Screening for primary aldosteronism and the use of the renin aldosterone ratio.

Registrar: C. Pretorius.Consultant: Dr. W.Grant.Screening for primary aldosteronism and the use of the renin aldosterone ratio.Table of contents.Introduction.Pathology.Evaluation of the RAAS axis.Conclusion.References.1. Introduction.RAAS system plays an integral role in the controle of:

Arterial pressureTissue perfusionExtracellular volumeNormal Physiology.

2. Pathology.2.1. Primary aldosteronism (PA).Group of disorders in which aldosterone production is:Inappropriately highRelatively autonomous from the renin angiotensin systemNonsuppressible by sodium loading

Effects of PA:CVS damageSuppression of plasma reninHypertensionSodium retensionPotassium excretion (hypokalemia)

Incidence of PA:

Previously: 180 mmHg, DBP > 110 mmHgb) Resistant hypertension, defined as SBP > 140 and DBP > 90 despite treatment with three hypertensive medications.c) Hypertension with adrenal incidentaloma, defined as an adrenal mass detected incidentally during imaging performed for extraadrenal reasons.d) Hypertension and spontaneous or diuretic-induced hypokalemia.e) Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age ( 1000Coloured: 19% normotensive patients had an A/R ratio > 1000Reason: Inherently low renin levels in these populations

Rayner et al. Screening for primary aldosteronism:normal ranges for aldosterone and renin in three South African population groups. S Afr Med J 2001; 91; 594599.

In South Africa:A/R ratio combined with a plasma aldosterone levelRayner et al. study: No normotensive patient had:A/R ratio > 1000 AND plasma aldosterone level > 750 pmol/l

Young from the Mayo clinic:- A/R ratio > 555 and/or aldosterone > 416 pmol/l should prompt investigation.Clinical pitfalls:False positives:Renal impairment: Decreased PRA sodium retension Elevated p-aldosterone hyperkalemiaDrugs

False negatives:Dietary salt restriction Elevated p-reninPregnancy Elevated p-reninMalignant hypertension Elevated p-reninHypokalemic patients Suppression of p-aldosterone

EFFECTS OF ANTIHYPERTENSIVE DRUGS ON PLASMA RENIN AND ALDOSTERONE Drug Renin Aldosterone Effect Diuretics Increased Increased False negative -blockers Decreased Minimal False positive Dihydropyridine Increased Minimal False negative calcium channel blocker -methyl dopa Decreased Minimal False positive

Drug. Renin. Aldosterone. Effect.

Clonidine Decreased Minimal False positive ACE inhibitors Minimal Minimal No effect

Verapamil Minimal Minimal No effect -blockers Nil Nil No effect Hydralazine Minimal Minimal No effect Angiotensin Not known Not known Potential for receptor false negative blockers but probably similar to ACE inhibitor

Drugs can affect the screening of patients with PA

Gallay et al. showed in a prospective study that patients with PA will still be identified in screening, using the ARR, despite hypertensive treatment.

Rayner et al. also showed that the ARR and p-adosterone can still be used even if the patient is using antihypertensive treatment.

Gallay, BJ, Ahmad, S, Xu, L, et al. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis 2001; 37:699.

A) ARR cutoff values, depending on assay and based on whether PAC, PRA, and DRC are measured in conventional or SI units. (Endocrine Society Clinical Practice Guideline 2008) PRA PRA (ng/ml/h) (pmol/litre/min) PAC (ng/dl) 20 1.6 30 2.5 40 3.1 PAC (pmol/liter) 750 60 1000 80B) ARR cutoff values used by Rayner et al. in a South African setting.ARR > 900 AND Aldosterone > 500 : Probable primary aldosteronism.ARR < 900 OR Aldosterone < 500: Unlikely to be primary aldosteronism.

BUT:Variability of assays between laboratories makes it difficult to provide firm recommendationsClinicians still have to make a clinical judgement with regards to the specific patientIf clinically indicated, further investigations should be done, even if the ARR and aldosterone levels are normalMeasurement of the ARR:

A. Preparation for ARR measurement: agenda1. Attempt to correct hypokalemia, after measuring plasma potassium in blood collected slowly with a syringe and needle (preferably not a Vacutainer to minimize the risk of spuriously raising potassium); avoid fist clenching during collection; wait at least 5 sec after tourniquet release (if used to achieve insertion of needle) and ensure separation of plasma from cells within 30 min of collection.2. Encourage patient to liberalize (rather than restrict) sodium intake.3. Withdraw agents that markedly affect the ARR (48) for at least 4 wk: a. Spironolactone, eplerenone, amiloride, and triamterene b. Potassium-wasting diuretics c. Products derived from licorice root (e.g. confectionary licorice, chewing tobacco)

4. If the results of ARR off the above agents are not diagnostic, and if hypertension can be controlled with relatively non interfering medications, withdraw other medications that may affect the ARR for at least 2 weeks.5. If necessary to maintain hypertension control, commence other antihypertensive medications that have lesser effects on the ARR.6. Establish OC and HRT status, because estrogen-containing medications may lower DRC and cause false-positive ARR when DRC (rather than PRA) is measured. Do not withdraw OC unless confident of alternative effective contraception.

B. Conditions for collection of blood1. Collect blood mid-morning, after the patient has been up (sitting, standing, or walking) for at least 2 h and seated for 515 min.2. Collect blood carefully, avoiding stasis and hemolysis.3. Maintain sample at room temperature (and not on ice, because this will promote conversion of inactive to active renin) during delivery to laboratory and before centrifugation and rapid freezing of plasma component pending assay.

C. Factors to take into account when interpreting results1. Age: in patients aged >65 yr, renin can be lowered more than aldosterone by age alone, leading to a raised ARR2. Time of day, recent diet, posture, and length of time in that posture3. Medications4. Method of blood collection, including any difficulty doing so5. Level of potassium6. Level of creatinine (renal failure can lead to false-positive ARR)B. Case confirmation of PA.Testing procedures:Oral sodium loadingSaline infusionFludrocortizone suppressionCaptopril challenge

Choice of test:CostPatient complianceLab routineLocal expertiseC. Subtype classification.Adrenal CT as initial study

If surgery is an option: Adrenal venous samplingDistinguishing between unilateral and bilateral disease is NBUnilateral disease: Unilateral adrenalectomy is the treatment of choiceBilateral disease: Medical treatment is the treatment of choice

Summary of the approach to the patient with possible PA.Patients with hypertension that are at increased risk for PA positive PA unlikely Use ARR to detect cases (Screening) negative positivePA unlikely Conduct confirmatory testing negative positive Adrenal CT

Adrenal CT

If surgery not desired If surgery desired AVS Treat with MR antagonist Bilateral Unilateral - Spirinolactone - Eplerone Treat with laparoscopic adrenolectomy

4. Conclusion.The widespread application of the A/R ratio and plasma aldosterone to screen for PA allows identification of patients with a potential surgical cure and the appropriate medical treatment of their hypertension. The accurate detection of these patients requires understanding of the limitations of the ratio. Patients with a positive test require confirmation of the diagnosis, but in certain circumstances a practical approach may be adopted with a trial of spironolactone therapy.Clinicians should still depend on clinical judgement and not only on laboratory results.Suggested guidelines should be used in the treatment of patients with possible PA.

5. References.1. Hiramatsu et al. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients. Arch Intern Med. 1981 Nov;141(12):1589-93.2. John W. Funder et al. Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab, September 2008, 93(9):32663281.3. Sau-Cheung Tiu et al. The Use of Aldosterone-Renin Ratio as a Diagnostic Test for Primary Hyperaldosteronism and Its Test Characteristics under Different Conditions of Blood Sampling, J Clin Endocrinol Metab, January 2005, 90(1):7278.4. Rayner BL, Screening and diagnosis of primary aldosteronism. Cardiovascular Journal South Africa, July-August 2002, 13(4): 166-70.5.Young WF. Primary aldosteronism: renaissance of a syndrome. Clinical Endocrinology, May 2007, 66(5): 607-18.6. Rayner et al. The aldosterone/renin ratio as a screening test for primary aldosteronism, SAMJ, April 2000; 90(4): 394-400.

7. Shwartz GL, Turner ST, Screening for primary aldosteronism in essential hypertension: diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity, Clinical Chemistry, February 2005; 51(2): 386-94.8. Steven A. Atlas, The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition, JMCP; October 2007: Vol. 13, No. 8, S-b.

9.Rossi, GP, Bernini, G, Caliumi, C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48:2293.10.Gallay, BJ, Ahmad, S, Xu, L, et al. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis 2001; 37:699.11. Montori, VM, Schwartz, GL, Chapman, AB, et al. Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. Mayo Clin Proc 2001; 76:877.

12. Struthers AD:Aldosterone: cardiovascular assault. Am Heart J 2002, 144:S2-7.

13. Brilla CG, Matsubara LS, Weber KT: Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 1993, 25:563-575.

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