Download Hyperaldosteronism - Joslin Diabetes Center

Aldosterone and Aldosterone
Antagonism
Bijan Roshan, MD, FASN
Instructor in Medicine, Harvard Medical School
Aldosterone and Its Inhibitors
Aldosterone
Spironolactone and
Eplerenone
MR (also affinity for 11-Betahydroxyglucosteroids)
Mineralocorticosteroid Receptor (MR)
• MR is comprised of 784 amino acids and is the longest
member of the oxosteroid receptor subgroup of the
nuclear receptor (NR) superfamily, which includes the
androgen receptor (AR), glucocorticoid receptor (GR),
and progesterone receptors (PR)
• The steroids aldosterone, cortisol, DOC, and 11-OHprogesterone are agonists of MR . Cortisone binds the
MR with very low affinity . Progesterone binds MR with
high affinity but is a poor activator of the receptor.
Cytosolic Receptor Signaling
Surface Receptor Signaling in
Non-Epithelial Cells
•
•
•
•
Function found in VSMC, skeletal muscle cells,
cardiovascular cells, adipose tissue, liver,
pancreas, brain, fibroblast, glomerular cells …
Stimulation by either mineralocorticoid or by
11-Betahydroxysteroids
Promotes inflammation, fibrosis, insulin
resistance, beta-cell dysfunction, oxidative
stress, endothelial dysfunction, …
Activation of p38MAPK and NADPH oxidase
via c-Src . Hypertension.2005;45:773-9.
Pathways and Effects of
Aldosterone Signaling.
Mol Cell Endocrinol. 2009;308(1-2):53-62
Randomized Aldacton Evaluation Study
(RALES) NEJM 1999; 341:709-7
•Randomized controlled double blind study
1663 Patients with CHF and EF<35%
•Blockade of aldosterone receptors by 25 mg daily
spironolactone, in addition to standard therapy
(including ACEI, loop diuretics, ..)
•The primary end point was death from all causes
RALES- Results
• 30 percent reduction in the risk of death among
patients in the spironolactone group was
attributed to a lower risk of both death from
progressive heartfailure and sudden death from
cardiac causes (p<0.001).
• 35 percent lowering risk of hospitalization in the
spironolactone group (p<0.001).
• Spironolactone group had a significant
improvement in the symptoms of heart failure, as
assessed on the basis of the New York Heart
Association functional class (P<0.001)
Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy and
Survival Study (EPHESUS)
NEJM 2003; 348(14):1309-21
• Hospitalized patients with CHF after acute MI
complicated by LV systolic dysfunction, EF<40%)
• Randomized, double-blind, placebo-controlled trial.
• Patients who met the eligibility criteria were randomized
3 to 14 days after AMI to receive 25-50 mg daily
eplerenone (n=3319) or placebo (n=3313) in addition to
standard therapy
• The primary end points were death from any cause and
death from cardiovascular causes or hospitalization for
heart failure, acute myocardial infarction, stroke, or
ventricular arrhythmia.
EPHESUS- Results 1
• Decreased all cause mortality (relative risk, 0.83; 95
percent confidence interval, 0.72 to 0.94; P=0.005).
• The rate of the other primary end point, death from
cardiovascular causes or hospitalization for
cardiovascular events, was reduced by eplerenone
(relative risk, 0.87; 95 percent confidence interval, 0.79
to 0.95; P=0.002), as was
• The secondary end point of death from any cause or any
hospitalization (relative risk, 0.92; 95 percent confidence
interval, 0.86 to 0.98; P=0.02). There was also a
reduction in the rate of sudden death from cardiac
causes (relative risk, 0.79; 95 percent confidence
interval, 0.64 to 0.97; P=0.03).
EPHESUS- Potassium Results
Circulation. 2008 ;118(16):1643-50
.
• 4.4% absolute increase in the incidence of K+
>5.5 mEq/L, a 1.6% increase of K+ 6.0 mEq/L.
• When all-cause mortality rates were evaluated
by quartiles of K+ changes, no indication was
found that serum K+ changes in the first 30 days
had any significant effect on all-cause mortality
• Patients were excluded if baseline K+ was >5.0
mEq/L or serum creatinine was >2.5 mg/dL
Aldoserone and HTN
• Retention of Salt and Water
• Reduced Endothelial Mediated Relaxation
(Am.J Physiol. 1992; 263:974-9)
• Increasing Pro-Infalmatory Adipokines
• Potentiate the effect of Angiotensin II
Adippose Factors Involved in
Obesity-related HTN
■ Aldosterone
■ Endothelin
■ Nonesterified fatty acids and other FFA
■ Interleukin 6
■ Leptin
■ Renin
■ Tumor necrosis factor
Obesity/Metabolic stimulation of
Aldosterone
• Secretion of Angiotensinogen and AT II by Visceral
Adipose Tissue
• Increased Renin Activity
• Aldosterone secretion increased by Non-esterified
FFAs
• Hyperinsulinemia
• Increased CNS sympathetic activity
• Production of a mineralocorticoid releasing factor by
adipose tissue .Acad Sci USA, 2003;100:14211-16 .
Complement C1q TNF –related protein 1 (CTRP1)?
FASEB J.2008;22:1502-11
• Increased cortisol and bounding to 11 -Beta
hydroxysteroid receptor in non-renal tubular cells
BMI Predicts Aldosterone Production in
Normotensive Adults in High Salt Diet. J Clin
Endocrinol Metab.2007; 92:4472-4475
• Urinary aldosterone secretion and No change in
basal serum aldosterone, serum K, supine PRA,
or 24 hour urine cortisol
• AngII-stimuated serum aldosterone are
increased in overweight (BMI >25, n=57),
compared with lean (BMI<25, n=63)
normotensive adults
BMI Predicts Plasma Aldosteron
Concentrations in overweight-Obese
primary HTN Patients.
J.Clin Endocrinol Metab.2008;93:2566-71
• PAPY study patient population used.
• BMI correlated with plasma aldosterone
concentration independent of age, sex,
sodium intake in primary HTN, but not in
primary aldosteronism patients
• No significant impact of BMI on Aldo/PRA
ratio in primary HTN patients
Aldosterone and Diabetes Mellitus
• Co-association with high BMI
• Increased adipokines causing reduced insulin receptor
expression and glucose uptake (Endocr
Res.2004:30:865-70)
• Reduced adiponectin
• Reduced insulin signaling via downregulation of insulin
receptor substrate-1 (Hpertension.2007;50:750-5)
• Increased hepatic gluconeogenesis.
• Decreased secretion of Insulin (hypokalemia dependent and independent)
• Beta-cell fibrosis
• Hyperinsulinemia increasing aldosterone
secretion
The protocol for the recruitment and investigation
of the PAPY (PA Prevalence in Hypertensives) study
population
Rossi, G. P. et al. J Am Coll Cardiol 2006;48:2293-2300
Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.
PAPY (PA Prevalence in
Hypertensives) study
• Newly diagnosed hypertensive patients
referred to hypertension centers in Italy
• Overall prevalence of Primary
Aldosteronism (PA) was 11.2%
• The prevalence of APA (adenoma causing
PA) was 4.8%
A substantial proportion of the patients with APA
and IHA did have hypokalemia (red bars) at the time
of presentation
Rossi, G. P. et al. J Am Coll Cardiol 2006;48:2293-2300
Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.
Prevalence of Primary Aldosteronism
(PA) in resistant HTN. Lancet.2008 13;371:1921-6
• 1616 patients with resistant HTN,
retrospective observational single center
study in Greece
• 338 patients (20.9%) had positive ARR
• 182 patients (11.3%) confirmed to have
PA based on Saline Intravenous and
fludrocortisone suppression test
• Conclusion: notion of an epidemic of
primary aldosteronism is not supported
Selective Aldosterone Blockade with
Eplerenone reduces albuminuria in patients with
type 2 DM. Clin JASN. 2006 Sep;1(5):940-51
Epstein, M. et al. Clin J Am Soc Nephrol 2006;1:940-951
Copyright ©2006 American Society of Nephrology
Percentage change in UACR over
time
Addition of ARB or Mineralocorticoid
Antagonism to Maximal ACE Inhibition in
Diabetic Nephropathy.
JASN 2009 Dec;20(12):2641-50
• Double-blind, placebo-controlled trial in 81 patients with
DM, HTN, and macroalbuminuria receiving lisinopril 80
mg once daily.
• Patients randomly assigned to placebo, losartan (100 mg
daily), or spironolactone (25 mg daily) for 48 wk
• Compared with placebo, the urine albumin-to-creatinine
ratio decreased by 34.0% in the group assigned to
spironolactone and by 16.8% in the group assigned to
losartan (both significant)
• Serum potassium level was significantly higher with the
addition of either spironolactone or losartan
Fasting Plasma Glucose and Serum
Lipids in patients with PA.
Hypertension.2009;53:605-610
• Controlled cross sectional study of 460
patients with PA (103 lateralized, 150
naturalized) and 1363 controls with
essential HTN matched for age and sex
• No significant difference in prevalence of
impaired fasting glucose or overt DM
between groups.
• No significant difference in lipids (TG,
total Cholesterol HDL, LDL)
Fasting Plasma Glucose and Serum
Lipids in patients with PA.
Hypertension.2009;53:605-610
• 61 patients with lateralized PA underwent
adrenalectomy. Comparison of
preoperative and postoperative results
showed:
• No significant difference for values of
FPG, total cholesterol, LDL, HDL. TG was
higher postoperatively (P<0.040) .
• Potassium increased postoperatively
(p<0.001)
Young W F. Endocrinology 2003;144:2208-2213
Confirming PA after high PAC/PRA
• Not needed in patients with spontaneous
hypokalemia, PAC >30 ng/dl AND undetectable
PRA.
Otherwise suppression tests:
• Saline Suppression Test
• Sodium loading and urine aldosterone
measurements (>12 mcg/24 hr is positive)
• Captopril and Fludrocortisone suppression tests
Types of primary aldosteronism (PA)
• Aldosterone-producing adenoma (APA)
• Primary (unilateral) adrenal hyperplasia
• Aldosterone-producing adrenocortical
carcinoma
• Bilateral idiopathic hyperplasia (IHA)
• Familial hyperaldosteronism (FH)
• Glucocorticoid-remediable aldosteronism
(FH type I) FH type II (APA or IHA)
Subtype evaluation of primary aldosteronism.
Young W F. Endocrinology 2003;144:2208-2213