angiotensin system blockers - Journal of the Renin

532509
research-article2014
JRA0010.1177/1470320314532509Journal of the Renin-Angiotensin-Aldosterone SystemKawada et al.
Original Article
A pilot study of the effects of eplerenone
add-on therapy in patients taking renin–
angiotensin system blockers
Journal of the Renin-AngiotensinAldosterone System
1–6
© The Author(s) 2014
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DOI: 10.1177/1470320314532509
jra.sagepub.com
Noritaka Kawada1, Yoshitaka Isaka2, Harumi Kitamura2, Hiromi
Rakugi2 and Toshiki Moriyama1
Abstract
Hypothesis: This study determined the parameters for predicting the clinical effects of eplerenone (Ep) add-on therapy
on blood pressure (BP) and proteinuria in patients taking angiotensin-converting enzyme inhibitors (ACEis) or angiotensin
II type I receptor blockers (ARBs).
Materials and methods: Patients were treated with a gradual increase of Ep to a final dose of 50 mg/day for 2 months.
In 35 patients, the efficacy of Ep was evaluated by peripheral BP, proteinuria, and the transtubular K gradient (TTKG).
Fifteen patients had additional analysis for central BP, plasma renin activity (PRA) and plasma aldosterone concentration
(PAC), measured in the supine position, and 24-hour urine collection before and after receiving Ep.
Results: Ep add-on therapy reduced the mean arterial pressure (p=0.0005) and central BP (p=0.009) independently
to the baseline PAC. Ep induced PRA, but failed to show effects on PAC, TTKG, or albuminuria. Correlation analysis
showed inverse relationships between the percent reduction in albuminuria and baseline PAC.
Conclusions: Ep add-on therapy in patients taking renin–angiotensin system blockers is expected to reduce BP, even in
patients with low PAC. In contrast, the anti-proteinuric action of Ep is dependent on baseline plasma aldosterone levels.
TTKG is not appropriate for evaluating the efficacy of Ep.
Keywords
Aldosterone, TTKG, CBP, albuminuria, eGFR
Introduction
Angiotensin-converting enzyme inhibitors (ACEis) and
angiotensin II type I receptor antagonists (ARBs) have
been established as the first-line agents for patients with
chronic kidney disease (CKD).1,2 Studies have shown that
these agents reduce proteinuria and preserve the glomerular filtration rate (GFR). Angiotensin II regulates aldosterone production. Therefore, it has been considered that the
blockade of angiotensin II action by ACEis or ARBs may
also blunt aldosterone production. Based on this speculation, and the facts that ACEis or ARBs are more effective
under salt restriction, consideration has been given to calcium (Ca) antagonists and thiazide diuretics as candidates
for second-line agents because these agents possess natriuretic action.3,4 Little attention has been paid to the clinical
effects of an aldosterone receptor antagonist (another
natriuretic agent) add-on in patients who are already
receiving an ACEi or ARB.
ACEi or ARB do reduce plasma aldosterone concentration (PAC) in the short term, but there are patients who
present with re-elevated PAC during the course of ACEi or
ARB treatment.5–7 It has also become apparent that there
are several aldosterone-independent pathways for mineralocorticoid receptor (MR) activation.8–10 These findings
have given impetus to investigating the effects of an antialdosterone agent add-on in patients who are already taking an ACEi or ARB. According to Navaneethan et al.,11
spironolactone, a classical aldosterone blocker, decreases
blood pressure (BP) and has anti-proteinuric effects in patients
with CKD undergoing therapy with renin–angiotensin
system (RAS) inhibitors. However, these investigators
also showed that the anti-proteinuric effects were highly
1Health
Care Center, Osaka University, Japan
of Geriatric Medicine and Nephrology, Osaka University
Graduate School of Medicine, Japan
2Division
Corresponding author:
Yoshitaka Isaka, Department of Geriatric Medicine and Nephrology,
Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita,
Osaka, 565-0871 Japan.
Email: [email protected]
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Journal of the Renin-Angiotensin-Aldosterone System
variable among the patients studied. Eplerenone (Ep) has
also been shown to have anti-proteinuric effects, but a high
prevalence of non-responders were found in the same
study.12 Presently, it is not known what causes the differences between responders and non-responders, but Yoneda
et al. have shown that subjects who developed higher
aldosterone concentration (aldosterone breakthrough)13
are more likely to develop proteinuria. Moranne et al.
found that initial plasma potassium and aldosterone concentrations, as well as higher decreases in sodium intake,
systolic BP (SBP), and estimated GFR (eGFR) from baseline to 1 year were factors that influence plasma aldosterone level.14
The aim of the present study was to determine whether
those parameters mentioned above, including initial
plasma potassium and aldosterone concentration, higher
decreases in sodium intake, SBP, and eGFR from baseline
to 1 year, as well as the transtubular K gradient (TTKG)
(an index of potassium secretion from the collecting ducts),
can predict the clinical effects of Ep add-on therapy on BP
and proteinuria in patients already taking ACEis or ARBs.
Materials and methods
Patients
Enrolled patients met the following inclusion criteria: (1) use
of an ACEi or ARB due to hypertension or CKD; (2) absence
of diabetic nephropathy; (3) eGFR >35 ml/min/1.73 m2;
(4) serum potassium level <4.8 mEq/l; (5) no history of
receiving potassium adsorbent therapy; and (6) provision of
informed consent to participate in the study.
The endpoint of the present study was BP. Serum
sodium, potassium and creatinine were also obtained to
assess the adverse effects of Ep administration. After the
2-month study period, patients who had successfully
increased the dose of Ep to 50 mg/day for 1 month were
used for analysis. The present study was conducted according to the principles of the Declaration of Helsinki and was
approved by the local ethics committee of our institution.
All patients provided informed, written consent prior to
participation.
Study design and statistics
During the course of the study, patients were treated with a
gradually increased dose of Ep, with an initial dose of 25
mg/day to a final dose of 50 mg/day for 2 months. This final
dose was selected under the consideration of possible risk of
hyperkalemia in subjects with CKD. Adverse side effects
were assessed and recorded for all patients. There was a
total of 35 study patients (Group A+B: male 19/female 16,
age 56.0 [45.0–68.5]; Group A: male 12/female 8, age 59.5
[49.5–68.5], Group B: male 7/female 8, age 51.0 [43.5–
68.5]). Group A and B subjects received same treatment but
the obtained parameters were different. In both Group A and
B subjects, the baseline peripheral BP (PBP), heart rate,
and serum and spot urine sodium/potassium/osmolality/
creatinine were evaluated. After 2 months, the efficacy of
Ep was evaluated by PBP, proteinuria, and TTKG in spot
urine. Subjects with proteinuria >0.1 g/gCrtn were used to
evaluate the anti-proteinuric action of Ep. In Group B subjects, in addition to the parameters obtained in Group A,
measurement of estimated central BP (CBP) by HEM9000AI (Omron, Kyoto, Japan),15 blood sampling in the
supine position and 24-hour urine collection were included
to evaluate the clinical impact of Ep add-on therapy on CBP,
plasma renin activity (PRA), PAC, TTKG24hr and urinary
albumin excretion. Among the 15 subjects in Group B, 14
subjects who excreted albumin >30 mg/day were used to
evaluate the anti-proteinuric action of Ep. Serum creatinine
was measured by an enzymatic method. The equation for
Japanese eGFR:
eGFR (ml/min/1.73 m2) = 194 × sCrtn−1.094 × Age−0.287 ×
0.739 (if female)
was applied to calculate the eGFR.16
Differences in laboratory findings between basal levels
and the levels at 2 months were tested by the Wilcoxon
rank sum test with continuity correction for correlated
samples. The r2 values given by correlation analysis of two
factors were converted to p-values according to sample
numbers. Continuous variables were expressed as mean ±
standard deviation or median and interquartile ranges, as
appropriate, and categorical variables were given as number and proportion. Statistical significance was set at
p<0.05. Statistical analyses were performed using R, version 3.0.1 (The R Foundation for Statistical Computing,
http://www.r-project.org/).
Results
Thirty-eight patients were enrolled in this study. During
the 2-month study period, three patients were excluded
from the protocol due to failure to increase the Ep dose to
50 mg/day or failure in maintaining continuous administration due to side effects, including general fatigue or
abnormal serum creatinine elevation.
In the total number of patients (Group A+B), administration of the 50 mg/day dose of Ep significantly reduced
PBP (SBP, diastolic BP [DBP], and mean arterial pressure
[MAP]) in the sitting position (Table 1 and Figure 1).
Heart rate, hemoglobin level, serum sodium, serum potassium, serum albumin, serum uric acid, blood urea nitrogen, serum creatinine, eGFR, urinary protein and TTKGspot
were not affected by the administration of Ep (Table 1 and
Figure 1). Among the parameters which have been
reported to regulate plasma aldosterone level,13,14 baseline
PAC was inversely correlated with baseline eGFR (Figure
2). No correlations were identified between baseline PAC
and serum potassium, sodium intake, TTKGspot, TTKG24hr
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Kawada et al.
Table 1. Changes in parameters after the administration of 50mg eplerenone (Group A+B).
parameters (Group A+B)
value
50mg
Baseline
Total number (male/female)
Age (years)
Etiology and number
IgA nephropathy
Membranous nephropathy
Vasculitis
Heminephrectomy
Focal segmental glomerulosclerosis
Minimal change nephropathy
Malignant hypertension
Unknown cause CKD stage2
Unknown cause CKD stage3A
Unknown cause CKD stage3B
Hypertension alone
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Mean arterial pressure (mmHg)
Heart rate (beat/min)
Hb (g/dl)
Serum sodium (mEq/l)
Serum potassium (mEq/l)
Serum albumin (mg/dl)
Serum uric acid (mg/dl)
BUN (mg/dl)
Serum creatinine (mg/dl)
eGFR (ml/min/1.73m2)
Spot urine
protein/creatinine ratio (g/gCrtn)
TTKG
35 (19/16)
56.0 [45.0–68.5]
Wilcoxon
p-value
–
–
11
2
2
2
1
1
1
2
9
1
3
131 [121–142]
79 [73–88]
96 [89–103]
67 [65–77]
13.3 [12.0–14.6]
139 [138–140]
4.2 [4.1–4.4]
3.9 [3.7–4.2]
6.7 [5.5–7.6]
17 [15–19]
0.98 [0.82–1.15]
54.3 [48.1–68.9]
–
–
–
–
–
–
–
–
–
–
–
122 [115–132]
74 [69–83]
90 [86–95]
74 [67–78]
13.1 [12.1–14.4]
139 [138–140]
4.2 [4.0–4.4]
3.9 [3.7–4.1]
6.6 [5.6–7.6]
18 [15–22]
0.98 [0.79–1.14]
56.2 [48.0–69.5]
0.87 [0.36–1.00]
5.3 [4.9–7.4]
0.60 [0.28–1.03]
5.6 [4.5–7.7]
–
–
–
–
–
–
–
–
–
–
–
–
–
p=0.001
p=0.003
p=0.0005
n.s. (p=0.22)
n.s. (p=0.63)
n.s. (p=0.10)
n.s. (p=0.53)
n.s. (p=0.27)
n.s. (p=0.46)
n.s. (p=0.07)
n.s. (p=0.72)
n.s. (p=0.73)
n.s. (p=0.13)
n.s. (p=0.94)
Figure 1. Box plots of systolic BP (SBP: panel A), diastolic BP (DBP: panel B), mean arterial pressure (MAP: panel C), proteinuria
(panel D), and transtubular K gradient (TTKGspot: panel E) before and after administration of 50 mg eplerenone (Ep) in the entire
group of subjects (Group A+B). Administration of Ep reduced SBP, DBP, and MAP, but had no effect on proteinuria or TTKGspot.
The values of the median and interquartile ranges are also shown in Table 1.
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Journal of the Renin-Angiotensin-Aldosterone System
or SBP. The administration of Ep reduced CBP, and
increased PRA (Figure 3). Ep had no effects on PAC,
TTKG24hr, or urinary albumin excretion in the Group B
patients (Figure 3).
To further investigate the effects of Ep on BP and proteinuria, the relationships between the parameters before
the administration of Ep and the percent changes in MAP,
CBP, and albuminuria after the administration of Ep were
tested by correlation analysis. The percent changes of
MAP or CBP with Ep administration showed no relationships with serum potassium, PAC, percent change in salt
intake, percent change in eGFR, TTKGspot, TTKG24hr, or
percent change in albuminuria (data not shown). Percent
change in albuminuria showed no relationships with serum
potassium, percent change in salt intake, or percent change
in eGFR, TTKGspot, TTKG24hr (data not shown), but rather,
an inverse relationship was identified with PAC (Figure 4).
This may represent the significant role of the direct or indirect action of plasma aldosterone on the occurrence or
prognosis of proteinuria.
Discussion
Figure 2. Correlation analysis between baseline plasma
aldosterone concentration (PAC) and baseline eGFR. An inverse
relationship was identified between basal PAC and eGFR.
The present study showed that the addition of an antialdosterone agent, eplerenone, in patients already taking
ACEis or ARBs reduces PBP and CBP independently to
the plasma aldosterone level. Aldosterone increases BP
by promoting sodium retention in the kidneys and by
direct action on the central nervous system and vessels.
Aldosterone generates its biological actions by binding
to a MR. Recent investigation has shown that MR activation is not entirely regulated by the aldosterone level.
Fujita et al. showed an alternative pathway of MR activation by small GTPase Rac1.9,10 These investigators
demonstrated that constitutive active Rac1 induces
nuclear translocation of MR even in the absence of
aldosterone. Therefore, the activators for Rac1 signaling
may stimulate MR independently of the aldosterone
Figure 3. Box plots of central BP (CBP: panel A), albuminuria (panel B), transtubular K gradient (TTKG24hr: panel C), plasma renin
activity (PRA: panel D), and plasma aldosterone concentration (PAC: panel E) before and after administration of 50 mg eplerenone
(Ep) in Group B subjects. Administration of Ep reduced CBP and increased PRA, but had no effect on albuminuria, TTKG24hr, or PAC.
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Kawada et al.
Figure 4. Correlation analysis between percent change
in albuminuria and baseline PAC. An inverse relationship
was identified between percent change in albuminuria and
baseline PAC.
level. MR can also be activated by glucocorticoids. The
affinity of cortisol for MR is identical to the affinity of
aldosterone, and the concentration of cortisol is 1000
times higher than aldosterone.17 In general, cells that
possess MR express 11β-hydroxysteroid dehydrogenase
type 2 (11βHSD2), which converts cortisol to inactive
cortisone.18,19 However, vascular smooth muscle cells
and distal tubule cells express marginal amounts of
11βHSD2. These cells activate MR by cortisol and
increase BP by promoting vasoconstriction or sodium
retention. This MR action can be blocked by Ep, and the
BP is reduced independently of the PAC.
Buter et al. have demonstrated that the beneficial effects
of ACEis are prominent under dietary salt restriction, but
are limited under salt loading.20 Therefore, the agents that
have natriuretic actions, including diuretics and Ca antagonists, have been considered as the best additive antihypertensive agents to ACEis or ARBs,3,4 including for use
in patients with CKD. Little attention has been paid to the
clinical impact of add-on therapy for aldosterone receptor
antagonists in patients who are already receiving ACEis or
ARBs. The present study has shown a steady BP-lowering
effect of Ep. As was discussed previously, the antihypertensive and natriuretic actions of anti-aldosterone
agents can theoretically be expected even under a low
aldosterone level. Therefore, we have concluded that Ep is
a useful candidate as an additive anti-hypertensive agent
for ACEis and ARBs.
Correlation analysis revealed that the subjects with
higher basal PAC were more likely to experience reduced
albuminuria with Ep. This finding is consistent with the
concept that proteinuria is more prominent in patients who
have had an aldosterone breakthrough.5–7 The effect of Ep
on proteinuria, which is dependent on the plasma aldosterone level, contrasts with the effect of Ep on BP, which is
independent of the plasma aldosterone level. The precise
mechanism of this differing action of Ep on BP and proteinuria is not known, but an explanation can be proposed
by the expression of 11βHSD2 in glomeruli. Glomerular
endothelial cells and podocytes have an established role in
proteinuria. These cells have been shown to express
11βHSD2,18 and MRs in these cells are activated only by
aldosterone, because cortisol is inactivated in these cells.
We have concluded that TTKG is not a useful index to
evaluate the efficacy of aldosterone receptor blockade.
The present study showed no correlation between the
TTKG and plasma aldosterone level, and, surprisingly, the
administration of Ep failed to lower the TTKG. The TTKG
is an index of potassium secretion in the collecting ducts.21
In the collecting duct cells, aldosterone promotes potassium secretion by activating renal outer medullary potassium channel. Therefore, a higher plasma aldosterone level
is expected to be correlated with a higher TTKG and a
lower plasma potassium level. The present study failed to
show any such relationship. A possible explanation is the
activation of a compensatory pathway that promotes potassium secretion under aldosterone receptor blockade, which
would include prostaglandins, nitric oxide, carbon monoxide and reduced oxidative stress.22–26
The present study results provide some clues about the
regulation of the plasma aldosterone level in subjects
receiving ACEis or ARBs. In primary aldosteronism, elevation of the PAC is accompanied by a low potassium level.
On the other hand, the present study found that the plasma
potassium level is not lower in subjects with high aldosterone levels. This result indicates that the aldosterone level of
these subjects is likely to be regulated not primarily, but
secondarily by other factors. We have shown that there is an
inverse correlation between PAC and eGFR. Besides the
well-recognized regulation effect by angiotensin II, plasma
potassium, endothelin and adrenocorticotropic hormone
have also been shown to play important roles in the regulation of aldosterone production.27,28 The elevation of aldosterone under lower eGFR may play a physiological role in
potassium homeostasis, because aldosterone can promote
potassium secretion from the collecting ducts. This may
compensate for the disturbed potassium excretion under
reduced GFR. Further investigation is necessary to understand the regulation of aldosterone production under the
administration of ACEis and ARBs.
In conclusion, Ep add-on therapy in patients who are
receiving RAS blockers reduces PBP and CBP. The antihypertensive effect of Ep is independent of the plasma
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Journal of the Renin-Angiotensin-Aldosterone System
aldosterone level. In contrast, the anti-proteinuric action of
Ep may be dependent upon the plasma aldosterone level.
The TTKG is not an appropriate means for evaluating the
efficacy of aldosterone receptor blockade.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
Conflicts of interest
The authors declare that there are no conflicts of interest.
References
1.Ruggenenti P and Remuzzi G. Proteinuria: Is the
ONTARGET renal substudy actually off target? Nat Rev
Nephrol 2009; 5: 436–437.
2. Shiga Microalbuminuria Reduction Trial (SMART) Group,
Uzu T, Sawaguchi M, et al. Reduction of microalbuminuria
in patients with type 2 diabetes: The Shiga Microalbuminuria
Reduction Trial (SMART). Diabetes Care 2007; 30:
1581–1583.
3. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus
amlodipine or hydrochlorothiazide for hypertension in highrisk patients. N Engl J Med 2008; 359: 2417–2428.
4. Bakris GL, Sarafidis PA, Weir MR, et al. Renal outcomes
with different fixed-dose combination therapies in patients
with hypertension at high risk for cardiovascular events
(ACCOMPLISH): A prespecified secondary analysis of a
randomised controlled trial. Lancet 2010; 375: 1173–1181.
5. Staessen J, Lijnen P, Fagard R, et al. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 1981; 91: 457–465.
6. Schjoedt KJ, Andersen S, Rossing P, et al. Aldosterone
escape during blockade of the renin-angiotensin-aldosterone
system in diabetic nephropathy is associated with enhanced
decline in glomerular filtration rate. Diabetologia 2004; 47:
1936–1939.
7. Sato A and Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med
Res 2001; 29: 13
8. Hadoke PWF, Iqbal J and Walker BR. Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease. Brit J Pharmacol 2009; 156: 689–712.
9. Shibata S, Mu S, Kawarazaki H, et al. Rac1 GTPase in
rodent kidneys is essential for salt-sensitive hypertension
via a mineralocorticoid receptor-dependent pathway. J Clin
Invest 2011; 121: 3233–3243.
10. Shibata S, Nagase M, Yoshida S, et al. Modification of
mineralocorticoid receptor function by Rac1 GTPase:
Implication in proteinuric kidney disease. Nat Med 2008;
14: 1370–1376.
11.Navaneethan SD, Nigwekar SU, Sehgal AR, et al.
Aldosterone antagonists for preventing the progression of
chronic kidney disease. Cochrane Database Syst Rev 2009;
3:CD007004.
12. Tsuboi N, Kawamura T, Okonogi H, et al. The long-term
antiproteinuric effect of eplerenone, a selective aldosterone
blocker, in patients with non-diabetic chronic kidney disease.
J Renin Angiotensin Aldosterone Syst 2012; 13: 113–117.
13. Yoneda T, Takeda Y, Usukura M, et al. Aldosterone breakthrough during angiotensin II receptor blockade in hypertensive patients with diabetes mellitus. Am J Hypertens
2007; 20: 1329–1333.
14. Moranne O, Bakris G, Fafin C, et al. Determinants and
changes associated with aldosterone breakthrough after
angiotensin II receptor blockade in patients with type 2 diabetes with overt nephropathy. Clin J Am Soc Nephrol 2013;
8: 1694–1701.
15. Takase H, Dohi Y and Kimura G. Distribution of central
blood pressure values estimated by Omron HEM-9000AI in
the Japanese general population. Hypertens Res 2013; 36:
50–57.
16. Matsuo S, Imai E, Horio M, et al. Revised equations for
estimating glomerular filtration rate (GFR) from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982–992.
17. Frey FJ, Odermatt A and Frey BM. Glucocorticoid-mediated
mineralocorticoid receptor activation and hypertension.
Curr Opin Nephrol Hypertens 2004; 13: 451–458.
18. Kataoka S, Kudo A, Hirano H, et al. 11beta-hydroxysteroid
dehydrogenase type 2 is expressed in the human kidney glomerulus. J Clin Endocrinol Metab 2002; 87: 877–882.
19. Hadoke PWF, Macdonald L, Logie JJ, et al. Intra-vascular
glucocorticoid metabolism as a mod-ulator of vascular
structure and function. Cell Mol Life Sci 2006; 63: 565–578.
20. Buter H, Hemmelder MH, Navis G, et al. The blunting of the
antiproteinuric efficacy of ACE inhibition by high sodium
intake can be restored by hydrochlorothiazide. Nephrol Dial
Transplant 1998; 13: 1682–1685.
21. Ethier JH, Kamel KS, Magner PO, et al. The transtubular
potassium concentration in patients with hypokalemia and
hyperkalemia. Am J Kidney Dis 1990; 15: 309–315.
22. Herrera M, Ortiz PA and Garvin JL. Regulation of thick
ascending limb transport: Role of nitric oxide. Am J Physiol
Renal Physiol 2006; 290: F1279–1284.
23. Flores D, Liu Y, Liu W, et al. Flow-induced prostaglandin
E2 release regulates Na and K transport in the collecting
duct. Am J Physiol Renal Physiol 2012; 303: F632–638.
24. Frindt G, Li H, Sackin H, et al. Inhibition of ROMK channels by low extracellular K+ and oxidative stress. Am J
Physiol Renal Physiol 2013; 305: F208–F215.
25. Wang Z, Yue P, Lin DH, et al. Carbon monoxide stimulates
Ca2+ -dependent big-conductance K channels in the cortical collecting duct. Am J Physiol Renal Physiol 2013; 304:
F543–F552.
26. Lu M and Wang WH. Reaction of nitric oxide with superoxide inhibits basolateral K+ channels in the rat CCD. Am J
Physiol Heart Circ Physiol 1998; 275: C309–316.
27. Bomback AS and Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol
2007; 3: 486–492.
28. Willenberg HS, Schinner S and Ansurudeen I. New mechanisms to control aldosterone synthesis. Horm Metab Res
2008; 40: 435–441.
Downloaded from jra.sagepub.com by guest on February 5, 2015

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