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Journal of Cardiac Failure Vol. 20 No. 9 2014

Perspective Effects of in Potentiating in Failure Patients With Diuretic Resistance

CHAO LIU, MD, AND KUNSHEN LIU, MD

Shijiazhuang, People’s Republic of China

ABSTRACT

Diuretic resistance in 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 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 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- complex and include delayed absorption of the diuretic, cular morbidity and mortality in the world and is an emerging reduced secretion of the diuretic into the tubular lumen, epidemic of the 21st century. Diuretics remain the corner- hypertrophy and hyperplasia of epithelial cells of the distal stone of therapy to relieve fluid retention in HF patients. convoluted tubule, development of renal dysfunction or car- However, after an initial adequate response to diuretics, pa- diorenal syndrome, and blunted renal responsiveness to tients with acute decompensated heart failure (ADHF) natriuretic peptides owing to decreased density of natriuretic develop and diuretic resistance. peptide receptors in the .1 Several approaches have Diuretic resistance is not uncommon, especially in pa- been tried to overcome diuretic resistance by targeting the tients with New York Heart Association functional class above mechanisms, including sequential blockade 3e4 symptoms, is reported to occur in w30% of patients with different diuretics, increasing diuretic dosage, and vari- with HF on diuretic therapy, and is a challenging clinical ation of administration route (intravenous). These ap- problem.1 The mechanisms of diuretic resistance in HF are proaches used alone or in combination have proved to be effective in some but not in all cases. Over the past decade, From the Heart Center, First Hospital of Hebei Medical University, several new drugs and devices, such as receptor Hebei University, Shijiazhuang, People’s Republic of China. blockers, adenosine A1-, recombinant hu- Manuscript received January 7, 2014; revised manuscript received June man B-type natriuretic peptide, low-dose , and ul- 6, 2014; revised manuscript accepted June 10, 2014. Reprint requests: Chao Liu, MD, or Kunshen Liu, MD, Heart Center, trafiltration, targeting decongestion and improvement in First Hospital of Hebei Medical University, Hebei Medical University, renal function in patients with ADHF have failed to show 89 Donggang Road, Shijiazhuang, Hebei Province 050031, China. Tel: benefit in large-scale randomized clinical trials.2e5 There- 86 311 8591 7033; Fax: 86 311 8591 7290. E-mails: dr.liuchao@gmail. com (C. Liu) or [email protected] (K. Liu) fore, there is urgent need for new drugs that improve renal Funding: Hebei Province Government (Hebei Provincial Major Medical responsiveness to diuretic therapy. Project LS201315). See page 628 for disclosure information. 1071-9164 Current Perspective of in HF Ó 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/). In vitro, glucocorticoids have variable affinities for miner- http://dx.doi.org/10.1016/j.cardfail.2014.06.353 alocorticoid receptor (MR), ie, properties,

625 626 Journal of Cardiac Failure Vol. 20 No. 9 September 2014 owing to their molecular similarity to . The 2013 Newly Emerging Potential Mechanisms of American Heart Association/American College of Cardiol- Glucocorticoids in HF ogy Foundation guidelines currently list ‘‘steroids’’ among common precipitants of ADHF.6 However, an enzyme, The mechanisms of diminished renal responsiveness to 11-beta hydroxysteroid dehydrogenase type II, exists in diuretics are complex. Several mechanisms have been pro- mineralocorticoid target tissues that can prevent MR posed, including blunted renal responsiveness to endoge- overstimulation by glucocorticoids and allow selective nous natriuretic peptides due to reduced natriuretic mineralocorticoid action by catalyzing the deactivation of peptide receptor A (NPR-A) in the kidney, renal vasocon- glucocorticoids to 11-dehydro metabolites.7 This is why striction, and inflammation activation.11 cortisol, which circulates at 100e1,000-fold higher concen- Glucocorticoids have been shown to play a key role in trations than aldosterone,8 and binds with equal affinity to body fluid control through mediating the gene expression MR, does not overstimulate MR in normal subjects or of NPR-A by binding to specific DNA sequences, ie, gluco- patients with stable HF. Although adverse effects, eg, facial corticoid response element (Fig. 1).12,13 We found that glu- and leg swelling, weight gain, and , have been cocorticoids could act on the hypothalamus as well as the implicated with the use of glucocorticoids, there are no kidney to assist in the normalization of extracellular fluid data supporting the concern of retention with the volume through up-regulating NPR-A density in the hypo- use of glucocorticoids in patients with HF. Weight gain, a thalamus and kidney.12,13 In the kidney, glucocorticoids common of chronic glucocorticoid use, is improved renal responsiveness to atrial natriuretic peptide actually induced mostly by increasing food intake through (ANP) by increasing NPR-A density in the renal inner med- the central regulation of appetite.9 Rather, there is ever ullary collecting duct.12 In the hypothalamus, glucocorti- more emerging evidence from nonhuman and clinical studies coids inhibited dehydration-induced intake by suggesting that glucocorticoids with minimal mineralocorti- potentiating hypothalamic response to ANP.13 The effects coid properties could potentiate diuretic effect in HF.10 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. Glucocorticoids in Diuretic Resistance  Liu and Liu 627 homeostasis. It is noteworthy that the effect of glucocorti- Ashbel et al assessed the effects of prednisone and meth- coids on NPR-A expression has been observed in both ylprednisolone in HF patients with blunted response to time- and dose-dependent patterns, ie, the NPR-A expression (80 mg/d).19 Compared with baseline, predni- in the hypothalamus and kidney increased with increasing sone doubled and methylprednisolone tripled daily glucocorticoid concentration and time. Moreover, there is ev- output after a 3-day treatment. As a result, both prednisone idence demonstrating that glucocorticoids can dilate renal and methylprednisolone reverted renal responsiveness to vasculature, thereby increasing renal plasma flow and furosemide, leading to a dramatic body weight reduction. glomerular filtration rate.14 The glucocorticoid-induced renal We evaluated the effect of prednisone (1 mg kgÀ1 dÀ1 involves multiple pathways, which include with a maximum dose of 60 mg/d) in 13 patients with increased renal prostaglandin, nitric oxide, and dopamine ADHF and diuretic resistance, defined as the failure to production.15 Finally, as antiinflammatory agents, glucocorti- attain a negative fluid balance despite use of furosemide coids may play a disease-modifying role in cardiorenal syn- (O200 mg/d), (O50 mg/d), spirono- drome. In HF, several neurohormones and proinflammatory lactone (O50e100 mg/d), and positive inotropic agents. cytokines are activated.11 Inflammatory response, in turn, All drugs were administered for $3 days before diuretic may further worsen renin-angiotensin-aldosterone and sym- resistance was diagnosed.20 Prednisone successfully pathetic activation and cause renal injury. reversed diuretic resistance in all patients and produced a Therefore, the antiinflammatory role of glucocorticoids in potent diuresis with significant body weight loss attenuating diuretic resistance in HF can not be excluded (9.4 6 3.1 kg) over 4 weeks as well as significantly and merits further investigations. decreased serum creatinine (sCr) from 1.52 6 0.70 mg/dL at baseline to 0.90 6 0.33 (P ! .01). Historical Review of Adrenocorticotropic (ACTH)/Glucocorticoid Use in HF Controlled Clinical Trials of Glucocorticoid Use of Steroids in PreeLoop Diuretic Era Use in HF

In the 1950s, physicians used ACTH/glucocorticoids in pa- To determine whether glucocorticoids cause sodium and tients with refractory HF based on the assumption that these water retention in patients with HF, 20 clinically stable HF patients suffer adrenal or pituitary insufficiency. Several case patients without overt fluid retention, who were receiving reports supporting the use of glucocorticoids to improve renal standard therapy, were randomized to receive predni- responsiveness to diuretic therapy in HF have been published sone (1 mg kgÀ1 dÀ1 with a maximum dose of 60 mg/d) or (Supplemental Table 1). In 3 large prospective clinical series, placebo for 7 days.21 During this period, prednisone caused ACTH/glucocorticoids successfully reversed mercurial striking diuresis and natriuresis (Fig. 2). Of note, there was 16e18 diuretic resistance in most of the cases. a 3-day latent period for prednisone to take effect. This study challenged the widespread notion that glucocorticoids Use of Steroids in Era cause renal sodium and water retention in patients with HF. With the introduction of loop diuretics into clinical prac- In patients with HF, diuretic use is often associated with tice, physicians discontinued the use of steroids. However, the development of .22 We found that predni- as the population of patients with end-stage HF increased sone could dramatically increase the renal responsiveness to dramatically, diuretic resistance became more common. diuretic therapy, lower serum uric acid concentration, and Recent data show that glucocorticoids can successfully over- improve renal function in HF patients with hyperuricemia.23 come diuretic resistance in this population who fail to To test whether glucocorticoids could prevent the devel- respond to loop or combined diuretic therapy.15,19,20 opment of renal dysfunction, which is often seen with

Fig. 2. The effect of prednisone on daily urine output and renal electrolyte 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.21 628 Journal of Cardiac Failure Vol. 20 No. 9 September 2014 diuretic therapy, 102 patients with ADHF were randomized susceptibility to , sleep disorder, hyperactivity, to receive glucocorticoids (1 20-mg dose of dexamethasone osteoporosis, and muscle wasting. In addition, all clinical followed by 1 mg kgÀ1 dÀ1 prednisone with a maximum evidence of glucocorticoid in HF is based on short-term dose of 60 mg/d for 7 days) plus diuretics or standard use. Therefore, long-term glucocorticoid use should be diuretic therapy alone.24 The change in sCr from baseline avoided in patients with HF. Additionally, glucocorticoids was À0.14 mg/dL in the glucocorticoid group versus were administrated as an add-on therapy in all clinical À0.02 mg/dL in the standard-treatment group (P ! .05). studies, and there is no evidence that they can improve Cardiovascular death within 30 days occurred in 3 patients renal function in the absence of diuretic therapy in HF. in the glucocorticoid group compared with 10 patients in ! the standard-care group (P .05). These patients were fol- Perspective lowed for a median of 19 months (range 1e36 months). The survival benefit in the glucocorticoid group persisted In light of the evidence provided, the short-term use of during the follow-up period (P 5 .037). Several key limita- glucocorticoids with minimal mineralocorticoid action in tions of this study compromised its interpretation. First, the patients with HF, when indicated for the treatment of other study was not powered to determine a difference in mortal- acute comorbid conditions, eg, acute , is safe and ity between groups. Second, the study was not blinded and perhaps even advantageous. The short-term use of gluco- allowed care providers to select and adjust diuretic doses corticoids, when added to maximum conventional therapy, (mean doses between groups were not recorded). Therefore, can potentiate renal responsiveness to diuretic therapy in considerable bias in the use of diuretics can exist, affecting patients with HF. However, a larger properly powered ran- the efficacy of glucocorticoid therapy. domized double-blind placebo-controlled study is war- In 1986, Stubbs et al studied the efficacy and safety ranted to demonstrate their safety and efficacy in such profile of methylprednisolone on mortality in patients with patients. The underlying mechanisms of using glucocorti- acute myocardial infraction complicated by ADHF. They coids to increase renal responsiveness to the diuretics are conducted 2 trials in different populations.25 The 1st trial complex and also need to be clarified further. 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- Acknowledgments tion was initiated O6 hours from the onset of chest pain (late intervention group). Patents in both trials were randomized The authors thank Professor Inder Anand, Director of the to receive methylprednisolone (30 mg/kg intravenously, Heart Failure Program at the Minneapolis VA Medical Cen- repeated 3 hours later) or placebo. Methylprednisolone ter, for his critical suggestion, comments, and extensive ed- improved HF outcomes. The pooled data showed that meth- iting. The authors also thank Professor Jian-Ming Li of ylprednisolone reduced mortality caused by pump failure Minneapolis VA Medical Center for his critical reading. (relative risk 0.51, 95% CI 0.28e0.94; P 5 .03). A hemody- namic and metabolic study was performed in a small subset Disclosures of patients from the study. That study revealed that glucocor- ticoids caused an increase in cardiac output and diuresis, but None. a decrease in 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 Supplementary Data À1 À1 prednisone (1 mg kg d with maximum dosage of Supplementary data related to this article can be found at 60 mg/d) or standard treatment. Adding prednisone to http://dx.doi.org/10.1016/j.cardfail.2014.06.353. 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/ References dL at the end of the study (P ! .01) in the patients given pred- nisone, whereas sCr increased from 1.2 mg/dL at baseline to 1. Ravnan SL, Ravnan MC, Deedwania PC. Pharmacotherapy in conges- tive heart failure: diuretic resistance and strategies to overcome resis- 1.3 mg/dL in patients receiving standard treatment. tance in patients with congestive heart failure. Congest Heart Fail 2002;8:80e5. Adverse Effects and Limitations of 2. Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Glucocorticoids in Heart Failure Goldsmith SR, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart fail- ure randomized trial. JAMA 2013;310:2533e43. Glucocorticoids have multiple adverse effects, especially 3. 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