, Atsushi Ogo, Shintaro Okamura, Shozo Miyauchi, Tomikazu Fukuoka, Shoichiro Izawa, Toshihiko Yanase, Shigeatsu Hashimoto, Masanobu Yamada, Yuichiro Yoshikawa, Tatsuya Kai, Tomoko Suzuki, Takashi Kawamura, Mitsuhide Naruse Journal of the Endocrine Society Endocrine Society Submitted: February 22, 2018 Accepted: May 21, 2018 First Online: May 24, 2018 Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but not yet copyedited. 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Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Surgical Outcomes after AVS in PA Correlation between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism 1 1 1 2 Hironobu Umakoshi , Mika Tsuiki , Maki Yokomoto-Umakoshi , Yoshiyu Takeda , Yoneda 2 3 3 4 5 Takashi , Isao Kurihara , Hiroshi Itoh , Takuyuki Katabami , Takamasa Ichijo , Norio 6 6 7 8 8 Wada , Yui Shibayama , Takanobu Yoshimoto , Kenji Ashida , Yoshihiro Ogawa , Junji 9 10 10 11 Kawashima , Masakatsu Sone , Nobuya Inagaki , Katsutoshi Takahashi , Minemori 12 13 14 15 16 Watanabe , Yuichi Matsuda , Hiroki Kobayashi , Hirotaka Shibata , Kohei Kamemura , 17 18 19 20 21 Michio Otsuki , Yuichi Fujii , Koichi Yamamto , Atsushi Ogo , Shintaro Okamura , 22 23 24 25 Shozo Miyauchi , Tomikazu Fukuoka , Shoichiro Izawa , Toshihiko Yanase , Shigeatsu 26 27 28 29 30 Hashimoto , Masanobu Yamada , Yuichiro Yoshikawa , Tatsuya Kai , Tomoko Suzuki , 31 1 Takashi Kawamura , Mitsuhide Naruse Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan; Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan, Department of Endocrinology, Metabolism and Nephrology, School of Medicine Keio University, Tokyo, Japan, Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan, Department of Endocrinology and Metabolism, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan, Department of Diabetes and Endocrinology, Sapporo City General Hospital, Sapporo, Japan, Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan, Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan, Department of Metabolic Medicine, Faculty of Life Science, Kumamoto University, Kumamoto University, Kumamoto, Japan, Department of Diabetes, Endocrinology and Nutrition Kyoto University, Kyoto, Japan, 11 12 Division of Metabolism, Showa General Hospital, Tokyo, Japan, Department of Endocrinology and Diabetes, Okazaki City Hospital, Okazaki, Japan, Department of Cardiology, Sanda City Hospital, Sanda, Japan, Division of Nephrology, Hypertension and Endocrinology, Nihon University School of Medicine, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita 16 17 University, Yufu, Japan, Department of Cardiology, Shinko Hospital, Kobe, Japan, Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan, Department of Cardiology, JR Hiroshima Hospital, Hiroshima, Japan, Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan, Clinical Research Institute, National Hospital Organization Kyusyu Medical Center, Fukuoka, Japan, Department of Endocrinology, Tenriyorozu Hospital, Tenri, Japan, 22 23 Department of Internal Medicine, Uwajima City Hopistal, Uwajima, Japan, Department of Internal Medicine, Matsuyama Red Cross Hospital, Matsuyama, Department of Endocrinology and Metabolism, Tottori University Hospital, Tottori, Japan, Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Division of nephrology, hypertension, endocrinology, and Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 diabetology/metabolism, Fukushima Medical University Hospital, Fukushima, Japan, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Department of Endocrinology and Diabetes Mellitus, Misato Kenwa Hospital, Misato, Japan, Department of Cardiology, Saiseikai Tondabayahsi Hospital, Tondabayashi, Japan Department of Public Health, School of Medicine, International University of Health and Welfare, Narita, Japan, Kyoto University Health Service, Kyoto, Japan Received 22 February 2018. Accepted 21 May 2018. Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cut-offs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main outcome measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2-4, in 66 of 101 with an LI between 4-10, and in 158 of 203 with an LI >10 (P<0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2–4, in 60 of 76 with an LI between 4-10, and in 127 of 155 with an LI >10 (P=0.024 for trend). After adjustment for confounders and using those with an LI between 2–4 as a reference, a clinical benefit was associated only with those with an LI >10 (OR 2.30; 95%CI 1.03–5.16); whereas, complete biochemical success was associated with those with an LI between 4–10 (OR 2.83; 95%CI 1.14–7.01) or LI >10 (OR 3.55, 95%CI 1.47–8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used and biochemical cure was sufficiently achieved when an LI >4 was used. Our study by standardized outcome measure validated that an LI >4 is suggest to be appropriate to determine unilateral disease in PA. We investigated the impact of AVS lateralization cut-offs on surgical outcome by standardized measures and validated that an LI &gt;4 is appropriate to determine unilateral disease in PA. INTRODUCTION Primary aldosteronism (PA) is the most common cause of endocrine hypertension (1,2), compared with essential hypertension, increasing cardio-metabolic complications (3,4). Adrenal venous sampling (AVS) is the criterion standard for subtype diagnosis of PA as recommended by clinical practice guidelines (5) for determining a treatment plan; unilateral hyperaldosteronism can be controlled by surgical treatment and bilateral hyperaldosteronism by specific medical treatments (6). Although AVS plays an important role in diagnostic strategies for PA, many outstanding issues remain (7), and one of the most crucial is the impact of AVS aldosterone lateralization cut-offs on surgical outcomes. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Several studies have investigated the relationship between the efficacy of unilateral adrenalectomy and AVS (8-10), but results on the effectiveness of surgical treatment have differed widely among studies (11). Although differences in the patient clinical backgrounds among the studies could have influenced the results, one of the most important factors is the lack of a criterion standard for evaluation of postoperative outcomes in PA. However, in recent years, an international consensus on clinical and biochemical outcome measures after adrenalectomy for unilateral PA was established (12), and thus postoperative outcomes based on AVS results can be assessed according to international standardized criteria. The aim of the present study was to investigate the impact of lateralization cut-offs in AVS on surgical outcomes based on recent international standardized criteria by analyzing a nationwide multicenter AVS cohort in Japan. METHODS Study design and patients The study was conducted as a part of the Japan Primary Aldosteronism Study (JPAS). The details of this study have been described elsewhere (13). We included patients diagnosed with PA who were adrenalectomized based on cosyntropin-stimulated AVS findings who underwent follow-up assessments of outcome (clinical and/or biochemical) at 6 months after surgery between January 2006 and December 2016 at 28 participating centers of the JPAS in Japan. We excluded patients with unsuccessful AVS, those with bilateral aldosterone suppression (14,15) during AVS (as a sampling error), and those with associated Cushing syndrome. Clinical findings including the patients’ characteristics and biochemical, imaging, and AVS results were retrospectively obtained from the JPAS registry. A surgical indication was determined by each investigator based on AVS findings using the guidelines from the Japan Endocrine Society (16) and local reference criteria combined with the clinical background of the patients. This retrospective study was analyzed using the dataset valid at June, 2017. The study was conducted according to clinical studies published by the Ministry of Health and Labor, Japan and was approved by the ethics committee of the National Hospital Organization Kyoto Medical Center, as the project leader, and by the institutional ethics committees of the participating centers. This observational study was registered as UMIN ID 18756. Diagnosis of primary aldosteronism The diagnosis of PA was made in accordance with the guidelines of the Japan Endocrine Society (16) and the Japan Society of Hypertension (17). PA was diagnosed by a ratio of plasma aldosterone concentration (PAC) (ng/dL) to plasma renin activity (PRA) (ng/mL/h) (ARR) > 20 and at least one positive result from confirmatory tests, including the captopril- challenge test, saline-infusion test, furosemide-upright test, and oral salt-loading test. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Antihypertensive medications were usually switched to calcium-channel blockers and/or α- adrenergic blockers, as appropriate, until the final diagnosis was made. Adrenal venous sampling AVS was performed in patients who opted for surgery. The details of the AVS procedure have been described previously (18). In brief, adrenal blood samples were collected sequentially at 24 centers and four centers where simultaneous catheterization was conducted. Cosyntropin was administered by bolus injection alone, bolus injection followed by continuous infusion, or continuous infusion alone throughout the procedure. Adrenal vein cannulation was defined as successful if the selectivity index was > 5 (5,16). The selectivity index was defined as the ratio of the cortisol concentration in the adrenal vein to that in the inferior vena cava. The lateralization index (LI) was calculated by dividing the aldosterone to cortisol ratio in the dominant adrenal vein by that in the non-dominant adrenal vein. The contralateral aldosterone suppression ratio (CLR) was calculated by dividing the aldosterone to cortisol ration in the non-dominant adrenal vein by that in the inferior vena cava. Bilateral aldosterone suppression (14,15) was defined as an aldosterone to cortisol ratio in both the dominant and non-dominant adrenal veins lower than that in the inferior vena cava. Definition of clinical and biochemical outcomes Biochemical and clinical outcomes after unilateral adrenalectomy were evaluated based on the recent international PASO (Primary Aldosteronism Surgical Outcome) consensus. In brief, the biochemical outcome was determined by the postoperative aldosterone to renin ratio and serum potassium concentration, and the clinical outcome was determined by postoperative blood pressure. Biochemical and clinical outcomes were classified as complete, partial, or absent success based on the response to surgery. A clinical benefit was defined as either complete or partial success. Details of the outcome criteria have been described previously by Williams et al (12). Assay methods PAC and PRA were measured using commercial kits. PAC was determined by radioimmunoassay (SPAC-S Aldosterone kit, Fuji Rebio, Co., Ltd, Tokyo, Japan) at all centers. The reference range of PAC in the supine position was 3.0–15.9 ng/dl. PRA was measured by radioimmunoassay or enzyme immunoassay. The reference range of PRA in the supine position was 0.3–2.9 ng/ml/h (PRA-FR RIA kit, Fuji Rebio, Co., Ltd, Tokyo, Japan) at 16 of the study centers, 0.2–2.3 ng/ml/h (PRA EIA kit, Yamasa, Co., Ltd, Choshi, Japan) at 8 centers, and 0.2–2.7 ng/ml/h (PRA RIA kit, Yamasa, Co., Ltd) at 3 centers. The plasma active renin concentration (ARC) was measured by immunoradiometric assay (Renin IRMA- FR kit, Fuji Rebio, Co., Ltd) at one center. The ARC was converted to a PRA value and divided by 5 according to the Japan Endocrine Society guideline (16), and the PRA value was used for the analyses. The reference range of ARC in the supine position was 2.5–21.4 pg/ml. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Measurements and statistical analysis Clinical and biochemical outcome was calculate with respect to the LI. We compared clinical characteristics between patients with and those without a surgical benefit. The LI was categorized into three groups: 2–4, 4–10, and > 10. The reason for this classification is that although an LI >4 is the most commonly used cutoff as a criterion for positivity, half of the centers involved in this study use more permissive cutoffs (LI 2–4) (19). An LI of 10 was derived from the area under the receiver operating characteristic curve for evaluating a clinical benefit (Supplemental Figure 1). The cutoff was determined as the value affording the optimal sensitivity and specificity (Youden’s index). For clinical utility, the LI value of 9.9 calculated from the analysis was changed to 10. We compared the baseline clinical characteristics among the three LI groups. We also compared the proportion of patients with surgical outcomes in terms of complete biochemical success and clinical benefit among the three LI groups. A logistic regression analysis was performed to evaluate the impact of the AVS results on surgical outcome. The adjusted variables evaluated in the analysis (age, sex, body mass index (BMI), systolic blood pressure, antihypertensive medication use, estimated glomerular filtration rate, serum potassium concentration, plasma aldosterone concentration, and presence of diabetes mellitus (DM)) were selected according to previous reports (11,12). Statistical analyses were performed using EZR statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (20). Continuous variables were expressed as mean with the standard deviation. Categorical variables were expressed as numbers and percentages. Continuous variables were analyzed using the Student’s t-test and categorical variables using Fisher’s exact test. Analysis of group difference used one-way ANOVA and Fisher’s exact test with a post hoc Bonferroni analysis. All tests were two-tailed, with P<0.05 indicating a significant difference. RESULTS Between January 2006 and December 2016, 481 patients with PA who had been adrenalectomized based on cosyntropin-stimulated AVS findings and who had available follow-up data regarding clinical and/or biochemical outcomes 6 months after surgery were recruited. Of these, 104 patients were excluded from the present study for the following reasons: 71 with unsuccessful cosyntropin-stimulated AVS, 10 with Cushing syndrome, and 23 with bilateral aldosterone suppression during AVS. In total, 377 patients (351 with a clinical outcome, 273 with a biochemical outcome, and 247 with both outcomes) were analyzed in the present study. Of these, 52 patients were with an LI between 2-4 and 106 were with an LI between 4-10, and 219 were with an LI>10 (Supplemental Figure 2). The clinical characteristics included a mean age of 53 years, nearly equivalent sex prevalence, moderate doses of antihypertensive medications used, and frequent hypokalemia Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 (Table 1). Complete biochemical success was found in 214 (78.4%) and partial biochemical success in 31 (11.4%) of the 273 patients with biochemical outcome data (Figure 1A). On the other hand, complete clinical success was observed in 95 (27.1%) and partial clinical success in 152 (43.3%) of the 351 patients with clinical outcome data; thus, 70% of patients achieved a clinical benefit (Figure 1B). The baseline characteristics of the participating patients evaluated with respect to the LI are summarized in Table 1. The significant differences in seven of 13 variables were found among three LI groups. A biochemical complete success was achieved in 27 of 42 (64.3%) with an LI between 2-4, in 60 of 76 (78.9%) with an LI between 4-10, and in 127 of 155 (81.9%) with an LI>10 (P=0.024 for trend) (Figure 1A). A clinical cure was achieved in 10 of 47 (21.3%) patients with an LI between 2-4, in 22 of 101 (21.8%) with an LI between 4-10, and in 63/203 (31.0%) with an LI>10 (P=0.071 for trend) and a clinical benefit was achieved in 29 of 47 (61.7%) patients with an LI between 2–4, in 60 of 101 (59.4%) with an LI between 4–10, and in 158 of 203 (77.8%) with an LI >10 (P<0.01 for trend) (Figure 1B). Using a criterion for positivity of LI >4, 187 of 231 (81%) showed a biochemical cure, whereas 85 of 304 (27.9%) showed a clinical cure and 218 of 304 (71.7%) patients showed a clinical benefit. We performed a logistic regression analysis to determine the impact of the AVS lateralization cut-offs on surgical outcome. In the univariate analysis, using the patients with an LI between 2–4 as the reference group, biochemical complete success and clinical benefits in terms of surgical outcomes were associated only those with an LI >10 but not those with an LI between 4-10 (Table 2). After adjustment for confounders, a complete biochemical success was associated with both an LI between 4–10 (OR 2.83; 95%CI 1.14–7.01) and LI >10 (OR 3.55, 95%CI 1.47–8.55) (Table 2), whereas a clinical benefit was associated with an LI >10 (OR 2.30; 95%CI 1.03–5.16) not but with an LI between 4–10 (OR 0.97; 95%CI 0.45–2.10). A criterion for positivity of LI >4 were associated with surgical outcomes in terms of the complete biochemical success but not clinical benefit (Table 2). Additionally, we evaluated a criterion of CLR<1 for surgical outcomes in terms of complete biochemical success and clinical benefit. Although a criterion for positivity of CLR<1 showed high proportion of complete success of biochemical outcome with equal to that of LI >10, no significant differences were found in patients with and without meeting a criterion of CLR<1 for biochemical and clinical outcomes (Table 2). DISCUSSION Our results demonstrated an association between AVS aldosterone lateralization cut-offs and surgical outcomes based on recent international criteria in unilateral adrenalectomized patients with PA. The major novelty of the present study was to correlate the LI cut-off and clinical and biochemical outcomes after adrenal surgery using the PASO criteria (12). The Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 results provided evidence that LI cut-off of 4 is an adequate cut-off to determine unilateral disease and to achieve good biochemical outcome, while the difference of clinical benefit for LI between 4 and 10, and that for LI >10 was relatively small, although it was statistically significant. Our study by standardized outcome measure validated that an LI >4 recommended by clinical guideline (5) is suggest to be appropriate to determine unilateral disease in PA. Before the recent international standardized criteria regarding the surgical outcome of patients with PA were established (12), the postoperative outcomes of patients with PA were usually determined by a combination of blood pressure, hormone profiles, serum potassium levels, and occasionally pathological findings based on local reference criteria (11). This is one of the reasons that resolution or improvement of PA has differed widely across studies that used different lateralization cut-offs of AVS. Although the receiver operating characteristic analysis showed an LI of 9.9 as the optimal cutoff (Youden’s index) for evaluating the clinical outcome (Supplemental Figure 1), the AUC (0.59; 95% CI 0.53–0.66), which afforded a sensitivity of 65% and a specificity of 57%, was not sufficient because a tendency, rather than a clear association, for clinical and biochemical outcomes in patients with this LI value was detected (Figure 1); thus, the best cutoff for the AVS LI was difficult to establish. Our results suggest that unilateral hyperaldosteronism may consist of heterogeneous etiologies. An international survey of AVS (AVIS study) (19) reported that an LI > 4 is the most common criterion associated with cosyntropin-stimulated AVS. Considering that more than 80% of patients can achieve complete success in terms of biochemical outcome determined by recent international standardized criteria with a commonly used criterion of LI >4 (Figure 1; Table 2), this cutoff is preferable when biochemical success is the goal. In the PASO study (12), PA patients with an LI >4 showed preferable surgical outcomes in terms of biochemical than those with an LI <4 in univariate analysis. In contrast, a higher LI value (LI > 10) was needed to obtain an independent surgical benefit in terms of clinical outcome (Table 2). We used nine variables for a logistic regression analysis and these variables were reported by the associated factor for surgical outcome of PA (11-12). In addition, similar significant difference of variables, especially in clinical outcome, between patients with surgical benefit and those without surgical benefit were seen in present study (Supplemental Table 1). In these confounders, age, BMI, and systolic blood pressure were predictors of clinical benefit, whereas but no clinical factors were associated with the outcome of biochemical benefit (data not shown), suggesting that clinical outcome depended on preoperative clinical findings, whereas biochemical outcome was determined by only AVS LI. Notably, 60% of patients with available clinical and biochemical outcome data, respectively, showed a surgical benefit in clinical and complete success in biochemical among the patients with an LI of 2–4 (Figure 1). Although an LI > 4 is the most commonly used AVS criterion, approximately half of the reference centers in AVIS used more Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 permissive LI values, ranging from 2 to 4 (19). We found a favorable tendency, albeit not a significant association, for a clinical benefit in patients with these LI values who also had higher systolic blood pressure, higher defined daily dose of anti-hypertensive medications, or lower serum potassium levels. We also found that younger patients achieved a good biochemical outcome more frequently than did older patients (P<0.01) (data not shown). While on AVS finding, contralateral aldosterone suppression was not associated with surgical benefits in terms of clinical and biochemical outcomes (data not shown). Additionally, we have reported that LI between 2 and 4 can be found even in patients with negative confirmatory testing for PA (22). Therefore, clinicians could send patients in these LI zone to surgery with careful consideration for patients’ characteristics. However, the results should be carefully interpreted because of the small number of patients and the fact that only selected patients underwent surgery in this subgroup. Contralateral aldosterone suppression has been secondary used by a decision criterion for laterality of hyperaldosteronism followed in LI (5, 23). In present study, a criterion of CLR<1 was not associated with outcomes in terms of complete biochemical success and clinical benefit. However, a criterion for positivity of CLR<1 showed high proportion of a surgical benefit with equal to that of LI>10, suggesting that a certain number of patients with CLR >1 showed complete success of biochemical outcome. Therefore, more permissive cut-off of CLR for a decision criterion of aldosterone laterality during non-ACTH stimulated AVS might be adopted. When comparing our results with those of PASO study (12), the proportion of patients who achieved a surgical benefit in terms of clinical outcome was smaller in our study (70% vs. 84%). This may be because of the slightly older age and lower systolic blood pressure of our participants (Table 1). Additionally, that of biochemical outcome was smaller in our study compared to PASO study (12). It may be derived from the fact that ARR cut-off of 20 for screening in Japan guideline (16) has been set aiming higher sensitivity to avoid false negatives and to not to overlook PA patients. The cut-off however may lead to f affect the biochemical outcome after surgery. Furthermore, our patients showed wide standard deviation of ARR (mean 103, IQR 55.1-212, range 8.2-1890), indicating the overlap to the normal range. Routine confirmatory testing may be needed when aldosterone to renin ratio is positive after surgery as suggested by PASO study. Additionally, high prevalence of positive KCNJ5 mutation has been reported in Japan (24). Since KCNJ5 mutated aldosterone- producing adenoma have a specific feature such as high CYP11B1 and low CYP11B2 (25), it may affect the lateralization of PA by AVS. Finally, racial difference and high salt intake may be related to the poor biochemical outcomes by forming bilateral hyperplasia with asymmetrical aldosterone production. In patients who had available data for pathological findings and assessment of biochemical outcome after surgery, 70% patients were diagnosed as aldosterone-producing adenomas based on the histological presence of adenoma and Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 complete biochemical success after surgery. Some of the remaining patients might have aldosterone producing lesions and histological details waits further analysis. LIMITATIONS Our study has several limitations. The main limitation of our study is its retrospective nature. A second limitation is that although a surgical indication is based essentially on the Japan Endocrine Society guidelines, details of the indication criteria used for adrenal surgery have not been completely standardized among centers. For this reason, our study included a heterogeneous patient population. A prospective standardized protocol study is needed to validate our results. A third limitation is the protocol used for cosyntropin administration. Cosyntropin administration is debated because cosyntropin administration improves the AVS (21), whereas it lost lateralization of aldosterone excess in some cases. There are many reports of the usefulness of non-cosyntropin-stimulated AVS in expert centers worldwide (19), and hence our results apply only to patients with cosyntropin-stimulated AVS. A fourth limitation is the small number of patients in the no biochemical success group. CONCLUSION Our study demonstrated the correlation between LI of AVS and post-operative outcomes using the standardized criteria. The results provided evidence that LI cut-off of 4 is an adequate cut-off to determine unilateral disease and to achieve good biochemical outcome, while the difference of clinical benefit for LI between 4 and 10, and that for LI >10 was relatively small. Our study by standardized outcome measure validated that an LI >4 recommended by clinical guideline is suggest to be appropriate to determine unilateral disease in PA. Sources of funding This study was supported in part by grants-in-aid for the Japan Primary Aldosteronism Study (JPAS) from the Practical Research Project for Rare/Intractable Disease from the Japan Agency for Medical Research and Development (15Aek0109122) and a grant from the National Center for Global Health and Medicine, Japan (27-1402) and a grant from Grant-in- Aid for Young Scientists (B) Grant Number 17K16173. Practical Research Project for Rare/Intractable Disease from the Japan Agency for Medical Research and Development, 15Aek0109122, Mitsuhide Naruse; National Center for Global Health and Medicine, Japan, 27-1402, Mitsuhide Naruse; Grant-in- Aid for Young Scientists (B), 17K16173, Hironobu Umakoshi Corresponding author and person to whom reprint requests should be addressed: Mitsuhide Naruse, MD, PhD, Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Fushimi-ku, Kyoto 612-8555, Japan, Phone: +81-75-641-9161, Fax: +81-75- 645-8409, E mail: mnaruse@kyotolan.hosp.go.jp Conflict of Interest/Disclosure The authors have nothing to disclose REFERENCES 1. 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What we still do not know about adrenal vein sampling for primary aldosteronism. Horm Metab Res 2010; 42:411-415 8. Webb R, Mathur A, Chang R, Baid S, Nilubol N, Libutti SK, Stratakis CA, Kebebew E. What is the best criterion for the interpretation of adrenal vein sample results in patients with primary hyperaldosteronism? Ann Surg Oncol 2012; 19:1881-1886 9. Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004; 136:1227-1235 Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 10. Mulatero P, Bertello C, Sukor N, Gordon R, Rossato D, Daunt N, Leggett D, Mengozzi G, Veglio F, Stowasser M. Impact of different diagnostic criteria during adrenal vein sampling on reproducibility of subtype diagnosis in patients with primary aldosteronism. Hypertension 2010; 55:667-673 11. Steichen O, Zinzindohoue F, Plouin PF, Amar L. Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review. Horm Metab Res 2012; 44:221-227 12. Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar L, Quinkler M, Deinum J, Beuschlein F, Kitamoto KK, Pham U, Morimoto R, Umakoshi H, Prejbisz A, Kocjan T, Naruse M, Stowasser M, Nishikawa T, Young WF, Jr., Gomez-Sanchez CE, Funder JW, Reincke M. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol 2017; 5:689-699 13. Umakoshi H, Tsuiki M, Takeda Y, Kurihara I, Itoh H, Katabami T, Ichijo T, Wada T, Yoshimoto T, Ogawa Y, Kawashima T, Sone T, Inagaki N, Takahashi K, Watanabe M, Matsuda Y, Kobayashi H, Shibata H, Kamemura K, Otsuki M, Fujii Y, Yamamto K, Ogo A, Yanase T, Suzuki T, Naruse M. Significance of Computed Tomography and Serum Potassium in Predicting Subtype Diagnosis of Primary Aldosteronism. J Clin Endocrinol Metab. 2017;doi: 10.1210/jc.2017-0177, epub ahead of print. 14. Wolley M, Gordon RD, Pimenta E, Daunt N, Slater GJ, Ahmed AH, Stowasser M. Repeating adrenal vein sampling when neither aldosterone/cortisol ratio exceeds peripheral yields a high incidence of aldosterone-producing adenoma. J Hypertens 2013; 31:2005-2009 15. Shibayama Y, Wada N, Umakoshi H, Ichijo T, Fujii Y, Kamemura K, Kai T, Sakamoto R, Ogo A, Matsuda Y, Fukuoka T, Tsuiki M, Suzuki T, Naruse M. Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism: analysis of data from the WAVES-J study. Clin Endocrinol 2016; 85:696-702 16. Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A. Guidelines for the diagnosis and treatment of primary aldosteronism--the Japan Endocrine Society 2009. Endocrine J 2011; 58:711-721 17. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, Imai Y, Imaizumi T, Ishimitsu T, Ito M, Ito S, Itoh H, Iwao H, Kai H, Kario K, Kashihara N, Kawano Y, Kim- Mitsuyama S, Kimura G, Kohara K, Komuro I, Kumagai H, Matsuura H, Miura K, Morishita R, Naruse M, Node K, Ohya Y, Rakugi H, Saito I, Saitoh S, Shimada K, Shimosawa T, Suzuki H, Tamura K, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, Umemura S. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res 2014; 37:253-387 18. Umakoshi H, Wada N, Ichijo T, Kamemura K, Matsuda Y, Fuji Y, Kai T, Fukuoka T, Sakamoto R, Ogo A, Suzuki T, Tsuiki M, Naruse M. Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism. Clin Endocrinol 2015; 83:768-773 Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 19. Rossi GP, Barisa M, Allolio B, Auchus RJ, Amar L, Cohen D, Degenhart C, Deinum J, Fischer E, Gordon R, Kickuth R, Kline G, Lacroix A, Magill S, Miotto D, Naruse M, Nishikawa T, Omura M, Pimenta E, Plouin PF, Quinkler M, Reincke M, Rossi E, Rump LC, Satoh F, Schultze Kool L, Seccia TM, Stowasser M, Tanabe A, Trerotola S, Vonend O, Widimsky J, Jr., Wu KD, Wu VC, Pessina AC. The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism. J Clin Endocrinol Metab 2012; 97:1606-1614 20. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Trans 2013; 48:452-458 21. Monticone S, Satoh F, Giacchetti G, Viola A, Morimoto R, Kudo M, Iwakura Y, Ono Y, Turchi F, Paci E, Veglio F, Boscaro M, Rainey W, Ito S, Mulatero P. Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism. Hypertension 2012; 59:840-846 22. Umakoshi H, Naruse M, Wada N, Ichijo T, Kamemura K, Matsuda Y, Fujii Y, Kai T, Fukuoka T, Sakamoto R, Ogo A, Suzuki T, Nanba K, Tsuiki M. Adrenal Venous Sampling in Patients with Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism. Hypertension 2016; 67:1014-1019. 23. Wolley MJ, Gordon RD, Ahmed AH, Stowasser M. Dose Contralateral Suppression at Adrenal Venous Sampling Predict Outcome Following Unilateral Adrenalectomy for Primary Aldosteronism? J Clin Endocrinol Metab 2015; 100:1477-1484 24. Kitamoto T, Suematsu S, Matsuzawa Y, Saito J, Omura M, Nishikawa T. Comparison of cardiovascular complications in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenomas. J Atheroscler Thromb. 2015; 22:191-200. 25. Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE, Williams TA, Mulatero P. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol. 2015; 15:146-54. Figure 1. Biochemical and clinical outcomes of adrenalectomized patients with primary aldosteronism. The proportion of patients with outcomes in terms of biochemical and clinical outcomes was assessed with respect to the LI, which was categorized into three groups (2–4, 4–10, and > 10). Complete biochemical success was in nearly 80% of the patients (A) and clinical benefit was achieved in nearly 70% (B). There was a tendency for favorable biochemical and clinical outcomes with an increasing LI value (P<0.01 for trend for biochemical outcome (A), P<0.01 for clinical outcome (B)). Using LI > 4 as a criterion for positivity, 187 of 231 (81%) patients showed complete biochemical success (A) and 218 of 304 (72%) patients showed a clinical benefit (B). Table 1 Comparison of baseline clinical characteristics in patients with respect to adrenal venous sampling lateralization index Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Total Pairwise comparison (P values) (n=377) LI 2-4 LI 2-4 LI 4-10 LI 2-4 (n = LI 4-10 LI >10 Overall vs LI 4- vs LI vs LI Characteristics 52) (n=106) (n=219) P value 10 >10 >10 Age, y 52.0±11.4 50.3±10.2 52.6±10.7 52.1±12.0 0.47 NA NA NA Female, (%) 46.9 53.8 34.9 51.1 0.01 0.079 1.0 0.019 Body mass index 24.4±4.2 25.1±3.7 25.0±3.8 23.9±4.4 0.028 1.00 0.19 0.06 Systolic blood pressure, mm 141±18 137±18 142±19 142±18 0.22 NA NA NA Hg Diastolic blood pressure, mm 86±12 84±12 88±12 86±12 0.078 NA NA NA Hg Duration of hypertension, y 10.6±9.0 7.5±7.1 10.9±9.1 11.2±9.2 0.031 0.092 0.027 1.0 Defined daily dose of 2.0±1.3 1.7±1.1 1.9±1.1 0.11 NA NA NA 2.1±1.4 antihypertensive medications Diabetes mellitus, (%) 16.4 13.4 22.1 14.4 0.22 NA NA NA Serum potassium, mEq/l 3.3±0.6 3.6±0.5 3.5±0.5 3.2±0.5 <0.01 0.49 <0.01 <0.01 Estimated glomerular filtration 78±22 87±23 78±20 77±22 <0.01 0.036 <0.01 1.0 rate, ml/min/1.73m2 Plasma aldosterone 35.7±24.7 <0.01 1.0 <0.01 <0.01 22.7±15.6 25.8±11.8 43.5±27.8 concentration, ng/dl Plasma renin activity, 0.37±0.42 0.42±0.32 0.40±0.30 0.34±0.48 0.3 NA NA NA ng/ml/h Ratio of plasma aldosterone 181±224 85.1±103 109±117 239±264 <0.01 1.0 <0.01 <0.01 concentration to plasma renin activity Notes: Data are presented as mean ± standard deviations unless otherwise indicated. Table 2 Surgical outcomes in terms of biochemical and clinical outcomes as determined by AVS findings in unadjusted and adjusted analyses Biochemical outcome Patients Complete success (%) Unadjusted OR (95% CI) Adjusted OR (95% CI) LI category 2-4 42 27 (64) 1.00 (reference) 1.00 (reference) 4-10 76 60 (79) 2.08 (0.90–4.82) 2.83 (1.14–7.01) >10 155 127 (82) 2.52 (1.19–5.35) 3.55 (1.47–8.55) AVS criterion LI <4 42 27 (64) 1.00 (reference) 1.00 (reference) LI >4 231 187 (81) 2.36 (1.16–4.81) 3.21 (1.44–7.18) CLR >1 29 22 (76) 1.00 (reference) 1.00 (reference) CLR <1 244 192 (79) 1.17 (0.48-2.90) 1.40 (0.54-3.66) Clinical outcome Patients Benefits (%) Unadjusted OR (95% CI) Adjusted OR (95% CI) LI category 2-4 47 29 (61) 1.00 (reference) 1.00 (reference) 1.00 (reference) 4-10 101 60 (59) 0.91 (0.45–1.85) 0.97 (0.45–2.10) >10 203 158 (77) 2.18 (1.11–4.28) 2.30 (1.03–5.16) AVS criterion LI <4 47 29 (61) 1.00 (reference) 1.00 (reference) LI >4 304 218 (72) 1.57 (0.83–2.98) 1.44 (0.70–2.99) CLR >1 37 26 (70) 1.00 (reference) 1.00 (reference) CLR <1 314 221 (70) 1.01 (0.48-2.12) 0.61 (0.27-1.40) Note: Adjusted for age, sex, body mass index, systolic blood pressure, defined daily dose of anti-hypertensive medications, estimated glomerular filtration rate, serum potassium concentration, plasma aldosterone concentration, and diabetes mellitus. Abbreviations; OR, odds ratio; CI, confidence interval; AVS, adrenal venous sampling; LI, Lateralization index; CLR, Contralateral ratio. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: ADVANCE ARTICLE: ADVANCE ARTICLE: Endocrinology Endocrinology JES http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Endocrine Society Oxford University Press

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Correlation between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism Hironobu Umakoshi, Mika Tsuiki, Maki Yokomoto-Umakoshi, Yoshiyu Takeda, Yoneda Takashi, Isao Kurihara, Hiroshi Itoh, Takuyuki Katabami, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Kenji Ashida, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Yuichi Fujii, Koichi Yamamto, Atsushi Ogo, Shintaro Okamura, Shozo Miyauchi, Tomikazu Fukuoka, Shoichiro Izawa, Toshihiko Yanase, Shigeatsu Hashimoto, Masanobu Yamada, Yuichiro Yoshikawa, Tatsuya Kai, Tomoko Suzuki, Takashi Kawamura, Mitsuhide Naruse Journal of the Endocrine Society Endocrine Society Submitted: February 22, 2018 Accepted: May 21, 2018 First Online: May 24, 2018 Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but not yet copyedited. The manuscripts are published online as soon as possible after acceptance and before the copyedited, typeset articles are published. They are posted "as is" (i.e., as submitted by the authors at the modification stage), and do not reflect editorial changes. No corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be differences between the Advance Article manuscripts and the final, typeset articles. The manuscripts remain listed on the Advance Article page until the final, typeset articles are posted. At that point, the manuscripts are removed from the Advance Article page. DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express or particular purpose, or non-infringement. Changes will be made to these manuscripts before publication. Review and/or use or reliance on these materials is at the discretion and risk of the reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising references to, products or publications do not imply endorsement of that product or publication. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Surgical Outcomes after AVS in PA Correlation between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism 1 1 1 2 Hironobu Umakoshi , Mika Tsuiki , Maki Yokomoto-Umakoshi , Yoshiyu Takeda , Yoneda 2 3 3 4 5 Takashi , Isao Kurihara , Hiroshi Itoh , Takuyuki Katabami , Takamasa Ichijo , Norio 6 6 7 8 8 Wada , Yui Shibayama , Takanobu Yoshimoto , Kenji Ashida , Yoshihiro Ogawa , Junji 9 10 10 11 Kawashima , Masakatsu Sone , Nobuya Inagaki , Katsutoshi Takahashi , Minemori 12 13 14 15 16 Watanabe , Yuichi Matsuda , Hiroki Kobayashi , Hirotaka Shibata , Kohei Kamemura , 17 18 19 20 21 Michio Otsuki , Yuichi Fujii , Koichi Yamamto , Atsushi Ogo , Shintaro Okamura , 22 23 24 25 Shozo Miyauchi , Tomikazu Fukuoka , Shoichiro Izawa , Toshihiko Yanase , Shigeatsu 26 27 28 29 30 Hashimoto , Masanobu Yamada , Yuichiro Yoshikawa , Tatsuya Kai , Tomoko Suzuki , 31 1 Takashi Kawamura , Mitsuhide Naruse Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan; Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan, Department of Endocrinology, Metabolism and Nephrology, School of Medicine Keio University, Tokyo, Japan, Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan, Department of Endocrinology and Metabolism, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan, Department of Diabetes and Endocrinology, Sapporo City General Hospital, Sapporo, Japan, Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan, Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan, Department of Metabolic Medicine, Faculty of Life Science, Kumamoto University, Kumamoto University, Kumamoto, Japan, Department of Diabetes, Endocrinology and Nutrition Kyoto University, Kyoto, Japan, 11 12 Division of Metabolism, Showa General Hospital, Tokyo, Japan, Department of Endocrinology and Diabetes, Okazaki City Hospital, Okazaki, Japan, Department of Cardiology, Sanda City Hospital, Sanda, Japan, Division of Nephrology, Hypertension and Endocrinology, Nihon University School of Medicine, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita 16 17 University, Yufu, Japan, Department of Cardiology, Shinko Hospital, Kobe, Japan, Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan, Department of Cardiology, JR Hiroshima Hospital, Hiroshima, Japan, Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Osaka, Japan, Clinical Research Institute, National Hospital Organization Kyusyu Medical Center, Fukuoka, Japan, Department of Endocrinology, Tenriyorozu Hospital, Tenri, Japan, 22 23 Department of Internal Medicine, Uwajima City Hopistal, Uwajima, Japan, Department of Internal Medicine, Matsuyama Red Cross Hospital, Matsuyama, Department of Endocrinology and Metabolism, Tottori University Hospital, Tottori, Japan, Department of Endocrinology and Diabetes Mellitus, Faculty of Medicine, Fukuoka University, Division of nephrology, hypertension, endocrinology, and Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 diabetology/metabolism, Fukushima Medical University Hospital, Fukushima, Japan, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Department of Endocrinology and Diabetes Mellitus, Misato Kenwa Hospital, Misato, Japan, Department of Cardiology, Saiseikai Tondabayahsi Hospital, Tondabayashi, Japan Department of Public Health, School of Medicine, International University of Health and Welfare, Narita, Japan, Kyoto University Health Service, Kyoto, Japan Received 22 February 2018. Accepted 21 May 2018. Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cut-offs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main outcome measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2-4, in 66 of 101 with an LI between 4-10, and in 158 of 203 with an LI >10 (P<0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2–4, in 60 of 76 with an LI between 4-10, and in 127 of 155 with an LI >10 (P=0.024 for trend). After adjustment for confounders and using those with an LI between 2–4 as a reference, a clinical benefit was associated only with those with an LI >10 (OR 2.30; 95%CI 1.03–5.16); whereas, complete biochemical success was associated with those with an LI between 4–10 (OR 2.83; 95%CI 1.14–7.01) or LI >10 (OR 3.55, 95%CI 1.47–8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used and biochemical cure was sufficiently achieved when an LI >4 was used. Our study by standardized outcome measure validated that an LI >4 is suggest to be appropriate to determine unilateral disease in PA. We investigated the impact of AVS lateralization cut-offs on surgical outcome by standardized measures and validated that an LI &gt;4 is appropriate to determine unilateral disease in PA. INTRODUCTION Primary aldosteronism (PA) is the most common cause of endocrine hypertension (1,2), compared with essential hypertension, increasing cardio-metabolic complications (3,4). Adrenal venous sampling (AVS) is the criterion standard for subtype diagnosis of PA as recommended by clinical practice guidelines (5) for determining a treatment plan; unilateral hyperaldosteronism can be controlled by surgical treatment and bilateral hyperaldosteronism by specific medical treatments (6). Although AVS plays an important role in diagnostic strategies for PA, many outstanding issues remain (7), and one of the most crucial is the impact of AVS aldosterone lateralization cut-offs on surgical outcomes. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Several studies have investigated the relationship between the efficacy of unilateral adrenalectomy and AVS (8-10), but results on the effectiveness of surgical treatment have differed widely among studies (11). Although differences in the patient clinical backgrounds among the studies could have influenced the results, one of the most important factors is the lack of a criterion standard for evaluation of postoperative outcomes in PA. However, in recent years, an international consensus on clinical and biochemical outcome measures after adrenalectomy for unilateral PA was established (12), and thus postoperative outcomes based on AVS results can be assessed according to international standardized criteria. The aim of the present study was to investigate the impact of lateralization cut-offs in AVS on surgical outcomes based on recent international standardized criteria by analyzing a nationwide multicenter AVS cohort in Japan. METHODS Study design and patients The study was conducted as a part of the Japan Primary Aldosteronism Study (JPAS). The details of this study have been described elsewhere (13). We included patients diagnosed with PA who were adrenalectomized based on cosyntropin-stimulated AVS findings who underwent follow-up assessments of outcome (clinical and/or biochemical) at 6 months after surgery between January 2006 and December 2016 at 28 participating centers of the JPAS in Japan. We excluded patients with unsuccessful AVS, those with bilateral aldosterone suppression (14,15) during AVS (as a sampling error), and those with associated Cushing syndrome. Clinical findings including the patients’ characteristics and biochemical, imaging, and AVS results were retrospectively obtained from the JPAS registry. A surgical indication was determined by each investigator based on AVS findings using the guidelines from the Japan Endocrine Society (16) and local reference criteria combined with the clinical background of the patients. This retrospective study was analyzed using the dataset valid at June, 2017. The study was conducted according to clinical studies published by the Ministry of Health and Labor, Japan and was approved by the ethics committee of the National Hospital Organization Kyoto Medical Center, as the project leader, and by the institutional ethics committees of the participating centers. This observational study was registered as UMIN ID 18756. Diagnosis of primary aldosteronism The diagnosis of PA was made in accordance with the guidelines of the Japan Endocrine Society (16) and the Japan Society of Hypertension (17). PA was diagnosed by a ratio of plasma aldosterone concentration (PAC) (ng/dL) to plasma renin activity (PRA) (ng/mL/h) (ARR) > 20 and at least one positive result from confirmatory tests, including the captopril- challenge test, saline-infusion test, furosemide-upright test, and oral salt-loading test. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Antihypertensive medications were usually switched to calcium-channel blockers and/or α- adrenergic blockers, as appropriate, until the final diagnosis was made. Adrenal venous sampling AVS was performed in patients who opted for surgery. The details of the AVS procedure have been described previously (18). In brief, adrenal blood samples were collected sequentially at 24 centers and four centers where simultaneous catheterization was conducted. Cosyntropin was administered by bolus injection alone, bolus injection followed by continuous infusion, or continuous infusion alone throughout the procedure. Adrenal vein cannulation was defined as successful if the selectivity index was > 5 (5,16). The selectivity index was defined as the ratio of the cortisol concentration in the adrenal vein to that in the inferior vena cava. The lateralization index (LI) was calculated by dividing the aldosterone to cortisol ratio in the dominant adrenal vein by that in the non-dominant adrenal vein. The contralateral aldosterone suppression ratio (CLR) was calculated by dividing the aldosterone to cortisol ration in the non-dominant adrenal vein by that in the inferior vena cava. Bilateral aldosterone suppression (14,15) was defined as an aldosterone to cortisol ratio in both the dominant and non-dominant adrenal veins lower than that in the inferior vena cava. Definition of clinical and biochemical outcomes Biochemical and clinical outcomes after unilateral adrenalectomy were evaluated based on the recent international PASO (Primary Aldosteronism Surgical Outcome) consensus. In brief, the biochemical outcome was determined by the postoperative aldosterone to renin ratio and serum potassium concentration, and the clinical outcome was determined by postoperative blood pressure. Biochemical and clinical outcomes were classified as complete, partial, or absent success based on the response to surgery. A clinical benefit was defined as either complete or partial success. Details of the outcome criteria have been described previously by Williams et al (12). Assay methods PAC and PRA were measured using commercial kits. PAC was determined by radioimmunoassay (SPAC-S Aldosterone kit, Fuji Rebio, Co., Ltd, Tokyo, Japan) at all centers. The reference range of PAC in the supine position was 3.0–15.9 ng/dl. PRA was measured by radioimmunoassay or enzyme immunoassay. The reference range of PRA in the supine position was 0.3–2.9 ng/ml/h (PRA-FR RIA kit, Fuji Rebio, Co., Ltd, Tokyo, Japan) at 16 of the study centers, 0.2–2.3 ng/ml/h (PRA EIA kit, Yamasa, Co., Ltd, Choshi, Japan) at 8 centers, and 0.2–2.7 ng/ml/h (PRA RIA kit, Yamasa, Co., Ltd) at 3 centers. The plasma active renin concentration (ARC) was measured by immunoradiometric assay (Renin IRMA- FR kit, Fuji Rebio, Co., Ltd) at one center. The ARC was converted to a PRA value and divided by 5 according to the Japan Endocrine Society guideline (16), and the PRA value was used for the analyses. The reference range of ARC in the supine position was 2.5–21.4 pg/ml. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Measurements and statistical analysis Clinical and biochemical outcome was calculate with respect to the LI. We compared clinical characteristics between patients with and those without a surgical benefit. The LI was categorized into three groups: 2–4, 4–10, and > 10. The reason for this classification is that although an LI >4 is the most commonly used cutoff as a criterion for positivity, half of the centers involved in this study use more permissive cutoffs (LI 2–4) (19). An LI of 10 was derived from the area under the receiver operating characteristic curve for evaluating a clinical benefit (Supplemental Figure 1). The cutoff was determined as the value affording the optimal sensitivity and specificity (Youden’s index). For clinical utility, the LI value of 9.9 calculated from the analysis was changed to 10. We compared the baseline clinical characteristics among the three LI groups. We also compared the proportion of patients with surgical outcomes in terms of complete biochemical success and clinical benefit among the three LI groups. A logistic regression analysis was performed to evaluate the impact of the AVS results on surgical outcome. The adjusted variables evaluated in the analysis (age, sex, body mass index (BMI), systolic blood pressure, antihypertensive medication use, estimated glomerular filtration rate, serum potassium concentration, plasma aldosterone concentration, and presence of diabetes mellitus (DM)) were selected according to previous reports (11,12). Statistical analyses were performed using EZR statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (20). Continuous variables were expressed as mean with the standard deviation. Categorical variables were expressed as numbers and percentages. Continuous variables were analyzed using the Student’s t-test and categorical variables using Fisher’s exact test. Analysis of group difference used one-way ANOVA and Fisher’s exact test with a post hoc Bonferroni analysis. All tests were two-tailed, with P<0.05 indicating a significant difference. RESULTS Between January 2006 and December 2016, 481 patients with PA who had been adrenalectomized based on cosyntropin-stimulated AVS findings and who had available follow-up data regarding clinical and/or biochemical outcomes 6 months after surgery were recruited. Of these, 104 patients were excluded from the present study for the following reasons: 71 with unsuccessful cosyntropin-stimulated AVS, 10 with Cushing syndrome, and 23 with bilateral aldosterone suppression during AVS. In total, 377 patients (351 with a clinical outcome, 273 with a biochemical outcome, and 247 with both outcomes) were analyzed in the present study. Of these, 52 patients were with an LI between 2-4 and 106 were with an LI between 4-10, and 219 were with an LI>10 (Supplemental Figure 2). The clinical characteristics included a mean age of 53 years, nearly equivalent sex prevalence, moderate doses of antihypertensive medications used, and frequent hypokalemia Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 (Table 1). Complete biochemical success was found in 214 (78.4%) and partial biochemical success in 31 (11.4%) of the 273 patients with biochemical outcome data (Figure 1A). On the other hand, complete clinical success was observed in 95 (27.1%) and partial clinical success in 152 (43.3%) of the 351 patients with clinical outcome data; thus, 70% of patients achieved a clinical benefit (Figure 1B). The baseline characteristics of the participating patients evaluated with respect to the LI are summarized in Table 1. The significant differences in seven of 13 variables were found among three LI groups. A biochemical complete success was achieved in 27 of 42 (64.3%) with an LI between 2-4, in 60 of 76 (78.9%) with an LI between 4-10, and in 127 of 155 (81.9%) with an LI>10 (P=0.024 for trend) (Figure 1A). A clinical cure was achieved in 10 of 47 (21.3%) patients with an LI between 2-4, in 22 of 101 (21.8%) with an LI between 4-10, and in 63/203 (31.0%) with an LI>10 (P=0.071 for trend) and a clinical benefit was achieved in 29 of 47 (61.7%) patients with an LI between 2–4, in 60 of 101 (59.4%) with an LI between 4–10, and in 158 of 203 (77.8%) with an LI >10 (P<0.01 for trend) (Figure 1B). Using a criterion for positivity of LI >4, 187 of 231 (81%) showed a biochemical cure, whereas 85 of 304 (27.9%) showed a clinical cure and 218 of 304 (71.7%) patients showed a clinical benefit. We performed a logistic regression analysis to determine the impact of the AVS lateralization cut-offs on surgical outcome. In the univariate analysis, using the patients with an LI between 2–4 as the reference group, biochemical complete success and clinical benefits in terms of surgical outcomes were associated only those with an LI >10 but not those with an LI between 4-10 (Table 2). After adjustment for confounders, a complete biochemical success was associated with both an LI between 4–10 (OR 2.83; 95%CI 1.14–7.01) and LI >10 (OR 3.55, 95%CI 1.47–8.55) (Table 2), whereas a clinical benefit was associated with an LI >10 (OR 2.30; 95%CI 1.03–5.16) not but with an LI between 4–10 (OR 0.97; 95%CI 0.45–2.10). A criterion for positivity of LI >4 were associated with surgical outcomes in terms of the complete biochemical success but not clinical benefit (Table 2). Additionally, we evaluated a criterion of CLR<1 for surgical outcomes in terms of complete biochemical success and clinical benefit. Although a criterion for positivity of CLR<1 showed high proportion of complete success of biochemical outcome with equal to that of LI >10, no significant differences were found in patients with and without meeting a criterion of CLR<1 for biochemical and clinical outcomes (Table 2). DISCUSSION Our results demonstrated an association between AVS aldosterone lateralization cut-offs and surgical outcomes based on recent international criteria in unilateral adrenalectomized patients with PA. The major novelty of the present study was to correlate the LI cut-off and clinical and biochemical outcomes after adrenal surgery using the PASO criteria (12). The Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 results provided evidence that LI cut-off of 4 is an adequate cut-off to determine unilateral disease and to achieve good biochemical outcome, while the difference of clinical benefit for LI between 4 and 10, and that for LI >10 was relatively small, although it was statistically significant. Our study by standardized outcome measure validated that an LI >4 recommended by clinical guideline (5) is suggest to be appropriate to determine unilateral disease in PA. Before the recent international standardized criteria regarding the surgical outcome of patients with PA were established (12), the postoperative outcomes of patients with PA were usually determined by a combination of blood pressure, hormone profiles, serum potassium levels, and occasionally pathological findings based on local reference criteria (11). This is one of the reasons that resolution or improvement of PA has differed widely across studies that used different lateralization cut-offs of AVS. Although the receiver operating characteristic analysis showed an LI of 9.9 as the optimal cutoff (Youden’s index) for evaluating the clinical outcome (Supplemental Figure 1), the AUC (0.59; 95% CI 0.53–0.66), which afforded a sensitivity of 65% and a specificity of 57%, was not sufficient because a tendency, rather than a clear association, for clinical and biochemical outcomes in patients with this LI value was detected (Figure 1); thus, the best cutoff for the AVS LI was difficult to establish. Our results suggest that unilateral hyperaldosteronism may consist of heterogeneous etiologies. An international survey of AVS (AVIS study) (19) reported that an LI > 4 is the most common criterion associated with cosyntropin-stimulated AVS. Considering that more than 80% of patients can achieve complete success in terms of biochemical outcome determined by recent international standardized criteria with a commonly used criterion of LI >4 (Figure 1; Table 2), this cutoff is preferable when biochemical success is the goal. In the PASO study (12), PA patients with an LI >4 showed preferable surgical outcomes in terms of biochemical than those with an LI <4 in univariate analysis. In contrast, a higher LI value (LI > 10) was needed to obtain an independent surgical benefit in terms of clinical outcome (Table 2). We used nine variables for a logistic regression analysis and these variables were reported by the associated factor for surgical outcome of PA (11-12). In addition, similar significant difference of variables, especially in clinical outcome, between patients with surgical benefit and those without surgical benefit were seen in present study (Supplemental Table 1). In these confounders, age, BMI, and systolic blood pressure were predictors of clinical benefit, whereas but no clinical factors were associated with the outcome of biochemical benefit (data not shown), suggesting that clinical outcome depended on preoperative clinical findings, whereas biochemical outcome was determined by only AVS LI. Notably, 60% of patients with available clinical and biochemical outcome data, respectively, showed a surgical benefit in clinical and complete success in biochemical among the patients with an LI of 2–4 (Figure 1). Although an LI > 4 is the most commonly used AVS criterion, approximately half of the reference centers in AVIS used more Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 permissive LI values, ranging from 2 to 4 (19). We found a favorable tendency, albeit not a significant association, for a clinical benefit in patients with these LI values who also had higher systolic blood pressure, higher defined daily dose of anti-hypertensive medications, or lower serum potassium levels. We also found that younger patients achieved a good biochemical outcome more frequently than did older patients (P<0.01) (data not shown). While on AVS finding, contralateral aldosterone suppression was not associated with surgical benefits in terms of clinical and biochemical outcomes (data not shown). Additionally, we have reported that LI between 2 and 4 can be found even in patients with negative confirmatory testing for PA (22). Therefore, clinicians could send patients in these LI zone to surgery with careful consideration for patients’ characteristics. However, the results should be carefully interpreted because of the small number of patients and the fact that only selected patients underwent surgery in this subgroup. Contralateral aldosterone suppression has been secondary used by a decision criterion for laterality of hyperaldosteronism followed in LI (5, 23). In present study, a criterion of CLR<1 was not associated with outcomes in terms of complete biochemical success and clinical benefit. However, a criterion for positivity of CLR<1 showed high proportion of a surgical benefit with equal to that of LI>10, suggesting that a certain number of patients with CLR >1 showed complete success of biochemical outcome. Therefore, more permissive cut-off of CLR for a decision criterion of aldosterone laterality during non-ACTH stimulated AVS might be adopted. When comparing our results with those of PASO study (12), the proportion of patients who achieved a surgical benefit in terms of clinical outcome was smaller in our study (70% vs. 84%). This may be because of the slightly older age and lower systolic blood pressure of our participants (Table 1). Additionally, that of biochemical outcome was smaller in our study compared to PASO study (12). It may be derived from the fact that ARR cut-off of 20 for screening in Japan guideline (16) has been set aiming higher sensitivity to avoid false negatives and to not to overlook PA patients. The cut-off however may lead to f affect the biochemical outcome after surgery. Furthermore, our patients showed wide standard deviation of ARR (mean 103, IQR 55.1-212, range 8.2-1890), indicating the overlap to the normal range. Routine confirmatory testing may be needed when aldosterone to renin ratio is positive after surgery as suggested by PASO study. Additionally, high prevalence of positive KCNJ5 mutation has been reported in Japan (24). Since KCNJ5 mutated aldosterone- producing adenoma have a specific feature such as high CYP11B1 and low CYP11B2 (25), it may affect the lateralization of PA by AVS. Finally, racial difference and high salt intake may be related to the poor biochemical outcomes by forming bilateral hyperplasia with asymmetrical aldosterone production. In patients who had available data for pathological findings and assessment of biochemical outcome after surgery, 70% patients were diagnosed as aldosterone-producing adenomas based on the histological presence of adenoma and Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 complete biochemical success after surgery. Some of the remaining patients might have aldosterone producing lesions and histological details waits further analysis. LIMITATIONS Our study has several limitations. The main limitation of our study is its retrospective nature. A second limitation is that although a surgical indication is based essentially on the Japan Endocrine Society guidelines, details of the indication criteria used for adrenal surgery have not been completely standardized among centers. For this reason, our study included a heterogeneous patient population. A prospective standardized protocol study is needed to validate our results. A third limitation is the protocol used for cosyntropin administration. Cosyntropin administration is debated because cosyntropin administration improves the AVS (21), whereas it lost lateralization of aldosterone excess in some cases. There are many reports of the usefulness of non-cosyntropin-stimulated AVS in expert centers worldwide (19), and hence our results apply only to patients with cosyntropin-stimulated AVS. A fourth limitation is the small number of patients in the no biochemical success group. CONCLUSION Our study demonstrated the correlation between LI of AVS and post-operative outcomes using the standardized criteria. The results provided evidence that LI cut-off of 4 is an adequate cut-off to determine unilateral disease and to achieve good biochemical outcome, while the difference of clinical benefit for LI between 4 and 10, and that for LI >10 was relatively small. Our study by standardized outcome measure validated that an LI >4 recommended by clinical guideline is suggest to be appropriate to determine unilateral disease in PA. Sources of funding This study was supported in part by grants-in-aid for the Japan Primary Aldosteronism Study (JPAS) from the Practical Research Project for Rare/Intractable Disease from the Japan Agency for Medical Research and Development (15Aek0109122) and a grant from the National Center for Global Health and Medicine, Japan (27-1402) and a grant from Grant-in- Aid for Young Scientists (B) Grant Number 17K16173. Practical Research Project for Rare/Intractable Disease from the Japan Agency for Medical Research and Development, 15Aek0109122, Mitsuhide Naruse; National Center for Global Health and Medicine, Japan, 27-1402, Mitsuhide Naruse; Grant-in- Aid for Young Scientists (B), 17K16173, Hironobu Umakoshi Corresponding author and person to whom reprint requests should be addressed: Mitsuhide Naruse, MD, PhD, Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Fushimi-ku, Kyoto 612-8555, Japan, Phone: +81-75-641-9161, Fax: +81-75- 645-8409, E mail: mnaruse@kyotolan.hosp.go.jp Conflict of Interest/Disclosure The authors have nothing to disclose REFERENCES 1. 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Dose Contralateral Suppression at Adrenal Venous Sampling Predict Outcome Following Unilateral Adrenalectomy for Primary Aldosteronism? J Clin Endocrinol Metab 2015; 100:1477-1484 24. Kitamoto T, Suematsu S, Matsuzawa Y, Saito J, Omura M, Nishikawa T. Comparison of cardiovascular complications in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenomas. J Atheroscler Thromb. 2015; 22:191-200. 25. Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE, Williams TA, Mulatero P. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol. 2015; 15:146-54. Figure 1. Biochemical and clinical outcomes of adrenalectomized patients with primary aldosteronism. The proportion of patients with outcomes in terms of biochemical and clinical outcomes was assessed with respect to the LI, which was categorized into three groups (2–4, 4–10, and > 10). Complete biochemical success was in nearly 80% of the patients (A) and clinical benefit was achieved in nearly 70% (B). There was a tendency for favorable biochemical and clinical outcomes with an increasing LI value (P<0.01 for trend for biochemical outcome (A), P<0.01 for clinical outcome (B)). Using LI > 4 as a criterion for positivity, 187 of 231 (81%) patients showed complete biochemical success (A) and 218 of 304 (72%) patients showed a clinical benefit (B). Table 1 Comparison of baseline clinical characteristics in patients with respect to adrenal venous sampling lateralization index Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Journal of the Endocrine Society; Copyright 2018 DOI: 10.1210/js.2018-00055 Total Pairwise comparison (P values) (n=377) LI 2-4 LI 2-4 LI 4-10 LI 2-4 (n = LI 4-10 LI >10 Overall vs LI 4- vs LI vs LI Characteristics 52) (n=106) (n=219) P value 10 >10 >10 Age, y 52.0±11.4 50.3±10.2 52.6±10.7 52.1±12.0 0.47 NA NA NA Female, (%) 46.9 53.8 34.9 51.1 0.01 0.079 1.0 0.019 Body mass index 24.4±4.2 25.1±3.7 25.0±3.8 23.9±4.4 0.028 1.00 0.19 0.06 Systolic blood pressure, mm 141±18 137±18 142±19 142±18 0.22 NA NA NA Hg Diastolic blood pressure, mm 86±12 84±12 88±12 86±12 0.078 NA NA NA Hg Duration of hypertension, y 10.6±9.0 7.5±7.1 10.9±9.1 11.2±9.2 0.031 0.092 0.027 1.0 Defined daily dose of 2.0±1.3 1.7±1.1 1.9±1.1 0.11 NA NA NA 2.1±1.4 antihypertensive medications Diabetes mellitus, (%) 16.4 13.4 22.1 14.4 0.22 NA NA NA Serum potassium, mEq/l 3.3±0.6 3.6±0.5 3.5±0.5 3.2±0.5 <0.01 0.49 <0.01 <0.01 Estimated glomerular filtration 78±22 87±23 78±20 77±22 <0.01 0.036 <0.01 1.0 rate, ml/min/1.73m2 Plasma aldosterone 35.7±24.7 <0.01 1.0 <0.01 <0.01 22.7±15.6 25.8±11.8 43.5±27.8 concentration, ng/dl Plasma renin activity, 0.37±0.42 0.42±0.32 0.40±0.30 0.34±0.48 0.3 NA NA NA ng/ml/h Ratio of plasma aldosterone 181±224 85.1±103 109±117 239±264 <0.01 1.0 <0.01 <0.01 concentration to plasma renin activity Notes: Data are presented as mean ± standard deviations unless otherwise indicated. Table 2 Surgical outcomes in terms of biochemical and clinical outcomes as determined by AVS findings in unadjusted and adjusted analyses Biochemical outcome Patients Complete success (%) Unadjusted OR (95% CI) Adjusted OR (95% CI) LI category 2-4 42 27 (64) 1.00 (reference) 1.00 (reference) 4-10 76 60 (79) 2.08 (0.90–4.82) 2.83 (1.14–7.01) >10 155 127 (82) 2.52 (1.19–5.35) 3.55 (1.47–8.55) AVS criterion LI <4 42 27 (64) 1.00 (reference) 1.00 (reference) LI >4 231 187 (81) 2.36 (1.16–4.81) 3.21 (1.44–7.18) CLR >1 29 22 (76) 1.00 (reference) 1.00 (reference) CLR <1 244 192 (79) 1.17 (0.48-2.90) 1.40 (0.54-3.66) Clinical outcome Patients Benefits (%) Unadjusted OR (95% CI) Adjusted OR (95% CI) LI category 2-4 47 29 (61) 1.00 (reference) 1.00 (reference) 1.00 (reference) 4-10 101 60 (59) 0.91 (0.45–1.85) 0.97 (0.45–2.10) >10 203 158 (77) 2.18 (1.11–4.28) 2.30 (1.03–5.16) AVS criterion LI <4 47 29 (61) 1.00 (reference) 1.00 (reference) LI >4 304 218 (72) 1.57 (0.83–2.98) 1.44 (0.70–2.99) CLR >1 37 26 (70) 1.00 (reference) 1.00 (reference) CLR <1 314 221 (70) 1.01 (0.48-2.12) 0.61 (0.27-1.40) Note: Adjusted for age, sex, body mass index, systolic blood pressure, defined daily dose of anti-hypertensive medications, estimated glomerular filtration rate, serum potassium concentration, plasma aldosterone concentration, and diabetes mellitus. Abbreviations; OR, odds ratio; CI, confidence interval; AVS, adrenal venous sampling; LI, Lateralization index; CLR, Contralateral ratio. Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: JES Downloaded from https://academic.oup.com/jes/advance-article-abstract/doi/10.1210/js.2018-00055/5001745 by Ed 'DeepDyve' Gillespie user on 12 July 2018 ADVANCE ARTICLE JOURNAL OF THE ENDOCRINE SOCIETY ADVANCE ARTICLE: ADVANCE ARTICLE: ADVANCE ARTICLE: Endocrinology Endocrinology JES

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Journal of the Endocrine SocietyOxford University Press

Published: May 24, 2018

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