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1 ARR [ ] /(PAC/PRA ARR) ( ) (EH) (ROC)ARR ARR EH (P<0.01) (PRA) (BMI) EH (P<0.01)(P>0.05) EH PRA (P>0.05) ARR 19.11(AUC) % 93.08% (YI) 0.86ARR AUC % 90.00% YI 0.82 ARR YI ARRARR [ ] [ ] R [ ] A [ ] (2017) [DOI] /j.issn Effects of gender on screening value of aldosterone-renin ratio for primary aldosteronism SONG Ye-qiong 1, WANG Lin 1,2, ZHU Jie 1, JIA Xiao-meng 1, PANG Ping 1, JIN Nan 1, ZANG Li 1, YANG Guo-qing 1, GU Wei-jun 1, DU Jin 1, WANG Xian-ling 1, GUO Qing-hua 1, YANG Li-juan 1, LV Zhao-hui 1*, BA Jian-ming 1, DOU Jing-tao 1, MU Yi-ming 1 1 Department of Endocrinology, General Hospital of PLA, Beijing , China 2 Department of First Internal Medicine, 316 Hospital of PLA, Beijing China * Corresponding author, metabolism301@126.com [Abstract] Objective To explore the potential influence of gender on screening value of aldosterone-renin ratio (ARR) for primary aldosteronism (PA). Methods The biochemical parameters were collected of 451 PA patients and 300 essential hypertension (EH) patients who were diagnosed in the General Hospital of PLA from 1992 to Each group was then divided into two groups by gender. The clinical characteristics were compared and then the receiver operating characteristic curve (ROC) was conducted to evaluate the best cut-off value. Results The plasma aldosterone concentration (PAC), serum sodium and ARR were much higher, but the plasma rennin activity (PRA), serum potassium and BMI were much lower in PA patients than in EH patients (P<0.01), and no significant difference existed between the two groups in age, duration of hypertension and blood pressure. The PRA was obviously lower in males than in females either in PA or in EH patients, but no significant difference existed between males and females in PAC (P>0.05). The best cut-off value of ARR in male PA patients was 19.11, the relevant area under the curve (AUC) was 0.968, the sensitivity and specificity was 92.44% and 93.08%, and the Youden index (YI) was The best cut-off value of ARR in female PA patients was 27.26, with AUC 0.956, sensitivity 92.07%, specificity 90.00% and YI 0.82, respectively. If the cut-off value was set at in males, the specificity would rise a little, but the sensitivity and YI would sharply decrease. Similarly, the sensitivity would increase a little but the specificity and YI would fall substantially if the cut-off value in females was set at The best cut-off value of ARR in men was smaller than the official value recommended by guidelines. Conclusion Gender is an important factor should be considered while ARR is used in PA screening, and the cut-off value of ARR in screening female PA patients should be setting higher. [Key words] hyperaldosteronism; sex factor; posture [ ]- - [ ] ( ) ( ) [ ] metabolism301@126.com

2 Med J Chin PLA, Vol. 42, No. 1, January 1, ( ) (low plasma renin activity PRA) [1] 5%~13% 20% [2] / (plasma aldosterone concentration/plasma renin activity PAC/PRA ARR) Hiramatsu [3] 1981 ARR [4-8] ARR 50 <50 [9] (essential hypertension EH) ARR /2 ( ) EH 3 140/90mmHg EH :00am PRA 4h PRA [10] 10% 15% PRA<0.79 g/(l h) <7.14 g/(l h) 0.93~6.56 g/(l h) 1.13~9.68 g/(l h) PAC 163.4~481.9pmol/L 337.9~1022.1pmol/L 180.1~819.9pmol/L 383.0~1758.9pmol/L 1.3 SPSS 19.0 MedCalc x±s M(Q 25 Q 75 ) t χ 2 (receive operate curve ROC) P< EH ARREH (P<0.01) PRA (BMI) EH (P<0.01) EH (P<0.01) (P>0.05 1) 2.2 EH (47.1± 11.1 vs 45.1± 10.3 P<0.05) BMI EH (44.9± 14.1 vs 50.1± 12.6 P<0.05) BMIEH PRA (P>0.05) ARR (P<0.01 2) 2.3 ARR/ ARR ROC (AUC) (YI)(+LR) (-LR) % 91.64% % 93.08% % 90.00% ( 1 3) Kappa Kappa (P<0.01) 2.4 ARR

3 EH Tab.1 Comparison of clinical data and biochemical parameters between PA and EH patients Item PA EH P value Age (year) a 46.07± ± Male/Female 225/ /140 <0.01 Supine PRA [ng/(ml.h)] b 0.1(0.1, 0.1) 0.7(0.3, 1.7) <0.01 Supine PAC (pmol/l) b (467.93, ) (306.15, ) <0.01 Supine ARR (ng/dl)/[ng/(ml.h)] b (118.23, ) 21.09(8.56, 48.91) <0.01 Upright PRA [ng/(ml.h)] b 0.2(0.1,0.5) 4.1(1.7, 7.6) <0.01 Upright PAC (pmol/l) b (537.63, ) (446.90, ) <0.01 Upright ARR(ng/dl)/[ng/(ml.h)] b (49.42, ) 5.40(2.91, 11.90) <0.01 Duration of hypertension (year) b 9(4, 13) 5(1, 11) SBP (mmhg) b 160(144.5, 180) 170(100, 120) DBP (mmhg) b 100(90, 110) 110(100, 120) Serum potassium (mol/l) a 2.83± 0.56(1.31, 4.71) 3.75± 0.45(1.90, 4.75) <0.01 Serum sodium (mol/l) a ± ± 2.14 <0.01 BMI (kg/m 2 ) b 24.95(22.83, 27.18) 26.60(23.90, 29.00) <0.01 PA. Primary aldosteronism; EH. Essential hypertension; PRA. Plasma renin activity; PAC. Plasma aldosterone concentration; ARR. Plasma aldosterone concentration/plasma renin activity; SBP. Systolic blood pressure; DBP. Diastolic blood pressure; BMI. Body mass index. a. Expressed by x±s (min, max); b. Expressed by M (Q 25,Q 75 ); 1ng/dl=27.7pmol/L 2 EH Tab.2 Clinical data and biochemical parameters of different gender patients with PA or EH Item PA EH Male Female Male Female Age (year) 47.07± ± (1) 44.92± ± (1) Supine PRA [ng/(ml h)] 0.1(0.1, 0.2) 0.1(0.1, 0.1) (1) 1.0(0.3, 2.2) 0.6(0.2, 1.3) (1) Supine PAC (pmol/l) (454.35, ) (475.90, ) (330.70, ) (281.88, ) (2) Supine ARR (ng/dl)/[ng/(ml.h)] (111.87, ) (128.66, ) 16.14(7.42, 42.55) 26.18(9.62, 57.85) (1) Upright PRA [ng/(ml h)] 0.2(0.1, 0.5) 0.1(0.1, 0.4) (1) 4.70(2.0, 8.8) 3.15(1.30, 6.25) (2) Upright PAC (pmol/l) (534.95, ) (542.10, ) 583.1(451.1, 717.1) (444.90, ) Upright ARR (ng/dl)/[ng/(ml.h)] (43.12, ) (56.85, ) (2) 4.4(2.68, 8.96) 7.7(3.2, 16.41) (2) Duration of hypertension (year) 10(5, 14.5) 8.5(3.38, 13) 5(1, 10) 5(2, 11) SBP (mmhg) 160(145, 180) 160(142, 180) 160(145.25, 180) 159(140.5, 171.5) DBP (mmhg) 100(90, 111.5) 100(90, 110) 100(90, 111) 92.5(93.84, 100) (2) Serum potassium (mol/l) 2.82± ± ± ± 0.40 Serum sodium (mol/l) ± ± 2.24 (1) ± ± 2.04 BMI (kg/m 2 ) 26.10(24.10, 28.20) 24.10(22.08, 25.75) (2) 27.30(24.80, 29.70) 25.30(23.20, 27.60) (2) (1)P<0.05, (2)P<0.01 compared with male; 1ng/dl=27.7pmol/L 1.0 Male 1.0 Female Sensitivity Sensitivity Sepcificity A 1 (A) (B) ROC Fig.1 The ROC curve for diagnosing primary aldosteronism in males (A) and females (B) Sepcificity B

4 Med J Chin PLA, Vol. 42, No. 1, January 1, ARR ROC Tab.3 ROC characteristics of screening PA patients by using ARR in each gender group Gender AUC 95%CI Best cut-off value Sensitivity Specificity YI +LR -LR Male Female Total AUC. The area under ROC curve; 95%CI. 95% confidence interval; YI. Youden index; +LR. Positive likehood ratio; -LR. Negative likehood ratio ARR 25.45ng/dl 27.26ng/dl ( 92.44% 88.10% 87.80%)( 93.08% 94.30% 94.34%) YI ( ) ARR 19.11ng/dl 25.45ng/dl ( 92.07% 95.59% 93.40%) ( 90.0% 81.50% 87.10%) ( ) ( 4) 4 ARR Tab.4 Diagnostic value of different ARR cut-off values for screeningpapatientsineachgendergroup Gender Cut-off value Sensitivity Specifity YI +LR -LR Male Female YI. Youden index; +LR. Positive likehood ratio; -LR. Negative likehood ratio 3 Hiramatsu [3] ARR( / ) 10 [11] [4-8] EH EH PRA ARR ARR [6-7] ARR Ahmed [12] ARR PRA PRA ARR PRA James [13] 9 PRA 27% Kaplan [14] EH PRA PRA ARR PRA EH James [13] Pizzolo [7] Miller [15] PRA ARR James [13] 2823 ARR( PRA ) ARR [16] ARRARR 56.25(10.73~115.39) 96.88(47.92~180.55) ARR James [13] [16] ARRARR ARR ( ) 20~40(ng/dl)/[ng/(ml.h)]

5 PRA ARR ROC AUC YI +LR -LR +LR YI -LR YI +LR ARR PRA ARR PRA [17] PRA PRA [18-19] SD PRA (r=0.904) [20] mrna [18,21] PRA [22] PRA [23] PRA PRA ARR [1] Li LL, Fan BP, Sun YX, et al. Mixed adrenal cortical adenoma: a case report[ J]. J Zhengzhou Univ(Med Sci), 2016,(6): [,,,. [J].( ), 2016,(6): ] [2] Sabbadin C, Fallo F. Hyperaldosteronism: screening and diagnostic tests[ J]. High Blood Press Cardiovasc Prev, 2016, 23(2): [3] HiramatsuK,YamadaT,YukimuraY,et al. Ascreeningtestto identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients[ J]. Arch Intern Med, 1981, 141(12): [4] Stowasser M, Taylor PJ, Pimenta E, et al. Laboratory investigation of primary aldosteronism[ J]. Clin Biochem Rev, 2010, 31(2): [5] Stowasser M, Ahmed AH, Pimenta E, et al. Factors affecting the aldosterone/renin ratio[ J]. Horm Metab Res, 2012, 44(3): [6] Fommei E, Ghione S, Ripoli A, et al. Theovariancycleasafactorof variability in the laboratory screening for primary aldosteronism in women[ J]. J Hum Hypertens, 2009, 23(2): [7] Pizzolo F, Raffaelli R, Memmo A, et al. Effects of female sex hormones and contraceptive pill on the diagnostic work-up for primary aldosteronism[ J]. J Hypertens, 2010, 28(1): [8] Ahmed AH, Gordon RD, Taylor PJ, et al. Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men?[ J]. J Clin Endocrinol Metab, 2011, 96(2): [9] Luo Q, Li NF, Zhang DI, et al. Potential effects of age on screening for primary aldosteronism[ J]. J Hum Hypertens, 2016, 30(1): [10] Liu HY, Tang ZQ, Lyv ZH. Clinical measurement to patients with aldosteronoma but normal tension[ J]. Clin J Endocrinol Metab, 2012, 28(2): [11] Stowasser M, Gordon RD, Gunasekera TG, et al. High rate of detection of primary aldosteronism, including surgically treatable forms, after "non-selective" screening of hypertension patients[ J]. J Hypertens, 2003, 21(11): [12] Ahmed AH, Gordon RD, Taylor PJ, et al. Are women more at risk of false-positive primary aldosteronism screening and unnecessary suppression testing than men[ J]. J Clin Endocrinol Metab, 2011, 96(2): [13] James GD, Sealey JE, Müller F, et al. Renin relationship to sex, race and age in normotensive population[ J]. J Hypertens, 1986,4(5): [14] Kaplan NM, Kem DC, Holland OB, et al. The intravenous furosemide test: a simple way to evaluate renin responsiveness[ J]. Ann Intern Med, 1976, 84(6): [15] Miller JA, Anacta LA, Cattran DC. Impact of gender on the renal responseto angiotensin [ J]. Kidney Int, 1999, 55(1): [16] Wang N, Tian G. Analysis of clinical characteristic in primary aldosteronism patients with different gender and pathological type[ J]. J Shanxi Med Univ, 2016, 47(2): [17] Reckelhoff JF, Fortepiani LA, Zhang H, et al. Gender differences in the response of SHR to acute and chronic superoxide dismutase mimetc, TEMPOL[ J]. Am J Hypertens, 2000, 13(4): S277-S278. [18] Ellison KE, Ingelfinger JR, Pivor M, et al. Androgen regulation of rat renal angiotensinogen messenger RNA expression[ J]. J Clin Invest, 1989, 83(6): [19] Katz FH, Roper EF. Testosterone effect on renin system in rats[ J]. Proc Soc Exp Biol Med, 1977, 155(3): [20] Reckelhoff JF. Gender differences in the regulation of blood pressure[ J]. Hypertension, 2001, 37(5): [21] Chen YF, Naf ti lan A J, Opar i l S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats[ J]. Hypertension, 1992, 19(5): [22] G o rd o n M S, C h i n W W, S h u p n i k M A. R e g u l at i o n o f angiotensinnogen gene expression by estrogen[ J]. J Hypertens, 1992, 10(4): [23] Ishibashi K, Oshima T, Matsuura H, et al. Effects of age and sex on sodium chloride sensitivity: Association with plasma renin activity[ J]. Clin Nephrol, 1994, 42(6): ( ) ( )

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