Transcript Screening1

Screening for primary aldosteronism and the use of
the renin aldosterone ratio.
Registrar: C. Pretorius.
Consultant: Dr. W.Grant.
Table of contents.
1.
2.
3.
4.
5.
Introduction.
Pathology.
Evaluation of the RAAS axis.
Conclusion.
References.
1. Introduction.
RAAS system plays an integral role in the controle of:
 Arterial pressure
 Tissue perfusion
 Extracellular volume
Normal Physiology.
2. Pathology.
2.1. Primary aldosteronism (PA).
Group of disorders in which aldosterone production is:
 Inappropriately high
 Relatively autonomous from the renin angiotensin system
 Nonsuppressible by sodium loading
Effects of PA:
 CVS damage
 Suppression of plasma renin
 Hypertension
 Sodium retension
 Potassium excretion (hypokalemia)
Incidence of PA:
 Previously: <1% of patients with ‘essential hypertension’
 RSA:
Community health centres: 7.1%
Academic hypertension clinic: 32%
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; 594–599
Rayner et al. Aldosterone/renin ratio as a screening test for primary aldosteronism. S Afr Med J 2000; 90: 387–394.
Subtypes of PA:
 Aldosterone producing adenomas
 Bilateral idiopathic hyperaldosteronism (bilateral adrenal hyperplasia)
 Familial hyperaldosteronism type I and type II
 Pure aldosterone producing adrenocortical carcinomas
Primary effect of aldosterone:
 Increases the number of open sodium channels in the luminal
membrane of the principal cells in the cortical collecting
tubule, leading to increased sodium reabsorption.
 Lumen is electronegative and the gradient favors the
secretion of cellular potassium into the lumen.
Clinical features:
a) Steady state: Aldosterone escape
- Sodium retension
- Potassium wasting
- Lack of oedema
Mechanisms of escape:
 Pressure natriuresis
 Increased atrial natriuretic peptide
 Decreased thiazide sensitive NaCl cotransporter that mediates
sodium reabsorption
b) Hypertension
 Mild volume expansion
 Increase in systemic vascular resistance: due to persistent
hypervolemia
 Suppression of renin release: low plasma renin activity
 Usually resistant hypertension
 Malignant hypertension is rare
c) Hypokalemia
 Inconsistent finding
 Urinary wasting of potassium
 Causes muscle weakness
 Some patients with PA have normal plasma potassium levels
d) Metabolic acidosis
 Increased urinary hydrogen excretion mediated by hypokalemia
and direct aldosterone effect
e) Mild hypernatremia
 Persistent volume expansion causes resetting of ADH release and
thirst.
f) Hypomagnesemia
 Urinary wasting
g) Other renal effects
 Increased GFR
 Increased urinary albumin excretion
2.2. Secondary aldosteronism.
Causes:
 Renovascular disease
 Diuretic therapy
 Cushing syndrome
 Licorice ingestion
 Congenital adrenal hyperplasia
 Liddle’s syndrome
 Renin secreting tumours
WHY IS THE DIAGNOSIS OF PA SO IMPORTANT?
1. Aldosterone producing adenomas can be surgically treated and cured.
2. PA have a higher CVS morbidity and mortality that age- and sex-matched patients
with essential hypertension and the same degree of blood pressure elevation
- Resistant hypertension
- Direct effects of aldosterone on the miocardium: Fibrosis, necrosis and hypertrophy
- Aldosterone causes endothelial dysfunction
3. Specific treatment is available
Struthers AD: Aldosterone: cardiovascular assault. Am Heart J 2002, 144:S2-7.
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.
.
3. Evaluation of the RAAS axis.
Available tests:
 Plasma renin concentration
 Plasma renin activity (PRA)
 Plasma aldosterone concentration (PAC)
 Urinary aldosterone concentration
ARR
Evaluation of RAAS:
A) Case detection (screening)
B) Confirmatory tests
C) Subtype Classification
A) Case detection: ARR and plasma aldosterone
level.
 ARR: First shown to be a usefull screening test to identify aldosterone
producing adenomas in 1981.
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.
Case detection of PA should be done (Endocrine Society clinical practice
guidelines of 2008):
a) Stage 2/Stage 3 hypertension.
Stage 2: SBP 160–179 mmHg, DBP 100–109 mmHg
Stage 3: SBP more > 180 mmHg, DBP > 110 mmHg
b) 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 (<40 yr).
f) All hypertensive first-degree relatives of patients with PA.
Use of the ARR:
 Use of A/R ratio alone:
Good sensitivity (75-100%) and specificity (75-100%)
Problem: Studies were done on white populations off hypotensive drugs
 Rayner et al: Study in black and coloured populations
Black: 32% of normotensive patients had an A/R ratio > 1000
Coloured: 19% normotensive patients had an A/R ratio > 1000
Reason: 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; 594–599.
In South Africa:
 A/R ratio combined with a plasma aldosterone level
 Rayner 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 – hyperkalemia
 Drugs
False negatives:
 Dietary salt restriction – Elevated p-renin
 Pregnancy – Elevated p-renin
 Malignant hypertension – Elevated p-renin
 Hypokalemic patients – Suppression of p-aldosterone
EFFECTS OF ANTIHYPERTENSIVE DRUGS ON PLASMA RENIN AND
ALDOSTERONE
Drug
Renin
Aldosterone
Effect
Diuretics
Increased
Increased
False negative
β-blockers
Decreased
Minimal
False positive
Dihydropyridine
Increased
Minimal
False negative
Decreased
Minimal
False positive
calcium channel
blocker
α-methyl dopa
Drug.
Renin.
Aldosterone.
Effect.
False positive
Clonidine
Decreased
Minimal
ACE inhibitors
Minimal
Minimal
No effect
Verapamil
Minimal
Minimal
No effect
α-blockers
Nil
Nil
No effect
Hydralazine
Minimal
Minimal
No effect
Angiotensin
receptor
blockers
Not known
Not known
Potential for
false negative
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
(ng/ml/h)
PRA
(pmol/litre/min)
PAC (ng/dl)
20
30
40
1.6
2.5
3.1
PAC (pmol/liter)
750
1000
60
80
B) 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 recommendations
 Clinicians still have to make a clinical judgement with regards to
the specific patient
 If clinically indicated, further investigations should be done, even
if the ARR and aldosterone levels are normal
Measurement of the ARR:
A. Preparation for ARR measurement: agenda
1. 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 blood
1. Collect blood mid-morning, after the patient has been up
(sitting, standing, or walking) for at least 2 h and seated for
5–15 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 results
1. Age: in patients aged >65 yr, renin can be lowered more than
aldosterone by age alone, leading to a raised ARR
2. Time of day, recent diet, posture, and length of time in that
posture
3. Medications
4. Method of blood collection, including any difficulty doing so
5. Level of potassium
6. Level of creatinine (renal failure can lead to false-positive
ARR)
B. Case confirmation of PA.
Testing procedures:
1. Oral sodium loading
2. Saline infusion
3. Fludrocortizone suppression
4. Captopril challenge
Choice of test:
 Cost
 Patient compliance
 Lab routine
 Local expertise
C. Subtype classification.
 Adrenal CT as initial study
 If surgery is an option: Adrenal venous sampling
- Distinguishing between unilateral and bilateral disease is NB
- Unilateral disease: Unilateral adrenalectomy is the treatment
of choice
- Bilateral 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
positive
PA unlikely
Conduct confirmatory testing
negative
positive
Adrenal CT
Adrenal CT
If surgery not desired
If surgery desired
AVS
Treat with MR antagonist
- Spirinolactone
- Eplerone
Bilateral
Unilateral
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):3266–3281.
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):72–78.
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): 38694.
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.
Thank you.