A C l i n i c a l A p p ro a c h t o t h e

A c u t e C a rd i o re n a l
S y n d ro m e
a b,c,
Jacob C. Jentzer, MD , Lakhmir S. Chawla, MD *

KEYWORDS
 Cardiorenal syndrome  Heart failure  Acute kidney injury  Diuretics
 Chronic kidney disease  Ultrafiltration  Acute heart failure syndromes

KEY POINTS
 Acute cardiorenal syndrome represents a unique form of acute kidney injury specific to
acute heart failure syndromes that is associated with adverse outcomes.
 Acute cardiorenal syndrome results from renal venous congestion, ineffective forward
flow, and impaired renal autoregulation caused by neurohormonal activation.
 Biomarkers reflecting different aspects of acute cardiorenal syndrome pathophysiology
may allow patient phenotyping to inform prognosis and treatment.
 Aggressive diuretic therapy to relieve congestion is the cornerstone of treatment in acute
cardiorenal syndrome.
 Adjunctive therapies may relieve congestive symptoms and/or improve renal function, but
no single therapy has been conclusively shown to reduce mortality in acute cardiorenal
syndrome.

INTRODUCTION

The medical community has increasingly recognized the complex relationship be-
tween the heart and kidneys over recent years. The term cardiorenal syndromes
(CRSs) encompasses a spectrum of disease states involving mutually interacting car-
diac and renal dysfunction. CRSs are defined as “disorders of the heart and kidneys

Disclosures: Nothing to disclose (Dr J.C. Jentzer); grants or honoraria from Alere, Astute and
Abbott (Dr L.S. Chawla).
a
Department of Critical Care Medicine, UPMC Presbyterian Hospital, University of Pittsburgh
Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA; b Division of Intensive Care
Medicine, Department of Medicine, Washington DC Veterans Affairs Medical Center, 50 Irving
Street, Washington, DC 20422, USA; c Division of Nephrology, Department of Medicine, Wash-
ington DC Veterans Affairs Medical Center, 50 Irving Street, Washington, DC 20422, USA
* Corresponding author. Division of Nephrology, Department of Medicine, Washington DC Vet-
erans Affairs Medical Center, 50 Irving Street, Washington, DC 20422.
E-mail address: minkchawla@gmail.com

Crit Care Clin 31 (2015) 685–703

http://dx.doi.org/10.1016/j.ccc.2015.06.006 criticalcare.theclinics.com
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686 Jentzer & Chawla

whereby acute or chronic dysfunction in one organ may induce acute or chronic
dysfunction of the other.”1,2 The term cardiorenal applies when cardiac dysfunction
drives renal dysfunction, as opposed to renocardiac, in which renal dysfunction drives
cardiac dysfunction.1,2 Patients may develop more than 1 CRS simultaneously
because of the bidirectional nature of cardiorenal interactions and shared risk factors
for cardiac and renal disease.3 Acute CRS represents a unique form of acute kidney
injury (AKI) developing in patients with acute cardiac dysfunction. For a broader over-
view of the CRSs, we refer readers to recent comprehensive reviews.3–5

EPIDEMIOLOGY OF ACUTE CARDIORENAL SYNDROME

Acute CRS is the best-recognized of the CRSs, and the subtype most frequently
encountered in acutely ill patients. Acute CRS was initially described as diuretic-
refractory volume overload with worsening renal function (WRF) during treatment of
decompensated heart failure (HF), which is considered forme fruste acute CRS. The
definition of acute CRS has broadened to include patients with declining glomerular
filtration rate (GFR) and increasing serum creatinine levels caused by acutely wors-
ening cardiac function, most often during hospitalization for an acute HF syndrome
(AHFS).1–9 AHFSs are a common and morbid complication of chronic HF, leading to
millions of hospitalizations each year worldwide.10,11 At least one-fourth of patients
hospitalized with AHFS may develop WRF, depending on the definition of WRF; an in-
crease in creatinine level greater than or equal to 0.3 mg/dL or greater than or equal to
25% from baseline has been used most commonly.4,6,7,9,12–15 Not all increases in
creatinine level during AHFS have the same prognostic relevance, and we suggest
that acute CRS should only include patients with treatment failure and persistent
congestion.7
Chronic kidney disease (CKD) is present in approximately half of all patients with
AHFS, so many patients with acute CRS have concomitant chronic CRS.6,9,12,16
The most important risk factor for WRF in AHFS is CKD, reflected by reduced GFR
with increased serum creatinine and cystatin C levels (Box 1).13–15,17–20 AKI is an
important contributor to the progression of CKD and HF, and both AKI and CKD are
associated with adverse outcomes in diverse patient populations.21 Patients with
CKD or WRF complicating AHFS have significantly increased mortalities compared
with patients with preserved renal function, and renal dysfunction is the most impor-
tant prognostic marker in AHFS.12,22–28 WRF during AHFS portends an adverse prog-
nosis independently of baseline renal function, and mortality increases progressively
with incremental increases in serum creatinine.1,2,6,7,12,26–29 The adverse prognosis
conferred by baseline renal dysfunction seems greater than the effect of
WRF.12,23,26–31 Transient WRF reflecting a reversible reduction in GFR seems less
harmful than persistent WRF suggesting established AKI, but even decreases in creat-
inine during hospitalization representing WRF on presentation may be associated with
adverse outcomes.5,32,33

BIOMARKERS IN ACUTE CARDIORENAL SYNDROME

Cardiorenal biomarkers reflecting different aspects of cardiac and renal dysfunction

predict acute CRS outcomes, but there are no definitive diagnostic tests for acute
CRS.36 Four major groups of cardiorenal biomarkers have been studied in acute
CRS, including clearance biomarkers reflecting GFR, natriuretic peptides reflecting
congestion, tubular injury biomarkers, and miscellaneous biomarkers reflecting neuro-
hormonal and/or inflammatory activation (Box 2). Levels of cardiac injury biomarkers
 Acute Cardiorenal Syndrome 687

Box 1
Risk factors for WRF in acute HF syndromes

Chronic kidney diseasea

Reduced baseline GFR
Increased serum creatinine level
Increased serum cystatin C level
Diuretic resistancea
Higher loop diuretic doses
Congestiona
Increased central venous pressure or right atrial pressure
Pulmonary edema
Increased HF severity
Increased New York Heart Association class
Increased number of HF exacerbations
Hypotensiona
Hyponatremia
Atrial fibrillation
Risk factors for renal disease
Older age
Hypertension
Diabetes mellitus
Magnitude of blood pressure reductiona
Use of vasodilators
Increased admission blood pressure
a
Commonly described risk factors.
Data from Refs.13–15,17–20,34,35

such as troponin may be increased in the setting of AHFS and acute CRS and carry an
adverse prognosis.37
Patients with acute CRS have increased levels of clearance biomarkers, including
creatinine, cystatin C, and blood urea nitrogen (BUN) from GFR reduction caused
by the combined effects of underlying CKD with chronic nephron loss, acute tubular
injury, and direct influence of AHFS.5 Acute CRS typically produces a gradual increase
in serum creatinine level corresponding with stage I AKI, whereas abrupt increases
meeting criteria for stage II or III AKI suggest severe HF or an intrinsic renal process
with higher risk of mortality.7,28–30,38–40 Increases in creatinine during aggressive vol-
ume removal and effective decongestive therapy have not been associated with a
higher risk of adverse outcomes, suggesting that WRF itself may not be an indepen-
dent contributor to adverse outcomes.23,41–44 Lack of an adverse effect of WRF
without residual congestion suggests that congestion is the primary determinant of
AHFS outcomes and that renal dysfunction contributes to adverse outcomes by
causing persistent congestion.41,43–46 Cystatin C may have higher sensitivity for
reduced GFR and AKI, so estimation of GFR using cystatin C may provide greater
prognostic value than creatinine-based estimates.22,46,47 BUN is the most strongly
688 Jentzer & Chawla

Box 2
Selected prognostic biomarkers in CRS

Renal clearance markers

Creatinine
Cystatin C
Blood urea nitrogen
Uric acid
Natriuretic peptides
B-type natriuretic peptide (BNP)
N-terminal pro-BNP
Mid-proANP
Tubular injury markers
Neutrophil gelatin-associated lipocalin
KIM-1
L-FABP
TIMP2
IGFBP7
Neurohormonal/inflammatory markers
GDF-15
FGF-23
Soluble ST2
Galectin-3
CA-125
Midproadrenomedullin
Abbreviations: CA, cancer antigen; FGF-23, fibroblast growth factor; GDF, growth differentia-
tion factor; IGFBP, insulin-like growth factor binding protein; L-FABP, liver-type fatty acid bind-
ing protein; KIM, kidney injury marker; Mid-proANP, midregional pro-A-type (atrial) natriuretic
peptide; TIMP-2, tissue inhibitor of metalloproteinases.
Data from Forni LG, Chawla LS. Biomarkers in cardiorenal syndrome. Blood Purif 2014;37
Suppl 2:14–9.

prognostic of the clearance biomarkers, reflecting the combined effects of reduced

GFR and neurohormonal activation.24,25,30 An increased BUN/creatinine ratio sug-
gests neurohormonal activation caused by decreased effective renal perfusion from
severe HF and carries adverse prognostic value in AHFS.43,48
Levels of tubular injury biomarkers, such as neutrophil gelatin-associated lipocalin
(NGAL), become increased early during AKI, and may differentiate true AKI with
tubular injury from reversible reductions in GFR without tubular injury.49–53 Increases
in levels of tubular injury biomarkers precede increases in clearance biomarker levels
during AKI and predict declines in GFR, allowing clinicians to recognize developing
AKI earlier.5,49–53 Plasma/serum NGAL predicts WRF and adverse outcomes in pa-
tients with AHFS, but showed only modest predictive value in some studies.5,54–58 Uri-
nary tubular injury biomarkers seem to have greater predictive accuracy for AKI than
plasma/serum NGAL, but have not been studied systemically in patients with AHFS.53
 Acute Cardiorenal Syndrome 689

The combined use of both clearance and tubular injury biomarkers can define various
AKI subgroups with different renal outcomes and pathophysiology (Fig. 1).49–52 Pa-
tients with normal levels of both biomarkers do not have AKI and are at low risk of
developing AKI. Patients with increased levels of tubular injury biomarkers in the
absence of increased clearance biomarker levels may have early AKI that poses a
risk for worsening GFR. Patients with acutely increased levels of clearance biomarkers
without increased levels of tubular injury biomarkers may have a potentially transient
or reversible change in GFR not associated with tubular injury.52 Patients with
increased levels of both biomarkers have established AKI with an increased risk of
severe, progressive, and/or persistent AKI and adverse outcomes.52
Natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal pro-
BNP (NT-proBNP) are significantly increased in acute CRS because of the combined
effects of both congestion and reduced GFR. Normal natriuretic peptide levels sug-
gest a cause of AKI other than typical acute CRS (ie, volume depletion). Natriuretic
peptide levels cannot distinguish between CRS subtypes and can be increased in pa-
tients with severely reduced GFR but no prior cardiac dysfunction (acute renocardiac
syndrome).40,59 Increased natriuretic peptide levels are prognostic in patients with
AHFS with or without acute CRS, and the degree of natriuretic peptide increase
may modify the relationship between WRF and adverse outcomes.43,44,46,60,61
Increased natriuretic peptide levels can identify residual congestion as a target for
therapy.61 Patients with AHFS with persistent congestion and increased natriuretic
peptide levels at hospital discharge have worse outcomes, especially in the presence
of acute CRS and/or WRF; WRF seems benign when natriuretic peptide levels are
normal.43–46,62 Other biomarkers reflecting neurohormonal and inflammatory path-
ways may provide insight into the underlying pathophysiology of acute CRS, but
they are outside the scope of this article.36
We propose a multibiomarker approach to acute CRS phenotyping using congestion
biomarkers (such as natriuretic peptide levels) and neurohormonal activation biomarkers
(such as BUN/creatinine ratio) to define each patient’s pathophysiology (Fig. 2).43 Pa-
tients with low levels of both biomarkers are in compensated HF and do not have acute

Tubular injury biomarkers

Normal Increased

AKI absent Subclinical AKI

Normal renal funcon Normal renal funcon
Normal

without tubular injury. without tubular injury.

Clearance biomarkers

Low risk for AKI Moderate risk for AKI

development progression

Reversible AKI Established AKI

Elevated

Reduced renal funcon Reduced renal funcon

without tubular injury. with tubular injury.
Low risk for AKI High risk for AKI
progression progression

Fig. 1. AKI subtyping based on clearance and tubular injury biomarkers. (Data from
Refs.49–52)
690 Jentzer & Chawla

Congeson biomarkers
Normal Elevated

Neurohormonal acvaon biomarkers

Chronic CRS Congesve CRS
Compensated HF with Congeson leading to

Normal
CKD causing low GFR. reduced GFR.
Treat with standard Treat with volume
chronic HF therapy removal alone

Refractory CRS
Hypovolemic AKI
Advanced HF causing
Increased

Volume depleon
severe CRS.
leading to reduced GFR.
Treat with volume
Treat with diurec
removal and consider
withdrawal and fluids
advanced therapies

Fig. 2. Proposed acute CRS phenotyping based on biomarkers reflecting congestion and
neurohormonal activation. (Data from Testani JM, Damman K, Brisco MA, et al. A
combined-biomarker approach to clinical phenotyping renal dysfunction in heart failure.
J Cardiac Fail 2014;20:912–9.)

CRS. Patients with low natriuretic peptide levels and increased markers of neurohor-
monal activation likely have hypovolemia (true prerenal AKI). Patients with increased
natriuretic peptide levels without increased markers of neurohormonal activation have
uncomplicated congestive acute CRS. Patients with increased levels of both biomarkers
have persistent congestion and marked neurohormonal activation, reflecting refractory
acute CRS, whereby congestion is severe enough to impair renal perfusion.43 This clas-
sification could be further refined using tubular injury biomarkers suggesting AKI, and
must be subjected to further investigation before it can be accepted.

PATHOPHYSIOLOGY OF CARDIORENAL SYNDROME

The mechanisms by which cardiac and renal dysfunction can interact to produce pro-
gressive bidirectional organ injury are reviewed elsewhere.3–5,8 Acute CRS results
from the interaction between renal venous congestion, reduced renal blood flow,
and impaired renal autoregulation; inflammatory pathways contribute to bidirectional
cardiac and renal dysfunction.8,9 Renal congestion is central to acute CRS and distin-
guishes acute CRS from other causes of AKI. Patients with HF decompensate
because of various triggering insults, leading to neurohormonal activation and fluid
retention that produce congestion, which in turn impairs renal function and aggravates
neurohormonal activation leading to a vicious cycle of fluid retention and worsening
congestion.8 Triggering insults include reductions in cardiac output from deteriorating
cardiac function and/or worsening sodium retention from a variety of causes. Neuro-
hormonal activation with sympathetic nervous system activation, renin-angiotensin-
aldosterone system (RAAS) activation, and nonosmotic vasopressin release occurs
in response to stimuli that are detected by the kidneys as a reduction in perfusion
pressure, including reduced cardiac output and/or increased venous congestion.8
Effective renal perfusion is decreased in AHFS because of reduced forward flow from
impaired cardiac function coupled with increased renal venous pressure, triggering
 Acute Cardiorenal Syndrome 691

glomerular hemodynamic changes and sodium retention from neurohormonal activa-

tion.9 Most patients with AHFS have adequate cardiac output to maintain renal blood
flow in the setting of preserved renal autoregulatory capacity and normal renal venous
pressure. Truly low cardiac output with inadequate renal perfusion from hypovolemia
or severe pump failure is an infrequent cause of renal dysfunction in AHFS.33,34,63,64
Impaired renal autoregulation is a major contributor to GFR reductions that occur
despite adequate cardiac output during AHFS treatment.9 The kidney normally main-
tains GFR despite reduced renal perfusion by autoregulation of glomerular arteriolar
tone; without normal renal autoregulation, the kidney cannot maintain GFR when
blood pressure is therapeutically reduced to normal levels.19,65–67 Drugs that antago-
nize renal autoregulation include loop diuretics, nonsteroidal antiinflammatory drugs,
and RAAS inhibitors.68,69 Loop diuretics increase tubular flow rate and trigger tubulo-
glomerular feedback, whereby adenosine binding to adenosine A1 receptors revers-
ibly decreases GFR to prevent excessive urine fluid and electrolyte loss via a
manner reversible by adenosine A1 receptor antagonism.68,70
Systemic venous congestion is the major driver of acute CRS, especially with
severely increased central venous pressures from right ventricular dysfunction and/
or tricuspid regurgitation.8,9,34,63,64,71 Increased central venous pressure reduces
glomerular perfusion pressure despite adequate cardiac output and renal blood
flow, triggering neurohormonal activation with sodium retention, diuretic resistance,
and an increased BUN/creatinine ratio.43,48 Increased intra-abdominal pressure can
compress the renal veins and renal parenchyma, impairing renal perfusion in patients
with significant ascites.72–74

CLINICAL ASSESSMENT OF CARDIORENAL SYNDROME

Volume overload and congestion are central to typical acute CRS, and we recommend
patients excluding hypovolemic and euvolemic patients from the definition of acute
CRS, which implies residual congestion.7 The cause of WRF developing early in the
course of AHFS treatment may be different from WRF episodes occurring later.9 Of
patients with AHFS developing WRF, one-third present with WRF, one-half develop
WRF during the first 48 hours of treatment, and the rest develop WRF after
48 hours.29,30,58 Late-onset WRF (developing after day 4) is associated with worse
outcomes than earlier WRF, and patients may be at risk for further deterioration in
renal function after hospital discharge.23,30,39,75
Most patients with WRF on presentation have typical congestive CRS caused by
renal venous congestion and/or intra-abdominal hypertension from volume overload,
suggested by increased jugular or central venous pressure with a dilated inferior vena
cava lacking respiratory variation on echocardiography.35,61,76 Patients with inade-
quate renal perfusion and clinical evidence of low cardiac output from severe pump
failure (low-output CRS) have true renal hypoperfusion requiring specialized therapy
and should be distinguished from most patients who have adequate renal blood
flow. When the severity of AKI seems out of proportion to the severity of HF, consider
acute renocardiac syndrome with primary AKI producing volume overload and resul-
tant cardiac dysfunction.40
During the first few days of ongoing AHFS treatment, patients with congestive CRS
often develop WRF as the result of impaired renal autoregulation in the setting of blood
pressure reduction from diuretic and/or vasodilator therapy.19,66,67 Episodes of WRF
occurring during effective decongestive therapy may not reflect true acute CRS, which
implies persistent congestion with WRF despite AHFS treatment.7 Episodes of modest
WRF during successful AHFS treatment seem benign, especially when accompanied
692 Jentzer & Chawla

by an increase in hemoglobin level, hematocrit, or serum protein or albumin levels

(hemoconcentration) resulting from effective diuresis.41,66,69
If a patient remains volume overloaded, then overdiuresis as the cause of WRF is
unlikely in the absence of signs of hypovolemia. Overdiuresis may occur in patients
with hypoalbuminemia and/or cirrhosis, who may be edematous despite normal filling
pressures. Patients with significant left ventricular hypertrophy and diastolic dysfunc-
tion are prone to reductions in cardiac output with excessive reduction of filling pres-
sures. Inadequate cardiac output may mimic overdiuresis with low blood pressure,
poor diuretic response, and progressive WRF, often with a high/increasing BUN/creat-
inine ratio and worsening hyponatremia despite positive fluid balance. Objective
assessment of cardiac output and filling pressures may be required to differentiate
overdiuresis from occult low-output CRS.
The need for hemodynamic assessment increases in proportion to the severity of
illness, and exclusion of low-output CRS is appropriate in critically ill patients. Transtho-
racic Doppler echocardiography can noninvasively estimate cardiac filling pressures
and cardiac output to identify occult congestion or hypoperfusion.35,61,76 A dilated infe-
rior vena cava, implying significant central venous congestion, seems to predict WRF in
patients with AHFS.35 The ESCAPE (Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness) study failed to show an improvement
in clinical or renal outcomes with pulmonary artery catheter–guided therapy in patients
with AHFS who were not critically ill, but does not exclude a role for invasive hemody-
namic monitoring in patients with medically refractory acute CRS.31

TREATMENT OF CARDIORENAL SYNDROME

No treatment has unequivocally improved short-term or long-term clinical outcomes in

patients with AHFS and/or acute CRS.10,11 Recent AHFS trials have included signifi-
cant numbers of patients with renal dysfunction, with a few studies focusing on patients
with acute CRS as defined by WRF in the setting of AHFS with persistent volume over-
load.77–82 Many studies use diuretic resistance as a proxy for acute CRS, reflecting a
narrower definition of acute CRS.83–86 Studies of acute CRS treatment have been
limited by small sample size, and in several cases the promising results of pilot studies
were not confirmed in a larger study.42,68,77–80,87–92 Relief of congestion remains the
primary treatment goal in patients with acute CRS, so modest WRF should be tolerated
during effective decongestive therapy.10,11,61 WRF developing during successful vol-
ume removal seems benign, and renal dysfunction in patients with AHFS who are
free from congestion has minimal adverse prognostic impact.41–46
Patients with typical congestive CRS with systemic congestion and volume over-
load have an improvement in renal function with volume removal alone, although tran-
sient WRF often occurs and must be tolerated if the patient is responding
appropriately. Patients with excessive diuretic intake, gastrointestinal fluid losses,
and/or poor fluid intake who have clinical signs of hypovolemia, such as orthostatic
hypotension, require diuretic withdrawal and careful administration of isotonic intrave-
nous fluids. In the presence of persistent congestion and volume overload, holding di-
uretics and administering fluids to correct WRF leads to a futile cycle of worsening
volume overload and congestive renal dysfunction. The few patients with advanced
HF resulting in low-output CRS require vasoactive drug support to improve forward
flow, restore renal function, and allow adequate decongestion. Patients with forme
fruste acute CRS showing diuretic resistance and WRF despite persistent volume
overload remain the greatest challenge, warranting aggressive decongestive therapy
and exclusion of low-output CRS (Fig. 3, Table 1).
 Acute Cardiorenal Syndrome 693

a
Fig. 3. Suggested approach to acute CRS therapy in the setting of acute HF. Consider
substituting vasopressin-2 antagonist if significant hyponatremia is present.

Diuretic Therapy
Loop diuretics are the first-line therapy for relief of volume overload and congestion in
patients with AHFS with or without acute CRS.10,11 Loop diuretic resistance is a
common problem in acute CRS and patients who require higher diuretic doses are a
high-risk population with poor outcomes, presumably because of the presence of

Table 1
Potential treatments studied in AHFS and/or acute CRS

Symptoms Creatinine Adverse Events

Fluid Removal Therapies
High-dose loop diuretics42,91 Y [ 4
Continuous loop diuretic infusion42,93,94 4 4 4
Combination diuretic therapy78,86,95 ? ? [
Vasopressin receptor antagonists81,96 Y 4 4
Adenosine receptors antagonists77,89,97 4 4 4
Ultrafiltration/hemodialysis78,88,98–100 Y [ [
Peritoneal dialysis/paracentesis74,101 Y ? ?
Glucocorticoids83,84 Y Y ?
Hypertonic saline85,102 Y Y ?
Vasoactive Therapies
Milrinone24,103 4 Y [
Dopamine80,90,91,94 4 4 4
Nitroglycerin92 Y 4 ?
Nitroprusside104,105 Y 4 ?
Nesiritide79,80,87,92,106,107 4 4 4
Other natriuretic peptides96,108–110 Y 4 ?
Serelaxin82,111 Y Y Y

Question marks (?) denote insufficient evidence from adequately powered randomized trials.
694 Jentzer & Chawla

advanced HF and/or CKD rather than a directly harmful effect of higher diuretic
doses.43,112–114 The DOSE (Diuretic Optimization Strategies Evaluation) study showed
improved diuresis and better symptom relief with 2.5-fold higher loop diuretic doses.42
Patients receiving higher diuretic doses had more frequent WRF, which was reversible
and not associated with an adverse clinical outcome, as seen in other studies of high-
dose diuretics in AHFS.42,91 Aggressive stepped diuretic algorithms have shown favor-
able safety and efficacy for the management of volume overload in AHFS and acute
CRS.78 Continuous infusion of loop diuretics improved natriuretic effects in some
studies, but DOSE did not show any difference in diuresis or renal function between
continuous and bolus loop diuretics at the same total daily dose.42,93 We use contin-
uous loop diuretic infusions when patients have marginal hemodynamics and/or require
very high diuretic doses, being sure to use the minimum possible infusion volume.
Overcoming loop diuretic resistance is often the primary treatment goal in patients
with acute CRS with persistent congestion despite WRF (see Fig. 3). Adding a thiazide
diuretic can augment diuresis and overcome diuretic resistance in AHFS, particularly in
patients who have been exposed to prolonged and/or high-dose loop diuretic ther-
apy.86 The effects of combination diuretic therapy on AHFS outcomes remains uncer-
tain, but patients receiving combination diuretic therapy seem more prone to true
overdiuresis and electrolyte disturbances.86,95 The stepped diuretic algorithm from
CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure)
showed good safety and efficacy using escalating doses of continuous furosemide infu-
sion (up to 30 mg/h) plus oral metolazone (up to 10 mg/d).78 Vasopressin-2 receptor an-
tagonists such as tolvaptan can augment diuresis, ameliorate hyponatremia, and
improve symptoms in patients with AHFS, but are not currently approved by the US
Food and Drug Administration for AHFS and do not seem to improve renal function.81,96
Selective adenosine A1 antagonists can augment diuresis and prevent the decrease in
GFR caused by loop diuretics.68,70,89 The PROTECT (Placebo-Controlled Randomized
Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hos-
pitalized with Acute Decompensated Heart Failure and Volume Overload to Assess
Treatment Effect on Congestion and Renal Function) study failed to show improvement
in renal function or clinical outcomes with the adenosine A1 antagonist rolofylline in pa-
tients with acute CRS, despite promising preliminary studies.77,89,97 Glucocorticoids
reversed diuretic resistance and improved renal function in small studies of acute
CRS, supporting a role for inflammation in the pathophysiology of acute CRS.83,84
Hypertonic saline seems to improve the response to high-dose loop diuretics in pa-
tients with AHFS with refractory diuretic resistance with or without hyponatremia.102
Hypertonic saline may improve cardiovascular function and relieve excess neurohor-
monal activation to reverse the profoundly sodium-avid state that drives diuretic resis-
tance in patients with acute CRS.85 Studies have shown improvements in diuresis,
natriuretic peptide levels, and renal function in patients treated with low-volume hyper-
tonic saline plus high-dose furosemide.85,102 The largest of these studies showed
improved clinical outcomes by adding 150 mL of intravenous 3% sodium chloride
twice daily to intravenous furosemide 250 mg twice daily, arguing for less-stringent
sodium restriction in patients with acute CRS.85

Vasoactive Drugs
A minority of patients have low-output CRS with severely impaired forward flow from
advanced HF, requiring vasoactive therapy to normalize renal perfusion (see
Fig. 3).10,11,115 Critically ill patients whose WRF is caused by low cardiac output may
have dramatic improvements in renal function with inotropic support, explaining why
low cardiac index did not predict WRF in patients with AHFS.34 Inotropes produce
 Acute Cardiorenal Syndrome 695

serious adverse effects in AHFS, arguing strongly against the empiric use of inotropic
drugs in acute CRS without objective evidence of low cardiac output and systemic hypo-
perfusion.115 In the OPTIME-HF (Outcomes of a Prospective Trial of Intravenous Milri-
none for Exacerbations of Chronic Heart Failure) study, milrinone failed to improve
symptoms or clinical outcomes in normotensive patients with AHFS, despite a minor
improvement in renal function.24,103 Prior studies suggested improvements in diuresis
and/or renal function when low-dose dopamine was added to loop diuretics.90,94 Subse-
quent studies failed to show any benefit of adding dopamine at 2 to 5 mg/kg/min to loop
diuretic therapy in terms of renal function, diuresis, or clinical outcomes.80,91 This mirrors
the failure of renal dose dopamine to improve outcomes in critically ill patients with AKI.116
Vasodilators are preferred to inotropes for AHFS, but likewise have not been shown
to improve renal function or outcomes.10,11,115 Vasodilators may improve forward flow
and renal perfusion in patients with impaired cardiac output, but may potentially
worsen renal function by reducing blood pressure in hypertensive patients with
impaired renal autoregulation.65,66,104,105 RAAS inhibitors that improve long-term out-
comes in chronic HF should be maintained during AHFS treatment whenever possible
and/or started before discharge.10,11 The optimal approach to WRF in patients on
RAAS inhibitors remains uncertain, but temporarily holding these drugs in the setting
of significant WRF is reasonable (especially when blood pressure is low). A reduction
in GFR is expected after starting an RAAS inhibitor, and an increase in creatinine up to
30% is acceptable and seems to be benign.69 Progressive renal dysfunction and hy-
potension after starting an RAAS inhibitor is concerning for advanced HF progressing
toward end stage, potentially warranting hemodynamic assessment.117
Nesiritide (recombinant human BNP) is the most extensively studied vasoactive
drug in AHFS, with early studies showing reductions in symptoms and congestion.92
Meta-analysis of early studies suggested higher rates of WRF with nesiritide in AHFS,
a finding that has not been confirmed in subsequent studies.87,106,107 The large
ASCEND study failed to show a meaningful benefit of nesiritide for improving symp-
toms, clinical outcomes, or renal function in AHFS.79,107 Small studies in patients
with acute CRS similarly failed to show any clinical or renal outcomes benefit with
nesiritide.80,106 Other recombinant natriuretic peptides remain under investigation
for management of AHFS and acute CRS.96,108–110 Serelaxin (recombinant human
relaxin-2) may be the first drug shown to improve outcomes in a randomized
controlled trial of patients with AHFS.82,111 In the RELAX-AHF (RELAXin in Acute Heart
Failure) trial, serelaxin improved symptoms and reduced the secondary end point of
mortality at 180 days, with improvement in markers of renal and hepatic function.82,111
Further study is required to confirm the efficacy of this promising new vasodilator ther-
apy in AHFS and acute CRS.

Extracorporeal Volume Removal

Ultrafiltration involves removal of fluid and electrolytes directly from the bloodstream
using a standard dialysis machine or a miniaturized device. Early studies, such as UN-
LOAD (Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute
Decompensated Congestive Heart Failure), suggested that ultrafiltration could
improve volume removal compared with diuretics as first-line therapy, with more
favorable effects on renal function and clinical outcomes.88 The subsequent CARR-
ESS study found that ultrafiltration did not improve volume removal or clinical
outcomes compared with an aggressive stepped diuretic algorithm when used as
first-line therapy in acute CRS.78 CARRESS showed a greater increase in creatinine
level and more adverse events with ultrafiltration compared with diuretic therapy,
arguing against the use of ultrafiltration as a first-line modality for fluid removal in acute
696 Jentzer & Chawla

CRS.78 Meta-analysis of studies comparing ultrafiltration with diuretic therapy in AHFS

suggests improved fluid removal with ultrafiltration without an increased risk of
adverse events, but the heterogeneity of the included studies and lack of aggressive
standardized combination diuretic regimens reduces the ability to generalize.99 Given
the results of CARRESS, we recommend the use of a stepped combination diuretic
algorithm as first-line therapy for volume overload in AHFS including diuretic-respon-
sive patients with acute CRS who are diuretic responsive, reserving ultrafiltration for
refractory diuretic resistance (see Fig. 3).78
Ultrafiltration can be an effective rescue therapy for patients with refractory volume
overload resistant to medical therapy, albeit at risk of further WRF and in some cases
progression to dialysis dependence.98,118 Patients with refractory acute CRS requiring
ultrafiltration as rescue therapy have high short-term and long-term mortalities, in
addition to significant rates of dialysis dependence that may support early dialysis
initiation in eligible patients.98,100 Several nonrandomized studies have found perito-
neal dialysis to be an effective alternative method of volume removal in acute CRS
with refractory diuretic resistance.101 Drainage of tense ascites may improve renal
function when intra-abdominal hypertension is contributing to WRF.73,74 Extracorpo-
real volume removal can restore diuretic responsiveness in some patients by relieving
congestive renal dysfunction.72,73,88,99,101

SUMMARY

Development of WRF in the setting of AHFS can occur from acute CRS and disease
processes mimicking acute CRS. Acute CRS results from relative decreases in renal
blood flow, deranged renal blood flow autoregulation, and renal venous congestion.
Congestion is central to the pathophysiology of AHFS and drives acute CRS in
most patients, distinguishing acute CRS from typical causes of AKI. We think that
acute CRS should only apply to patients with persistent congestion and WRF during
AHFS therapy. An accurate assessment of volume status and cardiac output may
distinguish true acute CRS from acute CRS mimics. Patients with low cardiac output
are less common than patients whose acute CRS is congestive and requires special-
ized therapy. No specific treatment of acute CRS exists, so optimal management of
AHFS including adequate decongestive therapy remains essential. Volume removal
is needed to relieve symptoms of congestion and typically resolves congestive
CRS. Various adjuncts and alternatives to loop diuretics have been explored in an
attempt to improve volume removal, renal function, and/or outcomes, but none has
shown unequivocal efficacy. Given the lack of effective therapies, the outcomes of pa-
tients with refractory CRS remain poor. Further study is needed to validate promising
early studies and identify new therapies for this high-risk population.

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