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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 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 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 ( % )


L V

S D ( % )



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 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 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 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 ( % )


L V E F ( % )



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 ( % )


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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10/18

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 ( % )


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

Renal Dysfungtion Ckd

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