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Perspective

Effects of Glucocorticoids in Potentiating Diuresis in Heart

Failure Patients With Diuretic Resistance

CHAO LIU, MD, AND KUNSHEN LIU, MD

Shijiazhuang, People’s Republic of China

ABSTRACT

Diuretic resistance in heart failure is defined as a state in which diuretic response is diminished or lost

before the therapeutic goal of relief from congestion has been reached. Diuretic resistance is very common

and is associated with poor outcomes. Over the past decade, several new drugs and devices targeting

decongestion and improvement in renal function in patients with heart failure have failed to show benefit

in randomized clinical trials. Glucocorticoids had been used to manage diuretic resistance before the

advent of loop diuretics. More recent evidence appears to confirm that glucocorticoids may also help

to overcome resistance to loop diuretics. This review tries to summarize the available evidence and poten-

tial mechanisms related to glucocorticoid therapy in patients with heart failure and its effect on diuretic

resistance. ( J Cardiac Fail 2014;20:625e629)

Key Words:   Heart failure, diuretic resistance, glucocorticoids.

Chronic heart failure (HF) is a leading cause of cardiovas-

cular morbidity and mortality in the world and is an emergingepidemic of the 21st century. Diuretics remain the corner-

stone of therapy to relieve fluid retention in HF patients.

However, after an initial adequate response to diuretics, pa-

tients with acute decompensated heart failure (ADHF)

develop cardiorenal syndrome and diuretic resistance.

Diuretic resistance is not uncommon, especially in pa-

tients with New York Heart Association functional class

3e4 symptoms, is reported to occur in   w30% of patients

with HF on diuretic therapy, and is a challenging clinical

problem.1 The mechanisms of diuretic resistance in HF are

complex and include delayed absorption of the diuretic,

reduced secretion of the diuretic into the tubular lumen,hypertrophy and hyperplasia of epithelial cells of the distal

convoluted tubule, development of renal dysfunction or car-

diorenal syndrome, and blunted renal responsiveness to

natriuretic peptides owing to decreased density of natriuretic

peptide receptors in the kidney.1 Several approaches have

been tried to overcome diuretic resistance by targeting the

above mechanisms, including sequential nephron blockade

with different diuretics, increasing diuretic dosage, and vari-

ation of administration route (intravenous). These ap-

proaches used alone or in combination have proved to be

effective in some but not in all cases. Over the past decade,

several new drugs and devices, such as vasopressin receptor

blockers, adenosine A1-receptor antagonist, recombinant hu-

man B-type natriuretic peptide, low-dose dopamine, and ul-

trafiltration, targeting decongestion and improvement in

renal function in patients with ADHF have failed to show

benefit in large-scale randomized clinical trials.2e5 There-

fore, there is urgent need for new drugs that improve renal

responsiveness to diuretic therapy.

Current Perspective of Corticosteroids in HF

In vitro, glucocorticoids have variable affinities for miner-

alocorticoid receptor (MR), ie, mineralocorticoid properties,

From the Heart Center, First Hospital of Hebei Medical University, Hebei University, Shijiazhuang, People’s Republic of China.

Manuscript received January 7, 2014; revised manuscript received June6, 2014; revised manuscript accepted June 10, 2014.

Reprint requests: Chao Liu, MD, or Kunshen Liu, MD, Heart Center,First Hospital of Hebei Medical University, Hebei Medical University,89 Donggang Road, Shijiazhuang, Hebei Province 050031, China. Tel:86 311 8591 7033; Fax: 86 311 8591 7290. E-mails: dr.liuchao@gmail.

com (C. Liu) or   ksliud@sohu.com (K. Liu)Funding: Hebei Province Government (Hebei Provincial Major Medical

Project LS201315).See page 628 for disclosure information.1071-9164 2014 The Authors. Published by Elsevier Inc. This is an open access

article under the CC BY-NC-ND license (http://creativecommons.org/ 

licenses/by-nc-nd/3.0/ ).

http://dx.doi.org/10.1016/j.cardfail.2014.06.353

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owing to their molecular similarity to aldosterone. The 2013

American Heart Association/American College of Cardiol-

ogy Foundation guidelines currently list ‘‘steroids’’ among

common precipitants of ADHF.6 However, an enzyme,

11-beta hydroxysteroid dehydrogenase type II, exists in

mineralocorticoid target tissues that can prevent MR

overstimulation by glucocorticoids and allow selective

mineralocorticoid action by catalyzing the  deactivation of glucocorticoids to 11-dehydro metabolites.7 This is why

cortisol, which circulates  at 100e1,000-fold higher concen-

trations than aldosterone,8 and binds with equal affinity to

MR, does not overstimulate MR in normal subjects or

patients with stable HF. Although adverse effects, eg, facial

and leg swelling, weight gain, and hypertension, have been

implicated with the use of glucocorticoids, there are no

data supporting the concern of sodium retention with the

use of glucocorticoids in patients with HF. Weight gain, a

common adverse effect of chronic glucocorticoid use, is

actually induced mostly by increasing food intake through

the central regulation of appetite.9 Rather, there is ever

more emerging evidence from nonhuman and clinical studies

suggesting that glucocorticoids with minimal mineralocorti-

coid properties could potentiate diuretic effect in HF.10

Newly Emerging Potential Mechanisms ofGlucocorticoids in HF

The mechanisms of diminished renal responsiveness to

diuretics are complex. Several mechanisms have been pro-

posed, including blunted renal responsiveness to endoge-

nous natriuretic peptides due to reduced natriuretic

peptide receptor A (NPR-A) in the kidney, renal vasocon-striction, and inflammation activation.11

Glucocorticoids have been shown to play a key role in

body fluid control through mediating the gene expression

of NPR-A by binding to specific DNA sequences, ie, gluco-

corticoid response element (Fig. 1).12,13 We found that glu-

cocorticoids could act on the hypothalamus as well as the

kidney to assist in the normalization of extracellular fluid

volume through up-regulating NPR-A density in the hypo-

thalamus and kidney.12,13 In the kidney, glucocorticoids

improved renal responsiveness to atrial natriuretic peptide

(ANP) by increasing NPR-A density in the renal inner med-

ullary collecting duct.12 In the hypothalamus, glucocorti-

coids inhibited dehydration-induced water   intake by

potentiating hypothalamic response to ANP.13 The effects

may work in concert to keep the body fluid volume in

Fig. 1. Potential potentiating diuretic mechanisms of glucocorticoids in heart failure. Glucocorticoids bind to and activate the cytoplasmic

glucocorticoid receptor, a ligand-dependent transcription factor. The ligand-activated receptor dimer activates natriuretic peptide receptor A

(NPR-A) gene expression by binding to specific DNA sequences (ie, glucocorticoid response element [GRE]) in the promoter regions of 

glucocorticoid-regulated NPR-A gene. The glucocorticoid receptor (GR) increases responsiveness to natriuretic peptides by activating

NPR-A gene expression in the hypothalamus and kidney.

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homeostasis. It is noteworthy that the effect of glucocorti-

coids on NPR-A expression has been observed in both

time- and dose-dependent patterns, ie, the NPR-A expression

in the hypothalamus and kidney increased with increasing

glucocorticoid concentration and time. Moreover, there is ev-

idence demonstrating that glucocorticoids can dilate renal

vasculature, thereby increasing renal plasma flow and

glomerular filtration rate.14

The glucocorticoid-induced renalvasodilation involves multiple pathways, which include

increased renal prostaglandin, nitric oxide, and dopamine

production.15 Finally, as antiinflammatory agents, glucocorti-

coids may play a disease-modifying role in cardiorenal syn-

drome. In HF, several neurohormones and proinflammatory

cytokines are activated.11 Inflammatory response, in turn,

may further worsen renin-angiotensin-aldosterone and sym-

pathetic nervous system activation and cause renal injury.

Therefore, the antiinflammatory role of glucocorticoids in

attenuating diuretic resistance in HF can not be excluded

and merits further investigations.

Historical Review of Adrenocorticotropic Hormone(ACTH)/Glucocorticoid Use in HF

Use of Steroids in PreeLoop Diuretic Era

In the 1950s, physicians used ACTH/glucocorticoids in pa-

tients with refractory HF based on the assumption that these

patients suffer adrenal or pituitary insufficiency. Several case

reports supporting the use of glucocorticoids to improve renal

responsiveness to diuretic therapy in HF have been published

(Supplemental Table 1). In 3 large prospective clinical series,

ACTH/glucocorticoids successfully   reversed mercurial

diuretic resistance in most of the cases.16e18

Use of Steroids in Loop Diuretic Era

With the introduction of loop diuretics into clinical prac-

tice, physicians discontinued the use of steroids. However,

as the population of patients with end-stage HF increased

dramatically, diuretic resistance became more common.

Recent data show that glucocorticoids can successfully over-

come diuretic resistance in this population   who   fail to

respond to loop or combined diuretic therapy.15,19,20

Ashbel et al assessed the effects of prednisone and meth-

ylprednisolone in HF   patients with blunted response to

furosemide (80 mg/d).19 Compared with baseline, predni-

sone doubled and methylprednisolone tripled daily urine

output after a 3-day treatment. As a result, both prednisone

and methylprednisolone reverted renal responsiveness to

furosemide, leading to a dramatic body weight reduction.

We evaluated the effect of prednisone (1 mg kg1

d1

with a maximum dose of 60 mg/d) in 13 patients with

ADHF and diuretic resistance, defined as the failure to

attain a negative fluid balance despite use of furosemide

(O200 mg/d), hydrochlorothiazide (O50 mg/d), spirono-

lactone (O50e100 mg/d), and positive inotropic agents.

All drugs were administered   f or   $3 days before diuretic

resistance was diagnosed.20 Prednisone successfully

reversed diuretic resistance in all patients and produced a

potent diuresis with significant body weight loss

(9.4   6   3.1 kg) over 4 weeks as well as significantly

decreased serum creatinine (sCr) from 1.52   6

0.70 mg/dL at baseline to 0.90 6  0.33 (P ! .01).

Controlled Clinical Trials of GlucocorticoidUse in HF

To determine whether glucocorticoids cause sodium and

water retention in patients with HF, 20 clinically stable HF

patients without overt fluid retention, who were receiving

standard drug therapy, were randomized to receive predni-

sone (1 mg kg1 d1 with a maximum dose of 60 mg/d) or

placebo for 7 days.21 During this period, prednisone caused

striking diuresis and natriuresis (Fig. 2). Of note, there was

a 3-day latent period for prednisone to take effect. This

study challenged the widespread notion that glucocorticoids

cause renal sodium and water retention in patients with HF.

In patients with HF, diuretic use is often associated with

the development of hyperuricemia.22 We found that predni-

sone could dramatically increase the renal responsiveness to

diuretic therapy, lower serum uric acid concentration, and

improve renal function in HF patients with hyperuricemia.23

To test whether glucocorticoids could prevent the devel-

opment of renal dysfunction, which is often seen with

Fig. 2.  The effect of prednisone on daily urine output and renal electrolyte excretion in clinically stable heart failure patients. The patients

were treated with prednisone or placebo for 7 days; n 5 10 in each group.  *Significant difference compared with placebo (P! .05). From

Liu et al.21

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diuretic therapy, 102 patients with ADHF were randomized

to receive glucocorticoids (1 20-mg dose of dexamethasone

followed by 1 mg kg1 d1 prednisone with a maximum

dose of 60 mg/d for   7   days) plus diuretics or standard

diuretic therapy alone.24 The change in sCr from baseline

was   0.14 mg/dL in the glucocorticoid group versus

0.02 mg/dL in the standard-treatment group (P ! .05).

Cardiovascular death within 30 days occurred in 3 patientsin the glucocorticoid group compared with 10 patients in

the standard-care group (P! .05). These patients were fol-

lowed for a median of 19 months (range 1e36 months).

The survival benefit in the glucocorticoid group persisted

during the follow-up period (P 5 .037). Several key limita-

tions of this study compromised its interpretation. First, the

study was not powered to determine a difference in mortal-

ity between groups. Second, the study was not blinded and

allowed care providers to select and adjust diuretic doses

(mean doses between groups were not recorded). Therefore,

considerable bias in the use of diuretics can exist, affecting

the efficacy of glucocorticoid therapy.

In 1986, Stubbs et al studied the efficacy and safety

profile of methylprednisolone on mortality in patients with

acute myocardial infraction complicated by   ADHF. They

conducted 2 trials in different populations.25 The 1st trial

was in patients whose medical intervention was initiated

within 6 hours of the onset of chest pain (early intervention

group), and the 2nd was in patients whose medical interven-

tion was initiatedO6 hours from the onset of chest pain (late

intervention group). Patents in both trials were randomized

to receive methylprednisolone (30 mg/kg intravenously,

repeated 3 hours later) or placebo. Methylprednisolone

improved HF outcomes. The pooled data showed that meth-

ylprednisolone reduced mortality caused by pump failure(relative risk 0.51, 95% CI 0.28e0.94; P 5 .03). A hemody-

namic and metabolic study was performed in a small subset

of patients from the study. That study revealed that glucocor-

ticoids caused an increase in cardiac output and diuresis, but

a decrease in blood volume.26

In 2010, Mady and Guindy reported their results on the use

of glucocorticoids to treat patients with ADHF refractory to

standard medical treatment.27 Forty patients received either

prednisone (1 mg kg1 d1 with maximum dosage of 

60 mg/d) or standard treatment. Adding prednisone to

standard treatment doubled daily urine output (P ! .001).

As a result, HF symptoms were markedly improved in 80%of the patients at the end of the study (P! .001). The level

of sCr was reduced from 1.6 mg/dL at baseline to 0.9 mg/ 

dLat the end ofthe study (P! .01) in the patients given pred-

nisone, whereas sCr increased from 1.2 mg/dL at baseline to

1.3 mg/dL in patients receiving standard treatment.

Adverse Effects and Limitations ofGlucocorticoids in Heart Failure

Glucocorticoids have multiple adverse effects, especially

when used in large doses and over the long term. These side

effects include disturbances in glucose tolerance,

susceptibility to infection, sleep disorder, hyperactivity,

osteoporosis, and muscle wasting. In addition, all clinical

evidence of glucocorticoid in HF is based on short-term

use. Therefore, long-term glucocorticoid use should be

avoided in patients with HF. Additionally, glucocorticoids

were administrated as an add-on therapy in all clinical

studies, and there is no evidence that they can improve

renal function in the absence of diuretic therapy in HF.

Perspective

In light of the evidence provided, the short-term use of 

glucocorticoids with minimal mineralocorticoid action in

patients with HF, when indicated for the treatment of other

acute comorbid conditions, eg, acute gout, is safe and

perhaps even advantageous. The short-term use of gluco-

corticoids, when added to maximum conventional therapy,

can potentiate renal responsiveness to diuretic therapy in

patients with HF. However, a larger properly powered ran-

domized double-blind placebo-controlled study is war-ranted to demonstrate their safety and efficacy in such

patients. The underlying mechanisms of using glucocorti-

coids to increase renal responsiveness to the diuretics are

complex and also need to be clarified further.

Acknowledgments

The authors thank Professor Inder Anand, Director of the

Heart Failure Program at the Minneapolis VA Medical Cen-

ter, for his critical suggestion, comments, and extensive ed-

iting. The authors also thank Professor Jian-Ming Li of 

Minneapolis VA Medical Center for his critical reading.

Disclosures

None.

Supplementary Data

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.cardfail.2014.06.353.

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