Primary aldosteronism clinical practice guidelines: a re-appraisal The Management of Primary Aldosteronism

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1 Primary aldosteronism clinical practice guidelines: a re-appraisal The Management of Primary Aldosteronism Prof. FRANCO MANTERO Division of Endocrinology University of Padua Italy

2 Case Detection, Diagnosis and Treatment of Primary Aldosteronism: an Endocrine Society Clinical Practice Guideline Funder JW. et al. J Clin Endocrinol Metab 2008

3 Results of the PAPY Study Final Diagnosis PA=126 (n=1125 pts) APA Right (n=25) APA Left (n=29) 100 Prevalence of APA PH N=999 IHA (n=72) 50 95,2 Overall Prevalence of PA = 11.2% 0 4,8 The PAPY Study Investigators. JACC, 2006.

4 Rate of cardiovascular events and cardiac structure in primary aldosteronism. Patients and controls. Primary Aldosteronism (n=124) Essential Hypertension (n=465) Odds Ratio (95%CI) p value Stroke (%) ( ) <0.001 Myocardial infarction (%) Atrial fibrillation (%) Echocardiograp hic LVH (%) Electrocardiogra phic LVH (%) ( ) <0.005* ( ) <0.0001* ( ) < ( ) <0.001 *Fishier exact test CI: confidence interval LVH: left ventricular hypertrophy Milliez et al, 2005 J Am Coll Cardiol

5 Wider role for aldosterone in human cardiovascular disease RALES study (NEJM, 1999;341:709) Ephesus study (NEJM, 2003;348:1309) Cardiac fibrosis Vascular inflammation & remodelling Vascular protection - eplerenone and spironolactone

6 Title: The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline (2015) Short title: Guidelines on Primary Aldosteronism Authors: John W. Funder (chair), Robert M. Carey, Franco Mantero, Mohammad Hassan Murad, Martin Reincke, Hirotaka Shibata, Michael Stowasser and William F. Young

7 1. Conclusions : Case Detection 1.1 We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia

8 1. Conclusions : 1.2 Case Detection JNC Stage 2 ( / mmhg) JNC Stage 3 (>180 mmhg / >110 mmhg) Drug resistant hypertension Hypertension with adrenal incidentaloma Hypertension plus a FH of early-onset HT/CVA at a young age (< 40Y) All first-degree relatives of PA patients

9 Prevalence of PA (%) Prevalence of PA By Severity of Arterial Hypertension (ESH/ESC Guidelines) in The PAPY Study PH IHA Left APA Right APA c 2 =32.4, p< Normal/ high The PAPY Study Investigators. JACC, Grade 1 HT Grade 2 HT Grade 3 HT Classification of BP and HT

10 1.3 We recommend case detection of Primary Aldosteronism in patients with sustained blood pressure over 150/100, and in patients with or hypertension (BP>140/90) with obstructive sleep apnea. (1 OO)

11 1. Conclusions: 1.2 Case Detection We recommend use of the plasma aldosterone-renin ratio (ARR) to detect cases of PA in these

12 Table 4-2. Factors that may affect the aldosterone-renin ratio and thus lead to false positive or false negative results Factor Effect on Effect on Effect on aldosterone renin levels ARR Potassium status Hypokalemia (FN) Potassium loading (FP) Dietary Sodium Sodium restricted (FN) Sodium loaded (FP) Advanced age (FP) Other conditions Renal impairment (FP) PHA-2 (FP) Pregnancy (FN) Renovascular HT (FN) Malignant HT (FN)

13 Table 4-1. Factors that may affect the aldosterone-renin ratio and thus lead to false positive or false negative results Factor Effect on Effect on Effect on aldosterone renin levels ARR Medications Beta-adrenergic blockers (FP) Central alpha-2 agonists (FP) (eg clonidine, alphamethyldopa NSAIDs (FP) K + -wasting diuretics (FN) K + -sparing diuretics (FN) ACE inhibitors (FN) ARBs (FN) Ca 2+ blockers (DHPs) (FN) Renin inhibitors * (FP)* (FN)* *Renin inhibitors lower plasma renin activity (PRA), but raise direct active renin concentrations (DRC). This would be expected to result in false positive ARR levels for renin measured as PRA and false negatives for renin measured as DRC.

14 Antihypertensive drugs allowed:. Ca channel blockers (non DHP). alfa 1antagonists. If necessary,keep ACEI,ARB,diuretics (but Renin should remain low) Antihypertensive to be absolutely withdrawn:. Beta blockers. Spironolactones

15 Table 5. ARR cut-off values, depending on assay and based on whether PAC, PRA and DRC are measured in conventional or SI units PRA PRA DRC DRC (measured (measured measured (measured in ng/ml/h) in pmol/l/min) in mu/l) in ng/l) PAC (as ng/dl) PAC (as pmol/l)

16 The aldosterone renin ratio based on the plasma renin activity and the direct renin assay for diagnosing aldosterone-producing adenoma Scatter plot of the within-patient values of plasma renin measured by the plasma renin activity and active renin method. Rossi GP at al, Journal of Hypertension, 2010

17 Hinchliffe et al, J. Chromatogr. B (2013) 19 23

18 2. Conclusions : Case Confirmation 2.1 Instead of proceeding directly to subtype classification, we recommend that patients with a positive ARR undergo testing by any of four confirmatory tests, to definitively confirm or exclude the diagnosis: Oral sodium loading Saline infusion Fludrocortisone suppression Captopril challenge

19 (%) Sensitivity ROC Curve Analysis and Plot vs Criterion Values of The Confirmatory Test (Saline Infusion) AUC= ,028 95%; CI= P< vsauc= Specificity Sensitivity (%) Specificity (%) Cutoff=6.8 ng/dl Sens.: 72.8% Spec.:76.1% Post-SAL plasma Aldosterone (ng/dl) The PAPY Study; J Hypertens,2007

20 Comparison between test: CAPT versus SIT The plot shows the Receiver Operator Characteristics curve of plasma Aldosterone after the Captopril (CAT) and the saline infusion test (SIT) for the identification of APA. The AUC under the SIT was higher than that under the CAT but the difference was borderline significant (p = 0.054). Rossi GP et al, Hypertension 2007

21 Stowasser M, J Clin Endocrinol Metab, 2015

22 Case Confirmation 2.1 Instead of proceeding directly to subtype classification, we recommend that patients with a positive aldosterone-renin ratio (ARR) should normally undergo one or more confirmatory tests to definitively confirm or exclude the diagnosis. (1 OO) However, in the setting of spontaneous hypokalemia, undetectable renin, and plasma aldosterone concentration (PAC) >20 ng/dl, we suggest that there may be no need for further confirmatory testing. (2 OOO)

23 3. Conclusions : Subtype Classification 3.1 We recommend that all patients with PA undergo adrenal CT scan as an initial study in subtype testing, and to exclude large masses that may represent adrenocortical cancer

24 Burton et al, J Clin Endocrinol Metab, 2012

The performance of adrenal CT imaging and AVS in distinguishing unilateral and bilateral aldosteronism CT correctly identified unilateral or bilateral disease in 53% of patients with successful AVS

25 The performance of adrenal CT imaging and AVS in distinguishing unilateral and bilateral aldosteronism CT correctly identified unilateral or bilateral disease in 53% of patients with successful AVS CT falsely suggested APA in 48 patients CT inaccurately suggested bilateral hyperplasia in 43 patients with unilateral disease CT indicated the wrong adrenal gland in 21.2% of patients AVS inaccurately predicted bilateral disease in 4 patients with PAH Young W et al, Surgery 2005

26 3. Conclusions : Subtype Classification 3.2 We recommend that when surgical treatment is practicable and desired by the patient, the distinction between unilateral and bilateral adrenal disease be made by adrenal venous sampling

27 Rossi GP et al, JCEM 97: , 2012

28 Rossi et al, Hypertension. 2014;63:

29 Kupers et al, J Clin Endocrinol Metab 97: , 2012

30 Riester et al, J Clin Endocrinol Metab 99: E1035 E1039, 2014

31 3.2 We recommend that when surgical treatment is practicable and desired by the patient, the distinction between unilateral and bilateral adrenal disease be made by adrenal venous sampling (AVS) by an experienced radiologist. (1 O) We suggest that in younger patients (< age 35) with spontaneous hypokalemia, marked aldosterone excess, and unilateral cortical adenoma on adrenal CT scan, AVS may not be needed before proceeding to unilateral adrenalectomy. (2 OOO)

32 Figure 1. (A) Sequences of tumor cdna, adjacent adrenal tissue, and peripheral blood gdna of KCNJ5 codons showing the c.455a>g substitution resulting in the p.y152c mutation. (B) Real-time PCR analysis of CYP11B2 and NR4A2 in HAC15 cells overexpressing KCNJ5 Y152C compared with cells overexpressing KCNJ5 WT and pcdna3.1 empty vector. Each bar represents the mean ± SE of relative fold change of gene expression in three independent experiments. Each assay was performed in triplicate, and glyceraldehyde-3-phosphate dehydrogenase was used as endogenous control. *, P <.05 compared with WT., P <.05 compared with KCNJ5 Y152C not treated with nifedipine. Monticone et al, J Clin Endocrinol Metab 2013;98:E1861-E1865.

33 Zennaro et al, Journal of Endocrinology (2015) 224, R63 R77

34 3.3 In patients with onset of confirmed PA earlier than 20 years of age and in those who have a family history of PA or of strokes at young age (<40 years), we suggest genetic testing for familial hyperaldosteronism type 1 (FH-1; glucocorticoid remediable aldosteronism [GRA]). (2 OO) In very young patients with PA, we suggest testing for germline mutations in KCNJ5 (2 OOO) causing FH-3.

35 4. Conclusions : Treatment 4.1 We recommend that treatment by unilateral laparoscopic adrenalectomy be offered to patients with documented unilateral PA (ie.aldosterone-producing adenoma [APA] or unilateral adrenal hyperplasia [UAH]). If a patient is unable or unwilling to undergo surgery, we recommend medical treatment with a mineralocorticoid receptor (MR) agonist.

36 4.1 We recommend that treatment by unilateral laparoscopic adrenalectomy be offered to patients with documented unilateral PA (i.e., aldosteroneproducing adenoma [APA] or unilateral adrenal hyperplasia [UAH]). (1 O) If a patient is unable or unwilling to undergo surgery, we recommend medical treatment including a mineralocorticoid receptor (MR) antagonist. (1 O) If an ARR-positive patient is unwilling or unable to undergo further investigations, we similarly recommend treatment including an MR antagonist. (1 OO)

37 4.2 In patients with PA due to bilateral adrenal disease, we recommend medical treatment with a MR antagonist (1 O); we suggest spironolactone (or canrenone/potassium canrenoate) as the primary agent with eplerenone as an alternative. (2 OOO)

38 CV EFFECTS OF ADRENALECTOMY & SPIRONOLACTONE: CHANGES DURING FOLLOW UP (mean 17 mo) ADX-treated Spiro-treated P value (n = 19) (n = 21) 24h SBP (mmhg) ** * NS 24h DBP (mmhg) ** * NS No. Drugs * < 0.01 IVS (mm) *** * NS PW (mm) *** NS LVM (g) *** ** <0.05 LVMI (g/m 2 ) *** ** <0.05 ESV (ml) *** <0.05 EDV (ml) *** * <0.001 * P<0.05, ** P<0.01 and *** P<0.001 for pre- vs post-treatment

39 4. Conclusions : Treatment 4.3 In patients with GRA, we recommend the use of the lowest dose of glucocorticoid that can normalize blood pressure and serum potassium levels rather than first-line treatment with an MR antagonist.

40 Primary Aldosteronism Guidelines Patients with hypertension that are at increased risk for PA PA unlikely Use ARR to detect cases 1 OO * PA unlikely Conduct confirmatory testing 1 OO * Adrenal CT (1 OO) + + If surgery desired If surgery not desired AVS (1 O) + + Subtype Testing* Bilateral Unilateral Treat with MR antagonist (1 OO) Treat with laparoscopic adrenalectomy (1 OO)

41 Algorithm for the detection, confirmation, subtype testing, and treatment of primary aldosteronism (PA). Patients with hypertension that are at increased risk for PA PA unlikely - PA unlikely - ARR to detect cases 1 + Confirmatory testing 1 + Adrenal CT (1 ) + Patient unwilling/unable to proceed Treat with MR antagonist 2 Subtype testing If surgery desired If surgery not desired AVS (1 ) Bilateral Unilateral Marked PA, young age, and + CT (2 ) Treat with MR antagonist (1 ) Treat with laparoscopic adrenalectomy (1 )

42 THANK YOU

43 Fig. 4. Proposed mechanism underlying aldosterone-producing adenoma and Mendelian aldosteronism. (A) Adrenal glomerulosa cells have a high resting K+ conductance, which produces a highly negative membrane potential (2). (B) Membrane depolarization by either elevation of extracellular K+ or closure of K+ channels by angiotensin II activates voltage-gated Ca2+ channels, increasing intracellular Ca2+ levels (1). This provides signals for increased expression of enzymes required for aldosterone biosynthesis, such as aldosterone synthase, and for increased cell proliferation. (C) Channels containing KCNJ5 with G151R, T158A, or L168R mutations conduct Na+, resulting in Na+ entry, chronic depolarization, constitutive aldosterone production, and cell proliferation. Choi et al, Science 2011, vol

44 3. Conclusions : Subtype Classification 3.3 In patients with onset of confirmed PA earlier than at 20 years of age and in those who have a family history of PA or of strokes at young age (<40 years), we suggest genetic testing for glucocorticoid-remediable aldosteronism (GRA).

46 Fernandes-Rosa et al, Hypertension. 2014;64: )

47 Rossi et al, Hypertension. 2014;63:

51 Case confirmation Instead of proceeding directly to subtype classification, we recommend that patients with a positive ARR undergo testing, by any of four confirmatory tests, to definitively confirm or exclude the diagnosis (1 ). The current literature does not identify a gold standard confirmatory test for PA. Confirmatory testing places a high value on sparing individuals with false-positive ARR tests costly and intrusive lateralization procedures. Four testing procedures (oral sodium loading, saline infusion, fludrocortisone suppression, and captopril challenge) are in common use, and there is currently insufficient direct evidence to recommend one over the others. J Clin Endocrinol Metab 93: , 2008

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