Aldosterone Blockade in CKD: Emphasis on

Pharmacology
Michael H. Schwenk, Jamie S. Hirsch, and Andrew S. Bomback

Besides its epithelial effect on sodium retention and potassium excretion in the distal tubule, aldosterone promotes inflamma-
tion and fibrosis in the heart, kidneys, and blood vessels. As glomerular filtration rate falls, aldosterone is inappropriately
elevated relative to extracellular fluid expansion. In addition, studies in CKD patients on angiotensin-converting enzyme inhib-
itors, angiotensin receptor blockers, and/or direct renin inhibitors have shown that aldosterone levels paradoxically rise in
approximately 30% to 40% of patients on these renin-angiotensin system-blocking drugs. Hence, there is interest in using
mineralocorticoid receptor blockers that directly target the inflammatory and fibrotic effects of aldosterone in CKD patients.
This interest, however, is tempered by a number of unresolved issues, including the safety of using such drugs in advanced
CKD and ESRD populations, and the potential for differences in drug efficacy according to race and ethnicity of patient popula-
tions. A better understanding of mineralocorticoid receptor blocker pharmacology should help inform future research directions
and clinical practice decisions as to how best to use these agents in CKD.
Q 2015 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Mineralocorticoid receptor antagonists, Chronic kidney failure, Pharmacokinetics, Hyperkalemia, Proteinuria

Introduction In CKD, this need to directly address aldosterone

Blockade of the renin-angiotensin-aldosterone system blockade with MRBs may be critically important for 2 rea-
(RAAS) is a mainstay of therapy for CKD, recommended sons. First, CKD can be considered a state of relative hy-
by virtually every international guideline as standard of peraldosteronism. Aldosterone levels, in relation to a
care in this condition. This RAAS blockade is almost cofactor of plasma renin activity, rise as glomerular filtra-
always accomplished through use of angiotensin- tion rate (GFR) falls.14-16 In healthy humans, there is an
converting enzyme inhibitors (ACEIs) or angiotensin inverse relationship between extracellular volume (ECV)
receptor blockers (ARBs). The past decade has seen re- and serum aldosterone concentration. In the setting of
newed interest in using agents that block aldosterone in low dietary sodium intake, levels of renin, angiotensin II,
the treatment paradigm of CKD. Mineralocorticoid recep- and aldosterone predictably rise but do not cause
tor blockers (MRBs), such as spironolactone and eplere- vascular inflammation and end-organ damage.17 Certain
none, have become a standard treatment add-on (ie, on diseases, including obesity,18-20 CKD,21,22 and ESRD,23
top of ACEIs and ARBs) in patients with chronic heart dis- are notable states of relative hyperaldosteronism despite
ease. As the use of dual RAAS blockade with ACEIs and ECV expansion, leading to proinflammatory mineralocor-
ARBs by nephrologists has fallen into decline and, likely, ticoid receptor (MR) activation.19,21,22,24 ECV expansion, in
ultimate extinction, it is conceivable that the combination turn, is invariably caused by excess sodium intake and an
of MRB plus ACEI or MRB plus ARB will become a new inherent defect in excreting salt that becomes more and
standard treatment strategy in CKD. In this review, we more profound as GFR declines,25 with the combination
survey the existing data on the rationale, efficacy, and of salt and aldosterone proving toxic.26-32 This may
safety of MRB therapy in CKD, with a specific focus on explain the frequent observation that sodium restriction
the pharmacology of these agents. augments the proteinuria and blood pressure-lowering ef-
fects of RAAS blockade.33,34
Rationale for Aldosterone Blockade Second, blockade of the distal components of the RAAS
In addition to its effect on distal tubular salt and potas- by ACEIs and ARBs may often be incomplete. In clinical
sium handling, numerous animal studies have shown trials of ACEIs and ARBs, plasma aldosterone levels, after
that aldosterone is intimately involved in vascular, an initial decline, have been shown to increase in some
myocardial, and kidney fibrosis. Independent of changes patients over the long term.35-40 This phenomenon,
in blood pressure and volume homeostasis, aldosterone- termed both “aldosterone escape” and “aldosterone
mediated activation of mineralocorticoid receptors in breakthrough” in the literature (we prefer and will use
nonepithelial tissues of the cardiovascular and kidney the term “aldosterone breakthrough” to avoid confusion
system promotes tissue inflammation and injury,1-8
manifest as myocardial fibrosis, left ventricular
hypertrophy (LVH),9,10 glomerulosclerosis, and severe From Clinical Trials Office, Research Pharmacy, Columbia University Med-
proteinuria.3,11,12 Thus, aldosterone’s nonepithelial ical Center, New York, NY; and Division of Nephrology, Department of Medi-
effects may play a more important role in the cine, Columbia University Medical Center, New York, NY.
Financial Disclosure: The authors declare that they have no relevant finan-
pathogenesis of chronic heart disease and CKD than its cial interests.
classical epithelial effects.13 Importantly, blockade of the Address correspondence to Andrew S. Bomback, MD, MPH, 622 West
RAAS at the level of angiotensin I or angiotensin II are, 168th Street, PH 4-124, New York, NY 10032. E-mail: [email protected]
in the least, inefficient and, potentially, completely inef- Ó 2015 by the National Kidney Foundation, Inc. All rights reserved.
fective against these nonclassical profibrotic actions of 1548-5595/$36.00
aldosterone. http://dx.doi.org/10.1053/j.ackd.2014.08.003

Advances in Chronic Kidney Disease, Vol 22, No 2 (March), 2015: pp 123-132 123
124 Schwenk et al

with “aldosterone escape” from the sodium-retaining ac- Notably, the vast majority of patients in these studies
tion of mineralocorticoids, an unrelated clinical entity), were diabetic; hence, the best evidence for using aldoste-
has been associated with important kidney outcomes rone blockade in proteinuric CKD is in the treatment of dia-
including refractory proteinuria and steeper declines in betic nephropathy. Mehdi and colleagues45 reported the
GFR. Aldosterone breakthrough occurs in 30% to 50% of results of a randomized, double-blind, placebo-controlled
patients on long-term ACEI or ARB therapy, and a similar trial of 81 patients with diabetic nephropathy, all of
prevalence rate of 30% to 40% has recently been shown in 2 whom received lisinopril 80 mg daily. The subjects were
studies examining the phenomenon with direct renin inhi- then randomly assigned to placebo, losartan 100 mg daily,
bition (Fig 1).41,42 In the largest study to date of aldosterone or spironolactone 25 mg daily for 48 weeks. Compared
breakthrough, a post hoc analysis of the efficacy of with placebo, albuminuria decreased by 34% (P ¼ .007) in
telmisartan compared with losartan in reducing the spironolactone group and by 17% (P ¼.2) in the losartan
proteinuria in hypertensive type 2 diabetic patients with group, with no difference in clinic and ambulatory blood
overt nephropathy study found that approximately 30% pressures between treatment groups. Epstein and col-
of 567 patients with diabetic nephropathy demonstrated leagues,46 in a larger study of diabetic patients using epler-
a rise of 10% or more in aldosterone levels above enone rather than spironolactone, reported similarly
pretreatment baselines while on ARB therapy. impressive results independent of blood pressure reduc-
The physiology behind aldosterone breakthrough re- tions. Two hundred sixty-eight patients, after open-label
mains unclear, although proposed theories suggest that run-in with enalapril 20 mg daily, were randomized to pla-
the phenomenon is more likely to occur when GFR de- cebo, eplerenone 50 mg daily, or eplerenone 100 mg daily.
clines. Plasma aldosterone levels are primarily regulated By Week 12, albuminuria was reduced by 7% in the placebo
by potassium and angio- group, by 41% in the eplere-
tensin II, the latter in none 50 mg daily group,
response to salt balance and CLINICAL SUMMARY and by 48% in the eplerenone
plasma volume. Therefore, 100 mg daily group (both
rising aldosterone levels in  Aldosterone has deleterious inflammatory and profibrotic eplerenone groups, P , .001
CKD patients on ACEIs or actions that affect the heart, kidneys, and blood vessels. vs placebo). More recently,
ARBs could simply reflect  Aldosterone is inappropriately elevated with respect to
in an open-label randomized
low GFR-associated alter- extracellular volume in CKD and oftentimes will rise after trial, Esteghamati and col-
ations in plasma potassium an initial decline during renin-angiotensin-aldosterone sys- leagues47 examined spirono-
concentration, total extracel- tem-blocking therapy (aldosterone breakthrough). lactone as add-on for ARBs
lular sodium, and effective in patients with urinary albu-
 In proteinuric CKD, mineralocorticoid-blocking therapy
blood volume in the sys- min excretion of 30 mg/d or
lowers proteinuria and blood pressure, but glomerular
temic arterial circulation. filtration rate decline is unchanged, with attendant risks of
more vs an ARB-ACEI com-
Indeed, if aldosterone break- hyperkalemia and gynecomastia. bination. The combination
through is mediated through of spironolactone and an
angiotensin II levels, the  In Stage 5 hemodialysis patients, preliminary studies have ARB significantly decreased
greater tendency toward not seen significant hyperkalemia with mineralocorticoid blood pressure, albuminuria
receptor blocker use, laying the groundwork for large
breakthrough in patients (by 59%), and estimated
clinical trials to explore aldosterone blockade’s effects on
with declining kidney func- cardiovascular morbidity and mortality in ESRD.
glomerular filtration rate
tion would have to be (eGFR; by approximately
viewed as a consequence, 8 mL/min/m2) at 18 months,
and not a cause, of target or- whereas an ARB-ACEI com-
gan injury. An alternative explanation for breakthrough bination had no significant effect on blood pressure or albu-
emerged in a comparison study of proteinuric CKD patients minuria but caused a drop in eGFR (by approximately
receiving an ARB, a direct renin inhibitor, or a combination, 9 mL/min/m2).
in which approximately one-quarter of patients had an The data supporting the use of MRBs in nondiabetic kid-
average rise in 24-hour urine and serum aldosterone levels ney diseases are not as robust as those in diabetic nephrop-
of 73% and 60%, respectively. In this study, aldosterone athy. Bianchi and colleagues48 randomized 128 patients
breakthrough was associated with body mass index, and with idiopathic glomerular diseases to intensive therapy
the authors speculated that obesity itself was a non- (ACEI, ARB, high-dose statin, and spironolactone) or con-
potassium non-volume stimulus to aldosterone produc- ventional therapy (ACEI and low-dose statin). Significantly
tion.42 greater proteinuria reduction and eGFR stabilization was
noted with intensive vs conventional therapy, although it
Aldosterone Blockade in CKD is difficult to determine whether this benefit comes solely
A number of small short-term clinical studies have exam- from the use of spironolactone. Furumatsu and col-
ined the effects of adding MRBs to ACEIs or ARBs in pro- leagues49 performed an open-label study in 32 nondiabetic
teinuric kidney disease. Two groups of authors have patients with proteinuria exceeding 0.5 g/d. After more
performed meta-analyses of these small trials and found than 12 weeks of combined ACEI and ARB treatment, pa-
that the addition of MRB therapy can reduce proteinuria by tients were assigned to either spironolactone 25 mg daily
up to 50% from baseline.43,44 Some, but not all, of this effect (a triple blockade group of ACEI 1 ARB 1 MRB) or
can be explained by reductions in blood pressure. diuretic (trichlormethiazide 1 mg daily or furosemide
 Aldosterone Blockade in CKD 125

Figure 1. Aldosterone breakthrough, the paradoxical rise in aldosterone production after initiation of renin-angiotensin-
aldosterone system (RAAS) blockade, occurs in approximately 30% to 50% of patients. The phenomenon was first described
in retrospective analyses of clinical trials of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs), but recent data have shown that breakthrough occurs even with more proximal blockade of the
RAAS via renin inhibition. In these data, adapted from Bomback et al,42 38% of CKD patients treated with an ARB, a renin in-
hibitor, or a combination of ARB 1 renin inhibitor demonstrated elevations in urine (A) and/or serum aldosterone (B) levels
within 3 months of starting RAAS blockade.

20 mg daily, a control group). After 1 year of treatment, the apy in CKD. Patients with resistant hypertension and CKD
urinary protein level decreased by 58% (P , .05) and uri- Stage 2 or 3 were evaluated after aldosterone blockade was
nary type IV collagen decreased by 40% (P ,.05) with triple added to pre-existing BP-lowering regimens (including a
blockade but remained unchanged in the controls. Mean diuretic and RAAS blocker). Patients with a baseline
serum creatinine, potassium, and blood pressure did not eGFR of 45 mL/min/1.73 m2 or less and baseline serum po-
change significantly in either treatment arm. tassium level greater than 4.5 mEq/L were identified as
The issue of safety when using MRB therapy in CKD having the highest risk for hyperkalemia (serum K . 5.5
(either diabetic or non-diabetic) is critically important, mEq/L), which occurred in 8 of the 46 patients in this
particularly in light of using these agents in patients cohort. Confirming this observation, Edwards and col-
already on ACEIs or ARBs. The risk for hyperkalemia leagues53 prospectively examined the safety of spironolac-
cannot be overlooked or understated.50,51 Most patients tone (added to ACEIs or ARBs) in more than 100 patients
in the trials mentioned earlier had eGFR levels more than with mild CKD 3a (eGFR 49-53 mL/min/1.73 m2) and, after
50 mL/min/1.73 m2, and all prospective trials of MRB 40 weeks of treatment, reported that the incidence of sig-
therapy have used baseline potassium level as an nificant hyperkalemia (K $ 6.0 mEq/L) was less than 1%.
exclusion criteria (usually restricting the medication to The most recent meta-analysis of MRB therapy (either
those whose potassium levels are consistently less than spironolactone or eplerenone), alone or in combination
5.0 mEq/L before MRB therapy). Although retrospective, with ACEIs and/or ARBs for preventing progression of
the analysis by Khosla and colleagues52 provides impor- CKD in adults (stages 2 and 3), examined 27 randomized
tant data on the safety (or lack thereof) of using MRB ther- controlled trials with 1549 patients. MRB therapy was
126 Schwenk et al

Figure 2. In a meta-analysis of treatment studies, mineralocorticoid receptor blocker therapy added to ACEIs or ARBs signif-
icantly reduced 24-hour urinary protein excretion compared with ACE inhibitors or ARBs alone. Abbreviations: ACEI,
angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; IV, of the interventions;
MRB, mineralocorticoid receptor blockers; SPL, spironolactone.
Reprinted with permission from Bolignano et al.54

compared with other antihypertensive therapy (including Aldosterone Blockade in ESRD

ACEIs and/or ARBs).54 No data were identified that Far fewer studies have examined the use of MRBs in pa-
related to “hard” outcomes such as mortality, cardiovascu- tients with ESRD. Two small studies confirmed a nondiu-
lar events, or progression to ESRD requiring dialysis or retic mechanism of MRBs in blood pressure control. In a
transplantation. Therapy with MRBs significantly reduced randomized, double-blind, placebo-controlled trial of 8
24-hour urinary protein excretion (Fig 2) and systolic and oligoanuric hemodialysis patients, spironolactone 50 mg
diastolic blood pressures; the difference in decrease in twice daily led to a decline in predialysis SBP from 142
GFR was not significant (Fig 3). Notably, the risk of hyper- to 131 mm Hg.55 In a similar cohort given eplerenone
kalemia with MRBs was doubled, and the risk for develop- 25 mg twice daily, predialysis SBP dropped from 166 to
ment of gynecomastia with spironolactone was 5-fold 153 mm Hg.56
higher.

Figure 3. In a meta-analysis of treatment studies, mineralocorticoid receptor blocker therapy added to ACEIs or ARBs did not
significantly affect estimated glomerular filtration rate compared with ACE inhibitors or ARBs alone. Abbreviations: ACEI,
angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; IV, of the interventions; SPL, spironolactone.
Reprinted with permission from Bolignano et al.54
 Aldosterone Blockade in CKD 127

Targeting aldosterone should yield benefits beyond pro- neal dialysis70 have safely received spironolactone for sys-
teinuria and blood pressure reduction given the numerous tolic CHF without significant hyperkalemia.
avenues of injury that aldosterone’s actions have in the A 6-month pilot study with the specific goal of deter-
cardiovascular system, making ESRD patients a poten- mining the risk of hyperkalemia during spironolactone
tially good target population for MRB therapy. Indeed, therapy was conducted in 50 Japanese, oligoanuric chronic
the absolute mortality benefit for spironolactone in hemodialysis patients who did not have a hyperkalemic
congestive heart failure (CHF) is highest among patients episode in the 2 months preceding the trial.71 Predialysis
with CKD.57 Similar reductions in cardiovascular serum potassium level was checked at baseline, 2 weeks,
morbidity and mortality should be seen in ESRD patients 4 weeks, 2 months, and 6 months after administration of
if treated with MRBs. In the chronic renal impairment in spironolactone 25 mg daily. No changes were made during
Birmingham study II spironolactone added to an ACEI the trial in existing therapy with ACEIs, ARBs, loop di-
for 10 weeks resulted in significant reductions in left ven- uretics, cation exchange resins, dialysis prescription, or di-
tricular mass index (LVMI) (11.4%), left ventricular (LV) etary potassium restriction. Mean potassium levels
mass (11.8%), and LVH prevalence (50%), whereas the increased from 4.96 6 0.72 to 5.26 6 0.76 mEq/L during
placebo-treated group showed no change.58 ESRD patients the study period, but no individual measurement was
typically have LVH, and LVMI correlates with aldosterone more than 6.8 mEq/L, nor was hyperkalemia a reason for
levels in nondiabetic patients on hemodialysis.59,60 In a stopping treatment with spironolactone. Development of
recent study of 328 hemodialysis patients, the median gynecomastia in 3 patients led to study withdrawal.
serum aldosterone level was 18.4 ng/dL, and the highest The same authors have recently reported a prospective
tertile (level .28 ng/dL, compared with level ,14 ng/dL) randomized study in which 309 hemodialysis patients
was associated with a doubling of mortality and received spironolactone 25 mg daily vs no MRB therapy
cardiovascular events in euvolemic patients.23 for 3 years.72 The primary objective of this study was to
In a small, randomized, double-blind, placebo- gauge spironolactone’s effect on cardiovascular and cere-
controlled trial of 11 hemodialysis patients with systolic brovascular mortality or hospitalization. The incidence of
CHF, those given spironolactone (25 mg thrice weekly af- the primary outcome in the spironolactone cohort was
ter dialysis) for 6 months had a significant improvement 5.7% compared with 12.5% in the control cohort
in LV ejection fraction (mean absolute increase 6% vs no (P ¼.017). The secondary outcome of death from all causes
change with placebo) and LV mass (mean decrease 8.4 g/ was similarly reduced in the treatment group, 6.4%,
m2 vs no change with placebo).61 In peritoneal dialysis compared with the non-MRB group, 19.7% (P ¼ .002). Hy-
subjects, spironolactone conferred similar benefits, with a perkalemia (defined as . 6.5 mEq/L) occurred in 2% and
30% improvement in ejection fraction (and no benefit gynecomastia in 10% of the spironolactone patients.
with placebo) after 6 months of therapy in a randomized Currently, a randomized placebo-controlled study of spi-
controlled trial.62 A subsequent placebo-controlled study ronolactone in hemodialysis patients is in progress (aldo-
in hemodialysis patients without CHF found no improve- sterone antagonist chronic hemodialysis interventional
ment in echocardiographic measures after 4 months on survival trial), hoping to enroll more than 800 patients,
spironolactone but significant improvement in endothelial with the primary end point of time until first nonfatal
function as measured by increased reactive hyperemia myocardial infarction or hospitalization for heart failure
(from 80% at baseline to 152% on spironolactone) with pro- or nonfatal stroke or cardiovascular death (NCT01848639).
longed duration (35 to 48 seconds, respectively). Heart rate
variability, a known mortality risk factor,63 was also signif-
icantly decreased.64 Pharmacokinetics of Mineralocorticoid Receptor
Spironolactone given for 3 years attenuated the vascular Blockers
calcification (decrease in mean aortic calcification index of Spironolactone and eplerenone are the 2 oral MRBs avail-
27%), as determined by aortic computed tomography, in 5 able for clinical use in the United States (canrenoate and
hemodialysis patients.65 Probing carotid intima-media canrenoate potassium are available elsewhere). Spirono-
thickness via ultrasonography in the carotid arteries, 53 lactone is referred to as a first-generation MRB, whereas
nondiabetic hemodialysis patients were followed for eplerenone is considered second generation, a reflection
2 years to examine the effect of MR activation on athero- of its more specific receptor binding (and resultant
sclerosis progression. Spironolactone-treated patients different side effect profile). Third-generation MRBs
(50 mg thrice weekly after dialysis) had statistically signif- (nonsteroidal in structure) and even fourth-generation
icant stabilization (5 of 6 areas evaluated) and even some MRBs (less or no effect on kidney tubular epithelial cells)
improvement (left internal carotid artery, mean 1.15 to are currently under development. Although spironolac-
0.84 mm), whereas the placebo-treated group had diffuse tone became available for clinical use in 1959, its clinical
progression over time in most areas.66 pharmacokinetics were not truly elucidated until nearly
These small studies are important as much for their efficacy 3 decades later. Early studies were unable to detect parent
signal as their safety signal. Although, in general, serum po- drug in the serum and attributed canrenone to be the main
tassium levels rise with MRB administration in hemodialysis metabolite and active moiety. Improvements in the speci-
patients, only rarely does therapy lead to clinically meaning- ficity of the assay (high-performance liquid chromatog-
ful hyperkalemia requiring medication or dialysate raphy) allowed detection of spironolactone and its
adjustments.67-69 Patients on continuous ambulatory sulfated metabolites to achieve accurate characterization
peritoneal dialysis62 and continuous cycler-assisted perito- of the drug’s pharmacokinetics (Table 1).
128 Schwenk et al

Table 1. Clinical Pharmacokinetics of Mineralocorticoid Receptor include heparin, trimethoprim-sulfamethoxazole, angio-

Blockers tensin-converting enzyme inhibitors/ARBs, b-blockers,
Parameter Spironolactone Eplerenone and potassium supplements, all of which may cause hy-
perkalemia. The impact of CKD or kidney replacement
Bioavailability Unknown* Unknown therapy on spironolactone pharmacokinetics has not
Tmax (h) 1-2 1-2
been reported.
Plasma protein $90 50
binding (%)
In healthy volunteers, oral administration of 100 mg
Vd/F (L) 10† 43-90 eplerenone in aqueous solution resulted in a mean Cmax
T½ (h) 1.3 4-6 of 1.72 6 0.28 mg/mL at 1.3 6 0.8 hours. Oral bioavailability
Ue (%) ,1 0.9-2.2 of eplerenone was nearly complete, as indirectly evidenced
Impact of Cirrhosis increases CKD does not by an average of 98.6% of the dose recovered within
comorbidities half-life affect half-life 24 hours in the urine and feces as either parent drug or me-
tabolites.76 The apparent volume of distribution of eplere-
Abbreviations: T½, terminal elimination half-life; Tmax, time of
maximum serum concentration; Ue, urinary excretion of unchanged none was 4.02 6 2.17 L and the plasma protein binding
drug; Vd/F, apparent volume of distribution (for 70-kg individual). ranged from 33% to 60%, primarily to a-1 acid glycopro-
*Spironolactone bioavailability increased when administered with tein. Thus, the percentage of unbound eplerenone in the
food. plasma (pharmacologically active) is about 5-fold greater
†High plasma protein binding of spironolactone explains its
lower Vd/F.
than that of spironolactone. In the plasma, eplerenone is
in reversible equilibrium with its open lactone ring form,
SC-70303, which is pharmacologically inactive. Eplerenone
The absolute bioavailability of spironolactone is un- is extensively metabolized by CYP3A4, primarily to a 6b-
known because an intravenous formulation is not avail- hydroxy metabolite (SC71597) and to a lesser degree to
able.73 The administration of spironolactone with food (a other metabolites. In contrast to spironolactone, all metab-
moderately fatty breakfast) increased its bioavailability olites are pharmacologically inactive. The eplerenone mean
compared with fasting administration in a crossover study terminal elimination half-life was 3 6 0.63 hours in this
in 9 healthy subjects. Bioavailability was assessed by study, although a higher range has been reported
comparing the 24-hour area under the time- (Table 1). The percentages of administered parent drug
concentration curve, which increased by 95% when chang- and metabolites recovered in the urine and feces were
ing from nonfasting to fasting administration, possibly 66.6 6 3.1% and 32.0 6 3.68%, respectively, mostly within
because of a decreased first-pass effect.74 In a study of 12 24 hours. The amount of the administered dose recovered
healthy adult men, spironolactone 100 mg (tablets) was as unchanged drug in the urine and feces was
administered orally after a light breakfast for 15 consecu- 1.65 6 0.28% and 0.81 6 0.44%, respectively.
tive days.75 The mean maximal serum concentration As part of a larger study, the pharmacokinetics of epler-
(Cmax) of spironolactone was 72 6 45 ng/mL at enone were studied in 4 cohorts of healthy subjects (n ¼ 31)
2.8 6 1.3 hours on Day 1 and 80 6 20 ng/mL at with normal kidney function (mean creatinine clearances
2.6 6 1.5 hours on Day 15, which was unchanged from of the 4 cohorts ranged from 102.4 to 116.3 mL/min/
Day 8, indicating steady-state conditions after 1 week (ie, 1.73 m2). Pharmacokinetic studies were performed after
no further drug accumulation at that point). Spironolac- oral administration of eplerenone 100 mg (tablets) as a sin-
tone is extensively metabolized in the liver to a number gle dose and after 5 daily doses (fasting).77
of active metabolites including the dethioacetylated Eplerenone reached a mean Cmax of 1.43 to 1.57 mg/mL at
metabolite canrenone and the sulfur-containing deriva- 2.22 6 0.75 hours after a single dose and 1.56 to 1.87 mg/mL
tives 7a-thiomethylspirolactone and 6b-hydroxy-7a-thio- at 1.57 to 2.26 hours after multiple (4 daily) doses. The
methylspirolactone. In this study of healthy adults, the eplerenone mean half-life after a single dose ranged from
metabolite 7a-thiomethylspirolactone reached maximal 3.16 to 4.44 hours. The mean apparent volume of distribu-
concentrations 5-fold higher than spironolactone and 2- tion ranged from 56.5 to 71.9 L. The mean apparent total
fold higher than canrenone. Steady-state mean terminal body clearance was from 7.83 to 10.24 L/h/70 kg during a
elimination half-lives of spironolactone, canrenone, 7a-thi- single dose and 7.02 to 9.02 L/h/70 kg after multiple
omethylspirolactone, and 6b-hydroxy-7a-thiomethylspir- dosing. The mean kidney clearance ranged from 0.15 to
olactone were 1.4 6 0.5, 16.5 6 6.3, 13.8 6 6.4, and 15 6 0.25 L/h after a single dose and 0.17 to 0.27 L/h after mul-
4 hours, respectively. These half-lives indicate that it tiple dosing, which represented a small portion of the total
would take more than 3 days to attain steady-state serum body clearance. This was further evidenced by urinary re-
concentrations of the active moieties, ie, when to expect covery of unchanged drug of only 1.7% to 2.9% during sin-
maximal aldosterone blockade when starting therapy gle and multiple doses.
and when to expect therapeutic or toxic effects to diminish The effect of decreased kidney function on eplerenone
when stopping therapy. pharmacokinetics was examined in 4 cohorts (n ¼ 31)
Plasma protein binding of spironolactone and canrenone with creatinine clearances of 50 to 80 mL/min (mild CKD),
to albumin is 90% or more. Approximately 10% to 15% of 30 to 49 mL/min (moderate CKD), less than 30 mL/min
spironolactone metabolites are excreted in the urine, but not on dialysis (severe CKD), and oligoanuric hemodi-
whereas unmetabolized spironolactone has not been alysis patients (ESRD). These cohorts were matched to the
recovered in the urine73 or reported to be less than 1%.75 earlier described normal kidney function cohorts.77 There
Drug interactions with spironolactone (and epleronone) was a nonsignificant trend of increasing area under the
 Aldosterone Blockade in CKD 129

concentration vs time curves, which increased as kidney creatinine level was , 2.5 mg/dL and serum potassium
function declined, except for the dialysis cohort. The level was , 5 mEq/L. Subsequent spironolactone dosage
apparent total body clearances also decreased nonsignifi- and potassium supplementation were then changed at
cantly in parallel, although the kidney clearance of eplere- the discretion of the clinician. Spironolactone was titrated
none was significantly decreased in the moderate and to a median daily dose of 25 mg (range 12.5-37.5 mg) in
severe CKD groups. The mean terminal elimination half- both groups. Neither group had changes in potassium
life ranged from 3.7 to 6.8 hours after a single dose in the supplementation or heart failure medications during the
CKD subgroups, although again these were not signifi- study nor did serum creatinine change. Caucasians experi-
cantly different from the normal kidney function cohorts. enced a median increase in potassium level of 0.5 mEq/L,
The amount of unchanged drug excreted unchanged in whereas for African Americans the potassium level
the nondialysis kidney dysfunction cohorts ranged from increased by 0.1 mEq/L (P , .01). Serum potassium level
0.9% to 1.9% and was significantly less in the severe CKD increased to .5 mEq/L in 8% of the African Americans
cohort. Overall, the investigators concluded that eplerenone vs 41% of the Caucasians (P , .01) in the course of the
total body clearance was unchanged with kidney dysfunc- study. These investigators concluded that African Ameri-
tion, was minimally removed by hemodialysis, and that cans with heart failure were less responsive to the kidney
dosing adjustment for kidney dysfunction was not neces- effects of spironolactone.81 In contrast, a prospective, ran-
sary. Eplerenone dosing adjustments should be made ac- domized, placebo-controlled trial by Flack and col-
cording to serum potassium response, however. leagues82 found that eplerenone was equally effective in
In volunteers 65 years or older, compared with volunteers both African Americans and Caucasians in reducing sys-
18 to 45 years old, eplerenone Cmax and area under the con- tolic and diastolic blood pressures.
centration vs time curve increased by 22% and 45%, respec- A recent post hoc analysis examined the importance of
tively.78 In black patients, compared with white patients, race in outcomes achieved in the randomized aldactone
steady-state Cmax and area under the concentration vs evaluation study trial, a prospective, randomized,
time curve were decreased by 19% and 26%, respectively.78 placebo-controlled study of spironolactone in patients
No differences in eplerenone pharmacokinetics have been with New York Heart Association class III or IV and serum
demonstrated in Japanese vs non-Japanese subjects.79 In creatinine of 2.5 mg/dL or less.83 The African American
all these situations, patient response (eg, blood pressure, subjects who received spironolactone showed no differ-
serum potassium) should be used to determine eplerenone ence in mortality, death, or hospitalization for heart failure
dosage. Because eplerenone is metabolized by CYP3A4, compared with the African American patients who
lower doses (25 mg) should be used when concurrently received placebo.84 In contrast, non-African Americans
administered with inhibitors of this enzyme (eg, ketocona- receiving spironolactone compared with placebo had a
zole, erythromycin, verapamil, fluconazole, saquinavir).79 significantly reduced risk of mortality (hazard
ratio ¼ 0.69) and death or hospitalization for heart failure
Racial Differences in Response to Aldosterone (hazard ratio ¼ 0.63). In concert with the previously cited
Blockade studies, non-African Americans receiving spironolactone
Response to MRB therapy, including changes in serum po- had greater increases in mean serum potassium level and
tassium and efficacy in reducing cardiovascular morbidity more instances of clinically significant hyperkalemia
and mortality, may differ according to race. In a retrospec- than African Americans. Conversely, African Americans
tive study that examined MRB therapy in Caucasians and had higher rates of hypokalemia than non-African Amer-
African Americans with heart failure, differing changes in icans among the spironolactone recipients.
the serum potassium concentrations were observed. Dur- The gene for aldosterone synthase (CYP11B2) has a poly-
ing stable spironolactone therapy, African Americans had morphism at position 344 (C-344-T) that is associated with
lower serum potassium concentrations than Caucasians enhanced aldosterone production. Aldosterone, by pro-
(4.2 6 0.4 vs 4.5 6 0.5 mEq/L, P ,.01) and were more likely moting cardiac fibrosis, oxidative stress, and inflamma-
to be receiving potassium supplementation. Caucasians tion, causes progression of left ventricular dysfunction
had double the increase in serum potassium concentration and heart failure. The role of this polymorphism and the
and triple the reduction in potassium supplementation response to MRB therapy on cardiac remodeling was stud-
compared with African Americans. These differences ied over 1 year and compared in African American and
were observed despite similar levels of spironolactone non-African American patients with chronic stable heart
dose, diuretic dose, beta-blocker dose, kidney function failure (n ¼ 104). The 344-C allele frequency was signifi-
(creatinine clearance), and higher ACEI/ARB and potas- cantly lower in African American patients (0.27) compared
sium supplementation doses in the African Americans.80 with non-African American patients (0.44). Baseline and 1-
In a follow-up prospective trial, changes in serum potas- year follow-up echocardiograms in 74 patients showed an
sium concentrations after initiation of spironolactone ther- improvement in cardiac remodeling (decreased left ven-
apy for heart failure were followed and compared in tricular end-systolic diameter) only in the 344-C allele
Caucasian and African American patients. All patients group and only in the African American patients.
had baseline serum creatinine level , 2.5 mg/dL and Increased spironolactone use in this group at follow-up
serum potassium level , 5 mEq/L and were receiving showed significant improvement in left ventricular end-
ACEIs or ARBs. Median creatinine clearances were about systolic diameter. The paradoxical results might be ex-
60 mL/min. Spironolactone therapy was initiated at plained by an increased susceptibility and enhanced
12.5 mg/d and increased to 25 mg/d at 1 week if the serum response to therapy.85
130 Schwenk et al

An alternative potential explanation for the differing re- 12. Hollenberg NK. Aldosterone in the development and progression of
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2001;345(23):1689-1697.
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