acute decompensated heart failure and the cardiorenal syndrome decompensated heart failure and...

Acute decompensated heart failure and the cardiorenal syndrome

Kelly V. Liang, MD; Amy W. Williams, MD; Eddie L. Greene, MD; Margaret M. Redfield, MD

T he term cardiorenal syndromehas been variably defined butcan be considered as a state ofadvanced cardiorenal dysregu-

lation manifest by one or more of threespecific features, including heart failure(HF) with concomitant and significantrenal disease (cardiorenal failure), wors-ening renal function (developing duringthe treatment of acute decompensatedHF (ADHF), and diuretic resistance (DR)(Table 1).

Cardiorenal Failure

Renal impairment in patients with HFis common and is increasingly recog-nized as an independent risk factor formorbidity and mortality (1– 6). In ananalysis of patients enrolled in the Can-desartan in Heart Failure Assessment ofReduction in Mortality and Morbidity(CHARM) study, Hillege et al. (7) showedthat the level of renal dysfunction was apotent independent predictor of death orHF admission (Fig. 1). The Acute Decom-pensated Heart Failure National Registry(ADHERE), a large database of 105,388patients with HF requiring hospitaliza-tion in the United States, reported that30% had an additional diagnosis consis-tent with chronic kidney disease (8). Ap-proximately 20% of patients had serumcreatinine (Cr) �2.0 mg/dL, 9% had Cr�3.0 mg/dL, and 5% were receiving dial-ysis therapy. Smith et al. (9) conducted asystematic review and meta-analysis of 16studies characterizing the association be-tween renal impairment and mortality in80,098 hospitalized and nonhospitalizedHF patients (1945 through May 2005).Renal impairment was defined variably asCr �1.0 mg/dL, Cr clearance (CrCl) or

estimated glomerular filtration rate(eGFR) �90 mL/min, or cystatin-C�1.03 mg/dL. Moderate to severe renalimpairment was defined as Cr �1.5 mg/dL, CrCl or eGFR �53 mL/min, or cysta-tin-C �1.56 mg/dL. A total of 63% ofpatients had any renal impairment, and29% had moderate to severe impairment.Adjusted all-cause mortality was signifi-cantly increased for patients with any re-nal impairment. Mortality worsened in-crementally across the range of renalfunction, with 15% increased risk for ev-ery 0.5-mg/dL increase in Cr and 7% in-creased risk for every 10-mL/min de-crease in eGFR (9).

Owan et al. (10) recently reported onsecular trends in the severity of renaldysfunction in patients with ADHF in6,440 consecutive unique patients hospi-talized for HF therapy at Mayo ClinicHospitals, Rochester, MN, from January1, 1987, to December 31, 2002. Over the16-yr time period, age and admission Crincreased, eGFR decreased, and hemoglo-bin decreased (Fig. 2). The more domi-nant role of renal dysfunction in HF wasalso stressed in the recent EvaluationStudy of Congestive Heart Failure and

From the Division of Nephrology and Hypertension(KVL, AWW, ELG) and Division of Cardiology (MMR),Mayo Clinic, Rochester, MN.

Supported, in part, by grant PO1HL-76611 fromthe National Institutes of Health, Bethesda, MD.

The authors have not disclosed any potential con-flicts of interest.

Address requests for reprints to: Margaret M. Red-field, MD, Heart Failure Group, Division of Cardiology,Mayo Clinic College of Medicine, Guggenheim 901,200 First Street SW, Rochester, MN 55905.

Copyright © 2007 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000296270.41256.5C

Heart failure is one of the leading causes of hospitalizations inthe United States. Concomitant and significant renal dysfunctionis common in patients with heart failure. Increasingly, the syn-drome of heart failure is one of cardiorenal failure, in whichconcomitant cardiac and renal dysfunctions exist, with eachaccelerating the progression of the other. One fourth of patientshospitalized for the treatment of acute decompensated heartfailure will experience significant worsening of renal function,which is associated with worse outcomes. It remains unclearwhether worsening renal function specifically contributes to pooroutcomes or whether it is merely a marker of advanced cardiacand renal dysfunction. Diuretic resistance, with or without wors-ening renal function, is also common in acute decompensatedheart failure, although the definition of diuretic resistance, itsprevalence, and prognostic implications are less well defined. Theterm cardiorenal syndrome has been variably associated withcardiorenal failure, worsening renal function, and diuretic resis-tance but is more comprehensively defined as a state of advancedcardiorenal dysregulation manifest by one or all of these specific

features. The pathophysiology of the cardiorenal syndrome ispoorly understood and likely involves interrelated hemodynamicand neurohormonal mechanisms. When conventional therapy foracute decompensated heart failure fails, mechanical fluid removalvia ultrafiltration, hemofiltration, or hemodialysis may be neededfor refractory volume overload. While ultrafiltration can addressdiuretic resistance, whether ultrafiltration prevents worseningrenal function or improves outcomes in patients with cardiorenalsyndrome remains unclear. Evidence regarding the potential re-nal-preserving effects of nesiritide is mixed, and further studieson the efficacy and safety of different doses of nesiritide in heartfailure therapy are warranted. Newer therapeutic agents, includ-ing vasopressin antagonists and adenosine antagonists, holdpromise for the future, and clinical trials of these agents areunderway. (Crit Care Med 2008; 36[Suppl.]:S75–S88)

KEY WORDS: cardiorenal syndrome; heart failure; congestiveheart failure; renal dysfunction; diuretics; ultrafiltration; vaso-pressin antagonists; adenosine antagonists; prognosis; therapy

S75Crit Care Med 2008 Vol. 36, No. 1 (Suppl.)

Pulmonary Artery Catheterization Effec-tiveness (ESCAPE) trial, where it was em-phasized that episodes of HF decompen-sation were less commonly associatedwith uncorrected vasoconstriction andmore commonly associated with renaldysfunction with requirement of higherdiuretic doses at discharge than histori-cally noted (11). Thus, the severity ofcardiorenal failure in patients hospital-ized for HF is increasing. Importantly,cardiorenal failure is equally prevalent inpatients with HF and normal ejectionfraction (diastolic HF) or reduced ejec-tion fraction (systolic HF) (9, 10, 12).

Worsening Renal Function

Several studies have established that�70% of patients will experience someincrease in Cr during hospitalization for

HF, with approximately 20% to 30% ofHF patients experiencing an increase of�0.3 mg/dL (10, 12–17). Worsening re-nal function occurs relatively early in thecourse of the hospitalization (13) (Fig. 3).Any change in Cr has been shown to beassociated with longer length of stay, in-creased costs, and increased short-termand long-term mortality (10, 12–17). Theassociation of worsening renal functionwith poorer outcomes is independent ofthe degree of baseline renal dysfunctionand many other pertinent covariables(10, 13, 17, 18). Nonetheless, it remainsunclear whether the worsening renalfunction itself contributes to the in-creased mortality or whether it merelyserves as a marker of more severe cardiacand/or renal dysfunction. Importantly,worsening renal function is as commonin diastolic HF as it is in systolic HF (9,10, 12). While the severity of underlyingrenal dysfunction in ADHF patients hasincreased over time, Owan et al. (10) didnot find any evidence of increases in theincidence of worsening renal functionover time.

Diuretic Resistance

In patients with ADHF associated withvolume overload, initial therapy focuseson sodium and fluid restriction and di-uretics. Diuretic resistance has been de-fined as persistent pulmonary congestionwith or without worsening renal functiondespite attempts at diuresis (Table 1). Theprevalence of DR depends in part on theaggressiveness of the diuretic dosing.While worsening renal function com-monly develops in the absence of persis-tent congestion when diuretic dosing hasbeen too high (termed overdiuresis),

worsening renal function also often oc-curs despite persistent pulmonary con-gestion in patients with DR. Both DR andworsening renal function are more com-mon in patients with underlying renaldysfunction, and the triad of cardiorenalfailure, DR, and worsening renal functiondespite marked persistent volume over-load represents the most extreme mani-festation of the cardiorenal syndrome.

RISK FACTORS FORCARDIORENAL SYNDROME

The common risk factors of hyperten-sion, diabetes mellitus, and atherosclero-sis explain the high prevalence of coexis-tent cardiac and renal dysfunction (18).Success in preventing death from HF,acute myocardial infarction, stroke, andnoncardiovascular disease may result in alonger exposure to risk factors for renaldysfunction contributing to more severerenal dysfunction in HF patients. Impor-tantly, CrCl or eGFR as estimated by thesimplified Modification of Diet in RenalDisease formula or Cockcroft-Gault for-mula is a better estimator of renal func-tion than serum Cr, as serum Cr mayoverestimate renal function in the HFpopulation, particularly in elderlywomen. On average, persons developingworsening renal function are older andhave a greater prevalence of prior HF,renal dysfunction, diabetes, and hyper-tension. In an elegant study by Forman etal. (12), the authors used Cox regressionanalysis in a large (1,004 patients), well-characterized, and regionally diverse HFpopulation to devise a risk score for pre-dicting which patients with ADHF woulddevelop worsening renal function. Thisanalysis yielded a scoring system where 1point each was assigned to history of HF,history of diabetes, and systolic bloodpressure �160 mm Hg at admission; 2points were assigned to plasma Cr 1.5–2.4mg/dL; and 3 points were assigned toplasma Cr �2.5 mg/dL. Thirty-five per-cent of the total sample had a score of �3and had a 43% likelihood of developingworsening renal function (12). Risk fac-tors for DR are not as well characterizedbut are likely similar to those for wors-ening renal function.

PATHOPHYSIOLOGY OF THECARDIORENAL SYNDROME

The pathophysiological features con-tributing to cardiorenal failure, worsen-

Table 1. Features of the cardiorenal syndrome

Cardiorenal failureMild: HF � eGFR 30–59 mL/min/1.73 m2

Moderate: HF � eGFR 15–29 mL/min/1.73 m2

Severe: HF � eGFR �15 mL/min/1.73 m2 ordialysis

Worsening renal function during treatment ofADHF

Change in creatinine �0.3 mg/dL or �25%baseline

Diuretic resistancePersistent congestion despite

�80 mg furosemide/day�240 mg furosemide/dayContinuous furosemide infusionCombination diuretic therapy (loop

diuretic � thiazide � aldosteroneantagonist)

HF, heart failure; eGFR, estimated glomerularfiltration rate by Modification of Diet in Renal Dis-ease equation; ADHF, acute decompensated heartfailure.

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Figure 1. Kaplan-Meier plot of cumulative incidence of cardiovascular death or unplanned admissionto hospital for the management of worsening heart failure stratified by approximate quintiles ofestimated glomerular filtration rate in mL/min/1.73 m2 (time in years). Reproduced with permissionfrom Hillege HL, Nitsch D, Pfeffer MA, et al: Renal function as a predictor of outcome in a broadspectrum of patients with heart failure. Circulation 2006; 113:671–678.

S76 Crit Care Med 2008 Vol. 36, No. 1 (Suppl.)

ing renal function, and DR are complexand interrelated.

Pathophysiology of CardiorenalFailure

In HF, decreases in left ventricularsystolic or diastolic function results in anumber of hemodynamic derangements,including decreased cardiac output,stroke volume, and arterial underfilling(19). The decrease in effective arterialblood volume is sensed by arterial barore-ceptors and causes the release of a cas-cade of neurohormones that producecompensatory mechanisms aimed at cor-recting the underfilling and restorationof organ perfusion. Activation of the re-nin-angiotensin-aldosterone system,sympathetic nervous system, endothelin,and arginine vasopressin promotes vol-

ume retention. These sodium-retainingvasoconstrictive systems are balanced byactivation of the vasodilatory, natriuretichormonal or cytokine systems, includingthe natriuretic peptides, prostaglandins,bradykinin, and nitric oxide (20, 21). Un-der normal physiologic conditions, thesepathways would act in concert to assist inthe preservation of volume status andvascular tone and thus optimize cardiacoutput and organ perfusion. However, inHF, they promote the perpetuation of avicious cycle of perturbations that ulti-mately result in chronic renal hypoxia,inflammation, and oxidative stress, whichmay adversely affect cardiac and renalstructure and function independent ofchanges related to underlying atherosclero-sis, hypertension, and diabetes (18, 22, 23).The HF state itself may promote irrevers-

ible structural and functional renal dis-ease even in the absence of intrinsic renaldisease, as is sometimes noted in youngerpatients with end-stage HF related to car-diomyopathies in the absence of athero-sclerosis, hypertension, or diabetes.

Pathophysiology of WorseningRenal Function During ADHFTreatment

The worsening renal function so oftenobserved during the treatment of ADHFis commonly ascribed to a prerenal state.This classification of acute worsening re-nal function is characterized by increasesin blood urea nitrogen out of proportionto Cr and implies underperfusion of thekidney, which may be related to volumedepletion or to decreases in cardiac out-put despite hypervolemia. As elegantlyemphasized by Nohria et al. (16), ascrib-ing worsening renal function duringADHF to existence of a prerenal state“does not clarify the mechanism or thesolution” of the worsening renal func-tion. While HF patients may developworsening renal function associated withlow or normal filling pressures with over-diuresis, worsening renal function morecommonly occurs early in the treatmentof the acute decompensation episodewhen patients are still markedly volumeoverloaded (13). Furthermore, extravas-cular volume redistributes rapidly inmarkedly volume-overloaded HF pa-tients, protecting against intravascular

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Figure 2. Secular trends in age, renal function, and hemoglobin in patients with acute decompensated heart failure in 6,440 consecutive patientshospitalized for heart failure therapy at Mayo Clinic Hospitals, Rochester, MN, from January 1, 1987, to December 31, 2002. MDRD, Modification of Dietin Renal Disease; GFR, glomerular filtration rate; BW, body weight; CrCl, creatinine clearance. Reproduced with permission from Owan TE, Hodge DO,Herges RM, et al: Secular trends in renal dysfunction and outcomes in hospitalized heart failure patients. J Card Fail 2006; 12:257–262.

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Figure 3. Occurrence of various degrees of worsening renal function (change in creatinine) through-out days of hospitalization. Reproduced with permission from Gottlieb SS, Abraham W, Butler J, et al:The prognostic importance of different definitions of worsening renal function in congestive heartfailure. J Card Fail 2002; 8:136–141.


volume depletion. Indeed, in patientswith less advanced cardiorenal dysregula-tion, vasodilators and diuretics typicallynormalize filling pressures without re-ducing cardiac output (15), and Ljung-man et al. (24) showed that renal bloodflow is preserved until the cardiac indexfalls below 1.5 L/m2. Thus, the simplisticassumption that worsening renal func-tion has developed in response to intra-vascular volume depletion or relative in-travascular volume depletion is likelyinaccurate and certainly does not identifya satisfactory therapeutic strategy (vol-ume replacement) for persistently con-gested HF patients with worsening renalfunction.

While a single dominant mechanismresponsible for worsening renal functionin all patients with persistent congestionmay never be defined, several contribut-ing factors have been emphasized. Insome patients, persistent vasoconstric-tion may be present, and use of vasodila-tors may improve cardiac output and re-nal perfusion. Unfortunately, thismechanism is less common in contempo-rary patients with long-standing and pre-viously treated HF, as noted previously(16). The adverse effect of congestion andhigh central (and thus renal) venouspressure must be emphasized. Renal per-fusion pressure not only is dependent onarterial pressure but is determined by thetransrenal perfusion pressure and thus isequal to mean arterial pressure minuscentral venous pressure. Pulmonary hy-pertension, right ventricular dysfunction,and tricuspid regurgitation may contrib-ute to extremely high renal venous pres-sures and reduce renal perfusion pressuredramatically. Indeed, Firth et al. (25)demonstrated the adverse effects of iso-lated elevation of central venous pres-sures on renal hemodynamics and so-dium excretion. Improvement of renalperfusion with HF therapy may be due toincreases in renal perfusion pressure me-diated by reduction in central venouspressure. Inability to reduce central ve-nous pressure may contribute to worsen-ing renal function in some patients.

Adenosine and tubuloglomerular feed-back may also play a role in the patho-physiology of cardiorenal syndrome.Adenosine binds to receptors on the af-ferent arteriole and causes local constric-tion, thereby reducing renal blood flow.Stimulation of A1 adenosine receptorsalso increases sodium resorption in theproximal and distal tubules, leading tosodium and water retention. An acute

increase in the delivery of sodium in thedistal tubule with diuretic therapy causesan increase in adenosine concentrationsvia tubuloglomerular feedback (TGF) atthe macula densa and afferent arterioles,which subsequently reduces glomerularfiltration rate (GFR) (26). While thispathway represents an appealing explana-tion as it is susceptible to interruptionwith specific A1 adenosine receptor an-tagonists, preliminary studies have re-ported that worsening renal function isnot prevented when volume is removedmechanically without diuretic adminis-tration in HF (27), suggesting that distalsodium delivery and TGF are not the solemechanisms responsible for worseningrenal function in ADHF. Patients withnew-onset HF will commonly develop mi-nor increases in Cr when angiotensinconverting enzyme inhibitors or angio-tensin receptor blockers are initiated, asangiotensin II preferentially constrictsthe efferent renal arterioles, maintainingGFR. However, the typical patient withworsening renal function during an acuteepisode of decompensation has beentreated with these agents for many years,and initiation of angiotensin convertingenzyme inhibitors or angiotensin recep-tor blockers is not commonly the expla-nation for worsening renal function, aspreviously established (12, 28).

Unilateral or bilateral renal athero-sclerosis is likely underrecognized in HFand may contribute to worsening renalfunction in many patients with ADHF.Renal artery atherosclerosis may be se-vere enough to compromise renal bloodflow (renal artery stenosis) and it alsopredisposes to renal atheroembolism,which is particularly common followinginterventions that instrument the vascu-lature, including angiography, angio-plasty, vascular surgery, and use of anintra-aortic balloon pump. Cholesterolemboli are thought to obstruct smallerrenal arteries, which can subsequentlylead to ischemic changes, precipitate hy-pertension, and ultimately cause progres-sion of renal failure due to glomerularand peritubular capillary injury. Choles-terol emboli may also induce acute in-flammatory changes (29, 30).

Use of drugs that perturb intrarenalhemodynamics, such as nonsteroidal in-flammatory drugs or contrast agents, in-fection, or obstruction, must always beexcluded in HF patients with worseningrenal function, but such easily identifiedinsults are not commonly the culprit.The pathophysiology of worsening renal

function is likely diverse, with multiplemechanisms contributing in any patient.A comprehensive evaluation to excludeknown causes of worsening renal func-tion is mandatory.

Pathophysiology of DiureticResistance in HF

In those patients with both renal in-sufficiency and HF, loop diuretics are thediuretics of choice. This is due to the factthat thiazides have been found to be in-effective in patients with GFR �25–30mL/min (31). To further understand howpatients with HF and renal dysfunctionbecome resistant to loop diuretics, onemust understand the pharmacology ofthe loop diuretic and the physiology ofcardiac and renal failure.

Oral absorption of loop diuretics, par-ticularly furosemide, is impaired in thepresence of gut hypoperfusion andedema, so intravenous administration ismore effective in ADHF. Loop diureticsare avidly bound to protein and must beactively secreted into the proximal tu-bule. Severe hypoalbuminemia may thusincrease the volume of distribution ofloop diuretics and impair their delivery tothe kidney. Coadministration of albuminwith diuretics is advocated in patientswith hypoalbuminemia to enhance deliv-ery of diuretics to the kidney, althoughefficacy of this strategy is not well proven.Loop diuretics are then actively secretedinto the tubular lumen and go down-stream to the thick ascending limb,where they block the Na/K/2Cl cotrans-porter (31). Problems arise in patientswith chronic renal dysfunction since or-ganic acids are accumulated that act indirect competition with diuretics for se-cretion at the proximal tubule. In HFthere is also reduced renal blood flow,and this further inhibits tubular deliveryof the diuretic (19). This sets the back-ground for what is known as the “brakingphenomenon,” where the response to thediuretic is reduced despite perception ofadequate dosing (32, 33). Two importantmechanisms contribute to this brakingphenomenon. First, an enhanced re-bound increase in sodium resorption me-diated by poorly defined mechanisms typ-ically occurs after a single daily dose ofdiuretics. This rebound phenomenon cancompletely negate the losses in sodiumachieved with a single bolus dose of di-uretic and may explain the enhanced ef-fectiveness of similar total doses given asa continuous infusion or twice-daily dos-


ing. Second, with chronic diuretic ther-apy, the distal tubular cells develop hy-pertrophy and enhanced sodium reuptakein response to the constant bombard-ment of solute delivery caused by thechronic blockade of the Na/K/2Cl trans-port (31). The effect of enhanced distaltubule sodium reuptake can be blockedby pairing loop diuretics with other di-uretics that inhibit distal nephron resorp-tion, such as thiazides.

APPROACH TO THECARDIORENAL SYNDROME

The development of worsening renalfunction and/or DR during the treatmentof the patient with cardiorenal failure is acommon and predictable but difficultclinical problem. There is no consistentlyeffective strategy, and much of the ap-proach is empirical (Table 2).

Recognize the CardiorenalSyndrome and Anticipate theDevelopment of WorseningRenal Function and/or DR

Patients developing the cardiorenalsyndrome in the setting of ADHF andpersistent congestion are usually thosewith long-standing HF who experience anepisode of decompensation despite ade-quate chronic HF therapy and who arealready on chronic high-dose diuretictherapy. A progressive increase in Cr overrecent years is typically evident and re-flects not only the underlying renal dis-ease but the additional effect of the HFstate as outlined previously. Patients withsevere diastolic dysfunction (regardless ofejection fraction), secondary pulmonaryhypertension, right ventricular dysfunc-

tion, marked functional tricuspid or mi-tral regurgitation, previous HF hospital-izations, a history of worsening renalfunction with previous ADHF episodes, ora history of transient dialysis (often aftercardiac surgery or contrast administra-tion) are at the highest risk. In many

patients, development of the cardiorenalsyndrome is a marker of the transition tostage D HF (Fig. 4). It is helpful to ad-dress the potential for worsening renalfunction with the patient at admission,including the prognostic implications ofcardiorenal syndrome and stage D. Anassessment of suitability for dialysis andadvanced HF therapies, such as cardiacsupport (left ventricular assist device) orreplacement (transplantation), should bemade. Unfortunately, the vast majority ofpatients developing cardiorenal syn-drome will not be candidates for ad-vanced HF treatments, such as transplan-tation or left ventricular assist device,due to age and comorbidities. Anticipa-tion of a very high risk for cardiorenalsyndrome may support use of differentstrategies, such as more gradual volumeremoval or early use of (potentially) re-nal-protective strategies (discussed sub-sequently). However, whether slower vol-ume removal or the variety of strategiesavailable to preserve renal function willaffect the development of the cardiorenalsyndrome or improve outcomes is un-known.

Optimize Heart Failure Therapy

While therapy for ADHF often focuseson volume removal, careful review of thepatient’s HF therapy addressing the ade-quacy of vasodilator therapy, blood pres-sure control, or the potential for addi-tional adjuvant therapy (digoxin, nitrates,cardiac resynchronization therapy) is im-portant. Addressing factors that can pro-vide additional symptom relief (paracen-tesis, thoracentesis) or optimize cardiacfunction (revascularization, correction ofvalve disease) should be considered earlyin the hospitalization. While the ESCAPEtrial did not show that early use of hemo-dynamically guided therapy improvedsurvival in severe HF (11), many centersare still aggressive in the use of pulmo-nary artery catheters in difficult patientswith cardiorenal syndrome to ensure thathemodynamics and standard HF thera-pies are optimized. In some cases, havingsuch data may reassure the managingcardiologist and the consulting nephrol-ogist that measures to improve cardiacfunction and renal perfusion have beenaddressed and may facilitate the decisionto offer renal replacement therapy,chronic palliative HF therapy, or hospicecare. Importantly, pulmonary arterycatheter guided therapy commonly in-cludes administration of an inotropic

Table 2. Approach to the patient with cardiorenalsyndrome

1. Anticipate2. Optimize HF therapy3. Evaluate renal structure and function

(ultrasonography accompanied by renal vascularevaluation with Doppler and resistive indices)

4. Optimize diuretic dosing5. Consider renal-specific therapies

a. Renal-dose dopamineb. Nesiritidec. Ultrafiltration and/or hemodialysis

6. Investigational therapiesa. Hypertonic saline � high-dose loop

diureticsb. Vasopressin antagonistsc. Adenosine antagonists

HF, heart failure.

ACC/AHAHF Stage

A

B

C

D

Health

CV Disease

LV Remodeling and Dysfunction

Overt HF

Terminal HF

Death

Cardiorenal Syndrome

Figure 4. Development of the cardiorenal syn-drome as a marker of the transition to stage Dheart failure (HF). ACC/AHA, American Collegeof Cardiology/American Heart Association; CV,cardiovascular; LV, left ventricular. Reproducedwith permission from Hunt SA, Baker DW, ChinMH, et al: ACC/AHA guidelines for the evaluationand management of chronic heart failure in theadult: Executive summary: A report of the Amer-ican College of Cardiology/American Heart Asso-ciation Task Force on Practice Guidelines (Com-mittee to Revise the 1995 Guidelines for theEvaluation and Management of Heart Failure):Developed in collaboration with the InternationalSociety for Heart and Lung Transplantation; en-dorsed by the Heart Failure Society of America.Circulation 2001; 104:2996 –3007; and repro-duced with permission from Hunt SA, AbrahamWT, Chin MH, et al: American College of Cardi-ology; American Heart Association Task Force onPractice Guidelines; American College of ChestPhysicians; International Society for Heart andLung Transplantation; Heart Rhythm Society.2005 guideline update for the diagnosis and man-agement of chronic heart failure in the adult: Areport of the American College of Cardiology/American Heart Association Task Force on Prac-tice Guidelines (Writing Committee to Updatethe 2001 Guidelines for the Evaluation and Man-agement of Heart Failure): Developed in collabo-ration with the American College of Chest Physi-cians and the International Society for Heart andLung Transplantation; endorsed by the HeartRhythm Society. Circulation 2005; 112:e154–235.


agent. Use of inotropic agents is consis-tently associated with poorer outcomes,whether in randomized trials or retro-spective registries, and their ability toimprove cardiac status in the hospitalmust not be equated with improved out-comes (34, 35).

Evaluate Renal Structure andFunction

A careful history should identify fac-tors that may be exacerbating disease andHF-related renal dysfunction, such as in-fection, use of nephrotoxic agents, or riskfactors for renal artery stenosis. Urinaly-sis, including microscopic analysis forurine eosinophils (seen in allergic inter-stitial nephritis or renal atheroembo-lism), renal ultrasound with Doppler im-aging of renal arteries, and assessment ofrenal resistive indices, should be per-formed to assess renal size, renal arterystenosis, or obstruction and to character-ize structural renal disease. If suspicionfor renal artery stenosis is high, one canconsider magnetic resonance imagingwith angiography, although this is in-creasingly difficult in patients with sys-tolic HF due to the presence of devices.Computed tomography angiography toassess for renal artery stenosis is oftenprecluded because of the potentially highrisk of contrast nephrotoxicity and renalatheroembolism. The risk-benefit ratio ofcontrast administration must be weighedcarefully as even gadolinium (used withmagnetic resonance angiography) carriesrisk of worsening renal function in HFpatients. The role of renal biopsy has notbeen well defined in this setting, andclearly the risk-benefit ratio must be con-sidered on an individual basis. However,in patients in whom the cause of acuterenal failure is unclear even after a thor-ough history, physical examination, andlaboratory and clinical investigations areperformed, renal biopsy may provide de-finitive diagnostic information that ishelpful in guiding therapy or prognosis.

Optimize Diuretic Dosing

Continuous infusion of loop diuretics(i.e., furosemide) may provide greater di-uresis and better safety profile comparedwith bolus injection. A meta-analysis ofstudies comparing continuous infusionvs. bolus injection of loop diuretics inacutely decompensated HF was per-formed by Salvador et al. (36) and in-cluded eight trials involving 254 patients

(urine output was greater in patientsgiven continuous infusion with aweighted mean difference of 271 mL/24hrs, p � .01). Electrolyte disturbances(hypokalemia, hypomagnesemia) werenot significantly different between thetwo groups (relative risk [RR] 1.47; 95%confidence interval [CI] 0.52–4.15; p �.5). There were fewer adverse effects (tin-nitus and hearing loss) after continuousinfusion compared with bolus injection(RR 0.06; 95% CI 0.01–0.44; p � .005). Inaddition, one study showed that the hos-pital duration of stay was significantlyshortened (by 3.1 days), one studyshowed lower cardiac mortality, and twostudies showed lower all-cause mortalityin patients treated with continuous infu-sion vs. bolus injection of furosemide.Therefore, most studies suggest a greaterdiuresis and better safety profile whenloop diuretics are given as a continuousinfusion. However, since the studies weresmall, mostly crossover trials and wererelatively heterogeneous, evidence is in-sufficient to definitively recommend onemethod of administering loop diuretics,and further larger studies are needed.

In addition to the mode of administra-tion of loop diuretics, the addition of thi-azide diuretics in combination with loopdiuretics has been shown to improve ef-ficacy and diuretic responsiveness in se-vere refractory HF (37, 38). Dormans andGerlag (38) found that in 20 patients withNew York Heart Association (NYHA) classIII and IV HF, edema, and diuretic resis-tance, addition of hydrochlorothiazide tofurosemide resulted in a mean bodyweight reduction of 6.7 � 3.3 kg perpatient. Mean daily urine volume in-creased and fractional sodium excretionincreased significantly (p � .001 forboth). Due to potentially dangerous ad-verse effects, such as hypokalemia, met-abolic alkalosis, and dehydration, carefulmonitoring of the patient is necessary ifcombination diuretics are used.

Consider Renal-SpecificTherapies

Renal Dose Dopamine. The use of low-dose or “renal dose” dopamine, at doses�5 �g/kg/min (usually 2–4 �g/kg/min),has been proposed in the past to preventor treat acute renal failure and to in-crease urine output in HF patients refrac-tory to loop diuretics. Physiologically,low-dose dopamine increases renal bloodflow and increases urine output by stim-ulating both dopaminergic (DA-1 and

DA-2) and adrenergic (both � and �) re-ceptors. Therefore, low-dose dopaminemay affect renal blood flow by direct va-sodilation (dopamine receptors), by in-creasing cardiac output (� receptors), orby increasing perfusion pressure via va-soconstriction (� receptors). At low doses(especially �2 �g/kg/min), dopaminergicreceptor effects predominate, resulting inrenal vasodilatation and increased renalblood flow. Dopamine also inhibits aldo-sterone release and inhibits sodium-potassium adenosine triphosphatase atthe tubular epithelial cell level, resultingin increased sodium excretion andthereby diuresis (39–43).

Several early studies showed signifi-cantly increased natriuresis, diuresis, andimproved renal function with use of low-dose dopamine (42, 44–55). Other studieshave also suggested a role for dobut-amine, ibopamine (a dopamine conge-ner), and fenoldopam in reducing renalvascular resistance, increasing cardiacoutput, and increasing natriuresis, urineflow, and CrCl (56–60). However, thesestudies were largely small, underpow-ered, and nonrandomized.

The overwhelming consensus amongstudies with more rigorous methodology(e.g., randomized prospective studieswith larger sample size) is that there is noconvincing scientific evidence of a bene-ficial effect with low-dose dopamine be-yond a possible natriuretic diuresis (39,40, 56, 61–81). Furthermore, dopaminehas significant potential side effects, in-cluding digital cyanosis and gangrene(82). Vargo et al. (83) found that dopa-mine does not enhance furosemide-induced natriuresis in patients with HF,and those investigators had to discon-tinue the trial after six of eight patientswere recruited because of adverse eventsand lack of natriuretic efficacy after addi-tion of dopamine to furosemide infusionin two of the patients. A large meta-analysis by Kellum and Decker (39) con-cluded that “the use of low-dose dopa-mine for the treatment or prevention ofacute renal failure cannot be justified onthe basis of available evidence and shouldbe eliminated from routine clinical use.”Therefore, based on these studies, there islittle if any role for renal dose dopaminein heart failure therapy in attempts topreserve renal function.

Nesiritide as Renal Protective Ther-apy. Nesiritide (synthetic human B-typenatriuretic peptide) is a potent vasodila-tor that has been used to rapidly reducecardiac filling pressures and improve dys-


pnea in patients with ADHF (84–87).Several early moderately sized controlledtrials (87–91) as well as large prospectiveregistries (92) suggested that nesiritidewas safe in the short-term managementof these patients. However, studies con-flict on nesiritide’s effects on renal func-tion, natriuresis, and diuresis.

Wang et al. (93) studied 15 patientswith NYHA class III or class IV HF (baselineCr 1.5 � 0.4 mg/dL, admission Cr 1.8 �0.8 mg/dL) with volume overload requir-ing hospital admission in a double-blind,placebo-controlled, crossover study ex-amining the effects of nesiritide (2 �g/kgbolus followed by an infusion of 0.01 �g/kg/min) vs. placebo given for 24-hr infu-sion periods. There were no differences inGFR (40.9 � 25.9 mL/min with placebovs. 40.9 � 25.8 mL/min with nesiritide),effective renal plasma flow, urine output(113 � 51 mL/hr with placebo vs. 110 �56 mL/hr with nesiritide), or sodium ex-cretion for any time interval or for theentire 24-hr period between the nesiritideand placebo study days (93).

Sackner-Bernstein et al. (94) per-formed a meta-analysis of randomized,double-blind, parallel-group controlledtrials of nesiritide (vs. placebo or activecontrol) in patients with ADHF to assessthe risk of worsening renal function,which suggested that nesiritide may haveadverse impacts on renal function. Wors-ening renal function was defined as anincrease in serum Cr �0.5 mg/dL. Afterrigorous methodological selection crite-ria, five randomized studies that included1,269 patients were analyzed. Use of ne-siritide at Food and Drug Administration(FDA)-approved doses (�0.03 �g/kg/min)significantly increased the risk of worsen-ing renal function compared with noni-notrope-based control (RR 1.52; 95% CI1.16–2.00; p � .003) or any control ther-apy, including noninotrope- and ino-trope-based therapies (RR 1.54; 95% CI1.19–1.98; p � .001). Even low-dose ne-siritide (�0.015 �g/kg/min) significantlyincreased risk (p � .012 and p � .006compared with noninotrope- and ino-trope-based controls, respectively), as didnesiritide at doses up to 0.06 �g/kg/min(p � .002 and p � .001, respectively).There was no difference in the need fordialysis between therapy groups (94).

Despite these negative studies, subse-quent studies and observations have sug-gested that nesiritide may still holdpromise as a renal-protective therapy inadvanced HF therapy when used in ap-propriate doses. Yancy and Singh (95)

reported a retrospective substudy of theFollow-Up Serial Infusions of Nesiritidetrial (FUSION I) assessing the feasibilityof outpatient administration of nesiritidein 138 patients with comorbid advancedHF and renal insufficiency (estimatedCrCl �60 mL/min). These patients,deemed high risk for the cardiorenal syn-drome, received one of three open-labeltreatments once weekly for 12 wks: stan-dard care, standard care plus nesiritide0.005 �g/kg/min, or standard care plusnesiritide 0.010 �g/kg/min. The primaryend point was safety, not efficacy. Nesirit-ide at these two doses was well toleratedwith no increase in incidence of worsen-ing renal function. The frequency of all-cause mortality and hospitalizationthrough week 12 was lower in patientsreceiving nesiritide. These findings sug-gest that adjunctive therapy with nesirit-ide on an outpatient basis may be bene-ficial for patients with advanced HF andrenal insufficiency (95).

Riter et al. (96) reported on the safetyof nonhypotensive low-dose nesiritide,such as 0.005 �g/kg/min or 0.0025 �g/kg/min without bolus, as opposed to theFDA-approved standard recommendeddose, including a bolus of 2 �g/kg fol-lowed by an infusion of 0.01 �g/kg/min inADHF. In this retrospective case-controlstudy, low-dose nesiritide was well toler-ated without a significant decrease in sys-tolic blood pressure, whereas there was asignificant decrease in systolic bloodpressure with standard-dose nesiritideand no nesiritide. The low-dose nesiritidegroup had improvement in renal functionand equivalent diuresis with lower furo-semide doses. These findings suggestedthat the lack of decrease in systolic bloodpressure in the low-dose nesiritide groupallowed the renal-protective effect of ne-siritide. Further prospective randomizedcontrolled trials to test the efficacy ofnonhypotensive low-dose nesiritide in pa-tients with ADHF are warranted (96).

Recently, in a preliminary report fromOwan et al. (97), use of standard dosenesiritide, despite lowering blood pres-sure, was associated with improved renalfunction indices at 24 hrs. This single-center, randomized trial included 72adult patients with ADHF and renal dys-function (mean Cr 1.75 � 0.59 mg/dLand eGFR 34.5 � 15.7 mL/min/1.73 m2)who were randomized on admission toreceive standard therapy (diuretic dosingalgorithm based on renal function) orstandard therapy plus adjuvant nesiritideat the standard dose of 2 �g/kg followed

by an infusion of 0.01 �g/kg/min for 48hrs. Diuretic responsiveness, measuredby change in weight and/or fluid balance,tended to be less with nesiritide at 24–72hrs and at discharge, but these trends didnot reach statistical significance. Theearly enhancement of renal function de-spite bolus diuretic dosing and hypoten-sive effects of adjunctive nesiritide ther-apy suggests that further studies to defineoptimal dose and/or routes of administra-tion for natriuretic peptides as renal pro-tective therapy in ADHF are warranted.Furthermore, preliminary findings froma trial in which nesiritide was adminis-tered at a standard dose (0.01 �g/kg/min)without a bolus to patients undergoingcardiac surgery have been reported, and amarked reduction in the incidence of re-nal dysfunction was noted (98). Thus, therole of nesiritide as a renal-protective anddiuresis-promoting therapy in ADHF re-mains promising but requires furtherstudy.

Ultrafiltration. When traditional medi-cal therapies fail or patients become resis-tant to diuretics, other therapeutic optionsmust be undertaken to relieve volume over-load. Ultrafiltration has been recognized asa viable treatment option by the Heart Fail-ure Society of America and the AmericanCollege of Cardiology/American Heart As-sociation for diuretic-resistant HF(strength of evidence � C) (99).

Ultrafiltration (UF) or slow continu-ous UF filters plasma water directlyacross a semipermeable membrane in re-sponse to a transmembrane pressure gra-dient, resulting in an ultrafiltrate that isisoosmotic compared with plasma water(100, 101). In contrast, hemodialysis in-volves the passage of solutes and waterfrom the blood across a semipermeablemembrane down a concentration gradi-ent between the blood and dialysate viadiffusion, allowing for changes in electro-lytes and small solutes. Hemofiltrationuses membranes (polyacrylonitrile orpolycarbonate) with greatly increased hy-draulic permeability, so that solute is re-moved by bulk flow (101, 102). In contin-uous venovenous hemofiltration, fluidand medium-sized solutes are removedby bulk flow and solvent drag at largevolumes per hour, with replacement flu-ids administered to the patient simulta-neously. This allows for clearance of po-tentially toxic solutes, while maintainingstable hemodynamics. Continuous veno-venous hemodiafiltration is essentiallycontinuous venovenous hemofiltrationwith the addition of dialysate on the other


side of the semipermeable membrane, al-lowing diffusion of small solutes to occursimultaneously with continuous veno-venous hemofiltration.

Extracorporeal UF for fluid removaldates from the advent of dialysis therapy,and its technique was proposed by Silver-stein et al. (103) in 1974 as a modificationof the standard hemodialysis circuit (100,103, 104). Since then, it has been studiedextensively and proven to be an effectivetreatment for patients with HF who arefluid overloaded and diuretic resistant,with fewer adverse effects than hemodi-alysis and peritoneal dialysis. UF pro-motes the resorption of systemic ex-travascular water and can effectively treatpulmonary edema in patients with HF.

Agostoni et al. (105) performed UF inoutpatients with moderate HF withoutvolume overload and showed dramaticphysiologic responses to a single UFtreatment to reduce right atrial pressureby 50%. Clinical and functional improve-ment was dramatic and lasted up to 6months. The radiographic score of lungwater, exercise tolerance (peak oxygenconsumption), dynamic lung compliance,ventilation, tidal volume, and deadspace/tidal volume ratio at peak exercise im-proved significantly (105). In addition,there were improvements in neurohu-moral responses (106). In contrast, furo-semide infusion at a dosage that achievedequivalent fluid removal produced clear-ing of the lungs, but this benefit was notsustained, and the dramatic improve-ments in lung function, exercise perfor-mance, and neurohumoral function ob-served with the UF treatment were notobserved with diuretic administration ti-trated to produce a similar reduction inright atrial pressure (106, 107). Theseremarkable observations suggest that thisform of therapy may have unique bene-fits, but these elegant studies have notbeen repeated in patients with ADHF andmarked volume overload.

Multiple retrospective case cohortstudies have been performed studying theefficacy of traditional UF in severe di-uretic refractory HF, with variable results(108 –120). Some studies showed sus-tained symptomatic improvement, somerestoration of diuretic responsiveness,and no deterioration in renal functionfollowing UF (108–113, 115, 116, 118–120), whereas others found only transientimprovement (109, 113–116, 118–120).In aggregate, these studies showed ahighly variable clinical response to UF insevere refractory, diuretic resistant HF.

Indeed, the morbidity and mortality ofthis patient population remained high de-spite UF, even when it was used success-fully in these cohorts. Therefore, the roleof UF to improve renal function, avoidthe need for chronic renal replacementtherapy, or modify outcomes in severeHF remains unclear.

Recently, a peripherally inserted UFdevice manufactured by HF Solutions(Aquadex, System 100) was approved bythe FDA for therapy in HF. This deviceallows UF to be performed at very lowflows (40 mL/min) using only a periph-eral intravenous catheter and a midlinecatheter in an antecubital vein, with only33–40 mL of extracorporeal blood at anygiven time. This simple machine is de-signed for use by nonnephrologists andnurses, avoiding the need for intensivecare or dialysis units.

Jaski et al. (121) performed the firstprospective observational study to verifythe safety and function of this device forrapid reversal of volume overload statesin patients with symptoms and signs offluid congestion. These investigators con-cluded that rapid removal of fluid couldbe safely achieved in volume overloadstates via peripherally inserted UF with-out the need for central venous catheterplacement.

Bart et al. (122) conducted a multi-center randomized controlled trial (RAP-ID-CHF) with the System 100 device andcompared a single 8-hr session of UF tousual care in patients admitted withADHF with volume overload. UF was suc-cessful in 18 of the 20 patients, but theprimary end point, weight loss after 24hrs, was 2.5 kg in the UF group vs. 1.86kg in the usual care group (p � .24). Thisstudy was limited by the small number ofpatients, short follow-up, variable use ofdiuretics in the UF group, lack of report-ing of incidence of worsening renal func-tion, and lack of data concerning variabil-ity in results (122).

Costanzo et al. (123) also studied thisdevice in a prospective observationalstudy to assess if early UF before use ofintravenous diuretics could reestablisheuvolemia and diuretic responsiveness(EUPHORIA trial). Twenty patients withvolume overload and diuretic resistancereceived UF within 4.7 � 3.5 hrs of hos-pitalization. This study did not include acontrol group, did not report incidence ofworsening renal function or dailychanges in Cr during hospitalization, butdid demonstrate that fluid could be re-

moved with UF in this HF population(123).

Dahle et al. (124) also reported suc-cessful use of the peripherally inserted UFdevice in a cohort of nine hospitalizedpatients with decompensated HF refrac-tory to standard inpatient medical ther-apy. In this study, UF was performed formuch longer durations (mean length oftime of UF therapy was 33.3 � 20.0 hrswith a mean volume removal of 7.0 � 4.9L). There was no statistically significantchange in renal function based on pre-and post-UF Cr, although this patientpopulation was relatively young with lesssevere renal dysfunction. Whether thesepatients were resistant to aggressive di-uretic dosing was unclear.

Liang et al. (125) described the initialexperience with the peripherally insertedUF device in a subset of 11 severe HFpatients with DR despite aggressive HFand diuretic therapy. Baseline Cr was 2.2 �0.8 mg/dL and CrCl was 35 � 17 mL/min.Nine patients had documented right ven-tricular dysfunction, six with severe tri-cuspid regurgitation. Of the total UFruns, 13 (41%) removed �3500 mL, 11(34%) removed 2500–3500 mL, and eight(25%) removed �2500 mL. Five patientsexperienced an increase in Cr of �0.3mg/dL. In these patients with severe car-diorenal syndrome, despite successful re-moval of fluid via the UF device, 50%ultimately required dialysis, and length ofstay, costs, and mortality rates were high(125).

Recently, Costanzo et al. reported onUltrafiltration vs. IV Diuretics for Pa-tients Hospitalized for Acute Decompen-sated HF (UNLOAD), a larger randomizedcontrolled trial using the System 100 UFdevice (126). Patients were randomizedwithin 24 hrs to UF vs. intravenous di-uretics. UF was performed at flows up to500 mL/hr. Weight loss at 48 hrs andfluid loss was greater in the UF groupthan the standard care group (p � .001for both), but change in dyspnea scorewas not statistically significant. Rate ofrehospitalization (18% in UF vs. 32% instandard care) and days of hospitalization(123 days vs. 330 days in standard care)were significantly lower in the UF groupcompared with the standard care group.Further analyses of the data from therecent UNLOAD trial showed that whilethere were no greater increases in serumCr or in the percent of patients with in-creases in serum Cr �0.3 mg/dL betweenthose treated with UF and those givenintravenous diuretics at all time intervals


(24 hrs, 48 hrs, and discharge), there wasalso no protective effect of UF (vs. diuret-ics) on renal function and there weretrends toward greater increases in creat-inine with UF (albeit in the setting ofgreater volume removal). There was alsono correlation between net fluid removedand changes in serum Cr in either the UFgroup or the intravenous diuretics group.These findings suggest that other mech-anisms besides volume depletion causeworsening renal function in HF patientsduring volume overload treatment (27).Importantly, UF was shown to removemore sodium and less potassium thandiuretics for an equivalent amount of vol-ume reduction (127). This critical differ-ence may promote more sustained vol-ume reduction and offer the potential forimproved long-term outcomes with UFcompared with diuretics. However, theexpense and complexity of treatmentlimit the potential use of UF as a first-linestrategy in all patients with ADHF.Whether rescue therapy with UF in pa-tients with established cardiorenal syn-drome will prove superior to standardcare remains to be established.

Investigational Therapies forCardiorenal Syndrome

Hypertonic Saline Plus Furosemide.Paterna et al. (128) described success intreating patients with refractory HF withthe combination of high-dose furosemideand small-volume hypertonic saline solu-tion. A total of 94 patients with refractoryHF with ejection fraction �35%, serumCr �2 mg/dL, blood urea nitrogen �60mg/dL, urine output �500 mL/day, andurine sodium excretion �60 mEq/daywere randomized to receive either high-dose intravenous furosemide (500–1000mg) plus hypertonic saline solution twicea day in 30 mins or intravenous bolusfurosemide (500–1000 mg) twice a day,for 4–6 days. Significant increases indaily diuresis and natriuresis, as well asimprovements in B-type natriuretic peptideand bioelectrical impedance measure-ments, were observed in the furosemideplus hypertonic saline solution group. Thehypertonic saline solution group alsoshowed a significant reduction in hospital-ization time and readmission rate.

Potential mechanisms of increased so-dium load in the therapy of HF may relateto an acute osmotic effect of hypertonicsaline to increase mobilization of ex-travascular fluid into the central circula-tion and renal circulation. Increases in

renal blood flow may facilitate diureticresponsiveness. In addition, direct intra-tubular effects of sodium flooding mayoverwhelm the rebound sodium reten-tion seen in diuretic therapy, thus reduc-ing the “braking phenomenon” discussedpreviously. Furthermore, neurohormonelevels may have been suppressed by hyper-tonic saline. The increased intravascularvolume and greater distal tubule sodiumdelivery may inhibit the renin-angioten-sin-aldosterone system, causing reduc-tions in aldosterone, angiotensin II, andvasopressin (or antidiuretic hormone) re-lease despite a temporary increase in se-rum osmolarity. There may also be asmall contribution of increased intravas-cular volume causing inhibition of anti-diuretic hormone release via volume/baroreceptors, leading to reduced freewater resorption via aquaporin channelsin the collecting tubules of the kidney(129). This novel strategy has yet to betested by other groups.

Vasopressin Antagonists in HeartFailure Therapy. Vasopressin antagonistsrepresent another promising class oftherapeutics that may improve aquaresisand hyponatremia in patients withchronic HF. Vasopressin, also known asarginine vasopressin or antidiuretic hor-mone, is a cyclic hexapeptide produced inthe hypothalamus and released from se-cretory granules in the posterior pituitarylobe in response to hyperosmolality, vol-ume depletion, angiotensin II, and sym-pathetic stimulation. Vasopressin causesvasoconstriction and renal water resorp-tion via the vasopressin receptor subtypesV1a (vascular), V2 (renal), and V3 (pitu-itary) receptors (130, 131). V1a receptors,found in vascular smooth muscle cellsand the kidney, mediate vasoconstrictionand prostaglandin production at supra-physiologic concentrations of vasopressin(132). V2 receptors, found in the renalcollecting tubules (principal cells), medi-ate renal water resorption via insertion ofaquaporin 2 channels into the luminalmembranes and also release of von Wil-lebrand factor and factor VIII from thevascular endothelium. V3 receptors,found in the pituitary gland, are respon-sible for stimulating adrenocorticotropichormone secretion by pituitary cortico-tropes.

In HF, vasopressin levels are elevateddue to signaling of the carotid sinusbaroreceptors functioning as volume re-ceptors in the setting of decreased effec-tive arterial blood volume from low car-diac output. When systemic blood

pressure drops sufficiently, as in ad-vanced HF, antidiuretic hormone secre-tion markedly increases to levels that farexceed those induced by changes inplasma osmolality. In addition, the vol-ume depletion can prevent the inhibitionof antidiuretic hormone release normallyinduced by a decrease in plasma osmola-lity, which contributes to the develop-ment of hyponatremia in HF.

Antagonism of the V1a and V2 recep-tors may be beneficial in HF patients(132–135). Antagonism of V1a receptorsincreases cardiac output, reduces totalperipheral vascular resistance, reducesmean arterial blood pressure, and inhib-its vasopressin-mediated cardiomyocytehypertrophy (132). Antagonism of V2 re-ceptors results in aquaresis, causing in-creased serum sodium concentration andreduced cardiac preload (132). In HF, twovasopressin antagonists have shownpromise in early clinical trials: 1)conivaptan (YM-087), an oral or intrave-nous V1a/V2-receptor antagonist; and 2)tolvaptan (OPC-41061), an oral specificV2-receptor antagonist.

The acute efficacy of intravenousconivaptan was evaluated in 142 patientswith symptomatic HF (NYHA class III andIV) in a randomized double-blind, short-term study (136). Conivaptan reducedpreload and increased urine output andserum sodium levels. The ADVANCE trialis a double-blind, placebo-controlledstudy of the safety and efficacy of 12 wksof chronic oral conivaptan therapy inthree doses compared with placebo onchronic HF symptoms in 345 patientswith NYHA class II–IV symptoms. Thistrial will assess functional capacity dur-ing treadmill exercise and the symptomsof heart failure (137). While a role for oralconivaptan therapy in HF is being testedin this clinical trial, currently only theintravenous formulation of conivaptanhas been developed and approved in theUnited States, and it is only approved fortreatment of patients with euvolemic hy-ponatremia.

Tolvaptan, an oral V2-receptor antag-onist, has been shown to induce aquare-sis in animals and humans (138–140). Ina randomized double-blind trial, 254 pa-tients with NYHA class I–III heart failurewere randomly assigned to administra-tion of tolvaptan at variable doses in com-bination with standard furosemide therapyfor 25 days (141). Tolvaptan significantlydecreased body weight, increased urinevolume, increased net fluid loss, de-creased urine osmolality, increased mean


total 24-hr urinary sodium excretion, in-creased serum sodium, and improvededema. Its effect was observed primarilyon the first day. In the Acute and ChronicTherapeutic Impact of a Vasopressin An-tagonist (ACTIV) in HF study (142), 319patients admitted for decompensated HFwere randomized to placebo vs. tolvaptanat variable doses plus routine therapy,including diuretics for up to 60 days. Af-ter 24 hrs, patients treated with tolvaptanhad a significant reduction in bodyweight compared with those adminis-tered placebo; this effect was not dosedependent. There was also an increase inmean urine output at 24 hrs and a slightincrease in mean serum sodium levelsfrom baseline in patients treated withtolvaptan. The Efficacy of Vasopressin An-tagonism in Heart Failure OutcomeStudy with Tolvaptan (EVEREST) trial isan ongoing international, multicenter,randomized, double-blind, placebo-controlled study designed to evaluate thelong-term efficacy and safety of oral once-daily tolvaptan in patients hospitalizedwith worsening HF (143).

The results of these ongoing trials willadd further insight into the potentialtherapeutic usefulness of vasopressin an-tagonists in the treatment of advancedHF and define their impact on the car-diorenal syndrome.

Adenosine Antagonists in Heart Fail-ure Therapy. Another promising newclass of therapeutic agents is the A1 aden-osine receptor antagonists. Plasma aden-osine levels are elevated in patients withHF, with increasing levels as the severityof disease increases (144). As noted pre-viously, TGF promotes release of adeno-sine, and adenosine binding to A1 recep-tors causes vasoconstriction of theafferent arteriole, decreased renal bloodflow and GFR, and enhanced sodium re-sorption by the proximal tubule. Antago-nism of A1 adenosine receptors has thepotential to improve renal function andovercome DR in patients with HF by dis-rupting the TGF loop (26, 145).

BG9719 (or CVT-124) is a selective A1adenosine receptor antagonist that hasbeen shown to cause a potassium-neutraldiuresis while maintaining renal functionin animal studies (146) as well as humanstudies (26, 147). In a pilot study of 12patients with NYHA class III or IV HF, therenal effects of placebo, CVT-124, and fu-rosemide were compared (147). Adminis-tration of CVT-124 increased sodium ex-cretion without decreasing GFR; in

contrast, furosemide decreased GFR sig-nificantly.

Gottlieb et al. (26) subsequently stud-ied 63 edematous patients with symptom-atic NYHA class II–IV HF with ejectionfraction �40% in a randomized, double-blind, ascending-dose, crossover studyevaluating three doses of BG9719 (givenas a loading dose followed by a 7-hr infu-sion) and placebo, in combination with80 mg of intravenous furosemide. BothBG9719 alone and furosemide alonecaused a large diuresis, but the additionof BG9719 to furosemide increased diure-sis. BG9719 alone improved GFR, whilefurosemide alone caused a decline inGFR. When BG9719 was added to furo-semide, it prevented the furosemide-mediated decline in GFR (Fig. 5). There-fore, A1 adenosine receptor antagonismmay preserve renal function while simul-taneously promoting enhanced responseto loop diuretics during treatment forheart failure.

Similar findings have been reported insmall, early studies with the A1 adenosinereceptor antagonist KW-3902 (148, 149).A large phase III multicenter study ofKW-3902 (PROTECT-1) in ADHF is cur-rently underway (150). The results oflarger randomized studies such as thisone are needed to determine whether A1adenosine receptor antagonists will pre-vent worsening renal function and avoidDR in patients with HF at risk for cardio-renal syndrome. In addition, adenosinemay exert negative inotropic and chrono-tropic effects via A1 receptors in theheart. Thus, A1-receptor antagonistscould potentially have positive inotropiceffects, and if used clinically, their cardiacsafety will need to be proven (145).

CONCLUSION

The cardiorenal syndrome is a com-plex and diverse pathophysiologic statemanifest by concomitant heart and kid-ney failure (cardiorenal failure), worsen-ing renal function during ADHF treat-ment, and diuretic resistance in thesetting of persistent congestion. The car-diorenal syndrome often heralds the tran-sition to end-stage, preterminal (stage D)HF. The challenge is to recognize thesyndrome, reverse it when possible, anddeal with its consequences for ADHFmanagement. An incomplete understand-ing of the pathophysiology and the lim-ited treatment options enhance the diffi-culty of defining satisfactory approachesin individual patients. The diversity in HFpatients in terms of age, type of HF, andunderlying disease and the variation inthe relative role of each of the features ofthe cardiorenal syndrome (cardiorenalfailure, worsening renal function, and di-uretic resistance) preclude the use of asingle approach. Emerging therapiesbring hope for better outcomes in thesechallenging patients, but currently avail-able strategies are largely unproven.

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BG9719 + furosemide

Furosemide alone

Figure 5. The relationship between change in urine volume and change in creatinine clearance forpatients receiving the 0.75-�g/mL concentration of the A1 adenosine receptor antagonist BG9719(CVT-124). BG9719 increased urine output when given with or without furosemide. The decrease inglomerular filtration rate (GFR) with furosemide alone was not seen when BG9719 was given.Reproduced with permissions from Gottlieb SS, Brater DC, Thomas I, et al: BG9719 (CVT-124), an A1adenosine receptor antagonist, protects against the decline in renal function observed with diuretictherapy. Circulation 2002; 105:1348–1353.


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