Cardiorenal syndrome: Definition, prevalence,

diagnosis, and pathophysiology

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

Contributor Disclosures

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

Literature review current through: May 2024. | This topic last updated: May 10, 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 prevalence of impaired renal function in patients with heart failure (HF), the
diagnosis of CRS, and the mechanisms by which acute HF leads to worsening kidney
function (type 1 CRS) will be reviewed here. However, it may be difficult to distinguish
between type 1 and 2 CRS (caused by chronic HF), and similar mechanisms may apply
to type 2.

Issues related to the prognosis and treatment of type 1 or 2 CRS are presented
separately. (See "Cardiorenal syndrome: Prognosis and treatment".)

DEFINITION AND CLASSIFICATION

There are a number of important interactions between heart disease and kidney
disease. The interaction is bidirectional, as acute or chronic dysfunction of the heart
or kidneys can induce acute or chronic dysfunction in the other organ. The clinical
importance of such relationships is illustrated by the following observations:
 ● Mortality is increased in patients with HF who have a reduced glomerular
filtration rate (GFR). (See "Cardiorenal syndrome: Prognosis and treatment",
section on 'Reduced GFR and prognosis'.)
● Patients with chronic kidney disease have an increased risk of both
atherosclerotic cardiovascular disease and HF, and cardiovascular disease is
responsible for up to 50 percent of deaths in patients with renal failure [1,2]. (See
"Chronic kidney disease and coronary heart disease", section on 'Introduction'.)
● Acute or chronic systemic disorders can cause both cardiac and renal dysfunction.

The term "cardiorenal syndrome" (CRS) has been applied to these interactions, but the
definition and classification have not been clear. A 2004 report from the National
Heart, Lung, and Blood Institute defined CRS as a condition in which therapy to relieve
congestive symptoms of HF is limited by a decline in renal function as manifested by a
reduction in GFR [3]. The reduction in GFR was initially thought to result from a
reduction in renal blood flow. However, various studies have demonstrated that
cardiorenal interactions occur in both directions and in a variety of clinical settings [4].
(See 'Pathophysiology' below.)

The different interactions that can occur led to the following classification of CRS that
was proposed by Ronco and colleagues [5]:
● Type 1 (acute) – Acute HF results in acute kidney injury (previously called acute
renal failure).
● Type 2 – Chronic cardiac dysfunction (eg, chronic HF) causes progressive chronic
kidney disease (CKD, previously called chronic renal failure).
● Type 3 – Abrupt and primary worsening of kidney function due, for example, to
renal ischemia or glomerulonephritis causes acute cardiac dysfunction, which
may be manifested by HF.
● Type 4 – Primary CKD contributes to cardiac dysfunction, which may be
manifested by coronary disease, HF, or arrhythmia.
● Type 5 (secondary) – Acute or chronic systemic disorders (eg, sepsis or diabetes
mellitus) that cause both cardiac and renal dysfunction.
PREVALENCE

HF is frequently accompanied by a reduction in glomerular filtration rate (GFR) via

mechanisms that will be described below. (See 'Pathophysiology' below.)

The prevalence of moderate to severe kidney impairment (defined as a GFR less than
60 mL/min per 1.73 m2; normal more than 90 mL/min per 1.73 m2) is approximately
30 to 60 percent in patients with HF [6-10]. The following observations are illustrative:
● In a systematic review of 16 studies of more than 80,000 hospitalized and
nonhospitalized patients with HF, moderate to severe kidney impairment (defined
as an estimated GFR less than 53 mL/minute, a serum creatinine of 1.5 mg/dL
[132 micromol/L] or higher, or a serum cystatin C of 1.56 mg/dL or higher) was
present in 29 percent of patients [6].
● The Acute Decompensated Heart Failure National Registry (ADHERE) database
reported data on over 100,000 patients with HF requiring hospitalization [9].
Approximately 30 percent had a diagnosis of chronic kidney disease (defined as a
serum creatinine greater than 2.0 mg/dL [177 micromol/L]). The mean estimated
GFR was 55 mL/min per m2, and only 9 percent had a normal estimated GFR
(defined as greater than 90 mL/min per 1.73 m2) [10].

In addition to these baseline observations, patients undergoing treatment for acute

or chronic HF frequently develop an increase in serum creatinine, which fulfills criteria
for type 1 or type 2 CRS [11-20]. In different series, approximately 20 to 30 percent of
patients developed an increase in serum creatinine of more than 0.3 mg/dL (27
micromol/L) [11,12,14,16,18], and, in one report, 24 percent had an increase of 0.5
mg/dL (44 micromol/L) or more [14]. Risk factors for worsening kidney function
during admission for HF include a prior history of HF or diabetes, an admission serum
creatinine of 1.5 mg/dL (133 micromol/L) or higher, and uncontrolled hypertension
[12,13,21]. The rise in serum creatinine usually occurs in the first three to five days of
hospitalization [12].

DIAGNOSIS
Impaired kidney function in patients with HF is defined as a reduction in glomerular
filtration rate (GFR). The most common test used to estimate GFR is the serum
creatinine concentration. However, older and sicker patients often have a reduction in
muscle mass and therefore in creatinine production. Thus, the GFR may be
substantially reduced in patients who have a serum creatinine that is in the normal
range or only mildly elevated. Estimation equations are available that provide a better
estimate of GFR than the serum creatinine alone by including known variables that
affect the serum creatinine independent of GFR (eg, age, weight, sex). These
equations require that the serum creatinine concentration be stable; they cannot be
used to estimate GFR in a patient who has a rising serum creatinine. These issues are
discussed in detail elsewhere. (See "Assessment of kidney function".)

Among patients with HF who have an elevated serum creatinine and/or a reduced
estimated GFR, it is important to distinguish between underlying kidney disease and
impaired kidney function due to the cardiorenal syndrome (CRS). This distinction may
be difficult and some patients have both underlying chronic kidney disease and CRS.

Findings suggestive of underlying kidney disease include significant proteinuria

(usually more than 1000 mg/day), an active urine sediment with hematuria with or
without pyuria or cellular casts, and/or small kidneys on radiologic evaluation.
However, a normal urinalysis, which is typically present in CRS without underlying
kidney disease, can also be seen in variety of renal diseases including nephrosclerosis
and obstructive nephropathy.

The blood urea nitrogen/creatinine ratio (BUN/Cr) is frequently used to aid in the
differentiation of prerenal renal failure from intrinsic renal disease. An elevated
BUN/Cr ratio is typically suggestive of a prerenal etiology, as long as other causes of a
high ratio (eg, increased urea production) are not present (see "Etiology and diagnosis
of prerenal disease and acute tubular necrosis in acute kidney injury in adults",
section on 'Blood urea nitrogen/serum creatinine ratio'). HF is a cause of prerenal
azotemia, although evidence suggests that worsening renal function due to HF is not
solely related to reduced cardiac output and frequently occurs in the setting of
volume overload [22,23] (see 'Pathophysiology' below):
In HF, an elevated BUN/Cr should not deter decongestive or diuretic therapies if
evidence of clinical congestion is present. (See 'Pathophysiology' below and
"Cardiorenal syndrome: Prognosis and treatment".)

Measurement of the urine sodium concentration (UNa) may also be helpful. UNa is
easily measurable and readily available. A UNa below 25 meq/L would be expected
with HF, since renal perfusion is reduced with associated activation of the renin-
angiotensin-aldosterone and sympathetic nervous systems, both of which promote
sodium retention. However, higher UNa values may be seen with concurrent diuretic
therapy if the measurement is made while the diuretic is still acting. (See "Evaluation
of acute kidney injury among hospitalized adult patients".)

There is a mounting evidence suggesting that UNa profiling can predict short-term
responsiveness to IV loop diuretics in patients with acute HF [24,25]. Low UNa
concentration from spot and continuous urine collection samples are associated with
diminished diuretic response, as well as increased risk of HF readmission and
cardiovascular mortality [25-30]. Natriuretic response from a single dose of loop
diuretic can be predicted rapidly from a spot urine sample collected one to two hours
after dose of loop diuretic is administered [25]. Spot urinary sodium may thus allow
clinicians to more rapidly interpret diuretic responsiveness, providing an opportunity
to intervene if sodium content is low, prompting aggressive diuretic titration [24,31]. A
position statement on use of diuretics in HF from the European Society of Cardiology
(ESC) proposes a spot urine sodium content of <50 to 70 mEq/L after two hours, or an
hourly urine output <100 to 150mL during the first six hours to identify a patient with
insufficient diuretic response [31].

PATHOPHYSIOLOGY

The pathogenesis of rising serum creatinine in setting of acute HF and aggressive

diuresis remains incompletely understood. The cardiorenal syndrome is most likely a
diverse group of pathophysiologically distinct processes with worsening renal
function embodying a common pathway of these mechanistically distinct pathways
[32]. Thus, the prognosis associated with worsening renal function (WRF) is likely
dependent on the mechanism behind a rising creatinine, which may not accurately
reflect pathologic renal injury [33]. Worsening renal function is not synonymous with
acute kidney injury.

A variety of factors can contribute to a reduction in glomerular filtration rate (GFR) in

patients with HF ( figure 1) [4,16,34,35]. The major mechanisms that have been
evaluated include neurohumoral adaptations, reduced renal perfusion, increased
renal venous pressure, and right ventricular dysfunction.

Neurohumoral adaptations — Impaired left ventricular function leads to a number

of hemodynamic derangements, including reduced stroke volume and cardiac output,
arterial underfilling, elevated atrial pressures, and venous congestion [36]. These
hemodynamic derangements trigger a variety of compensatory neurohormonal
adaptations, including activation of the sympathetic nervous system and the renin-
angiotensin-aldosterone system and increases in the release of vasopressin
(antidiuretic hormone), and endothelin-1 which promote salt and water retention and
systemic vasoconstriction. These pathways lead to the disproportionate reabsorption
of urea compared with that of creatinine [22,37,38]. In the setting of HF, blood urea
nitrogen therefore represents a surrogate marker of neurohormonal activation
[39,40]. These adaptations overwhelm the vasodilatory and natriuretic effects of
natriuretic peptides, nitric oxide, prostaglandins, and bradykinin [20,34,41].

Neurohumoral adaptations can contribute to preservation of perfusion to vital organs

(the brain and heart) by maintenance of systemic pressure via arterial
vasoconstriction in other circulations, including the renal circulation, and by
increasing myocardial contractility and heart rate. However, systemic vasoconstriction
increases cardiac afterload, which reduces cardiac output, which can further reduce
renal perfusion. The maladaptive nature of these adaptations is evidenced by the
slowing of disease progression and reduction in mortality with the administration of
angiotensin inhibitors and beta blockers in patients with HF with reduced ejection
fraction. These issues are discussed in detail elsewhere. (See "Primary pharmacologic
therapy for heart failure with reduced ejection fraction" and "Pharmacologic therapy
of heart failure with reduced ejection fraction: Mechanisms of action".)

Chloride handling — In patients with HF, chloride plays an important role in fluid
homeostasis, neurohormonal activation, and diuretic resistance [42]. Chloride is a
primary modulator of tubuloglomerular feedback and has a unique role in
homeostasis that is distinct from that of sodium [43].

Hypochloremia, which commonly occurs during acute HF therapy, interferes with the
kidney’s regulator role in electrolyte homeostasis and diuresis, and evidence suggests
that a change in serum chloride is a primary determinant of changes in plasma
volume and in activation of the renin-angiotensin-aldosterone system [44]. In patients
with HF who are receiving diuresis, hypochloremia is frequently accompanied by a
metabolic alkalosis (chloride depletion alkalosis). Despite clinical evidence of
persistent volume overload, alkalosis in this setting is frequently and inappropriately
attributed to intravascular volume depletion (ie, "contraction alkalosis"), which may
lead to premature deescalation of decongestive therapies. If the patient has evidence
of hypervolemia, metabolic alkalosis in this setting is more likely attributable to
abnormal electrolyte homeostasis that results in chloride depletion alkalosis, which is
characterized by elevated urine chloride levels [45].

Coadministration of acetazolamide with loop diuretics can reduce chloride loss,

though the clinical efficacy of acetazolamide administration is uncertain.

Hemodynamic factors

Reduced systemic blood pressure — The importance of differing mechanisms of

WRF and their associations with subsequent outcomes was demonstrated by an
analysis of 386 patients enrolled in the Evaluation Study of Congestive Heart Failure
and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial [32]. In this
subgroup analysis, reduction in systolic blood pressure was greater in patients who
experienced worsening renal function (odds ratio 1.3 per 10 mmHg reduction).
Among patients with reduced systolic blood pressure (SBP), WRF was not associated
with worsened survival; however, in patients without SBP reduction, WRF was strongly
associated with increased mortality (adjusted hazard ratio 5.3). Similar findings have
been reported elsewhere [46]. Compared with changes in SBP, changes in cardiac
output have not been associated with WRF [32,46]. Collectively, these findings suggest
that regulation of renal blood flow and glomerular filtration are more dependent on
pressure rather than flow, and that blood pressure rather than cardiac output or
congestion is more closely associated to changes in renal function during acute HF
hospitalization.

Reduced renal perfusion — As mentioned above, an original definition described

the cardiorenal syndrome (CRS) as a disorder in which therapy to relieve congestive
symptoms of HF (eg, loop diuretics) is limited by a reduction in GFR; the fall in GFR
was thought to result from a decline in cardiac output of as much as 20 percent due
to the reduction in ventricular preload [3,47]. A similar reduction in renal perfusion
may be induced by acute decompensated HF prior to treatment. However, some
patients initially have little or no reduction in cardiac output with loop diuretic therapy
because they are on the flat part of the Frank-Starling curve in which changes in left
ventricular end-diastolic pressure have little or no effect on cardiac performance
( figure 2), while others have an increase in GFR following diuretic therapy that may
be mediated by a reduction in renal venous pressure and/or right ventricular dilation.
(See 'Increased renal venous pressure' below and 'Right ventricular dilation and
dysfunction' below.)

The following observations suggest that reduced cardiac index is not the primary
driver for renal dysfunction in patients hospitalized for HF:
● The ESCAPE trial evaluated the effectiveness of pulmonary artery catheterization
in 433 patients with acute decompensated HF [48]. There was no correlation
between the cardiac index and either the baseline GFR or worsening kidney
function, and increasing the cardiac index did not improve renal function after
discharge. Similar findings were noted in another report in which HF patients
with worsening kidney function did not have lower cardiac outputs or filling
pressures than those without worsening kidney function [15].
● Among 575 patients undergoing pulmonary artery catheterization in the
randomized or registry portions of the ESCAPE trial, there was a weak but
significant inverse correlation between cardiac index and estimated GFR (eGFR),
such that higher cardiac index was paradoxically associated with worse eGFR [49].
Cardiac index was not associated with either BUN or the BUN/Cr ratio.

It has been suggested that, although reductions in cardiac index lead to a reduction in
renal blood flow, the GFR is initially maintained by an increase in the fraction of renal
plasma flow that is filtered (ie, the filtration fraction) [50]. In a study of patients with
chronic HF, the GFR was similar in patients with a cardiac index of more than 2.0 and
1.5 to 2.0 L/min per m2 (respective filtration fractions 24 and 35 percent) but
substantially reduced in patients with a cardiac index below 1.5 L/min per m2 (38
versus 62 and 67 mL/min per 1.73 m2).

In addition, hypotension, which can reduce the GFR independent of renal blood flow,
is an uncommon finding in patients hospitalized for acute decompensated HF. In the
ADHERE registry of over 100,000 such patients, 50 percent had a systolic blood
pressure of 140 mmHg or higher, while less than 2 percent had a systolic blood
pressure below 90 mm/Hg [9].

Increased renal venous pressure — Both animal and human studies have shown
that increasing intra-abdominal or central venous pressure, which should also
increase renal venous pressure, reduces the GFR [4,51]. In an initial study in 17
normal adults, for example, raising the intra-abdominal venous pressure to
approximately 20 mmHg led to average reductions in renal plasma flow and GFR of 24
and 28 percent, respectively [52]. An adverse impact of venous congestion on kidney
function has also been described in animal models as manifested by a reduction in
GFR [53-56] and sodium retention [53,57,58].

Subsequent studies in patients with HF demonstrated an inverse relationship

between venous pressure and GFR when the central venous pressure was measured
directly [59-61] or elevated jugular venous pressure was diagnosed on physical
examination [62]:
● In one report, 58 of 145 patients (40 percent) hospitalized for acute
decompensated HF developed worsening kidney function, defined as an increase
in serum creatinine of at least 0.3 mg/dL (27 micromol/L) [59]. These patients had
a significantly higher central venous pressure (CVP) than those with stable renal
function (18 versus 12 mmHg) and the frequency of worsening kidney function
was lowest in patients with a CVP less than 8 mmHg. The predictive value of CVP
was independent of systemic blood pressure, pulmonary capillary wedge
pressure, cardiac index, and estimated GFR. In contrast to the importance of CVP,
 the cardiac index on admission and an improvement in cardiac index with therapy
had a limited impact on the frequency of worsening kidney function.
● Similar findings were noted in another study in which a higher CVP was also
associated with a significant increase in mortality at a median follow-up of more
than 10 years (hazard ratio 1.03 per 1 mmHg increase in CVP) [60].
● In a series of 40 consecutive patients with acute decompensated HF, 24 had an
elevation in intra-abdominal venous pressure (IAVP) which was defined as 8
mmHg or higher [61]. At baseline, these patients, compared with those with a
normal IAVP, had a significantly higher serum creatinine (mean 2.3 versus 1.5
mg/dL [203 versus 133 micromol/L]) and a significantly lower estimated GFR
(mean 40 versus 63 mL/min). In addition, there was a strong correlation between
the degree of reduction in IAVP with therapy and improvement in GFR. Changes
in IAVP and GFR did not correlate with any other hemodynamic variable
( figure 3).

Increases in renal venous pressure may also contribute to the association between
the degree of tricuspid regurgitation (TR) and worsening kidney function. In a review
of 196 patients with TR, those with at least moderate TR had a lower estimated GFR
[63]. In addition, there was a linear relationship between the severity of TR and the
magnitude of impairment in GFR.

The mechanisms by which increased renal venous pressure might lead to a reduction
in GFR are not well understood [16,51].

Right ventricular dilation and dysfunction — Right ventricular (RV) dilation and
dysfunction may adversely affect kidney function through at least two mechanisms:
● The associated elevation in central venous pressure elevation can lower the GFR
as discussed in the preceding section.
● RV dilation impairs left ventricular (LV) filling, and therefore forward output, via a
ventricular interdependent effect (also known as the reverse Bernheim
phenomenon) [64]. Increased pressure within a distended RV increases LV
extramural pressure, reducing LV transmural pressure for any given intracavitary
LV pressure and inducing leftward interventricular septal bowing, thereby
diminishing LV preload and distensibility and reducing forward flow [65,66]. An
 intact pericardium plays a role in ventricular interaction, but experimental
observations suggest that the pericardium is not critical to the interaction [67].

Thus, a reduction in RV filling pressure during treatment of HF may lead to an

increase in GFR, both by reducing renal venous pressure and by diminishing
ventricular interdependent impairment of left ventricular filling [68].

Associations with heart failure with preserved ejection fraction — Renal

dysfunction is frequently seen in patients with HF with preserved ejection fraction
(HFpEF) [69] (as well as those with reduced ejection fraction). Endothelial dysfunction
and a proinflammatory state have emerged as important mediators of cardiorenal
interactions. Renal dysfunction can lead to metabolic derangements resulting in
systemic inflammation and microvascular dysfunction, which can cause
cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis [69].

In a study of patients with acute decompensated HFpEF, 38 (36 percent) of 104

subjects developed worsening renal function (WRF; increase in serum creatinine of
≥0.3 mg/dL) within 72 hours of hospitalization [70]. While linear and volumetric
measures of right atrial and right ventricular (RV) chamber size did not differ
significantly between those patients with versus those without WRF, those with WRF
had significantly reduced RV function and increased RV free wall thickness. Again,
these associations do not prove causality between renal dysfunction and adverse RV
remodeling and dysfunction. Many of these observations are similar to those seen in
HFrEF and is not clear which, if any, of these findings are unique to patients with
preserved versus reduced EF.

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
 ● Definition and classifications – 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. In type 1 CRS, acute heart failure (HF) leads to worsening kidney
function. In type 2 CRS, chronic HF causes progressive chronic kidney disease.
(See 'Definition and classification' above.)
● Prevalence – The prevalence of moderate to severe kidney impairment (defined
as a glomerular filtration rate [GFR] less than 60 mL/min per 1.73 m2) is
approximately 30 to 60 percent in patients with HF. In addition to these baseline
observations, patients undergoing treatment for acute or chronic HF frequently
develop an increase in serum creatinine, which fulfills criteria for type 1 or type 2
CRS. (See 'Prevalence' above.)
● Diagnosis – Among patients with HF who have an elevated serum creatinine
and/or a reduced estimated GFR, it is important to distinguish between
underlying kidney disease and impaired kidney function due to the CRS. (See
'Diagnosis' above.)
● Pathophysiology – A variety of factors can contribute to a reduction in GFR in
patients with HF. The major mechanisms that have been evaluated include
neurohumoral adaptations, reduced renal perfusion, increased renal venous
pressure, and right ventricular dysfunction. (See 'Pathophysiology' above.)

ACKNOWLEDGMENT

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