Giornate Nefrologiche Pisane 2009 Bianchi uso antialdosteronici

Gli Anti-Aldostenonici in
Nefrologia:
istruzioni per l’uso
Stefano Bianchi
Unita’ Operativa Nefrologia
Ospedale San Donato, Arezzo
stefano.bianchi@usl8.toscana.it

Angiotensinogen
Angiotensin I
Angiotensin II
ACE
Renin
Bradykinin
Inactive
peptides
Nonrenin
Non-ACE
Vaso-
constriction
Aldosterone secretion
Sodium and fluid
retention
AT1 receptor
Cell
growth
Sympathetic
activation
Renin-Angiotensin-Aldosterone System
Renin inhibitors
ARBs
Aldosterone
Antagonists

Primary aldosteronism, a new
clinical syndrome
Jerome W Conn
J Lab Clin Med 1955; 45:3-17
Konstitution des aldosterons, des
neuen mineralocorticoids
Simpson SA, Tait JF, Wettstein A,
Neher R, vonEuw J, Schindler O,
Reichstein T
Experientia 1954; 10:132-3
Jerome W Conn
1907-1981

Aldosterone
MR
Epithelial Cells
(Kidney, Colon,
Salivary glands etc)
“Slow”
(hours)
> Sodium and water
reabsorption
> Potassium excretion
> Intravascular volume
> Blood pressure

Aldosterone
MR
Fibroblasts,
Myocytes
Endothelial Cells
etc
Epithelial Cells
(Kidney, Colon,
“Slow”
(hours)
MR
“Slow”
(hours)
Enhanced cardiac
remodelling
LV hypertrophy
LV dysfunction
Heart failure
↑Endothelial dysfunction
↑PAI – 1
↑Vascular inflammation
↑Oxidative stress
↑Endothelin and Angio II receptors
↑Proliferation of myocytes and
fibroblasts
↑Perivascular and interstitial fibrosis
> Sodium and water
reabsorption
> Blood pressure

Aldosterone induces a vascular inflammatory
phenotype in the rat heart
Rocha R et al. Am J Physiol Heart Circ Physiol, 2002
A) Coronary and myocardial lesions
induced by 4 wk of aldosterone/ salt
treatment
B) Vascular inflammatory lesions and
fibrinoid necrosis of small coronary
arteries (arrows) accompanied by a severe
perivascular inflammatory response
C) Coronary lesion in the heart of a rat that
received aldosterone/salt treatment for 4
wk. The majority of cells infiltrating
the lesions were identified as macrophages.
D) Myocardium of an animal receiving
aldosterone/salt treatment for 4 wk, in the
presence of the selective aldosterone blocker
eplerenone, showing no lesions.

Immunohistochemistry
Representative photomicrographs of
sections from uninephrectomized,
saline-drinking rats receiving either
vehicle, aldosterone infusion, or
aldosterone infusion plus eplerenone
for 4 wk. Sections were
immunostained with specific
antibodies against each molecule
ED1: monocyte/macrophage
CD3: T cell
OPN: osteopontin
VCAM-1: vascular cell adhesion
molecule-1
ICAM-1: intracellular adhesion
molecule-1
Aldosterone induces a vascular inflammatory
phenotype in the rat heart
Rocha R et al. Am J Physiol Heart Circ Physiol, 2002

Aldosterone blockade:
Trials in HF and post-MI-LV dysfunction
Pitt B et al. N Eng J Med. 1999
Pitt B et al. N Eng J Med. 2003
RALES
0.75
0.60
1.00
0
Placebo
Spironolactone
Months
Probability
of survival
24 366
30% Risk reduction
RR 0.70 (0.60–0.82)
P < 0.001
30
0.00
12 18
0.90
0.45
22
10
2
6 24 300
Eplerenone
Months
18
14
6
3612
EPHESUS
15% Risk reduction
RR 0.85 (0.75–0.96)
P = 0.008
Cumulative
Incidence of CV
events(%)
Placebo
0
18

Aldosterone
MR
Fibroblasts,
Myocytes
Endothelial Cells
etc
Epithelial Cells
(Kidney, Colon,
“Slow”
(hours)
MR MMR
Epithelial and
non-Epithelial Cells
Increased systemic resistance
and heart rate
Vasoconstriction of pre-
glomerular afferent and (mostly)
post-glomerular efferent arterioles
Increased endothelial cell volume
Others…..
“Slow”
(hours)
“Fast”
(minutes)
↑Endothelial dysfunction
↑PAI – 1
↑Vascular inflammation
↑Oxidative stress
↑Proliferation of myocytes and
fibroblasts
> Sodium and water
reabsorption
> Blood pressure

Non genomic actions of aldosterone
MMR
Epithelial and
non-Epithelial cells
Increased systemic resistance
and heart rate
Vasoconstriction of pre-glomerular
afferent and (mostly) post-
glomerular efferent arterioles
Increased endothelial cell volume
Others
“Fast”
(seconds-minutes)
M
M
R
Aldosterone
Intracellular signals
cAMP
DAG
IP3 etc
>Ca++
MAK phosphorylation
Spiro and Eple do not block
Aldosterone

Aldosterone-induced Vasoconstriction in Afferent
and Efferent Arterioles of Rabbits
Arima S et al. J Am Soc Nephrol, 2003

Jerome W Conn
1907-1981
Clinical Characteristics of Primary
Aldosteronism from an Analysis of 145 Cases
Jerome W Conn, M.D., Ralph F Knopf, M.D. and Reed M Nesbit, M.D.
Ann Arbor, Michigan
Ann J Surg 1964:107:159-72
Table VII
RENAL STUDIES IN 113 CASES OF PRIMARY
ALDOSTERONISM
Renal Function Normal Impaired
Proteinuria
•Absent 12 …
•Present … 69
Concentrating ability 16 69
Pitressin response 9 33
PSP excretion 12 6
Other indices of renal
function: BUN, Cl urea,
Cl creat, Cl inul, Cl pah 46 27
→85%
→36%

Nephrologists overlooked the role of
aldosterone in chronic kidney disease (?)
1. Chronic renal disease is characterized by
high aldosterone levels

0,5
1
1,5
2
2,5
3
3,5
4
0 50 100 150 200 250 300
Basal aldosterone
pg/ml
Basalproteinuria
g/gcreatinine
Regression line between plasma aldosterone levels and
proteinuria in 165 subjects with chronic kidney disease
Bianchi S et al. Kidney Int, 2006

0
50
100
150
200
250
300BasalAldosteronepg/ml
30 40 50 60 70 80 90 100 110 120
Basal GFR, mL/min
Relationship between plasma aldosterone and GFR levels
in 165 subjects with chronic kidney disease
R=.482 p<.0001

2. Many of the deleterious effects of AII are
mediated by aldosterone

2. Many of the deleterious effects of AII are
mediated by aldosterone
3. “Aldosterone escape” is common in the majority
of patients treated with drugs inhibiting the RAAS

Plasma ACE
(nmol/mL/min)
Plasma
Aldosterone
(ng/dl)
100-
80-
60-
40-
20-
0
0 4hr 24hr 1 2 3 4 5 6
* * * * * * * *
Hospital Months
100-
80-
60-
40-
20-
0
*
Aldosterone is Not Adequately Suppressed
by ACE inhibitors
Biollaz J et al.
J Cardiovasc Pharmacol, 1982
Enalapril 20 mg bid
p<.001
p<.01

60
40
20
0
-20
-40
Change in
Aldosterone
from
baseline
(%)
17 weeks 43 weeks
Candesartan 4 mg
Candesartan 8 mg
Candesartan 16 mg
Candesartan 4 mg
+Enalapril 20 mg
Candesartan 8 mg
+Enalapril 20 mg
Enalapril 20 mg
RESOLVD Investigators ACC, 1998
Aldosterone “Escape” Despite Ace inhibition
and Angiotensin II Blockade

Aldosterone-induced Renal Injury
Progression of renal diseaseProgression of renal disease
Systemic hypertensionSystemic hypertension
MR
Fibroblasts,
Myocytes
Endothelial cells
Kidney
↑Endothelial dysfunction ↑PAI – 1
↑Vascular inflammation ↑Oxidative stress,
Podocyte dysfunction ↑Endothelin and
Angio II receptors. Mesangial
proliferation, interstitialinflamation, and
renal fibrosis
MR
Epithelial Cells
(Kidney, Colon,
SodiumSodium
retentionretention
PotassiumPotassium
lossloss
Electrolyte transportElectrolyte transport
Aldosterone Aldosterone

8 weeks after
5/6 nephrectomy
(biopsy)
After 4 weeks of
treatment
(autopsy)
CONTROLS
progression
SPIRO
regression
SPIRO+AT1RA
regression
Regression of Existing Glomerulosclerosis by Inhibition
of Aldosterone
Jean Claude Aldigier, Talerngsak Kanjanbuch, Li-Jun Ma, Nancy J. Brown, and Agnes B. Fogo
Departments of Pathology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

The Janus Effect: Two Faces of aldosterone
Physiological effects (acute):
Maintenance of body fluid
Composition
Sodium reabsorption
Potassium secretion
Hydrogen ion secretion
Pathophysiological effects
(chronic):
Hypokalemic alkalosis
Hypertension
Inflammation
Fibrosis

The Renin-Angiotensin-Aldosterone System (RAAS)
Progression of renal and cardiovascular disease
Angiotensinogen
Angiotensin I
Angiotensin II
Aldosterone
Inflammation and
interstitial fibrosis
Cardiac Hypertrophy
Endothelial dysfunction
Inflammation
Glomerular sclerosis
Tubular damage
HR variability ↓
Baroreceptor sensitivity ↓
> Sodium and water
reabsorption
> Blood pressure

Aldosterone Antagonists and
Chronic Kidney Disease
• Proteinuria
• Renal function
• Potential side effects

Do aldosterone antagonists reduce
proteinuria?

0,5
1
1,5
2
2,5
3
3,5
4
0 50 100 150 200 250 300
Basal aldosterone
(pg/ml)
Basalproteinuria
(g/gcreatinine)
Regression line between baseline plasma aldosterone levels
and proteinuria in 165 subjects with chronic kidney disease
r=0.766
P<0.0001
Long-Term Effects of Spironolactone on Proteinuria and
Kidney Function in Patients with Chronic Kidney Disease

Spironolactone in Chronic Renal Disease
Background
therapy
NS50%ACEis and/or
ARBs
8Non-DN (n=32)Bianchi S. et al
(2005)
Bianchi S. et al
(2006)
NS38%ACEis12DN and non-DN (n=32)Sato A. et al
(2005)
NS42%ACEis12Dn and Non-DN
(n=22)
Chrysostomou A
(2006)
NS25%ACEis24T2 DM with micro- or
macro-albuminuria
(n=15)
Sato A. et al
(2003)
NS54%ACEis4DN and Non-DN (n=8)Chrysostomou A.
et al. (2001)
Reduction of
BP (mm Hg)
Reduction of
Proteinuria
Duration
(weeks)
Study PopulationAuthor (year)
Spironolactone 25 mg added on top of previous antiproteinuric treatment
DN=Diabetic Nephropathy; Non-DN=Non Diabetic Nephropathy
Non DM (n=83) 52 Aceis and/or 54% 6/3
ARBs

Spironolactone Reduces Proteinuria in Patients
with non Diabetic Chronic Kidney Disease
1.32
1.15 1.05
1.57
2.09
0
0.5
1
1.5
2
2.5
Basal 2 wks 4 wks 8 wks 12 wks
Optimal Care + Spiro
Optimal Care
STOP SPIRO
*
* *
** δ
* p <.001 vs 8 wks
** p<.0001 vs basal
δ p< .05 vs basal
Bianchi S et al. Am J Kidney Dis, 2005
Urinaryproteinexcretion
gr/24hours

5 -
4 -
3 -
2 -
1 -
0 -
Basal 2 wks 4 wks 8 wks 12 wks
Proteinuria,gr/24hrs
Spironolactone Reduces Proteinuria in Patients
with Chronic Kidney Disease
Stop spiro

Effect of Spironolactone on Proteinuria
0
0.5
1
1.5
2
2.5
Basal 1 3 6 9 12 Months
Conventional
therapy
Conventional
therapy plus
Spironolactone
*p<0.001 vs. CT
**p<0.01 vs. CT
**
*
*
* *
Proteinuria gr/gr creat

• Proteinuria
• Renal function

Effect of spironolactone on GFR in patients
with chronic kidney disease
*p<0.01
2,4,8 weeks of treatment with Spiro
Post: 4 weeks after discontinuation of Spiro
ReductionofGFR
vsbasalvalues(%)
2-
4-
6-
8-
2wks 4wks 8wks Post
-4.6%
-6%
-6.2%
-1.8%
*
*
*

*
*
*
* * *
*
**
Conventional therapy
Conventional therapy +Spironolactone
*p<0.001 vs basal GFR
**p<0.0001 vs basal GFR
%reductionofGFR
vsbasalvalues
Long-Term Effects of Spironolactone on GFR
in Patients with Chronic Kidney Disease
-2
-4
-6
-8
-10
-12
1 3 6 9 12
Months

Monthly rate of decrease in GFR in patients with
CKD treated with spironolactone and in controls
Spironolactone -0.323±0.044 ml/min
Controls -0.474±0.037 ml/min*
* p<0.01

• Proteinuria
• Renal function
- Endocrine disorders
- Hyperkalemia

<000160Gynecomastia in men
Endocrine disorders
ns4*2*Hyperkalemia
(K+>6 mEq/L)
p
Conventional
Therapy + Spiro
(n=83)
Conventional
therapy
(n=82)
Long-term effects of spironolactone on proteinuria and
kidney function in patients with chronic kidney disease
(Adverse effects)
*All patients developing hyperkalemia had eGFR<60 ml/min
5 out of 6 patients did not discontinue the study

Rates of Hyperkalemia
and Death After
Publication of RALES
500% ↑ in spironolactone Rx
(p<0.001)
275% ↑ in hosp for
Hyperkalemia (p<0.001)
285% ↑ in death due to
Hyperkalemia (p<0.001)
Juurlink, et al. NEJM 2004

Aldosterone Blockade:
limiting hypekalemia
(Relative) contraindications
eGFR<30 mL/min
Serum potassium >5 mEq/L
Potassium monitoring
Before starting therapy then 1 week, 1 month, and every
3 months
If serum potassium >6 mEq/L without a precipitating
factor,(e.g., NSAID) discontinue aldosterone blockade

Reducing the Risk of Hyperkalemia
During Aldosterone Blockade
Withdraw potassium supplements and discontinue other meds
that interfere in K+ excretion
Low K+ diet (<70 mEq/d)
Use low doses – spironolactone 25 mg /eplerenone 50 mg and start
diuretic therapy when K>5 mEq/L
Monitor potassium regularly
Pause (or decrease) RAAS blocking agents during dehydration
Particular caution when GFR is severely reduced

• Dual ( or triple) block is like driving
a Ferrari: exciting, powerfull, but
risky. If you do not know how to do
it, you could soon find yourself in
deep trouble

RAAS not RAS
(aldosterone is included in the system)
Do not forget!

Summary (1)
• Aldosterone plays a significant role in the
pathogenesis of renal disease
• Initial studies designed to evaluate the efficacy
of aldosterone blockade in animals and
humans are encouraging

Summary (2)
• Because of the potential serious toxicity, and
lack of more definitive studies, at present these
agents should not be used routinely as a means
of treating people with CKD or ESRD
• Clinical studies are warranted to address more
definitively the safety and the efficacy of
aldosterone antagonism in CKD and ESRD

Antiproteinuric Effects of Mineralocorticoid Receptor
Blockade in Patients With Chronic Renal Disease
Sato A et al. AJH, 2005
Spiro 25 mg/day
Thirty-two outpatients with
diabetic (17 patients) and
non diabetic (15 patients)
renal disease with persistent
proteinuria (> 0.5 g/d), after
medical treatment for 10 to
14 months, including an
ACE inhibitor (trandolapril)
were treated with Spiro for
12 weeks
BP during spiro treatment did not significantly
change when compared with the basal values

160-
120-
90-
60-
30-
0
*
Conventional
Therapy
2
1.5
1
0.5
0
δ
Conventional
Therapy
* p<.001 δ p<.01
PAS/PAD
(mmHg)
Albuminuria
(mg/24h)
20 type 2 diabetic pts
Age (yrs) 58±10
Duration diabetes (yrs) 12±6
BMI (kg/m2
) 35±7
A1C (%) 7.9
UAE (mg/24/h) >300
GFR (ml/min/1.73 m2)
>30
RAAS blocking agents
ACE inhibitors 4/20
ARBs 11/21
Both ACEis and ARBs 5/20
Diuretics 16/20
Dihydropyridines 16/20
Β-Blockers 13/20
Statins 18/20
Low-dose aspirin 20/20
Beneficial Effects of Adding Spironolactone to Raccomended
Antihypertensive Treatment in Diabetic Nephropathy
Rossing P et al. Diabetes Care, 2005
Conventional
Therapy
+ Spiro 25 mg/day
Conventional
Therapy
+ Spiro 25 mg/day
*

0
-5
-10
-15
-20
-25
0 3 6 9 12
Months
ChangeineGFR
(mL/min/1.73m2)
*
*
*
*
P<.0001
Placebo
Spiro
Effect of Spironolactone in type II
Diabetic Nephropathy
van den Meiracker et al. J Hyperten, 2006

Effect of aldosterone in different tissue
Extra adrenal glands sites of
aldosterone’synthesis

0
100
200
300
400
500
600
700
800
900
Normal Adrenalectomy
0
5
10
15
20
25
0
5
10
15
20
25
Undetectable
*
*
*
A Plasma Aldosterone Levels
B Renal Interstitial Fluid
C Kidney Tissue
Xue C et al. Hypertension 2005
A B
C
Aldosterone in Normal and Adrenalectomized Rats
pg/ml
pg/mlpg/mgkidneyweight

0
20
40
60
80
100
120
0
50
100
150
200
250
300
350
0
100
200
300
400
500
600
700
800
Xue C et al. Hypertension 2005
Renal Aldosterone Synthesis
(expressed as % total renal CYP11B2mRNA)
Renal Cortex Medulla Normal salt High salt Low salt
┬
*
┬
*
┬
┬
*
**
Control Ang II Ang II+
Valsartan
%totalrenalCYP11B2mRNA)
┬
┬┬
┬

Lumen Interstitial fluid
(blood)
CortisolCortisone 11β-HSD2
Aldosterone
HRE
Gene
Endoplasmic
reticulum
Sgk1
CHIF, KI-ras, PI3K, etc
Na+ Na+
H2O H2O
K+ K+
Na+
K+
ATP
ADP
ENa+channel
α,β,γ subunits
Na+/k+
ATPase
•••
• •
• •
•
•• •
•
• •
Spironolactone
Eplerenone
MR
The classical genomic action of aldosterone
on epithelial cell.
Nedd4-2

CortisolCortisone 11β-HSD2
Aldosterone
HRE
Gene
Endoplasmic
reticulum
Sgk1
CHIF, KI-ras, PI3K, etc
Na+ Na+
H2O H2O
K+ K+
Na+
K+
ATP
ADP
ENa+channel
α,β,γ subunits
Na+/k+
ATPase
•••
• •
• •
•
•• •
•
• •
Spironolactone
Eplerenone
MR
P
P
Nedd4-2
Lumen Interstitial fluid
(blood)
The classical genomic action of aldosterone
on epithelial cell.

Nongenomic Vascular Action of Aldosterone in the
Glomerular Microcirculation
SHUJI ARIMA,* KENTARO KOHAGURA,* HONG-LAN XU,* AKIRA SUGAWARA,*TAKAAKI ABE,*
FUMITOSHI SATOH,* KAZUHISA TAKEUCHI,* and SADAYOSHI ITO*
Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University School of Medicine, Sendai, 980-8574,
Japan
Abstract. Aldosterone (Aldo) accelerates hypertension, proteinuria, and
glomerulosclerosis in animal models of malignant hypertension or chronic renal failure.
Aldo may exert these deleterious renal effects by elevating renal vascular resistanceand
glomerular capillary pressure. To test this possibility, directly examined were the action
of Aldo on the afferent (Af) and efferent (Ef) arterioles (Arts). Examined were the effect
of Aldo added to both the bath and lumen on the intraluminal diameter (measured at
the most responsive point) of rabbits. Aldo caused dose-dependent constriction in both
arterioles with a higher sensitivity in Ef-Arts. Vasoconstrictor action of Aldo was not
affected by a mineralocorticoid receptor antagonist spironolactone and was reproduced
by membrane-impermeable albumin-conjugated Aldo, suggesting that the
vasoconstrictor actions are nongenomic. Pretreatment with neomycin (a specific
inhibitor of phospholipase C) abolished the vasoconstrictor action of Aldo in both
arterioles. In addition, the vasoconstrictor action of Aldo on Af-Arts was inhibited by
both nifedipine and efonidipine, whereas that on Ef-Arts was inhibited by efonidipine
but not nifedipine. The results demonstrate that Aldo causes nongenomic
vasoconstriction by activating phospholipase C with a subsequent calcium mobilization
thorough L- or T-type voltage-dependent calcium channels in Af- or Ef-Arts,
respectively. These vasoconstrictor actions on the glomerular microcirculation may play
an important role in the pathophysiology and progression of renal diseases by elevating
renal vascular resistance and glomerular capillary pressure.
Arima S et al. J Am Soc Nephrol, 2003

MR
Fibroblasts,
Myocytes
Endothelial cells
Kidney
Reduced availability of endothelial NO
Endothelial dysfunction
MR
Epithelial Cells
(Kidney, Colon,
SodiumSodium
retentionretention
PotassiumPotassium
lossloss

MR
Fibroblasts,
Myocytes
Endothelial cells
Kidney
Stimulation of PAI-1 synthesis
MR
Epithelial Cells
(Kidney, Colon,
SodiumSodium
retentionretention
PotassiumPotassium
lossloss

MR
Fibroblasts,
Myocytes
Endothelial cells
Kidney
vascular NADPH oxidase activity and
plasma markers of oxidative stress
MR
Epithelial Cells
(Kidney, Colon,
SodiumSodium
retentionretention
PotassiumPotassium
lossloss

MR
Fibroblasts,
Myocytes
Endothelial cells
Kidney
Renal hemodynamic effect
↑ RVR ↑↑ FF
Glomerular hypertension
MR
Epithelial Cells
(Kidney, Colon,
SodiumSodium
retentionretention
PotassiumPotassium
lossloss

Role of Aldosterone in the Remnant Kidney Model in the Rat
E.L. Greene, S. Kren, and T.H. Hostetter
Department of Medicine, Renal Division, University of Minnesota, Minneapolis,
Minnesota 55455
UPE(mg/24h)
Control REM REM+ REM+AII+
AIIA Aldo
§
*
Green et al. J Clin Invest, 1996
PlasmaAldosterone(pg/ml)
Control REM REM+ REM+AII+
AIIA Aldo
*p<0.01 vs REM **p<0.05 vs REM+AIIA
§p<0.01 vs REM+AIIA
*
160
140
120
100
80
60
40
20
0
600
500
400
300
200
100
0

Podocyte Injury and Proteinuria in aldosterone-
infused rats with partially nephrectomy
Nephrin Staining
Electron microscopy
Ctrl Aldo0
0.2
0.4
0.6
0.8
1
1.2
1.4
Ctrl Aldo
/βactin
Nephrin gene expression
Ctrl
2W
0
100
200
300
400
500
Urinary Protein
Excretion
mg/day
Ctrl
2W
Ctrl
4W
Ctrl
6W
Aldo
2W
Aldo
4W
Aldo
6W
Aldo
2W
Aldo
4W
Aldo
6W
**
**
**
**
** **
Shibata S, Fujita T et al. Hypertension 49;355-464, 2007

600-
400-
200-
0-
тPlasmaAldo(pg/ml)
Control Remnant
REM Control
Systolic BP 185±26 124±18
(mmHg)
UPE 121±54* 11±2
(mg/24h)
Glom.sclerosis 37.2±26.5* 1.9±1.2
(%)
P Aldosterone 526±50* 50±12
(pg/ml)
Adrenal weight 63±4* 51±4
(mg)
*
*p<.0001
Green et al. J Clin Invest, 1996
Role of Aldosterone in the Remnant Kidney Model in the Rat
E.L. Greene, S. Kren, and T.H. Hostetter
Department of Medicine, Renal Division, University of Minnesota, Minneapolis, Minnesota 55455

Regression of Existing Glomerulosclerosis by
Inhibition of Aldosterone
Jean Claude Aldigier, Talerngsak Kanjanbuch, Li-Jun Ma, Nancy J. Brown, and
Agnes B. Fogo
Departments of Pathology and Medicine, Vanderbilt University Medical Center,
Nashville, Tennessee
In this study, the effects of inhibition of aldosterone on regression of existing hypertension-related
glomerulosclerosis were investigated. Adult male Sprague Dawley rats (220 to 250 g) underwent 5/6
nephrectomy (Nx). Severity of glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were
divided into four groups with equal biopsy sclerosis and then randomized by group to 4-wk treatments as
follows: Control with no further treatment (CONT; n 6); spironolactone (SP) alone (200 mg/kg per d, by
gavage, n 6); or SP combined with nonspecific triple antihypertensive drugs (TRX; reserpine,hydralazine,
and hydrochlorothiazide in drinking water; SPTRX, n 7) or with angiotensin type 1 receptor antagonist
(AT1RA; losartan in drinking water; SPAT1RA, n 8). When the rats were killed 12 wk after Nx, autopsy
glomerulosclerosis index (SI; 0 to 4 scale) was compared with biopsy SI in the same rats. Systolic BP was
increased at 8 wk after Nx and continued to increase at 12 wk after Nx in the CONT and SP groups but not in
SPTRX- or SPAT1RA-treated rats. Serum creatinine at 12 wk was significantly decreased in all SP-treated
groups versus CONT. CONT rats had on average a 157% increase in SI from biopsy to killing at 12 wk,
compared with only 84% increase in SP rats, with regression of SI in some rats.
The effects on glomerulosclerosis by SP were further enhanced (when systolic BP was controlled by TRX or
by AT1RA). It is concluded that inhibition of aldosterone by SP not only slows development of
glomerulosclerosis but also induces regression in some rats of existing glomerulosclerosis.
J Am Soc Nephrol 16: 3306–3314, 2005.

1 3 6 9 12
All patients
Patients with GFR<60 mL/min
Patients with GFR>60 mL/min
*
*
*
*
** *
*
*
*
*
* #
*
*
*
* *
*p<0.001 vs. basal proteinuria
#p<0.05 vs. patients with eGFR <60 mL/min
**p< 0.01 vs. patients with eGFR <60 mL/min
%reductionofproteinuria
vsbasalvalues
Long-Term Effects of Spironolactone on Proteinuria and
Kidney Function in Patients with Chronic Kidney Disease
Months of treatment
0-
20-
40-
60-
80-

Five endothelial cells (numbered 1–5)
of bovine aorta imaged at 37°C using
the atomic force microscope.
Image recorded during
aldosterone incubation
(5 min aldosterone)
Image representing the
corresponding subtraction
image (volume difference).
Atomic Force Microscopy on Living Cells: Aldosterone-Induced
Localized Cell Swelling
Kidney Blood Press Res 1998;21:256–258
S.W. Schneidera, P. Pagela, J. Storcka, Y. Yanob, B.E. Sumpioc, J.P. Geibeld, H. Oberleithner

Aldosterone Aldosterone+Amiloride

Incomplete Blockade of Aldosterone
by ACE-Is & ARBs
Angiotensinogen
Ang I
Ang II
Renin
ACEACE-I Chymase
ARB
Aldosterone
Incomplete
Receptor Blockade
[K+], ACTH (acutely)
Adipose tissue factors, NO,
Endothelin, Norepinephrine,
Serotonin., ANP, others)
Non RAAS stimulators
of aldosterone secretion

Aldosterone
MR
Podocytes
In rats treated with aldosterone and
high-salt diet:
- MR is present in cultured podocytes
- Nephrin and podocin, components of the slit
diaphragms are markedly suppressed while desmin
expression, a marker for podocyte injury is
enhanced
- Transmission electron microscopy analysis shows
severe degeneration changes of podocytes and
foot processes retraction
- The infusion of aldosterone antagonists nullified
almost completely the podocyte damage
Non-epithelial Actions of Aldosterone

Type 2 diabetic rats at 52 wk of age
treated with spiro at 20 mg/kg per d
for 8 mo.
Sang-Youb H et al. J Am Soc Nephrol, 2006

Type II diabetics rats at 52 wk of
age
ED-1
MIF
TGF-1
treated with spiro at 20 mg/kg per d for 8 mo
Spironolactone Prevents Diabetic Nephropathy through an
Anti-Inflammatory Mechanism in Type 2 Diabetic Rats
J Am Soc Nephrol, 2006

MR
Fibroblasts,
Myocytes
Endothelial cells
Kidney
MR
Epithelial Cells
(Kidney, Colon,
SodiumSodium
retentionretention
PotassiumPotassium
lossloss
↑Endothelial dysfunction ↑PAI – 1
↑Vascular inflammation ↑Oxidative stress
↑Proliferation of and fibroblasts

Quantitative analysis of nephrin gene expressions in the glomeruli
of control and aldosterone infused rats
Nephrin/β-actin
1.2
1
0.8
0.6
0.4
0.2
0
Ctrl Aldo Aldo Aldo+
2 wks 2wks 4wks Eplerenone
**
**
Modified from: Shibata S et al. Hypertension, 2007
Control rat
Aldosterone-
infused rat
Aldosterone-
infused rat+
Eplerenone
Micrographs of immunostaining for nephrin in the
glomeruli of control, aldosterone-infused animals,
and aldosterone-infused rats receiving eplerenone
P<.0001

Transmission electron micrographs of control and
aldosterone-infused rats at 2 weeks
Control rats show normal structure
of podocytes.
In aldosterone-infused rats, podocytes
exhibit degeneration of the cell body
and retraction of the foot processes.
Shibata S et al. Hypertension. 2007

Giornate Nefrologiche Pisane 2009 Bianchi uso antialdosteronici

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