Case Conference Samer BaniHani PGY5 Nephrology Consultation Reason

Case Conference Samer Bani-Hani PGY-5

Nephrology Consultation • Reason for the Consult: Persist Hypo. Kalemia Ø H/P: • 52 year-old male referred to nephrology clinic for hypokalemia. His onset of hypokalemia began in 2007. Pt was started on KCL 20 meq/day and increased to 80 meq/day and HCTZ was discontinued however K level persist low.

• PMH: 1. HTN 2. DM 3. Allergic rhinitis • Medication 1. Lisinopril 40 mg QD 2. Atenolol 50 mg QD 3. Amlodipine 10 mg QD 4. KCL 40 meq BID 5. Spirolactone 25 mf QD

Physical Examination • Vital signs 135/75 , 70 , Afebrile , 18 • HEENT: NCAT, PERRL, EOMi, Thyroid normal in size and texture • Chest: CTAB • CV: Regular rythm, no M/R/G • Abd: soft, NTND, +BS • Ext: no CCEx 4, DTRs brisk w/nl relaxation phase

Labs • 2007 before HCTZ 144 | 95 | 8 / ----------- 92 3. 1 | 37 | 0. 85 • On HCTZ 144 | 106| 7 / ------------92 2. 5 | 33 | 0. 85 • After starting Spirolactone 141 | 104 | 7 / ---------- 173 4. 3 | 29 | 1. 0 • CT: 2010: 1. 4 cm left adrenal nodule that has low attenuation. • CT: 6/2011 A 2 cm x 1. 4 cm x 1 cm oval nodule on the inferior aspect of the anterior limb of the left adrenal gland with characteristics • 6/2011: Rennin <0. 15 ng/ml/hr Aldosterone 14. 8 ng/dl

Primary Aldosteronism

Prevalence of Primary Aldosteronism • Most common form of secondary hypertension. • Hypertension associated with low renin and increased aldosterone levels that are not suppressed by appropriate testing • Conn, 1955: 34 -year-old woman with hypertension, intermittent paralysis, hypokalemia and metabolic alkalosis. • Prevalence among nonselected hypertensive 5% and 13%. • With an estimated prevalence of 10% 8. 5 million people in the US have primary aldosteronism. Mosso L et al. Primary aldosteronism and hypertensive disease. Hypertension 2003

Prevalence of Primary Aldosteronism According to HTN severity • • The prevalence of primary aldosteronism increases with severity of hypertension. Mosso and colleagues showed that prevalence was 1. 99% in subjects with STAGE 1 HTN(according to the Joint National Committee 6); 8. 02% in STAGE 2 HTN; and 13. 2% in STAGE 3 HTN Mosso L et al. Hypertension 2003; 42(2): 161 -165

Prevalence of PA inpatients with resistant hypertension q Resistant hypertension is defined as BP that remains elevated despite use of three antihypertensive agents, ideally one of which is a diuretic q Among patients with resistant hypertension, the prevalence of primary aldosteronism has been reported to be 17– 22%. David A. Calhoun Aldosteronism and Hypertension CJASN 2006

Aldosterone Synthesis • Aldosterone, produced in the ZONA GLOMERULOSA, is synthesized and released mainly in response to renin-dependent production of ANGIOTENSIN II; however, adreno corticotropic hormone (ACTH), serum potassium, and dopamine also affect its production and secretion.

Aldosterone Action

Inhibition and Stimulation • Aldosterone is stimulated by a number of factors but the most important include angiotensin II, hyperkalemia, and ACTH. • Angiotensin II and hyperkalemia stimulate both the synthesis and stimulation of aldosterone synthase in the zona glomerulosa. • Aldosterone inhibition occurs predominantly by ANP and hypokalemia

Aldosterone regulates blood pressure through a number of mechanisms

Aldosterone and Kidney Fibrosis Serum and glucocorticoid induced kinase 1 Nuclear factor-KB Reactive oxygen species Brem AS , Am J Kidney Dis. 2011

Cardiovascular Events and Primary Aldosteronism Rate of Cardiovascular Events and Cardiac Structure in Primary Aldosteronism Primary Aldo (n=124) Essential HTN (n=465) Odds ratio (95% CI) p value Stroke (%) 12. 9 3. 4 4. 2 (2. 0 -8. 6) < 0. 001 Myocardial infarction (%) 4. 0 0. 6 6. 5 (1. 5– 27. 4) < 0. 005* Atrial fibrillation 7. 3 0. 6 12. 1 (3. 2 -45. 2) <0. 0001* Echo LVH (%) 34 24 1. 6 (1. 1 -2. 5) < 0. 01 EKG LVH (%) 32 14 2. 9 (1. 8 -4. 6) < 0. 001 Cardiovascular events (stroke, myocardial infarction and atrial fibrillation) are more common in patients with primary aldosteronism than in subjects with essential hypertension, a finding that is inde pendent of blood pressure. Milliez P et al. J Am Coll Cardiol 2005; 45(8): 1243 -1248

Clinical Features • Hypertension • Hypo. Kalemia • Metabolic alkalosis – Due to increased urinary H+ excretion mediated both by direct stimulatory effect of aldosterone on distal acidification • Muscle weakness – It is primarily due to hypokalemia

• Lack of edema: – Although aldosterone initially induces sodium and water retention, this is followed within a few days by a spontaneous diuresis (called aldosterone escape) that returns excretion to the level of intake and partially lowers the extracellular fluid volume toward normal. – The mechanisms responsible for the escape phenomenon are incompletely understood, but at least three factors may be important: q increased secretion of atrial natriuretic peptide (ANP) induced by the hypervolemia q decreased abundance of the thiazide-sensitive Na-Cl cotransporter that mediates sodium reabsorption in the distal tubule q pressure natriuresis.

Hypokalemia: an inconsistent finding • • With increasing use of the plasma aldosterone to plasma renin activity ratio as a case detection test from PA in HTN patients, more normokalemic patients are being identified In a multicenter review using this approach, approximately 60 percent of patients with primary aldosteronism were not hypokalemic Mulatero et al J Clin Endocrinol Metab, March 2004

Subtypes

DDx of Aldosteronism from Essential Hypertension Aldo. Producing Adenoma Adrenal Hyperplasia Low-renin essential HTN Age Middle-aged Older Hypokalemia Plasma renin levels Plasma aldo suppressibility to volume Frequent Very low Less common Low Uncommon Low Very high High-normal Normal Minimal Partial Complete

Glucocorticoid Remediable Aldosteronism The mutation is fusion of the promoter region of the gene for CYP 11 B 1 and the coding sequences of CYP 11 B 2 resulting in ACTHdependent activation of the aldosterone synthase effect on cortisol, corticosterone, and cortisol precursors

Who to Screen? 1. Hypertension and spontaneous or low dose diuretic-induced hypokalemia 2. Severe hypertension (>160 mm. Hg systolic or >100 mm. Hg diastolic) or drug-resistant hypertension (defined as suboptimally-controlled hypertension on a three-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic) 3. Hypertension with adrenal incidentaloma 4. Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years) 5. All hypertensive first-degree relatives of patients with primary aldosteronism Endocrine Society guidelines 2008

Screening for PA : ARR q. Aldosterone-Renin Ratio (ARR)>20 and Aldosterone level>15 ng/dl q. Morning testing q. K+ repletion q. Mineralocorticoid receptor antagonists (spironolactone and eplerenone) and high-dose amiloride (e. g. >5 mg daily) should be dis continued 6 weeks before blood sampling to avoid direct interference with the results q. Confirmatory testing should be performed

Factors May affect ARR

Confirmatory test for Primary Aldosteronism

CT • Initial study to determine subtype (adenoma versus hyperplasia) and exclude adrenal carcinoma • The diagnosis of an adrenal carcinoma should be suspected when a unilateral large (>4 cm) adrenal mass is found on CT • An abnormality in both glands suggests adrenal hyperplasia; however, patients with hyperplasia may also have normal appearing adrenal glands on CT

Limitations – Lots of False Positives • Only can image adenoma if > 1 cm • Of these, 1/3 are incidentaloma (no lateralization on adrenal vein sampling) – Lots of False Negatives • Up to 1/3 of adenomas are missed because of small size (lateralize on adrenal vein sampling)

Adrenal vein sampling • It is a Measurement of aldosterone in samples of adrenal venous blood, obtained by an experienced radiologist • is the criterion standard test to distinguish between unilateral adenoma and bilateral hyperplasia. • Unilateral disease is associated with a marked (usually fourfold greater than contralateral adrenal) increase in PAC on the side of the tumor, whereas there is little difference between the two sides in patients with bilateral hyperplasia. • Indications — The Endocrine Society recommends AVS to confirm unilateral disease in all patients with primary aldosteronism who would like to pursue surgical management (unilateral adrenalectomy). • Other centers approach is slightly different, they recommend AVS in such patients when the CT scan is normal, shows bilateral abnormalities, or shows a unilateral abnormality, but the patient is over age 40.

Procedure • Some centers perform AVS with or without cosyntropin stimulation. • Why Cosyntropin? Ø To minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS, which could potentially confound the interpretation of lateralization data. Ø To maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal vein. Ø To maximize the secretion of aldosterone from an APA • Aldosterone and cortisol concentrations are measured in the blood from all three sites (right adrenal vein, left adrenal vein, and IVC). • The complication rate in published studies is 2. 5 percent or less. • The most common complication is groin hematoma; adrenal hemorrhage and adrenal vein dissection are rare.

• Confirming successful catheterization — The cortisol concentrations from the adrenal veins and IVC are used to confirm successful cannulation of both adrenal veins. With cosyntropin infusion, the adrenal vein to IVC cortisol ratio is typically more than 10: 1; a ratio of at least 5: 1 is required to be confident that the adrenal veins were successfully catheterized • Cortisol-corrected ratios — Dividing the right and left adrenal vein plasma aldosterone concentrations (PAC) by their respective cortisol concentrations corrects for the dilutional effect of the inferior phrenic vein flow into the left adrenal vein • • At Mayo Clinic, where AVS is performed with cosyntropin infusion, the mean cortisol-corrected aldosterone ratio (APA-side PAC/cortisol to normal adrenal PAC/cortisol) in patients with confirmed APA is 18: 1 In patients with presumed IHA, the mean cortisol-corrected aldosterone ratio is 1. 8: 1 ; a ratio less than 3: 1 is suggestive of bilateral aldosterone hypersecretion

Cont Limitation • • • The limitations of adrenal CT were illustrated in a study of 203 patients with primary aldosteronism who were evaluated with both CT and AVS CT correctly identified unilateral or bilateral disease in 103 (53. 0%) of 194 patients that had successful AVS CT falsely suggested APA in 48 patient CT finding inaccurately suggested bilateral hyperplasia in 43 patients with unilateral disease When CT and AVS results both suggested unilateral disease, CT indicated the wrong adrenal gland in 12 (21. 2%) of 57 patients AVS inaccurately predicted bilateral disease in 4 patients with APA and in 1 patient with PAH William F. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004

Subtype Evaluation of Primary Aldosteronism

Treatment of primary aldosteronism • GENERAL PRINCIPLES — Establishing the correct subtype diagnosis is essential since the treatment of primary aldosteronism is based upon whether the adrenal aldosterone hypersecretion is unilateral (adenoma, unilateral hyperplasia, or carcinoma) or bilateral (idiopathic adrenal hyperplasia or glucocorticoid-remediable aldosteronism). Ø Surgery is curative only in patients with unilateral disease. Ø Patients with bilateral idiopathic adrenal hyperplasia are treated with a mineralocorticoid antagonist. Ø Patients with glucocorticoid-remediable aldosteronism should receive physiologic doses of a glucocorticoid

Bilateral Adrenal Hyperplasia — There are two forms of primary aldosteronism due to bilateral adrenal zona glomerulosa hyperplasia: Idiopathic adrenal hyperplasia — Ø is generally a milder disease than adrenal adenoma, with less hypersecretion of aldosterone and less hypokalemia. ØSuch patients should be treated with an aldosterone (mineralocorticoid receptor) antagonist. Glucocorticoid-remediable aldosteronism: ØChronic treatment with physiologic doses of a glucocorticoid normalizes blood pressure and corrects hypokalemia

Cont Medical Therapy • MR affinity 20 X > spironolactone • Potency of effect 75% of spironolactone • Binding affinity for androgen and progesterone receptors 1000 -fold lower than spironolactone

Unilateral Adrenal Adenoma or Hyperplasia • Responsible for the hypersecretion of aldosterone in 30 to 60 % of cases of primary aldosteronism , while unilateral hyperplasia is less common (about 3 percent) • Surgery: Preferred therapy Hypertension improved in all and is cured in 35 to 60 % of patients Preferred laparoscopic adrenalectomy over open adrenalectomy Preoperatively, hypertension should be controlled and hypokalemia should be corrected with a mineralocorticoid receptor antagonist (eg, spironolactone or eplerenone). – The blood pressure response to spironolactone preoperatively often predicts the blood pressure response to unilateral adrenalectomy in patients with aldosterone-producing adenoma – –

Failure of Surgical Treatment • Persistent hypertension may be related to Ø underlying essential hypertension and/or Ø the development of nephrosclerosis after a prolonged period of uncontrolled hypertension. Ø It is also possible that an error in subtype assignment has been made and that the patient has bilateral adrenal hyperplasia, a disorder that should be treated medically, not with unilateral adrenalectomy. As many as one-third of patients thought to have a unilateral lesion on imaging studies have bilateral adrenal hyperplasia on adrenal vein sampling

Aldosteronoma Resolution Score (ARS) • • • is a scoring system that has been proposed to help identify patients at low or high likelihood of complete resolution of hypertension after adrenalectomy In a study of 100 patients with primary aldosteronism seen at a single tertiary center, four clinical features provided the best predictive model for complete resolution of hypertension after adrenalectomy and was externally validated using an independent series of 67 patients from another center The likelihood of complete resolution of hypertension for patients with ARS scores of 0 to 1, 2 to 3, and 4 to 5 was 27, 46, and 75 percent, respectively Zarnegar R et Ann Surg. 2008

Medical therapy • Aldosterone antagonists — Although laparoscopic adrenalectomy is more cost-effective over time , the administration of an aldosterone (mineralocorticoid receptor) antagonist is an effective alternative in patients who refuse or are not candidates for surgery. • The efficacy of this approach was illustrated in a study of 24 patients with adenomas who were treated medically for at least five years.

• • OBJECTIVE: To demonstrate the efficacy of medical management of aldosteroneproducing adenomas in terms of blood pressure and serum potassium concentration and to discuss morbidity associated with medical management DESIGN: Retrospective cohort study. PATIENTS: 24 patients with documented aldosterone-producing adenomas who were treated medically for at least 5 years RESULTS: From the time of diagnosis to the time of last follow-up, systolic blood pressure decreased from 175 mm Hg to 129 mm Hg (95% CI for difference, 37. 1 to 53. 8 mm Hg) and diastolic blood pressure decreased from 106 mm Hg to 79 mm Hg (CI for difference, 20. 8 to 33. 9 mm Hg). Serum potassium concentration increased from 3. 0 mmol/L to 4. 3 mmol/L (CI for difference, 1. 1 to 1. 5 mmol/L) Ghose RP et al. Medical management of aldosterone-producing adenomas. Ann Intern Med. 1999