20/10/2023, 08:33 Cardiorenal syndrome: Prognosis and treatment - UpToDate

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Cardiorenal syndrome: Prognosis and treatment

AUTHORS: Michael S Kiernan, MD, James E Udelson, MD, FACC, Mark Sarnak, MD
SECTION EDITOR: Stephen S Gottlieb, MD
DEPUTY EDITOR: Todd F Dardas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2023.

This topic last updated: May 12, 2022.

INTRODUCTION

Acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction
in the other organ. In addition, both heart and kidney function can be impaired by an acute
or chronic systemic disorder. The term "cardiorenal syndrome" (CRS) has been applied to
these interactions.

The prognosis and treatment of type 1 and 2 CRS will be reviewed here. Issues related to the
prevalence of a reduced glomerular filtration rate in patients with heart failure (HF), the
diagnosis of type 1 and 2 CRS, and the mechanisms by which acute and chronic HF lead to
worsening renal function are discussed separately. (See "Cardiorenal syndrome: Definition,
prevalence, diagnosis, and pathophysiology".)

REDUCED GFR AND PROGNOSIS

A reduced baseline glomerular filtration rate (GFR) is generally associated with a worse
prognosis in patients with heart failure (HF). However, the prognostic significance of
worsening renal function (WRF) likely depends upon its cause. (See 'Change in glomerular
filtration rate during therapy for heart failure' below.)

An analysis of the PROTECT trial identified multiple different trajectories in renal function
during hospitalization for acute heart failure [1]. The most common trajectories were in-
hospital transient rise in serum creatinine (19 percent), sustained increase (17.6 percent), and
decrease (14.5 percent). After multivariable adjustment, no trajectory of change was

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associated with significantly better or worse outcomes, questioning the prognostic

importance of changes in renal function during acute HF.

Reduced baseline glomerular filtration rate — The prevalence of moderate to severe

reductions in GFR (less than 60 mL/min per 1.73 m2) in patients with HF has ranged from 30
to 60 percent in large clinical studies [2,3]. This observation is important clinically because
the baseline GFR is a predictor of mortality in both acute and chronic HF [2-9].

The following observations illustrate the range of findings:

● A systematic review of 16 studies included more than 80,000 patients with HF [2]. The
patients were categorized as having normal renal function (estimated GFR [eGFR] 90
mL/min or higher), mildly impaired renal function (eGFR 53 to 89 mL/min, serum
creatinine greater than 1.0 mg/dL [88.4 micromol/L], or serum cystatin C greater than
1.03 to 1.55 mg/dL), or moderately to severely impaired renal function (eGFR less than
53 mL/min, serum creatinine of 1.5 mg/dL [133 micromol/L] or higher, or serum
cystatin C of 1.56 mg/dL or higher). Serum cystatin C may be a better marker of GFR
than serum creatinine under certain circumstances because unlike creatinine
production, cystatin C production is less dependent upon muscle mass and therefore
less influenced by nutritional status [10]. (See "Assessment of kidney function".)

The mortality rate at a follow-up of one year or more was 24 percent in those with a
normal eGFR compared with 38 and 51 percent in patients with mild and moderate to
severe reductions in eGFR, respectively (adjusted hazard ratio [HR] 1.6 and 2.3). It was
estimated that mortality increased by approximately 15 percent for every 10 mL/min
reduction in eGFR.

● Similar findings were noted in a report of 2680 patients with chronic HF in the CHARM
program who were followed for a median of almost three years [4]. All-cause mortality
increased significantly when the baseline eGFR was below 75 mL/min per 1.73 m2
(adjusted HR 1.09, 95% CI 1.06-1.14 for every 10 mL/min per 1.73 m2 decrease in eGFR
below 75 mL/min per 1.73 m2). The adjusted HR increased from 1.20 at an eGFR of 60 to
75 mL/min per 1.73 m2 to 2.92 at an eGFR below 45 mL/min. This effect was
independent of the left ventricular ejection fraction (LVEF), but all-cause mortality
increased continuously with reductions in LVEF below 45 percent (adjusted HR 1.18,
95% CI 1.13-1.23 per 5 percent decrease in LVEF).

● Among 4917 patients with a continuous-flow LV assist device (LVAD), worse preimplant
renal dysfunction correlated with lower survival rate with an approximately 20 percent
lower two-year survival in patients with eGFR <30 mL/min compared with those with
eGFR ≥60 mL/min [11]. The major reduction in survival occurred within the first three
months after LVAD implantation.

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Change in glomerular filtration rate during therapy for heart failure — Worsening or
improving GFR is associated with increased mortality risk in some patient populations but
the cause of worsening GFR influences its prognostic significance [5,12-21]. Most of the data
on the relationship between change in GFR and outcomes were obtained from patients
hospitalized for worsening HF.

The prevalence of WRF in patients with HF was illustrated by a study of 3,570,865 United
States veterans with an eGFR ≥60 mL/min/1.73 m2 of which 156,743 were diagnosed with HF
[22]. Incident chronic kidney disease (CKD) was 69.0/1000 patient-years in patients with HF
versus 14.5/1000 patient-years in those without. Twenty-two percent of HF patients
compared with 8.5 percent of patients without HF experienced a rapid decline in eGFR. HF
patients had greater than two times the risk of incident CKD, a composite of incident CKD or
mortality, as well as rapid eGFR decline.

Association between change and prognosis — The association between worsening renal
function and mortality are illustrated by a meta-analysis of eight studies with more than
18,000 patients with HF [15]. Five studies involved hospitalized patients and three involved
outpatients. The following findings were noted:

● Worsening renal function, defined as an elevation in serum creatinine of 0.3 mg/dL (27
micromol/L) or more, occurred in 26 percent of patients.

● All-cause mortality was significantly higher in the patients with worsening renal
function compared with those with a serum creatinine that was unchanged or
increased by less than 0.2 mg/dL (18 micromol/L): 43 versus 36 percent. The findings
were the same in hospitalized and nonhospitalized patients.

● The mortality risk increased progressively with the degree of worsening renal function.
The respective odds ratios were:

• 1.03 (not significant) when the serum creatinine rose by 0.2 to 0.3 mg/dL (18 to 27
micromol/L) or the eGFR declined by less than 5 to 10 mL/min per 1.73 m2.

• 1.48 when the serum creatinine rose by 0.3 to 0.5 mg/dL (27 to 44 micromol/L) or
the eGFR declined by 11 to 15 mL/min per 1.73 m2.

• 3.22 when the serum creatinine rose by more than 0.5 mg/dL (44 micromol/L) or the
eGFR declined by more than 15 mL/min per 1.73 m2.

However, other evidence suggests that patients with improving or worsening renal function
may have worse outcomes. Fluctuating renal function may occur in a sicker cohort of
patients with significantly worse survival than patients with stable renal function, as
illustrated by the following studies:

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● An analysis of data on 401 patients enrolled in the ESCAPE trial found that patients with
an improvement or a decline in estimated GFR during treatment of acute
decompensated HF had similar outcomes [19]. Compared with patients with a stable
GFR, those with either an improvement or a decline in GFR were significantly more
likely to have a reduced cardiac index and to require intravenous inotrope and
vasodilator therapy, and had a significantly higher rate of all-cause mortality.

● Similarly, an observation study of 903 patients found that those with improved GFR
during hospitalization for HF had worsened survival compared with patients with stable
renal function [20]. This finding was largely restricted to patients who developed
recurrent renal dysfunction post-discharge.

Importance of cause of worsening renal function — The mechanism of worsening renal

function in HF is important in determining its prognostic significance. An analysis of data on
6337 subjects enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) showed that
early worsening renal function was associated with increased mortality in the overall
population [21]. However, in the enalapril group, early worsening renal function was not
associated with increased mortality, while in the placebo group, the association with
mortality was strengthened. A significant survival benefit from enalapril therapy was
observed in patients who continued enalapril despite early worsening renal function. These
findings suggest that worsening renal function is not always a marker of adverse clinical
outcome. On the contrary, in the case of angiotensin converting enzyme inhibitor
administration, it is a manifestation of the agent’s pharmacologic properties, which exert a
favorable effect on long-term outcome.

Other studies of renin-angiotensin-aldosterone system (RAAS) inhibition have similarly

demonstrated beneficial effects on long-term outcomes despite an initial early decline in
renal function [23,24]. An analysis of data from the Heart failure End point evaluation of
Angiotensin II Antagonist Losartan (HEAAL) trial found that 150 mg losartan compared with
50 mg was associated with increased risk of acute rise in serum creatinine as well as with
greater long-term reductions in eGFR, but that despite these effects, high-dose losartan
retained its net clinical benefit and was associated with reduced risk of death or HF
hospitalization [25]. Early decline in GFR in the setting of initiation of RAAS antagonists may
reflect antagonism of angiotensin II-mediated efferent arteriolar constriction.

In addition, as noted below, treatment of decompensated HF with diuretics may improve

survival despite worsening renal function. (See 'Diuretics' below.)

In an analysis of the ESCAPE trial, in-hospital WRF was not associated with increased risk of
mortality among patients who were successfully decongested at discharge [26]. Transient
increases (bumps) in serum creatinine during decongestion may be predominantly
functional or hemodynamic in nature. Increases in creatinine observed during aggressive
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decongestion may thus be clinically benign events, not signifying true injury nor associated
with subsequent adverse outcomes [27]. In an analysis of the Renal Optimization Strategies
Evaluation – Acute Heart Failure (ROSE-AHF) trial, 283 patients with baseline and 72-hour
urine tubular injury biomarkers were analyzed [28]. There was no correlation between
change in tubular injury biomarkers and metrics of diuresis and decongestion. Changes in
renal filtration markers, serum creatinine, and cystatin C during aggressive diuresis were not
associated with changes in markers of renal tubular injury, KIM-1, NGAL, and NAG. Thus,
transient increases in serum creatinine most likely reflect temporary changes in renal
filtration rather than acute kidney injury [28]. Other investigations have similarly found a lack
of association between serum and urinary NGAL and subsequent WRF defined by rising
serum creatinine [29,30].

In contrast, in the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart

Failure) trial, intensive volume removal resulted in worsening creatinine in about half of the
patients, and was associated with a rise in tubular injury biomarkers [31]. Decongestion and
renal functional recovery at 60 days, however, were superior in patients with increased
tubular injury markers, suggesting the primary importance of adequate decongestion over
transient changes in renal function during therapy.

The importance of mechanism of WRF as reflected by change is systemic blood pressure is

discussed separately. (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and
pathophysiology", section on 'Reduced systemic blood pressure'.)

Blood urea nitrogen — An elevation in blood urea nitrogen (BUN) or blood urea is also
associated with increased mortality in patients with HF [18,32-34], an effect that may be
independent of the serum creatinine and GFR [32,33]. A probable contributing factor is that a
disproportionate increase in BUN is often seen with a reduction in renal perfusion (ie,
prerenal azotemia). (See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and
pathophysiology".)

Other prognostic indicators — Microalbuminuria is associated with increased event rates

among ambulatory patients with HF with reduced ejection fraction [35]. In patients with
advanced HF, baseline proteinuria prior to surgery has similarly been associated with an
increased risk of requiring renal replacement therapy, as well as increased mortality
following LVAD implantation [36,37]. Baseline proteinuria added increment risk of poor
outcome independent of a high versus low baseline estimated GFR.

However, modest increases in urine albumin-to-creatinine ratio (UACR) observed shortly after
initiating angiotensin receptor-neprilysin inhibitor therapy is not associated with adverse
events. It is suspected that that modest increase in UACR associated with sacubitril/valsartan
use reflects an acute intrarenal hemodynamic effect, likely due to the actions of natriuretic
peptides [38].
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Hypochloremia has also been recognized to independently predict adverse outcomes in HF

patients [39].

MANAGEMENT

Given the limitations imposed by impaired renal function on the ability to correct volume
overload and the frequent association between impaired or worsening renal function and
mortality in patients with heart failure (HF), it is possible that effective treatment of the
cardiorenal syndrome (CRS) could improve patient outcomes. On the other hand, the worse
prognosis in patients with HF and impaired renal function could primarily reflect a reduced
glomerular filtration rate (GFR) being a marker of more severe cardiac disease. In this
setting, improving renal function alone would not necessarily improve patient outcomes.
(See 'Reduced GFR and prognosis' above.)

There are no medical therapies that have been shown to directly increase the GFR
(manifested clinically by a decline in serum creatinine) in patients with HF. On the other hand,
improving cardiac function can produce increases in GFR, indicating that types 1 and 2 CRS
have substantial reversible components. (See "Cardiorenal syndrome: Definition, prevalence,
diagnosis, and pathophysiology", section on 'Definition and classification' and "Cardiorenal
syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on
'Pathophysiology'.)

Improvement in cardiac function — Evidence suggesting that improvement in cardiac

function is associated with improved renal function in patients with types 1 and 2 CRS comes
from studies of left ventricular assist devices (LVADs) and cardiac resynchronization therapy:

● A study of 4917 patients with continuous-flow LVADs enrolled in the INTERMACS

registry demonstrated improvements in serum creatinine and reductions in blood urea
nitrogen (BUN) among patients with baseline moderate or severe renal dysfunction.
Improvements in estimated GFR (eGFR) were noted within one month of LVAD
implantation and persisted over a two-year period of follow-up [11]. However, a
separate analysis of data from the INTERMACS registry found that early improvements
in eGFR with LVAD use were transient and typically only sustained for a period of weeks
to months [40].

● Analysis of data from an observational study and from the MIRACLE trial found that
cardiac resynchronization therapy improved the LV ejection fraction and the eGFR in
selected patients with HF and moderately reduced baseline eGFR (30 to 59 mL/min)
[41,42]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice
of system", section on 'Rationale for CRT'.)

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Diuretics — Diuretics, typically beginning with a loop diuretic, are first-line therapy for
managing volume overload in patients with HF as manifested by peripheral and/or
pulmonary edema. In patients with HF, an elevated BUN/creatinine ratio should not deter
diuretic therapy if clinical evidence of congestion is present. Issues related to diuretic dosing,
the time course of the diuresis, the side effects of diuretic therapy, and the management of
refractory edema in these patients are discussed elsewhere. (See "Use of diuretics in patients
with heart failure".)

A post hoc analysis compared the decongestive efficacy of urine-output guided diuretic
adjustment with standard therapy for the management of cardiorenal dysfunction in acute
decompensated HF [43]. Patient data from subjects randomized to the stepwise
pharmacologic care algorithm in the CARRESS-HF trial and those who developed worsening
renal function in the DOSE-AHF and ROSE-AHFs trials were included. Compared with
standard therapy, the stepwise pharmacologic care algorithm resulted in greater weight
change and more net fluid loss after 24 hours with slight improvement in renal function.

The effect of diuretic-induced fluid removal on the glomerular filtration rate (usually
estimated from the serum creatinine) is variable in patients with HF:

● Some patients have an increase in serum creatinine that is presumed to be mediated at

least in part by a reduction in renal perfusion due to a decline in cardiac output induced
by the fall in cardiac filling pressures [44]. (See "Cardiorenal syndrome: Definition,
prevalence, diagnosis, and pathophysiology", section on 'Reduced renal perfusion'.)

● Some patients have no change in serum creatinine that may reflect maintenance of
cardiac output perhaps because they are on the flat part of the Frank-Starling curve
where changes in LV end-diastolic pressure have little or no effect on cardiac
performance ( figure 1).

● Some patients have a reduction in serum creatinine mediated perhaps in part by one or
both of the following mechanisms:

• Reductions in intraabdominal and renal venous pressures. (See "Cardiorenal

syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on
'Increased renal venous pressure'.)

• Reduction in right ventricular dilatation, which may improve LV filling and function
via ventricular interdependence (alleviation of the reverse Bernheim phenomenon).
(See "Cardiorenal syndrome: Definition, prevalence, diagnosis, and
pathophysiology", section on 'Right ventricular dilation and dysfunction'.)

Among patients with decompensated HF, the best outcomes may occur with aggressive fluid
removal even if associated with mild to moderate worsening of renal function. Support for

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aggressive fluid removal comes from the following studies:

● A study of 336 patients with decompensated HF in the Evaluation Study of Congestive

Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial found
that hemoconcentration was associated with worsening renal function as well as a
lower mortality rate [45]. Hemoconcentration was defined as baseline-to-discharge
increases in the top one-third of the group in at least two of the following: hematocrit,
serum albumin, and serum total protein. Patients with hemoconcentration were treated
with higher doses of loop diuretics and more fluid loss, lost more weight, and had
greater reductions in intracardiac filling pressures compared with patients without
hemoconcentration. Hemoconcentration was strongly associated with worsening renal
function (odds ratio 5.3), but also was associated with a significantly lower 180 day
mortality rate (adjusted hazard ratio [HR] 0.16, 95% CI 0.02-0.44). Although the total
number of deaths was small (n = 29), this study suggests that aggressive decongestion
in the face of worsening renal function may favorably affect survival.

● An analysis of data from the EVEREST (Efficacy of Vasopressin Antagonism in heart

Failure Outcome Study with Tolvaptan) trial demonstrated that hemoconcentration was
associated with greater risk of in-hospital worsening renal function, though renal
parameters generally returned to baseline within four weeks of discharge [46]. Despite
this association, every 5 percent increase in in-hospital hematocrit change was
associated with a decreased risk of all-cause mortality (HR 0.81, 95% CI 0.70-0.95).

Another analysis from the EVEREST trial evaluated the association between eGFR,
markers of volume overload, and changes in hemoconcentration [47]. While a decline in
eGFR was associated with high risk of both death and the composite outcome, this did
not hold true if there was evidence of decongestion (defined as a decline in B-type
natriuretic peptide [BNP], N-terminal pro-BNP, or weight, or an increase in hematocrit,
albumin, or total protein). Thus, worsening eGFR was not associated with a higher risk
of adverse outcomes if markers of decongestion were improving.

Additionally, the timing of hemoconcentration may be important, as a study of 845

consecutive inpatients with HF found that hemoconcentration achieved late during the
hospitalization was associated with improved survival while early hemoconcentration was
not associated with improved survival compared with no hemoconcentration [48]. Late
hemoconcentration was associated with higher average daily loop diuretic doses and greater
weight loss than early hemoconcentration.

These findings provide support for the recommendation included in the 2013 American
College of Cardiology/American Heart Association HF guidelines that the goal of diuretic
therapy is to eliminate clinical evidence of fluid retention such as an elevated jugular venous
pressure and peripheral edema [49]. The rapidity of diuresis can be slowed if the patient
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develops hypotension or worsening renal function. However, the goal of diuretic therapy is
to eliminate fluid retention even if this leads to asymptomatic mild to moderate reductions in
blood pressure or renal function. (See "Use of diuretics in patients with heart failure".)

Renin-angiotensin system antagonists

General effects — Angiotensin inhibition with an angiotensin converting enzyme (ACE)

inhibitor, angiotensin receptor-neprilysin inhibitor (ARNI), or an angiotensin II receptor
blocker (ARB) is a standard part of the therapy of HF with reduced ejection fraction, being
associated with symptomatic improvement, reduced hospitalization for HF, and enhanced
survival. (See "Primary pharmacologic therapy for heart failure with reduced ejection
fraction", section on 'Primary components of therapy'.)

Despite the above benefits, ACE inhibitor or ARB therapy for HF is not generally associated
with an improvement in renal function. Although a minority of patients have an increase in
GFR after initiation of ACE inhibitor or ARB therapy, most have a moderate reduction in GFR
that can often be ameliorated by reducing the intensity of diuretic therapy. Additionally,
there is a dose effect. Compared with low-dose ARB therapy in chronic HF, high-dose losartan
is associated with sustained reductions in eGFR. Despite this effect, high-dose losartan is
associated with improved long-term clinical outcomes [25]. The supportive data and
management are presented separately. (See "Primary pharmacologic therapy for heart
failure with reduced ejection fraction", section on 'Sacubitril-valsartan, ACE inhibitor, or ARB'.)

An analysis of the SOLVD trials showed that chronic eGFR decline over median three-year
follow-up was not significantly different between the enalapril and placebo arms [50]. These
findings may encourage clinicians that ACE inhibitors will not only promote survival but also
have no detrimental, albeit also no beneficial, longer-term effect on kidney function among
patients with HFrEF.

Determining a threshold of eGFR decline that can still be tolerated after initiating ACE
inhibitor therapy among patients with HFrEF remains a challenging question. An analysis
from the SOLVD trials incorporated assumptions regarding the varying degrees of
hemodynamic medication-related decline and found that in most models, up to a 15 percent
eGFR decline after enalapril initiation was still associated with significant mortality benefit,
and up to 40 percent eGFR decline with enalapril was still associated with significant
protection against hospitalizations for heart failure [51]. These results give reassurance to
clinicians that, at least among stable HFrEF outpatients without advanced chronic kidney
disease (CKD; patients with creatinine >2.5 mg/dL were excluded), there should be
compelling reason beyond a moderate eGFR decline to withdraw this beneficial class of
medications.

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While clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in HF have

not specifically focused on patients with the CRS, subgroup analyses of patients with and
without CKD as well as cohort studies have demonstrated that the beneficial effect of RAAS
antagonism on clinical outcomes is not mitigated by concomitant CKD [23,52-54]. While RAAS
antagonists retain their clinical benefit in HF among patients with CKD, the risk of adverse
events including hyperkalemia and worsening renal function is higher than in patients
without CKD [23,24,52,54-56]. Patients with CKD should be monitored closely during periods
of drug initiation and titration and should receive periodic monitoring of electrolytes and
creatinine throughout the duration of therapy [49].

ARNI — An analysis of data from the PARADIGM-HF trial found that a decrease in eGFR
during follow-up was less with ARNI therapy compared with treatment with an ACE inhibitor,
despite a greater increase in the urine albumin-to-creatinine ratio (UACR) in ARNI-treated
patients [35]. Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in
eGFR; eGFR decreased by 10.2 mL/min/1.73m2 (95% CI 12.1-8.3 mL/min/1.73m2) in patients
assigned to enalapril and by 7.8 mL/min/1.73m2 (95% CI 9.6-9.6 mL/min/1.73m2) in those
assigned to sacubitril/valsartan between screening and end of follow-up [35]. The clinical
benefit (on cardiovascular death and HF hospitalization) of sacubitril/valsartan compared
with enalapril was consistent in patients with and without CKD and across stages of CKD,
including stage 3B.

In a CKD population with baseline mean eGFR of 34 mL/min/17.3 m2, sacubitril-valsartan was
well tolerated, with similar rates of adverse events when compared with irbesartan [57].
Given the prevalence of concomitant CKD among patients with HF, these data provide some
reassurance regarding tolerability of ARNI therapy in this high-risk population.

The indications for ARNI therapy in patients with HFrEF and HFpEF are discussed elsewhere.
(See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section
on 'Primary components of therapy' and "Treatment and prognosis of heart failure with
preserved ejection fraction", section on 'Secondary therapies'.)

Sodium-glucose co-transporter 2 inhibitors — In patients with HFrEF, but not in patients

with HFpEF, sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of
cardiovascular and kidney outcomes:

● In a meta-analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart

Failure and Reduced Ejection Fraction (EMPEROR-Reduced) and Dapagliflozin in Patients
With Heart Failure and Reduced Ejection Fraction (DAPA-HF) trials, the combined renal
endpoint was reduced among patients randomized to SGLT2 inhibitor therapy
compared with placebo (HR 0.62, 95% CI 0.43-0.010; p = 0.013) [58].

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● In another meta-analysis comprised of 14,113 patients with HFrEF who were enrolled
among seven trials, SGLT2 inhibitor treatment was associated with a lower incidence of
a significant decrease in renal function when compared with placebo [59].

● In patients with HFpEF, treatment with empagliflozin was not found to improve renal
outcomes [60].

The indications for SGLT2 inhibitor treatment are discussed elsewhere. (See "Primary
pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Sodium-
glucose co-transporter 2 inhibitors' and "Treatment and prognosis of heart failure with
preserved ejection fraction", section on 'Sodium-glucose co-transporter 2 inhibitors'.)

Vasodilators — Intravenous vasodilators used in the treatment of acute decompensated HF

include nitroglycerin and nitroprusside. (See "Treatment of acute decompensated heart
failure: Specific therapies", section on 'Vasodilator therapy'.)

With respect to effects on the CRS, the Acutely Decompensated Heart Failure National
Registry (ADHERE) database of almost 100,000 patients defined worsening renal function as
a rise in serum creatinine between admission and discharge of more than 0.5 mg/dL (44
micromol/L) or more than 0.3 mg/dL (27 micromol/L) with a serum creatinine more than 1.5
mg/dL (133 micromol/L) [61]. The rate of worsening renal function was significantly higher
when intravenous diuretics were given with nitroglycerin or nesiritide compared with
intravenous diuretics alone (relative risk 1.20 and 1.44, respectively). However, a causal effect
could not be distinguished from patients requiring combination therapy having more severe
HF.

Inotropic drugs — Intravenous administration of inotropic (calcitropic) drugs, such as

dobutamine, dopamine, and milrinone, has a role in the treatment of cardiogenic shock in a
subset of patients with acute decompensated HF. However, both routine use of short-term
intravenous therapy in patients with acute decompensated HF and prolonged therapy with
oral inotropic drugs other than digoxin have been associated with an increase in mortality.
As a result, the main role of inotropic drugs other than digoxin is in the management of
cardiogenic shock. The supporting data and management are discussed in detail elsewhere.
(See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Summary
and recommendations' and "Treatment of acute decompensated heart failure in acute
coronary syndromes" and "Treatment of acute decompensated heart failure: Specific
therapies", section on 'Inotropic agents' and "Prognosis and treatment of cardiogenic shock
complicating acute myocardial infarction", section on 'Vasopressors and inotropes'.)

The role of inotropes in patients with CRS is uncertain and the routine use of inotropes
cannot be recommended given their lack of proven efficacy and their association with

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adverse events when used outside of selected patients with cardiogenic shock or acute
decompensated HF.

Although it has been proposed that inotropic agents might improve renal function in
patients with severe HF by increasing renal blood flow and possibly by reducing renal venous
pressure, data supporting such a potential benefit are limited as illustrated by the following
observations regarding use of dopamine:

● A potential role for dopamine in improving or preserving renal function in HF was

suggested by small series indicating that dopamine can significantly increase the GFR in
patients with moderate or severe HF [62,63]. Dopamine increased renal blood flow at
doses of 2 to 10 mcg/kg/min in such patients [62,64]. This effect appears to be due to
dilation of both large conductance and small resistance renal blood vessels [64].
Dopamine also caused significant increases in cardiac output at doses in the range of 5
to 10 mcg/kg/min, but the proportionate increase in renal blood flow was greater than
the increase in cardiac output.

● The clinical efficacy and safety of dopamine for preservation of renal function in
patients with HF has not been established.

• A report from the DAD-HF trial of 60 patients with acute decompensated HF found
that the combination of dopamine 5 mcg/kg/min plus low-dose furosemide (5mg/h
continuous infusion) produced similar urine output as high-dose furosemide (20
mg/h) with reduced risk of worsening renal function (defined as rise in serum
creatinine of >0.3 mg/dL from baseline to 24 hours; 7 versus 30 percent) [65].

• The Renal Optimization Strategies Evaluation (ROSE) trial also tested the hypothesis
of whether low-dose dopamine (2mcg/kg/min) (n = 122) would improve urine output
and renal function compared with placebo (n = 119) among patients hospitalized
with HF and concomitant renal disease [66]. Low-dose dopamine did not enhance
decongestion or improve renal function when added to diuretic therapy.

Ultrafiltration — Ultrafiltration refers to the removal of isotonic fluid from the venous
compartment via filtration of plasma across a semipermeable membrane. In HF patients,
ultrafiltration is most often considered in patients with acute decompensated HF and diuretic
resistance and/or impaired renal function. By removing isotonic fluid, ultrafiltration tends to
maintain physiologic electrolyte balance, in contrast to diuretic therapy. (See "Management
of refractory heart failure with reduced ejection fraction", section on 'Ultrafiltration'.)

Three randomized trials (UNLOAD, RAPID-CHF, and CARESS-HF) compared ultrafiltration with
diuretic therapy in patients with acute decompensated HF [67-69]. The mean baseline serum
creatinine levels were 1.5, 1.7, and 2.0 mg/dL (133, 150, and 177 micromol/L), respectively. In
UNLOAD and RAPID-CHF, ultrafiltration was associated with a significantly greater rate of
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fluid loss than diuretic therapy but no difference in serum creatinine. In CARESS-HF,
ultrafiltration was compared with stepped pharmacologic therapy (including bolus plus high
doses of continuous infusion loop diuretics, addition of thiazide diuretic [metolazone], and
selected intravenous inotrope and/or vasodilator therapy) in patients with worsening renal
function and persistent congestion [69]. Although weight loss was similar in ultrafiltration
and stepped pharmacologic therapy groups, ultrafiltration therapy caused an increase in
serum creatinine and a higher rate of adverse events. (See "Management of refractory heart
failure with reduced ejection fraction", section on 'Ultrafiltration'.)

Thus, although ultrafiltration may be helpful for fluid removal in acute decompensated HF in
patients unresponsive to diuretic therapy, the available evidence does not establish
ultrafiltration as first line therapy for acute decompensated HF or as an effective therapy for
CRS. The 2013 American Heart Association/American College of Cardiology guidelines note
that ultrafiltration is reasonable for patients with refractory congestion not responding to
medical therapy [49].

Vasopressin receptor antagonists — Neurohormonal activation in patients with HF results

in the nonosmotic release of antidiuretic hormone (arginine vasopressin), which leads to free
water retention and hyponatremia that parallels the severity of the HF [70]. (See "Predictors
of survival in heart failure with reduced ejection fraction", section on 'Neurohumoral
activation and heart rate' and "Hyponatremia in patients with heart failure", section on
'Predictor of adverse prognosis'.)

Tolvaptan is a selective vasopressin 2 receptor antagonist that produces a water diuresis, not
a salt diuresis as induced by conventional diuretics. Tolvaptan is approved only for the
treatment of hyponatremia in patients with HF. (See "Hyponatremia in patients with heart
failure", section on 'Vasopressin receptor antagonists'.)

The effects of tolvaptan therapy on clinical outcomes in patients with HF were evaluated in
the following randomized trials:

● In the EVEREST Outcome trial, tolvaptan had no effect on the co-primary end points of
all-cause mortality, mortality or HF hospitalization, or seven-day patient global
assessment compared with placebo [71]. However, there were significant benefits in a
number of secondary end points including an increase in urine output, resulting in
reduced dyspnea and edema and an increase in serum sodium. There was also a
statistically significant, but not clinically significant, greater increase in serum creatinine
with tolvaptan (0.08 versus 0.03 mg/dL [7.1 versus 2.7 micromol/L] with placebo).

● In a study of 250 patients with acute HF selected for greater potential benefit from
vasopressin receptor inhibition based on evidence of CKD, hyponatremia, or diuretic
resistance, tolvaptan administration was not associated with greater early

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improvement in dyspnea compared with placebo [72]. However, the tolvaptan group
showed greater early and sustained weight loss, associated with progressively greater
improvement in dyspnea scores, reaching a maximum at three days.

● A separate study of 257 patients with acute HF randomized within 24 hours of

presentation demonstrated similar findings whereby tolvaptan administration did not
result in a higher early response rate (defined as greater dyspnea relief without the
need for rescue therapy or death) despite evidence of greater weight loss and a trend
toward greater dyspnea scores over three days [73].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Heart failure in
adults".)

SUMMARY

● Reduced GFR and prognosis – Reduced glomerular filtration rates (GFR) are common
in patients presenting with heart failure (HF) and are associated with increased
mortality. A systematic review found that mortality increased by approximately 15
percent for every 10 mL/min reduction in estimated GFR. (See 'Reduced GFR and
prognosis' above.)

● Change in GFR during HF therapy – A fall in GFR during treatment of HF has often
been associated with increased mortality in clinical studies in which the risk of mortality
increased progressively with the degree of worsening renal function. However, other
evidence suggests that patient outcomes may be improved with aggressive fluid
removal even if accompanied by a rise in serum creatinine. (See 'Change in glomerular
filtration rate during therapy for heart failure' above.)

● Management – Given the limitations imposed by impaired renal function on the ability
to correct volume overload and the strong association between impaired or worsening
renal function and adverse clinical outcomes in patients with HF, it is possible that
effective treatment of the cardiorenal syndrome (CRS) would improve patient
outcomes. On the other hand, the worse prognosis associated with CRS could primarily
reflect a reduced GFR being a marker of more severe cardiac disease. In this setting,
improving renal function alone would not necessarily improve patient outcomes. (See
'Management' above.)

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There are no medical therapies that have been shown to directly increase GFR in
patients with the CRS. On the other hand, improving cardiac function can produce
increases in GFR, indicating that types 1 and 2 CRS have substantial reversible
components. (See 'Management' above.)

• Diuretics – The effect of diuretic-induced fluid removal on the GFR is variable in

patients with HF. Although fluid removal may result in increases in serum creatinine
and rising serum creatinine is associated with worse prognosis in patients with HF,
aggressive decongestion leading to worsening renal function may be associated
with improved survival. (See 'Diuretics' above.)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Marvin Konstam, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 15619 Version 27.0

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GRAPHICS

Frank-Starling curves in heart failure

Idealized family of Frank-Starling curves produced by worsening

ventricular function in heart failure. In ventricles with normal cardiac
performance, there is a steep and positive relationship between
increased cardiac filling pressures (as estimated from the LVEDP or
pulmonary capillary wedge pressure) and increased stroke volume
or cardiac output (top curve). By comparison, during progression
from mild to severe myocardial dysfunction, this relationship is right
shifted (ie, a higher filling pressure is required to achieve the same
cardiac output) and flattened so that continued increases in left
heart filling pressures lead to minimal increases in cardiac output at
the possible expense of pulmonary edema. The onset of mild heart
failure results in an initial reduction in cardiac function (from point A
to point B), a change that can be normalized, at least at rest, by
raising the LVEDP via fluid retention (point C). Diuretic therapy
reduces left ventricular filling pressure at the expense of mildly
decreased cardiac output (moving from point C to point B). By
comparison, normalization of stroke volume is not attainable in
severe heart failure (bottom curve).

LVEDP: left ventricular end-diastolic pressure.

Graphic 58693 Version 8.0

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Contributor Disclosures
Michael S Kiernan, MD No relevant financial relationship(s) with ineligible companies to
disclose. James E Udelson, MD, FACC Grant/Research/Clinical Trial Support: Cytokinetics [Heart failure,
hypertrophic cardiomyopathy]; GE Healthcare [Imaging]; Heartflow [Cardiac imaging]; Medtronic [HF].
Consultant/Advisory Boards: Alleviant [Heart failure]; Bayer [Heart failure]; Cardurion [Heart failure];
Imbria [CAD, heart failure]; Medtrace [Nuclear imaging]; Merck [Heart failure]; Reprieve [Heart failure];
Sequana [Heart failure]. All of the relevant financial relationships listed have been mitigated. Mark
Sarnak, MD Consultant/Advisory Boards: Akebia [Steering committee, hypoxia inducible factor
therapy]; Cardurion [Heart failure]. All of the relevant financial relationships listed have been
mitigated. Stephen S Gottlieb, MD Grant/Research/Clinical Trial Support: BTG International [Renal
dysfunction]; Cytokinetics [Heart failure]; Ionis [Amyloidosis, heart failure]; NovoNordisk [Amyloidosis];
Pfizer [Amyloidosis]. Consultant/Advisory Boards: AstraZeneca [Amyloidosis]; Cytokinetics [Heart
failure]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD,
MS No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
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