renal dysfungtion ckd
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Renal dysfunction in acute and chronic heart failure: prevalence,incidence and prognosis
John G. F. Cleland • Valentina Carubelli •
Teresa Castiello • Ashraf Yassin • Pierpaolo Pellicori •
Renjith Antony
Published online: 17 March 2012
Springer Science+Business Media, LLC 2012
Abstract Most patients with heart failure have mild or
moderate renal dysfunction. This reflects the combinedimpact of chronic renal parenchymal disease, renal artery
disease, renal congestion and hypoperfusion, neuroendocrine
and cytokine activation and the effects of treatments for heart
failure. Remarkably, with good treatment, the average annual
rate of decline in renal function is similar in patients with
chronic heart failure and healthy people of a similar age. Urea
appears to be a stronger marker of an adverse prognosis than
creatinine-based measures of renal function. Recent evidence
suggests that minor, transient increases in creatinine in the
setting of acute heart failure are not prognostically important
but persistent deterioration does indicate a higher mortality.
The poor prognosis of patients with worsening renal function
ensures that few require renal dialysis but this may change as
methods to prevent sudden death improve and new ways are
found to control fluid congestion. Reversing renal dysfunction
and stopping its progression remain important targets for
treatment of heart failure.
Keywords Renal dysfunction Heart failure Prognosis
Prevalence Incidence
Introduction
Over the last decade, research has shown that renal dys-
function is a major determinant of outcome in patients with
heart failure. This has given rise to the concept of a car-
diorenal syndrome [1, 2] with a ‘vicious cycle’ of deteri-oration, but whether the heart is the ‘chicken’ or the ‘egg’
in this concept is unclear. It is likely that the aetiology of
renal dysfunction in patients with heart failure is much
more complex (Fig. 1) and represents a matrix of interac-
tions and the sum total of independent but interacting
processes with effects on both the kidney and the heart.
This article provides an updated review of the prevalence
and prognostic significance of renal dysfunction in acute
and chronic heart failure. In addition, this review will
consider the aetiology of renal dysfunction and its natural
history in patients with heart failure; when does it occur, is
it reversible and how fast does it progress?
Which renal marker?
For more than 100 years, clinicians have used measurements
of creatinine as an index of renal function. Most of the epi-
demiology of renal dysfunction focuses either on serum cre-
atinine itself or on calculated creatinine clearance using either
the Cockroft–Gault or one of the ‘modification of diet in renal
disease’ (MDRD) equations to estimate glomerular filtration
rate (eGFR) [3]. These various measures of renal function are
highly correlated. In multivariable prognostic models, serum
creatinine performs about as well as the derived measures
since these models usually already contain all of the variables
in the equation used to calculate renal function, such as age,
sex and body mass. However, in some groups of patients, for
instance, those with muscle wasting or cachexia, creatinine-
based measurements may underestimate the severity of renal
dysfunction [3].
There is growing evidence that other blood markers of
renal dysfunction including cystatin-C [4, 5] and serum
J. G. F. Cleland (&) V. Carubelli T. Castiello A. Yassin
P. Pellicori R. Antony
Department of Cardiology, Hull York Medical School,
University of Hull, Castle Hill Hospital, Kingston upon Hull
HU16 5JQ, UK
e-mail: [email protected]
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Heart Fail Rev (2012) 17:133–149
DOI 10.1007/s10741-012-9306-2
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urea [6–8] are superior to creatinine when it comes to
predicting prognosis in patients with heart failure. Up to
50% of filtered urea is reabsorbed in the renal tubules;
therefore, it is as much a marker of renal tubular reab-
sorption as of GFR [9, 10]. Serum urea concentrations may
be a better measure of intravascular dehydration anddiuretic resistance than creatinine. Serum urea also rises
during the periods of increased protein catabolism due to
either worsening heart failure or concomitant problems
such as infection and reduced dietary protein [11]. Urea
may be a better marker of prognosis than creatinine pre-
cisely because it reflects a constellation of renal dysfunc-
tion, diuretic resistance and cachexia rather than just the
GFR. This may be its strength rather than its weakness as a
prognostic marker. On the other hand, this does not explain
why cystatin-C, thought to be a more specific measure of
GFR, is a better marker of prognosis than creatinine. Ele-
vated plasma concentrations of cystatin-C indicate a worseprognosis even when serum creatinine is normal [4, 12]. As
this group of patients has a very high mortality (40% at
1 year), it may reflect deceptively low serum creatinine in
patients with cardiac cachexia and a low skeletal muscle
mass, a situation where creatinine is known to underesti-
mate GFR. Urea and cystatin-C have not been compared,
head-to-head, in a multivariable prognostic model. How-
ever, the prevalence of renal dysfunction classified by
either cystatin-C or urea is poorly described. The bulk of
the literature is based on measures of renal function derived
from creatinine-based measures of renal dysfunction.
Aetiology of renal dysfunction in heart failure
Many cardiologists view renal dysfunction as a barometer
of cardiac function. This is true, in part, but a gross over-
simplification [13]. Reduced cardiac output leads to renal
vasoconstriction and an excessive fall in renal blood flow.
This is partially compensated for by efferent arteriolar
vasoconstriction, largely mediated by angiotensin II, which
leads to an increase in filtration fraction (the ratio of GFR
to renal blood flow), which is the hallmark of the renal
response to heart failure. A fall in GFR is a relatively late
response, occurring only with a substantial fall in cardiac
output. Renal blood flow is dependent on the arterial per-
fusion pressure, renal vascular resistance and the renalvenous pressure [14, 15]. In heart failure, arterial pressure
tends to fall, renal vasoconstriction occurs, and central and
renal venous pressures rise, resulting in a marked fall in
renal blood flow. Reductions in venous compliance will
cause a further rise in renal venous pressure [16–18].
Oedema can affect any organ, and presumably, the kidney
is no exception. Renal parenchymal oedema will lead to a
rise in pressure within the renal parenchyma due to
restraint by the renal capsule, and oedema of abdominal
Fig. 1 Schematic diagram
showing factors likely to be
important in the genesis of renal
dysfunction in patients with
heart failure. Note that much of
the renal dysfunction may pre-
date the development of heart
failure. Mechanisms linking
heart failure to renal
dysfunction are shown in an
approximate sequence of events.
Renal vein obstruction and renal
parenchymal oedema are
probably late-stage phenomena.
Important consequences of renal
dysfunction are salt and water
retention, anaemia and further
neuroendocrine and cytokine
activation
134 Heart Fail Rev (2012) 17:133–149
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organs and ascites may lead to a rise in intra-abdominal and
renal venous pressure [19–22]. This would be expected to
lead to a substantial decline in renal function and to
diuretic resistance. The relative importance of each of these
determinants of renal blood flow will vary from one patient
to the next.
Heart failure is also characterised by neuroendocrine
activation that may either help sustain renal function ormake it worse [23, 24]. Renin–angiotensin system activa-
tion causes renal vasoconstriction but, because this is
predominantly in the efferent arteriole, it helps maintain
GFR. Activation of the sympathetic nervous system causes
afferent arteriolar constriction and, at least in theory,
should cause a rise in renal vascular resistance and a fall in
renal blood flow and GFR. Endothelin is also a powerful
vasoconstrictor, although less specific for the renal circu-
lation [25, 26]. Increases in adenosine may also contribute
to renal dysfunction and sodium retention [27, 28].
Inflammatory cytokines and galectin-3 might also be
responsible for renal glomerular damage [29]. However,protective systems are also activated. Natriuretic peptides
may cause renal afferent vasodilatation, helping sustain
GFR [30], although systemic administration of at least
some natriuretic peptide analogues does not improve renal
function [31]. Increases in vasodilator prostaglandins also
probably play a key role in protecting the kidney in heart
failure [32–34].
However, this is a very heart failure-centric view of
renal dysfunction that may be of little relevance to most
patients during the greater part of the course of their dis-
ease. Most patients with heart failure have had decades of
cardiovascular disease preceding the onset of heart failure.
Most of the renal dysfunction observed at the onset of heart
failure is probably long-standing and reflects the effects of
hypertension, diabetes mellitus and renal atherosclerosis on
the kidney. In other words, renal dysfunction precedes, and
may often beget, heart failure rather than the other way
around [35, 36]. Most patients with heart failure have a past
medical history of hypertension. Many patients have long-
standing diabetes mellitus. The prevalence of atheroscle-
rotic renal disease in this population is high [37, 38], which
may not only cause renal artery stenosis but also lead to
damage to the kidney by local activation of inflammatory
cytokines.
A further substantial cause of renal dysfunction in heart
failure is doctors, or at least the medications they prescribe
[13, 39]. Although renal dysfunction is a strong predictor
of a poor outcome, many treatments for heart failure make
renal function worse, but nonetheless improve prognosis
[40–42]. Initiation of ACE inhibitors, angiotensin receptor
blockers, beta-blockers and aldosterone antagonists all
cause a sudden, usually modest, reduction in GFR but may
then slow the rate of subsequent deterioration after this
initial decline. There is an association between the use and
dose of diuretics used and the severity of renal dysfunction
[43] although this was not confirmed in a short-term study
comparing lower and higher doses of intravenous loop
diuretics given for 48–72 h [46]. Exactly how diuretics
cause renal dysfunction is not clear. It cannot simply be
due to renin–angiotensin or sympathetic nervous system
activation, or the problem would disappear with the use of ACE inhibitors and beta-blockers, but these therapies
usually exacerbate renal dysfunction in patients treated
with diuretics. The problem may be due to the disruption of
the medullary concentration gradient and tubulo-glomeru-
lar feedback, mediated, in part, by adenosine [44]. The
excessive rise in urea compared to creatinine implies
increased tubular reabsorption. However, the relationship
between diuretic dose and renal dysfunction may be yet
another of those ‘chicken and egg’ vicious cycles of heart
failure. Declining renal dysfunction may require larger
diuretic doses to control fluid retention. It gets even more
complex! Effective diuresis in patients with severe con-gestion can lead to a paradoxical improvement in renal
function, possibly due to a reduction in renal venous
pressure [19–22]. Use of higher doses of diuretics in acute
heart failure is associated with a greater rise in serum
creatinine, but this does not translate into a worse prognosis
[45, 46]. Switching from diuretics to ultrafiltration [47] or
arginine vasopressin antagonists [48] does not reduce the
rate of renal dysfunction and may exacerbate it, implying
that renal dysfunction is a generalised problem with
‘dehydrating’ therapies. The importance of activation of
renal vasodilator prostaglandins is demonstrated by the
adverse effects of nonsteroidal inflammatory drugs on renal
function in patients with heart failure [39]. Manipulation of
natriuretic peptides can worsen or improve renal function
depending on the circumstances [31, 49].
If cardiac function was such an important determinant of
renal function, then powerful interventions to improve
heart function should lead to improved renal function.
There is no evidence that any pharmacological intervention
to improve cardiac function improves renal function sub-
stantially, as noted above. Cardiac resynchronisation ther-
apy (CRT) can cause dramatic improvements in cardiac
function. There is anecdotal evidence that this may lead to
an improvement in renal function, but this may be related
to the withdrawal of diuretics rather than due directly to
improved cardiac function. In the cardiac resynchronisation
in heart failure study (CARE-HF), a large randomised
controlled trial, CRT did not improve renal function
compared to pre-treatment values but did prevent the
longer-term deterioration observed in the control group
[50]. Heart transplantation causes a sudden large change in
cardiac function, and yet renal function often declines,
which can only be partially attributed to the use of
Heart Fail Rev (2012) 17:133–149 135
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cyclosporin [51]. Implantation of a left ventricular assist
device can lead to improvement in renal function in
patients with severe heart failure, but this may apply only
to patients with a relatively short history of renal dys-
function and where intrinsic renal disease has been exclu-
ded [52]. In summary, there is remarkably little evidence
that improving cardiac function will improve renal function
for many patients, and this may reflect the fact that cardiachaemodynamics are the ‘junior partner’ in causing renal
dysfunction in heart failure.
Prevalence, incidence and prognosis of renal
dysfunction in acute heart failure
Epidemiological studies report that 17–30% of patients
with acute heart failure have renal dysfunction according to
the local investigator at the time of enrolment, but studies
rarely provide a definition of renal dysfunction [53–55]
(Table 1). There is evidence of substantial under-reporting[56]. Rates seem somewhat lower in Europe than in North
America, which may reflect the inclusion of younger
patients from Eastern Europe. The EuroHeart Failure
Surveys suggest that only about 10% of patients will have a
serum creatinine[200 lmol/L, and another, single-centre
epidemiological study reported 17% [57, 58]. Age-related
decline in renal function with the super-added effects of
intrinsic renal disease, impaired cardiac function and drug
therapies accounts for the high prevalence of renal dys-
function in acute heart failure. Generalised atherosclerotic
disease is common in patients with heart failure including
the renal arteries. Many patients have a prior history of
hypertension, and studies report that mean systolic blood
pressure hovers around 140 mmHg on admission, indicat-
ing that many patients had high blood pressure at admis-
sion. Diabetes is reported in 30–45% of patients. The
prevalence of hypertension and diabetes as well as renal
dysfunction is higher in North America than in Europe,
perhaps reflecting the older age of the patients and higher
rates of obesity in North America.
If renal dysfunction is defined as a serum creatinine
[130 lmol/L (*1.5 mg/dL), then almost half of the
patients with acute heart failure are affected in most epi-
demiological studies [56, 57]. A similar proportion of
patients have renal dysfunction if defined as a serum urea
[10 mmol/L, equivalent to a blood urea nitrogen (BUN)
of 28 mg/dL. If renal dysfunction is defined in chronic
kidney disease (CKD) stages, then fewer than 10% of
patients with acute heart failure will have normal renal
function, with about 25, 45, 15 and 5% classified in stages
II–V, respectively[56, 57, 59].
Worsening heart failure is often associated with wors-
ening renal function, and presumably, one will often
exacerbate the other. Various definitions of worsening
renal function can be used. Using a definition of a rise in
serum creatinine to[200 lmol/L, one study suggested that
19% of patients would be affected [58]. Using a definition
of an increase by[0.3 mg/dL (26.5 lmol/L), a large study
(n = 20,063) of US Medicare patients aged [65 years
reported an incidence of 17.8% [60]. Another smaller US
study suggested an incidence of 45% using the same def-inition and 25% if the threshold was raised to 0.5 mg/dL
(44.2 lmol/L) [61]. Major determinants of the risk of WRF
are pre-existing renal dysfunction, the severity of heart
failure, diuretics and other treatments for heart failure,
anaemia and either a very high blood pressure or a low one
[43, 62, 63].
Some observational studies suggested that transient
increases in serum creatinine, even of modest degree, were
associated with an adverse prognosis [61]. There appeared
to be a dose–response relationship with a hazard ratio of
1.67 for a rise in serum creatinine of [0.3 mg/dL and 2.90
for elevations[0.5 mg/dL. However, if true, the relation-ship is not strong [60]. Renal function measured at [54], or
even prior to [64], admission is a much stronger predictor
of prognosis, perhaps because this is the best measure of
the underlying severity of chronic renal dysfunction. Only
if increases in creatinine are persistent or large are they
associated with an adverse outcome. Accordingly, minor
changes in creatinine should be considered neither a target
for therapy in clinical trials of heart failure nor a reason to
change guideline-indicated treatment. However, large
reductions in GFR associated with worsening heart failure
greatly complicate management and portend an unfavour-
able outcome unless the cause can be reversed. The defi-
nition and incidence of severe reductions in GFR in the
setting of acute heart failure are not well described.
Renal function at the time of admission is a strong
predictor of outcome (Fig. 2) [54]. There is growing evi-
dence that urea is a stronger predictor of outcome than
creatinine in patients with acute heart failure [7]. In the
acute decompensated heart failure national registry
(ADHERE), observations on 33,046 hospitalisations
revealed that a serum urea of 15 mmol/L (43 mg/dL) was
the strongest predictor of prognosis, with systolic blood
pressure \115 mmHg and serum creatinine above
approximately 250 lmol/L (2.75 mg/dL) adding further
predictive information [53]. In ADHERE, 22% of patients
had a urea [15 mmol/L. Inpatient mortality was 9.0% in
this group, accounting for about half of all deaths. Mor-
tality in patients with urea\15 mmol/L was 2.7%. About
half of patients will develop a substantial rise in serum urea
during admission, and about 20% will develop an increase
in serum urea to[20 mmol/L (56 mg/dL). In contrast to
changes in creatinine, transient increases in urea may be
associated with an adverse outcome [64].
136 Heart Fail Rev (2012) 17:133–149
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T a b l e 1
P r e v a l e n c e o f r e n a l d y s f u n c t i o n i n e p i d e m i o l o g i c a l s t u d i e s o f a c u t e h e a r t f a i l u r e
S t u d y
Y e a r
N
A g e ( y e a r s )
W o m e n ( % )
C A D ( % )
D i a b e t e s ( % )
S y s B P ( m m H g )
L V S D ( % )
R e n a l d y s f u n c t i o n
S t r o n g e s t p r o g n o s t i c
m a r k e r s #
C o m m e n t
A D H E R E [ 5 3 , 5 6 ]
6 5 , 2 7 5
7 3 5 2
5 8 4 4
1 4 4
5 4
P r e v a l e n t : 3 0 %
M e a n U r e a : 1 1 . 4 m m
o l / L
M e a n S C r : 1 5 9 l m o l / L
U r e a C 1 5 . 4 m m o l / L
S y s B P \ 1 1 5
A l s o , S C r , a g e a n d H R i n
o t h e r a n a l y s e s
I n p a t i e n t m o r t a l i t y o f
2 . 7 % v 9 . 0 % b e l o w
a n d a b o v e u r e a
t h r e s h o l d
O P T I M I Z E - H F [ 5 4 , 7 9 ]
4 8 . 6 1 2
7 3 5 2
4 6 4 2
1 4 3
4 9
P r e v a l e n t : 2 0 %
M e a n U r e a : N R
M e a n S C r : 1 5 9 l m o l / L
S C r , s y s B P , a g e , H R a n d S .
S o d p r e d i c t e d I P m o r t a l i t y
U r e a n o t r e p o r t e d
S e e F i g . 2 . S a m e
v a r i a b l e s p l u s w e i g h t
a n d c o m o r b i d i t i e s
p r e d i c t e d 6 0 - d a y
m o r t a l i t y
U R G E N T [ 8 0 ]
5 2 4
7 0 4 3
4 3 3 7
1 4 0
5 0
P r e v a l e n t : 2 6 %
M e a n U r e a : 8 m m o l / L
M e a n S C r : 8 8 l m o l / L
N R
M o r t a l i t y n o t r e p o r t e d
A L A R M - H F [ 8 1 ]
4 , 9 5 3
6 8 y r s
3 8
3 1 4 5
1 3 0
3 6
P r e v a l e n t : 2 1 %
M e a n U r e a : N R
M e a n S C r : N R
N R
1 2 % i n p a t i e n t m o r t a l i t y
M E A S U R E - H F [ 8 2 ]
1 8 2
6 9 3 3
6 1 5 0
1 3 0
6 8
P r e v a l e n t : 4 4 %
M e a n U r e a : N R
M e a n S C r : 1 3 3 l m o l / L
N R
5 % i n p a t i e n t m o r t a l i t y
a n d 6 % a t 6 0 d a y s
E F F E C T [ 5 5 ]
4 , 0 3 1
7 6 5 1
3 7 ( M I )
3 4
1 4 8
5 1
P r e v a l e n t : N R
M e a n U r e a : 1 0 m m o
l / L
M e a n S C r : 1 3 0 l m o l / L
M o r t a l i t y a t 3 0 d a y s : a g e ,
S B P , R R , s o d i u m , B U N ,
C O P D , c a n c e r , d e m e n t i a
S i m i l a r v a r i a b l e s
p r e d i c t e d m o r t a l i t y a t
1 y e a r
E H F S - I [ 5 7 ]
1 1 , 3 2 7
7 1 4 7
6 8 2 7
N R
E F \ 4 0 % i n 5 1 %
o f m e n a n d i n
2 8 % o f w o m e n
P r e v a l e n t : 1 7 %
S C r [ 1 5 0 l m o l / L 1 6
%
S C r [ 2 0 0 l m o l / L 7 %
A g e , H b , S C r , S . S o d ,
L V E F , A F
1 2 - w e e k f o l l o w - u p
D e a t h 1 3 . 5 %
R e a d m i s s i o n 2 4 . 2 %
E H F S - I I [ 5 8 , 8 3 ]
3 , 5 8 0
7 0 3 8 . 7
5 3 . 6 3 2 . 8
1 3 5
3 8 %
S C r [ 1 7 7 l m o l / L : 1 7 %
S y s B P \ 1 1 0 m m H g
A l s o , a g e , f r a i l t y , v a s c u l a r
d i s e a s e , d i a b e t e s , S . S o d
I n - h o s p m o r t a l i t y 6 . 7 %
# t h e r a p i e s a r e e x c l u d e d a s t h e s e m a y b e c o n f o u n d e d b y i n d i c a t i o n ( f o r e x a m p l e , s i c k e r p a t i e n t s m a y n o t r e c e i v e a b e t a - b l o c k e r s o i t i s u n c l e a r w h e t h e r w o r s e o u t c o m e i n p a t i e n t s n o t g i v e n a
b e t a - b l o c k e r i s d u e t o a n i n t r i n s i c a l l y w o r s e p r o g n o s i s o r p o o r e r m a n a g e m e n t o r b o t h ) . P r e v a l e n t a n d i n c i d e n t r e n a l d y s f u n c t i o n a r e t h e r a t e s r e p o r t e d b y i n v e s t i g a t o r s u n l e s s o t h e r w i s e s p e c i fi e d
N R n o t r e p o r t e d ,
A F a t r i a l fi b r i l l a t i o n , L V S D l e f t v e n t r i c u l a r s y s t o l i c d y s f u n c t i o n .
U r e a m e a n o r m e d i a n s e r u m u r e a . T o
c o n v e r t u r e a t o B U N m u l t i p l y b y 2 . 8 . S C
r m e a n o r m e d i a n s e r u m
c r e a t i n i n e i n l m o l / L ( d i v i d e b y 8 8 . 4 t o c o n v e r t t o m g / d L ) . S y s B P s y s t o l i c b l o o d p r e s s u r e .
S .
S o d s e r u m s o d i u m c o n c e n t r a t i o n , H R h e a r t r a t e ,
R R r e s p i r a t o r y r a t e . H b
h a e m o g l o b i n ,
L V E F l e f t
v e n t r i c u l a r e j e c t i o n f r a c t i o n . F o r a c
r o n y m s p l e a s e r e f e r t o r e l e v a n t r e f e r e n c e
Heart Fail Rev (2012) 17:133–149 137
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Renal dysfunction is common in trials of acute heart
failure (Table 2), but treatments for acute heart failure thatcause transient renal dysfunction have not generally led to
worse outcomes [27, 65]. Use of higher doses of diuretics is
often blamed for worsening renal function, and some
observational studies do suggest a link, although others do
not [66]. A randomised controlled trial comparing higher
and lower doses of furosemide confirms that using higher
doses initially causes a greater rise in creatinine but the
difference is short-lived and disappears by day 7 [46].
Regardless of diuretic dose, about 25% of patients devel-
oped worsening renal function in the study by day 7.
However, higher doses of diuretic were associated with a
somewhat better outcome despite their adverse effect on
renal function. Ultrafiltration is an alternative method to
remove fluid from a congested patient that avoids the
potential renal toxicity of diuretics. However, ultrafiltration
leads to a similar increase in creatinine, and the incidence
of worsening renal function ([0.3 mg/dL increase) was
again about 20% and similar in those assigned to diuretic or
ultrafiltration [47]. Readmission rates appeared lower with
ultrafiltration. The efficacy of vasopressin antagonism in
heart failure (EVEREST) study showed that tolvaptan, an
arginine vasopressin antagonist, could increase fluid loss,
reduce weight and lower conventional diuretic dose
requirements compared to placebo. This was associated
with a small acute and persistent rise in creatinine despite
the use of lower doses of loop diuretics in patients assigned
to tolvaptan. Interestingly, plasma concentrations of urea
fell and remained lower, perhaps reflecting reduced tubular
reabsorption [65]. The reported incidence of renal failure
was about 6% in each group. There was no difference in
prognosis between groups. More recently, the PROTECT
study, comparing placebo and rolofylline, an adenosine A1
receptor antagonist, reported a 14% incidence of worsening
renal function, defined as a rise in serum creatinine of
0.3 mg/dL or more at day 7 that persisted until at least day
14 [27]. The incidence of worsening renal function was
somewhat greater in patients who received rolofylline, but
there was no difference in morbidity and mortality between
groups.
In summary, renal dysfunction is common in patients
with acute heart failure and is likely to be a major deter-minant of the response to diuretics and the deployment of
life-saving therapies such as ACE inhibitors and aldoste-
rone receptor antagonists. However, it is the underlying
chronic severity of renal dysfunction, rather than transient
changes, which is the major determinant of prognosis,
although severe reductions in renal function that might lead
to the need for renal dialysis must surely be associated with
an adverse prognosis.
Prevalence, incidence and prognosis of renal
dysfunction in chronic heart failure
In large, epidemiologically representative patient populations
with chronic heart failure, fewer than 10% will have normal
renal function, about 60% of patients will have an estimated
GFR\60 mL/min/1.73 m2, and mostof these willbe inCKD
stage 3A (45–59 mL/min/1.73 m2) or 3B (30–45 mL/min/
1.73 m2) (Table 3). About 10% of patients will be in class 4
(15–29 mL/min/1.73 m2) [1, 67]. Currently, it is rare to find
more severe renal dysfunction in outpatients with chronic
heart failure for reasons explained further below. This may
change. Major determinants of renal dysfunction are age, a
prior history of hypertension, evidence of atherosclerotic
coronary or peripheral artery disease, the severity of heart
failure, the intensity of diuretic therapy and lower diastolic
blood pressure [67]. A combined approach to management
including withdrawing aspirin [33], reducing the doses of
diuretics and ACEinhibitorsand switching to carvedilol as the
preferred beta-blocker may cause a modest improvement in
chronic renal function [39]. Although in cross-sectional
studies renal dysfunction is poorly related to systolic blood
pressure, hypotension may be an important reason for a
decline in renal functionin an individual patient.Clinical trials
of heart failure have, over the years, shown a similar high
prevalence of renal dysfunction despite excluding many
patients with more severe renal dysfunction [68–70]
(Tables 4, 5, and 6).
Although many epidemiological studies and trials have
reported on the prevalence of renal dysfunction in patients
with chronic heart failure, remarkably few have reported on
its incidence and persistence in the outpatient setting. De
Silva et al. [67] reported that of 1,216 patients with chronic
heart failure, renal function would deteriorate within
6 months by one CKD class in 18% of patients but by two
Fig. 2 Data from the OPTIMIZE-HF study. In-hospital mortality
according to systolic blood pressure (SBP) and serum creatinine (SCr)
concentration. Patients with a systolic blood pressure[100 mmHg
and serum creatinine\2.0 mg/dL (*177 lmol/L) have an inpatient
mortality of only 2.6% [54]
138 Heart Fail Rev (2012) 17:133–149
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T a b l e 2
P r e v a l e n c e a n d / o r i n c i d e n
c e o f r e n a l d y s f u n c t i o n i n r a n d o m i s e d c o n t r o l l e d t r i a l s o f a c u t e h e a r t f a i l u r e
S t u d y
Y e a r
N
A g e ( y e a r s )
W o
m e n ( % )
C A D ( % )
D i a b e t e s ( % )
S y s B P ( m m H g )
L V
S D ( % )
R e n a l d y s f u n c t i o n
S t r o n g e s t p r o g n o s t i c
m a r k e r s #
C o
m m e n t
O P T I M E - H F [ 8 4 ]
9 4 9
6 6 3 4
5 1 4 4
1 2 0
2 4
M e a n U r e a 9 m m o l / L
M e a n S C r 1 2 8 l m o l / L
M e a n e G F R 5 1 m L / m i n
I n c i d e n c e
;
G F R [ 2 5 % : 1 2 %
:
B U N [ 2 5 % : 3 9 %
O f d e a t h a t 6 0 d a y s : a g e ,
S B P , N Y H A , U r e a , S .
S o d
O f d e a t h / r e a d m a t 6 0 d a y s :
B U N , S B P , H b , h / o P C I
6 0 - d a y m o r t a l i t y 9 . 6 % a n d
d
e a t h o r r e a d m 3 5 . 1 %
E S C A P E [ 8 5 ]
4 3 3
5 6 2 6
5 0 3 5
1 0 6
2 0
M e a n U r e a 1 3 m m o l / L
M e a n S C r 1 3 3 l m o l / L
P e r s i s t e n t R D 4 5 %
W R F 3 0 %
B N P , u r e a , r e s u s c i t a t i o n o r
v e n t i l a t i o n d u r i n g h o s p , S .
S o d , a g e , l o o p d i u r e t i c s
d o s e , 6 M W D
6 - m o n t h m o r t a l i t y 1 8 . 7 %
a
n d r e a d m 6 4 %
B a
s e l i n e ?
d i s c h a r g e r e n a l
i m p a i r m e n t b u t n o t W R F ,
p
r e d i c t e d d e a t h / r e a d m
E V E R E S T [ 6 5 ]
4 , 1 3 3
6 6 2 6
6 6 3 9
1 2 0
2 8
P r e v a l e n t : 2 7 %
M e a n U r e a 1 1 m m o l / L
M e a n S C r 1 2 4 l m o l / L
I n c i d e n t : 2 %
R a l e s , p e r i p h e r a l o e d e m a ,
S . S o d , G F R , B N P ,
K C C Q
M e a n F U 9 . 9 m o n t h s
A l l - c a u s e m o r t a l i t y 2 6 %
D e
a t h o r C V r e a d m 4 1 %
V E R I T A S [ 8 6 ]
1 , 4 4 8
7 0 4 0 . 5
6 8 4 8
1 3 1
2 7
B a s e l i n e C K D 3 7 %
M e a n U r e a 1 0 m m o l / L
M e a n S C r 1 1 5 l m o l / L
I n c i d e n t : N R
N R
D e
a t h / d e a t h o r W H F
7 - d a y s : 1 . 3 / 2 6 %
3 0 - d a y s : 4 . 4 / 3 2 . 5 %
S U R V I V E [ 8 7 ]
1 , 3 2 7
6 7 2 8
7 6 3 3
1 1 6
2 4
S C r [ 2 2 0 l m o l / L i n
7 %
N T - p r o B N P ( B N P ) a n d S C r
D e
a t h
5 - d a y s : 5 %
3 1 - d a y s : 1 3 %
1 8 0 - d a y s : 2 7 %
P R O T E C T [ 2 7 ]
2 , 0 3 3
7 0 3 3
7 0 4 6
1 2 4
3 2 . 4
P r e v a l e n t : N R
M e a n U r e a 1 0 m m o l / L
M e a n S C r 1 2 4 l m o l / L
M e a n C C 5 1 m L / m i n
I n c i d e n t 1 4 . 4 %
U r e a
7 - d a y s : 1 . 8 %
1 8 0 - d a y s : 1 7 . 6 %
D e
a t h / r e a d m ( C V o r r e n a l )
a
t 6 0 - d a y s : 2 8 . 6 %
3 C P O [ 8 8 ]
1 , 0 6 9
7 8 5 6 . 9
6 3 3 1
1 6 N R
N R
N R
D e
a t h
7 - d a y s : 1 0 %
3 0 - d a y s : 1 6 %
# t h e r a p i e s , e x c e p t d i u r e t i c d o s e , a r e e x c l u d e d a s t h e s e m a y b e c o n f o u n d e d b
y i n d i c a t i o n . P r e v a l e n t r e n a l d y s f u n c t i o n a r e t h e r a t e s r e p o r t e d b y i n v e s t i g a t o r s .
N R n o t r e p o r t e d ,
U r e a s e r u m
u r e a -
t o c o n v e r t t o B U N m u l t i p l y
b y 2 . 8 , S C r s e r u m c r e a t i n i n e i n l m o l / L ( d i v i d e b y 8 8 . 4 t o c o n v e r t t o m g / d L ) , S y s B P s
y s t o l i c b l o o d p r e s s u r e ,
S . S o d s e r u m s o d i u m
c o n c e n t r a t i o n , H R h e a r t
r a t e , R
R r e s p i r a t o r y r a t e , H
b h a e m o g l o b i n , B
N P b r a i n n a t r i u r e t i c p e p t i d e , N
T - p r o B N P a m i n o - t e r m i n a l p r o - B N P , 6
M W D 6 - m
i n w a l k d i s t a n c e , K
C C Q K a n s a s C i t y c a r d i o m y o p a t h y q u e s t i o n n a i r e ,
R e a d m r e a d m i s s i o n ,
L V S D l e f t v e n t r i c u l a r s y s t o l i c d y s f u n c t i o n , e G F R e s t i m a t e d g l o m e r u l a r fi l t r a t i o n r a t e ,
C V c a r d i o v a s c u l a r , C C c r e a t i n i n e c l e a r a n c e , F U f o l l o w - u p ,
L V E F l e f t v e n t r i c u l a r
e j e c t i o n f r a c t i o n ,
W H F w o r s e n i n g r e n a l f a i l u r e ,
N Y H A N e w Y o r k h e a r t a s s o c i a t i o n c l a s s , C K D c h r o n i c k i d n e y d i s e a s e . F
o r a c r o n y m s p l e a s e r e f e r t o r e l e v a n t r e f e r e n c e
Heart Fail Rev (2012) 17:133–149 139
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classes in only 1%. However, renal function also improved
in some patients: by one class in 11% and by two classes in
0.6%. Both baseline serum creatinine and change in serum
creatinine at 6 months were independent predictors of long-
term prognosis (Fig. 3). In the studies of left ventricular
dysfunction (SOLVD) treatment and prevention trials, 16%
of patients assigned to enalapril and 12% assigned to pla-
cebo had a rise in serum creatinine by [44 lmol/L over2 years ( p = 0.003 for the difference between enalapril and
placebo) [71]. Patients followed for four or more years had a
25% chance of worsening renal function as defined above.
Older patients and those treated with diuretics were at
increased risk of declining renal function, especially if
treated with an ACE inhibitor. Patients with diabetes were
also at increased risk of developing renal dysfunction, but
the risk was reduced by enalapril. As less than half of
patients in SOLVD received diuretics, one can assume a
substantially higher rate of worsening renal function in
patients with left ventricular dysfunction treated with
diuretics. In the carvedilol or metoprolol European trial(COMET) study, a similar pattern was observed to the above
study of de Silva with about 8% of patients having a fall in
serum creatinine of [20 lmol/L by 1 year and 15% an
increase by more than this amount [72]. Introduction of
either metoprolol or carvedilol was associated with an acute
decline in eGFR of about 2 mL/min and then only an
average of about 1 mL/min/year thereafter, a rate very
similar to that observed in healthy older people. This may
reflect the combined effects of ACE inhibitors and beta-
blockers on long-term renal function. Few patients with
heart failure have grossly elevated blood pressure once they
have received effective therapy, which might account for the
rather similar average rate of decline in eGFR in patients
with heart failure and the normal population. Over 5 years of
follow-up, eGFR fell below 30 mL/min in only 8.8% of
patients assigned to carvedilol and 11.3% of those assigned
to metoprolol ( p = 0.020).
All substantial trials have shown that measures of renal
function are powerful markers of prognosis in heart failure.
The big remainingissues are which measure is most strongly
related to prognosis and, since risk changes over time, how
often it needs to be measured. Creatinine-based measures
have been used traditionally, but urea and cystatin-C [5, 73,
74] may be stronger markers. Evidence on both will accu-
mulate rapidly in the next few years, and it is likely that
creatinine-based measures of renal function will be dis-
placed, perhaps by urea since it is so widely available and
inexpensive. Use of time-dependent prognostic models
using serial measures will make the link between renal
markers andprognosis even stronger [67, 75]. Renal function
is an important determinant of plasma natriuretic peptide
concentrations [76]. Indeed,it is likely that one ofthe reasons
why this family of peptides provides such powerful T a b l e 3
E p i d e m i o l o g i c a l s t u d i e s o
f i n c i d e n t r e n a l d y s f u n c t i o n i n c h r o n i c h e a
r t f a i l u r e
S t u d y
Y e a r
N F U M o r t a l i t y ( %
)
A g e ( y e a r s )
W o m e n ( % )
C A D ( % )
D i a b e t e s ( % )
S y s B P ( m m H g )
L V E F ( % )
R e n a l d y s f u n c t i o n
S t r o n g e s t p r o g n o s t i c
m a r k e r s #
C o
m m e n t
H u l l L i f e L a b [ 6 7 ]
1 , 2 1 6
1 . 4 y e a r s
2 2
7 1 3 1
6 5 2 1
1 3 5 m m H g
M e a n U r e a : 9 m m o
l / L
M e a n S C r : 1 2 3 l m
o l / L
3 2 % S C r [ 1 3 0 l m
o l / L
5 7 % e G F R \ 6 0 m L / m i n
I n c i d e n t W R F : 1 3 %
a t 6 m
L V E F , C O P D , u r e a
B a
s e l i n e s e r u m u r e a
s
t r o n g e r p r e d i c t o r t h a n
S
C r . M o s t o f p r o g n o s t i c
i n f o r m a t i o n f r o m b a s e l i n e
r e n a l f u n c t i o n
V a l u e s f o r u r e a a n d c r e a t i n i n e a r e m e d i a n o r m e a n
W R F w o r s e n i n g r e n a l f u n c t i o n , W
R F w o r s e n i n g r e n a l f a i l u r e , C A D c o r o n a r y
a r t e r y d i s e a s e , e G F R e s t i m a t e d g l o m e r u l a
r fi l t r a t i o n r a t e ,
L V E F l e f t v e n t r i c u l a r e j e c
t i o n f r a c t i o n ,
S C r s e r u m
c r e a t i n i n e , S y s B P s y s t o l i c b l o o d p r e s s u r e , C O P D c h r o n i c o b s t r u c t i v e p u l m o n
a r y d i s e a s e , F U f o l l o w - u p
140 Heart Fail Rev (2012) 17:133–149
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T a b l e 4
R e n a l d y s f u n c t i o n , p r e v a l
e n t a n d / o r i n c i d e n t , r e p o r t e d i n s e l e c t e d s t u d i e s o f v a s o d i l a t o r s , a n g i o t e n s i n - c o n v e r t i n
g - e n z y m e i n h i b i t o r s , a n g i o t e n s i n r e c e p t o r
b l o c k e r s a n d a l d o s t e r o n e
r e c e p t o r a n t a g o n i s t s
S t u d y
Y e a r
N F U M o
r t a l i t y
A g e ( y e a r s )
W o m e n ( % )
C A D
( % )
D i a b e
t e s ( % )
S y s B P
( m m H g )
L V E F ( % )
R e n a l d y s f u n c t i o n
S t r o n g e s t
p r o g n o s t i c m a r k e r s o r
o t h e r c o m
m e n t s
V - H e F T - I [ 8 9 ]
6 4 2 2 3 y e a r s
3 0 %
5 8 0
4 4 2 0
1 1 9
3 0
N o t r e p o r t e d
L V E F , V O 2 , a n d C T R . V e n t r i c u l a r
a r r h y t h m
i a s i n V - H e F T - I I
V - H e F T - I I [ 9 0 ]
8 0 4 2 . 5
y e a r s
3 5 %
6 0 0
5 3 2 0
1 2 6
E F 2 9
N o t r e p o r t e d
C O N S E N S U S [ 9 1 , 9 2 ]
2 5 3 0 . 5
y e a r s
3 5 %
7 1 3 0
7 3 2 3
1 2 1
M e
a n S C r : 1 2 8 l m o l / L
S C r d o u b l e d i n 3 % a s s i g n e d
t o
p l a c e b o a n d 1 1 %
a s s i g n e d t o e n a l a p r i l a t
6
m o n t h s
F a l l i n b l o o d p r e s s u r e a n d , t o a
l e s s e r e x t e n t , d o s e o f f u r o s e m i d e
p r e d i c t e
d W R F
S O L V D - P [ 4 0 , 9 3 ]
4 , 2 2 8
3 . 1
y e a r s
1 5 %
5 9 1 1 . 5
8 3 1 5
1 2 6
2 8
M e
a n S C r 1 0 6 l m o l / L
e G F R \ 6 0 m L / m i n : 2 0 %
A g e , L V E
F , D M , A F , s e x
S O L V D - T [ 9 3 , 9 4 ]
2 , 5 6 9
3 . 5
y e a r s
3 8 %
6 1 1 9 . 7
7 1 2 6
1 2 5
2 5
M e
a n S C r 1 0 6 l m o l / L
e G F R \ 6 0 m L / m i n : 3 6 %
I n c
i d e n t [ 1 7 7 l m o l / L
# e
n a l a p r i l 1 0 . 7 %
# p
l a c e b o 7 . 7 % ( p \
0 . 0 1 )
A T L A S [ 6 9 , 9 5 ]
3 , 1 6 4
3 . 8
y e a r s
3 8 %
6 4 2 1
6 5 1 9
1 2 6
2 3
U r e a : N R
M e
a n S c r : 1 2 1 l m o l / L
W R
F a s a n A E : 8 . 4 %
A g e , s e x ,
I H D , H R , S C r
A - H e F T [ 9 6 ]
1 , 0 5 0
0 . 9
y e a r s
8 %
5 6 4 0
2 3 4 0
1 2 6
2 4
1 7 %
r e p o r t e d t o h a v e r e n a l
i n
s u f fi c i e n c y ( d e fi n e d b y
h i s t o r y a l o n e )
V a l - H e F T [ 9 7 ]
5 , 0 1 0
1 . 9
y e a r s
2 0 %
6 3 2 0
5 7 2 6
1 2 4
2 7
M e
a n e G F R 5 7 m L / m i n
B N P , N Y
H A , S C r , a g e , L V E D D ,
H b , E F , C R P , B M I , l o w s y s B P ,
D M , 3 r d h e a r t s o u n d , b i l i r u b i n ,
s e x , p r o
t e i n u r i a
C H A R M - a d d e d [ 9 8 ]
2 , 5 4 8
3 . 4
y e a r s
3 1 %
6 4 2 1
6 2 3 0
1 2 5
2 8
e G F R \ 6 0 m L / m i n 3 3 %
I n c
i d e n t : 7 %
G F R , L V E F , B M I , H b , D M ,
b i l i r u b i n , Q R S , E C G L V H ,
R D W , H
b A 1 c , B N P
Heart Fail Rev (2012) 17:133–149 141
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T a b l e 4
c o n t i n u e d
S t u d y
Y e a r
N F U M o r t a l i t y
A g e ( y e a r s )
W o m e n ( % )
C A
D ( % )
D i a b e t e s ( % )
S y s B P
( m m H g )
L V E F ( % )
R e n a l d y s f u n c t i o n
S t r o n g e s t
p r o g n o s t i c m a r k e r s o r
o t h e r c o m
m e n t s
C H A R M - p r e s e r v e d [ 9 9 , 1 0 0 ]
3 , 0 2 3
3 . 0 y e a r s
1 6 %
6 7 4 0
5 7 2 8
1 3 6
5 4
G F R \ 6 0 m L / m i n 3 5 %
I n c i d e n t : 5 %
P E P – C H F [ 1 0 1 ]
8 5 0
7 6
3 9
1 4 0
M
e a n S C r : 9 6 l m o l / L
U n c h a n g e d a t 1 y e a r o n
p l a c e b o :
b y 4 l m o l / L
o n p e r i n d o p r i l
N T - p r o B N P , a g e , I H