Download Changes in Renal Function in Congestive Heart Failure

Curr Heart Fail Rep (2013) 10:285–295
DOI 10.1007/s11897-013-0170-8
PREVENTION OF HEART FAILURE (M ST. JOHN SUTTON, SECTION EDITOR)
Changes in Renal Function in Congestive Heart Failure
Guido Boerrigter & Berthold Hocher & Harald Lapp
Published online: 26 October 2013
# Springer Science+Business Media New York 2013
Abstract Both cardiovascular and renal diseases are common
and frequently coexist in the same patient. Indeed, renal dysfunction has been shown to be a more powerful independent
predictor of poor outcomes in heart failure (HF) than left ventricular ejection fraction or functional class. Furthermore, acute
kidney injury is a frequent therapeutic concern in heart failure.
Consequently, there has been much interest in developing new
renoprotective treatments and novel biomarkers to monitor renal
function. Additionally, given the crucial cardiorenal interaction
and interdependence, the concept of a cardiorenal syndrome
with five different subtypes has been advanced to better categorize patients and facilitate research.
Keywords Cardiorenal syndrome . Heart failure . Chronic
kidney disease . Acute kidney injury . Diuretics .
Ultrafiltration . Creatinine . Cystatin C . Diuretic resistance .
Glomerular filtration rate
require large healthcare expenditures [1]. Given that both are
often the result of general vascular disease, it is not surprising
that they frequently coexist in the same patient. Indeed, in recent
years, renal dysfunction and worsening renal function have been
demonstrated to be important independent predictors of poorer
outcomes in HF [2–5]. And because both the heart and kidneys
have crucial functions in maintaining homeostasis, it is also no
surprise that dysfunction of one organ could negatively affect
function of the other, a condition that has been termed
"cardiorenal syndrome" (CRS). Given the heterogeneity of
cardiac and renal disease and their presentations, attempts have
been made to categorize CRS into 5 types [6].
Here we will review (1) relevant pathophysiology of renal
function and cardiorenal interaction, (2) conventional and
emerging biomarkers for monitoring renal function, (3) classifications for chronic kidney disease (CKD), acute kidney
injury (AKI), and CRS, (4) HF treatment strategies as they
relate to renal function, and (5) novel therapeutic strategies.
Introduction
Both cardiovascular and renal diseases are increasing in prevalence, are major contributors to morbidity and mortality, and
G. Boerrigter (*) : H. Lapp
HELIOS Klinikum Erfurt, Nordhäuser Str. 74,
99089 Erfurt, Germany
e-mail: [email protected]
H. Lapp
e-mail: [email protected]
B. Hocher
Institute of Nutritional Science, University of Potsdam,
14558 Potsdam, Nuthetal, Germany
e-mail: [email protected]
B. Hocher
Center for Cardiovascular Research, Charité, Berlin, Germany
H. Lapp
University Witten-Herdecke, Witten, Germany
Renal Physiology and Neurohumoral Relevance to Heart
Failure
The basic functional unit of the kidney is the nephron (Fig. 1).
Blood flows through the afferent arteriole into the capillaries of
the glomerulus and exits via the efferent arteriole. Renal
autoregulation by differential regulation of the vascular tone of
the afferent and efferent arteriole can adjust the hydrostatic
pressure in the glomerulus and maintain a relatively constant
glomerular filtration rate (GFR). The filtrate flows through
different segments of the tubule, which differ in their water
permeability and their expression of transporters and channels,
the activity of which are to some extent regulated by the autonomic nervous system and neurohormones. Along the nephron,
molecules are reabsorbed or secreted, and water follows passively according to the water permeability of the segment.
Importantly, the site of action of diuretics also differs along the
tubule, and most diuretics have to be secreted by the tubular cells
into the lumen to be active. At the juxtaglomerular apparatus, the
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Curr Heart Fail Rep (2013) 10:285–295
Fig. 1 Schematic of a single
nephron with major sites of action
of some conventional diuretics.
The juxtaglomerular apparatus,
located at the junction of the
afferent arteriole and the distal
tubule, contains renin-secreting
cells. Aldo, aldosterone, AQP-2,
aquaporin 2 water channel, AVP,
arginine vasopressin, ENaC,
epithelial sodium channel, MR,
mineralocorticoid receptor, V2 Receptor, vasopressin 2 receptor.
Adapted from Boerrigter G,
Costello-Boerrigter LC, Burnett
JC Jr, Alterations in Renal
Function in Heart Failure. In:
Mann DL, editor. A Companion
to Braunwald’s Heart Disease.
Second Edition. Saunders/
Elsevier 2011, with permission
from Elsevier.
distal tubule comes in close contact with the afferent arteriole.
Under physiological conditions, increased delivery of sodium to
the distal tubule leads to an increase in afferent vascular tone,
thus reducing hydrostatic pressure in the glomerulus and decreasing GFR.
Of note, loop diuretics both increase sodium delivery to the
distal tubule and inhibit this feedback mechanism [7, 8]. If GFR
decreases (e.g., due to systemic hypotension) then sodium delivery to the distal tubule decreases. This is sensed by the macula
densa, with consequent release of renin and activation of the
renin-angiotensin-aldosterone system (RAAS). Angiotensin II
can increase efferent vascular tone, thus increasing GFR.
Furthermore, relative arterial underfilling with decreased activation of baroreceptors will increase sympathetic tone [9]. As a
result, vasoconstriction and renal sodium and water reabsorption
will be promoted, all in an effort to increase blood pressure.
Arginine vasopressin (AVP) is released in response to an increase
in plasma osmolality. By promoting the insertion of the
aquaporin-2 water channel in the collecting duct via the
V2- receptor, AVP promotes free water reabsorption and thus
reduces plasma osmolality. Furthermore, AVP via the V1a receptor can cause vasoconstriction. In HF, AVP may be released
independently of plasma osmolality and contribute to
hyponatremia and fluid retention.
Renal venous congestion can decrease renal perfusion
pressure and increase renal interstitial pressure, both of which
decrease glomerular filtration [10]. Some studies have shown
that central venous pressure is a better predictor of low GFR
than cardiac output or systemic arterial pressure [11, 12].
Furthermore, abdominal congestion has been associated with
cardiorenal syndrome [13]. Of note, venous congestion is also
associated with increased atrial stretch, which, in addition to
cardiac stress, is an important stimulus for the release of the
pleiotropic cardiac natriuretic peptides ANP and BNP, which
promote vasodilation and renal sodium excretion [14].
Assessing and Monitoring Renal Function
A biomarker should ideally have the following features: (a)
provide objectivity in the evaluation and diagnosis of patients,
especially those in whom signs and symptoms are not very
sensitive or specific, (2) help with correct triage by assessment
of prognosis and risk stratification, (3) help to guide objectively
therapy or management, (4) enable an optimum screening
process, and (5) guide the delivery of cost-effective medical
care. In addition, the test should have high sensitivity, specificity, reproducibility, and accuracy; it should have a low coefficient of variation; it should be easy to perform and analyse; it
should be applicable across sexes, ethnicity, and age spectra;
and it should make physiological sense [15].
Besides urine flow, the most important renal functional
parameter is GFR. The gold standard for measuring GFR is
determining the clearance of a compound, such as inulin, that
is freely filtered and neither secreted nor reabsorbed by the
kidney. However, clearance methods are expensive and cumbersome. The creatinine clearance can be calculated from
serum creatinine and the urine volume and creatinine concentration in a 24-h urine collection; however, these are timeconsuming and are prone to collection error. Therefore, equations that estimate GFR based on serum creatinine (or cystatin
C) and anthropometric variables have been developed and
continue to be refined for specific patient populations. It was
recently reported that the CKD-EPI equation was more accurate and provided a better risk assessment in patients with HF
and reduced ejection fraction than the Modification of Diet in
Curr Heart Fail Rep (2013) 10:285–295
287
Renal Disease (MDRD) equation that was often used previously [16–18]. Of note, these equations should only be used in
patients with stable serum creatinine. Creatinine is not only
filtered but is also secreted by the kidney, and its production is
dependent on muscle mass. Due to the kidney’s capacity to
compensate, an increase in serum creatinine will usually occur
only after the loss of about 50 % of the nephrons. Given the
shortcomings of creatinine, alternative markers are being evaluated. Cystatin C has emerged as a good albeit imperfect alternative to creatinine [19••]. It is produced at relatively constant
levels by all nucleated cells, and is filtered and completely
reabsorbed and then metabolized by the kidney. Consequently,
cystatin C levels rise with CKD.
When interpreting a biomarker such as creatinine, it is
important to know what constitutes a significant change as
compared to noise; i.e., random variation due to the limited test
accuracy and inconsequential physiological variation. In
healthy young men, repeated creatinine measurements over
48 hours showed a median intraindividual coefficient of variation of 4.2 % [20]. In a general population sample with low
prevalence of CKD (few people with serum creatinine
>1.5 mg/dL), the within-person coefficient of variation of two
blood samples collected approximately 18 days apart was
7.6 % (eGFR CKD-EPI: 6.6 %) [21]. It would be interesting
to know the variability in stable patients with HF and CKD.
Presumably, the variability would be larger due to factors such
as a decreased ability for compensation, secondary to a reduced
number of nephrons with reduced renal functional reserve and
the impact of drugs such as diuretics and inhibitors of the
angiotensin-converting enzyme (ACE) [22].
Importantly, after an AKI affecting GFR, it takes some time
for creatinine to rise appreciably. Furthermore, creatinine may
be too insensitive a marker to clearly indicate AKI, especially if
compensatory mechanisms of the kidney are activated.
Therefore, it would be desirable to have a biomarker that would
quickly indicate that kidney injury had occurred so that appropriate steps could be initiated as early as possible. Indeed, there
is currently a good deal of research dedicated to finding new
markers of early AKI [23]. As an example, neutrophil
Table 1 Classification of chronic
kidney disease according to Kidney Disease Outcomes Quality
Initiative (KDOQI) [27]
CKD stage
1
2
3
4
5
CKD chronic kidney disease,
GFR glomerular filtration rate
gelatinase-associated lipocalin (NGAL) is a 21 kD-protein released during cellular stress to act, among other things, to bind
free iron and thus reduce oxidative stress. Its plasma and urine
concentrations increase shortly after AKI [24]. Haase et al.
dichotomized 1,296 patients based on their level of serum
creatinine and NGAL [25]. Patients in whom both markers were
increased had the highest rate of adverse outcomes in terms of
need for renal replacement therapy, mortality, ICU, and hospital
length-of-stay, whereas patients in whom neither marker increased had the lowest incidence. Patients with only NGAL or
only creatinine increased had intermediate rates, suggesting that
there is a subset of patients with tubular injury that goes
undetected when only creatinine is considered. Kashani et al.
reported the discovery and validation of two biomarkers of AKI
that predicted subsequent AKI within 12 hours after sample
collection, specifically urine concentrations of the two cell-cycle
inhibitors insulin-like growth factor-binding protein-7
(IGFBP7) and tissue inhibitors of metalloproteinase-2 (TIMP2) [26•]. Taken together, the discovery of novel markers that
indicate AKI earlier than conventional markers seems to be just
around the corner, and it may turn out that a multimarker
approach is the best. With these new tools, novel and earlier
interventions can be tested and will hopefully lead to better
renoprotection.
Classification of Renal Disease
Given the heterogeneity and wide spectrum of cardiac and
renal disease, management and treatment of the disease may
need to be tailored. Over the years, several classifications and
definitions have been proposed and refined to categorize
patients with renal disease.
Chronic Kidney Disease (CKD)
The CKD classification by Kidney Disease Outcomes Quality
Initiative (KDOQI, Table 1) categorizes patients according to the
presence of kidney damage (i.e.,. albuminuria or proteinuria) and
Description; findings need to be present for ≥3 months
GFR (mL/min/1.73 m2)
Kidney damage with normal or relatively high GFR
≥90
(Kidney damage is defined as pathologic abnormalities
or markers of damage, including abnormalities in
blood or urine test or imaging studies)
Kidney damage with mild reduction in GFR
Moderate reduction in GFR
Severe reduction in GFR. Preparation for renal
replacement therapy
Established kidney failure, which includes end-stage
renal disease (defined as a need for renal replacement
therapy, i.e., dialysis or kidney transplantation)
60-89
30-59
15-29
<15
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Curr Heart Fail Rep (2013) 10:285–295
the level of GFR, and the findings must be present for at least
3 months [27]. The CKD classification by Kidney Disease:
Improving Global Outcomes (KDIGO) categorizes patients
according to GFR (G1: ≥ 90; G2: 60–89; G3a: 45–59; G3b:
30–44; G4: 15–29; G5 <15 mL/min/1.73 m2) and persistent
albuminuria (A1: <30; A2: 30–300; A3: >300 mg/g creatinine)
[19••].
CRS type 4: Primary CKD contributes to decreased cardiac
function
CRS type 5: An acute or chronic systemic disorder promotes
combined cardiac and renal dysfunction
Change in Renal Function in Congestive Heart Failure
Acute Kidney Injury (AKI)
Improving Renal Function
With regard to acute renal injury, many definitions and terms
(e.g., “worsening renal function”) have been proposed and
used in the past. The Risk, Injury, Failure, Loss, End-stage
Kidney Disease (RIFLE) and Acute Kidney Injury Network
(AKIN) criteria were proposed in 2004 and 2007, respectively
[28, 29]. The most recent suggestion for a classification
(Table 2) was made by KDIGO [30••]. A critique from a
U.S. perspective was published by the KDOQI [31••]. One
criticism was the inclusion of urine output, a decrease in
which would be considered an appropriate response in the
setting of prerenal failure.
Cardiorenal Syndrome Types 1–5
Recognition of the interdependency of the heart and kidneys
has helped to advance the concept of cardiorenal syndrome, in
which dysfunction of one of the organs impacts the function of
the other. Ronco et al. have proposed the classification of 5
types of CRS, the pathophysiology and gaps of knowledge of
which have recently been reviewed [29, 32••, 33–37]:
CRS type 1: Rapid worsening of cardiac function leads to
AKI
CRS type 2: Chronic abnormalities in cardiac function cause
progressive CKD
CRS type 3: Abrupt and primary worsening of kidney function leads to acute cardiac dysfunction
Table 2 Classification of Acute
Kidney Injury (AKI) according to
Kidney Disease: Improving
Global Outcomes (KDIGO)
[30••]
Stage
1
If renal dysfunction is due, at least in part, to heart failure, then
improving cardiac function would be expected to improve
renal function. This can be seen in cases of successful treatment of acute decompensated HF. There is also evidence of
improved renal function with heart transplantation, ventricular
assist device implantation, and cardiac resynchronization therapy [38, 39].
Prevention of Worsening Renal Function
In patients with CKD, the prevention of additional kidney injury
is critical. The use of nonsteroidal anti-inflammatory drugs
(NSAIDs) should be discouraged in CKD, as they interfere with
the synthesis of prostaglandins important for renal function in
CKD and HF [40]. Drug doses may need to be adjusted for the
degree of CKD. With regard to intravenous contrast media, there
is the concern of contrast-induced AKI (CI-AKI, also referred to
as contrast-induced nephropathy (CIN)). Alternative imaging
techniques should be considered. If contrast needs to be given,
the amount should be as low as reasonably possible. Many
interventions have been tested for the prevention of CI-AKI.
However, only hydration has definitively been shown to be
beneficial [30••]. An innovative approach in reducing renal
exposure to contrast media during coronary angiography and
intervention is the use of a coronary sinus catheter that removes
the contrast from the circulation [41, 42].
Serum creatinine
Urine output
1.5–1.9 times baseline
<0.5 ml/kg/h for 6–12 hours
OR
2
3
≥0.3 mg/dl (≥26.5 μmol/l) increase
2.0–2.9 times baseline
3.0 times baseline
<0.5 ml/kg/h for ≥12 hours
<0.3 ml/kg/h for ≥24 hours
OR
OR
Increase in serum creatinine to ≥4.0 mg/dl (≥353.6 μmol/l)
Anuria for ≥12 hours
OR
Initiation of renal replacement therapy
OR
In patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m2
Curr Heart Fail Rep (2013) 10:285–295
289
Of note, serum creatinine can change in hospitalized patients
even in the absence of contrast administration. It is useful to
know this background variation before attributing any change in
serum creatinine to prior contrast administration. Newhouse
et al. reported that significant increases in serum creatinine, both
in absolute and relative terms, are frequently seen in hospitalized
patients not receiving contrast; if they had received contrast, the
increase would likely have been attributed to the contrast [43].
Bruce et al. reported similar changes in serum creatinine in
patients undergoing imaging studies both with and without
contrast administration [44].
as C-reactive protein), urine sample (infection, sodium, protein,
leukocytes, erythrocytes, cell casts), monitoring of urine output,
abdominal ultrasound for obstructive nephropathy, and electrocardiogram (ischemia, arrhythmia, electrolyte disturbance).
Patients with obstructive uropathy should be seen by a
urologist; patients with suspected intrinsic renal disease, by a
nephrologist. In patients in whom hypovolemia is suspected as
the cause for the renal deterioration (e.g., due to overdiuresis,
lack of intake, blood loss), fluid resuscitation should be
attempted. The following discussion will focus on changes in
renal function due to heart failure.
Worsening Renal Function
Change in Renal Function due to Therapy
In general, a change in renal function can be due to trivial
random variation as well as prerenal, intrarenal, and postrenal
causes. Furthermore, the change can be rapidly reversible and
thus ultimately inconsequential or irreversible, contributing to
further decline in renal function. If relevant worsening of renal
function is detected, it is important to identify and, if possible,
treat the causes, prevent further aggravation by discontinuing
or reducing potentially nephrotoxic medications, and use intravenous iodinated contrast media judiciously.
Heart failure and its treatment can contribute to deterioration of
renal function in a variety of ways. In stable heart failure, ACE
inhibitors can be expected to raise serum creatinine given that
they act to decrease efferent vascular tone and thus reduce
glomerular filtration pressure. A serum creatinine increase of
about 30 % (depending on the baseline value) can usually be
tolerated. However, ACE inhibitors should be carefully titrated,
and in the setting of an acute renal function decline, the ACE
inhibitor is frequently reduced or paused. Overdiuresis can lead
to volume depletion with subsequent increase in creatinine due
to hypotension. If hypotension appears to contribute to renal
dysfunction, hypotensive drugs may need to be paused.
Progression of Chronic Kidney Disease
Usually, renal function starts to decline in the fourth decade of
life at a rate of about 8 mL/min/1.73 m2 per decade. As muscle
mass, and thus creatinine production, decreases, serum creatinine remains relatively unchanged. In patients with CKD, the
remaining nephrons must compensate for the loss of other
nephrons. This is associated with hyperfiltration and intraglomerular hypertension, both of which promote further nephron loss. Important factors that promote progression of CKD
are hypertension, hyperglycemia, and hyperlipidemia. ACE
inhibition or antagonism of the angiotensin II type 1 receptor,
which reduce hyperfiltration and intraglomerular hypertension
by dilating the efferent arteriole, can reduce long-term renal
decline [45, 46].
Identify Causes of Renal Function Decline
The major workup in a HF patient with deterioration of renal
function should consider the major prerenal, intrarenal, and
postrenal causes of renal function decline such as low cardiac
output and systemic hypotension, hypovolemia, venous congestion, renal ischemia, renal toxins, obstructive nephropathy, systemic infection, or inflammatory diseases. The workup usually
includes history, physical examination (signs of congestion or
dehydration), vital signs (hypotension, heart rate), blood sample
(electrolytes, creatinine or cystatin C, blood urea nitrogen, Btype natriuretic peptide or aminoterminal B-type natriuretic peptide, troponin, complete blood count, inflammatory markers such
Change in Renal Function due to Acute Decompensated Heart
Failure
In acute decompensated HF (ADHF), renal function can be
impacted by multiple factors, including low cardiac output,
systemic hypotension, renal venous congestion, and neurohumoral activation. If a precipitating cause for worsening cardiac
function can be identified, such as hypertension, ischemia, arrhythmias, or anemia, it should be treated appropriately. If there
is hypotension without fluid overload, fluid resuscitation should
be attempted. If this does not improve blood pressure and cardiac
output, vasopressors or inotropes, or both, may be required.
Often, volume overload is a problem, which increases
cardiac preload and afterload, promoting further deterioration
of cardiac function. Worsening cardiac function and venous
congestion will cause the kidney to further retain sodium and
fluid, thus aggravating congestion and cardiac overload.
Treating volume overload can improve both cardiac and renal
function by reducing cardiac preload and afterload, potentially
reducing valvular regurgitation and decreasing venous congestion. Hence, diuretic therapy can improve renal function.
Diuretic Therapy
Conventional diuretics such as loop diuretics continue to be
the mainstay of therapy. In recent years, there was a discussion
290
as to whether diuretic use contributed to worse outcomes or
whether the use of diuretics, including their dose, was simply
a marker of more severe disease [47, 48]. The use of diuretics
can lead to excessive volume loss, disturbances of electrolyte
and acid base homeostasis, and neurohumoral activation.
Many diuretics have been around for decades and therefore
have not been tested in the now-standard randomized controlled trials. However, the frequently dramatic improvements
with the use of diuretics suggest that a comparison with
placebo would be unethical.
Diuretic approaches can differ with respect to doses
employed, route of administration, duration of therapy, and
combination with other diuretics. Postdiuretic sodium retention occurs when, after diuretic administration, the diuretic
levels fall below efficacious levels. This can be remedied by
more frequent or continuous administration. Loop diuretics
will increase sodium delivery to the distal nephron, where
sodium can be reabsorbed as this segment is not responsive
to the loop diuretic effect. However, addition of a thiazide or
thiazide-like diuretic, which acts in the distal nephron, can
significantly increase sodium excretion in combination with
loop diuretics ("sequential nephron blockade" or combination
diuretic therapy) [49–51]. In addition, a mineralocorticoid
receptor antagonist such as spironolactone or eplerenone can
promote sodium excretion, especially in states in which aldosterone metabolism in the liver is impaired [49, 52].
With regard to the use of loop diuretics, the Determining
Optimal Dose and Duration of Diuretic Treatment in People
With Acute Heart Failure (DOSE-AHF) trial addressed two
important questions: the dose to be used and the mode of
administration – specifically, bolus administration vs. continuous administration [53•]. Patients with acutely decompensated
chronic HF were randomized in a 2x2 factorial design to either
low-dose or high-dose furosemide and either bolus or continuous intravenous administration. Low-dose was considered the
usual oral loop diuretic dose given IV, whereas high-dose was
defined as 2.5 times the usual oral loop diuretic dose (accounting for potency and bioavailability, the oral torsemide dose was
converted into the equivalent oral furosemide dose by multiplying by 2; the bumetanide dose was converted into the
furosemide dose by multiplying by 40). Bolus administration
was as efficacious as continuous administration, and high-dose
loop diuretic resulted in better decongestion. Interestingly, the
high-dose regimen also resulted in a significant increase in
serum creatinine, which, however, was not associated with
worse outcomes during the follow-up of 60 days. While it is
doubtful that the follow-up was sufficient and the study adequately powered to demonstrate a difference, it would be
important to know whether treatment was actually associated
with relevant AKI with long-term consequences for renal function, or whether the increase in serum creatinine reflected only
brief phases of hypovolemia during aggressive diuresis, with
no negative impact on renal function. Novel markers of renal
Curr Heart Fail Rep (2013) 10:285–295
function and longer-term follow-up may be helpful in further
elucidating these isssues. It may also be worthwhile to test
whether a more renal-protective diuresis can be achieved, for
example, by monitoring hematocrit or hemoglobin [54–56].
Too rapid an increase in hematocrit could indicate that volume
loss via diuresis exceeds the plasma refill rate, leading to
intravascular hypovolemia. Furthermore, blood urea nitrogen
is an important predictor of poor outcomes in HF, perhaps due
to the fact that AVP, which is activated in more severe HF,
promotes urea reabsorption [57–60]. It should be noted that the
patients enrolled in the DOSE-AHF trial were not required to
show diuretic resistance or worsening renal function. A trial
enrolling only such patients may show different results regarding continuous infusion.
Ultrafiltration
In the setting of renal dysfunction, if medical therapy is unable
to control fluid status adequately, hyperkalemia, or acid base
status, or if patients become uremic, then, in consultation with
nephrology, some form of renal replacement therapy (RRT)
needs to be commenced. Theoretically, it may even be beneficial to use RRT to remove sodium and fluid at an earlier stage
in HF patients with fluid overload. In the Ultrafiltration Versus
Intravenous Diuretics for Patients Hospitalized for Acute
Decompensated Heart Failure (UNLOAD) trial, early ultrafiltration was compared to conventional loop diuretic in patients
with ADHF and hypervolemia [61]. Of note, patients did not
need to demonstrate diuretic resistance. Ultrafiltration resulted
in greater fluid and weight loss at 48 h, with no increase in
serum creatinine and no difference in dyspnea or hospital
length of stay. Interestingly, rehospitalization rate during 90day follow-up was lower in the ultrafiltration group, which was
a secondary efficacy endpoint. In the more recent Cardiorenal
Rescue Study in Acute Decompensated Heart Failure
(CARRESS-HF), ultrafiltration was compared to a specified
diuretic step-up approach in HF patients with hypervolemia
and worsened renal function, which was defined as an increase
in serum creatinine of at least 0.3 mg/dL (26.5 μmol/L) within
12 weeks before or 10 days after the index admission for HF
[62••]. The bivariate primary endpoint was change in body
weight and change in serum creatinine. Ultrafiltration resulted
in the same amount of weight loss as the pharmacological
approach, but was associated with significantly increased serum creatinine. Furthermore, ultrafiltration was associated with
a higher rate of adverse events in the 60-day follow-up, specifically higher incidences of renal failure, bleeding complications, and intravenous catheter-related complications.
As was alluded to in correspondence subsequent to the
article, with ultrafiltration, creatinine is removed at the concentration it is found in the plasma. In CARRESS-HF, the fluidremoval rate was 200 mL/h, which corresponds to a creatinine
clearance of 3.3 mL/min. This highlights the fact that
Curr Heart Fail Rep (2013) 10:285–295
ultrafiltration removes salt and fluid but does not replace some
other important kidney functions – specifically, the concentration of certain metabolic waste products in the urine. Indeed, the
ultrafiltration group also had significantly higher BUN levels. If,
by design, a large amount of fluid is removed by ultrafiltration,
then less will be filtered and excreted by the kidney. Serum
creatinine, therefore, appears to be a suboptimal outcome parameter for studies with ultrafiltration. Indeed, cystatin C levels
were not different between groups. Nevertheless, outcomes
generally favored the pharmacologic treatment arm.
As usual, the results of this trial apply mainly to the patient
population enrolled and the specific treatment strategies used
(e.g., diuretic regimen, ultrafiltration dose, and duration). It
should be noted that outcomes with either treatment were
generally poor, with many people not achieving proper decongestion and with high hospital readmission rates. The
ongoing Aquapheresis Versus Intravenous Diuretics and
Hospitalizations for Heart Failure (AVOID-HF) trial compares
ultrafiltration with a diuretic strategy in patients as the initial
treatment; i.e., not patients selected for already demonstrating
worsening renal function.
Novel Therapeutic Strategies
Challenges regarding the development of new drugs for
cardiorenal disease include not only choosing the best dose
and duration of administration, but also the appropriate patient
selection (e.g., blood pressure level and degree of renal dysfunction). In this section, we will discuss a few evolving
therapeutic strategies.
Antagonists of AVP
Tolvaptan, a V2-antagonist, acts as a powerful aquaretic by
antagonizing AVP-induced insertion of the aquaporin-2 water
channel in the collecting duct. In the Efficacy of Vasopressin
Antagonism in Heart Failure: Outcome Study with Tolvaptan
(EVEREST), a fixed dose of 30 mg of tolvaptan increased
serum sodium and reduced body weight without affecting
short-term or long-term outcomes [63, 64]. Given that
30 mg of tolvaptan showed quite a variable effect in a study
by Udelson et al., there is the possibility that some patients had
significant hypovolemia which may have led to neurohumoral
activation and adverse outcome, potentially offsetting the
benefit of better decongestion that other patients experienced
[65, 66]. It may be useful to test tolvaptan with more individualized dose titration. Furthermore, given that tolvaptan does
not block the V1A receptor with its vasoconstricting actions,
the development of a V1a/V2-receptor antagonist for chronic
therapy may be useful (the V1a/V2 receptor antagonist
conivaptan is only approved for intravenous administration
due to liver toxicity).
291
Adenosine Antagonists
Adenosine via the adenosine A1 receptor plays an important
role in renal regulation by promoting vasoconstriction and
sodium reabsorption [67, 68]. It is also a mediator of
tubuloglomerular feedback. Several studies have reported
renal-enhancing properties of a variety of adenosine A1 antagonists in clinical development [69–71]. However, in the largest
study yet, the pivotal Placebo-Controlled Randomized Study of
the Selective Adenosine A1 Receptor Antagonist Rolofylline
for Patients Hospitalized with Acute Decompensated Heart
Failure and Volume Overload to Assess Treatment Effect on
Congestion and Renal Function (PROTECT), rolofylline did
not meet the study’s endpoints [72]. While rolofylline use was
associated with more patients fulfilling the trial’s “improved”
definition, this was offset in the overall results by more patients
with rolofylline fulfilling the “worsened” criteria (defined as
persistent serum creatinine increase, which was defined as an
increase of 0.3 mg/dL or more on both day 7 and day 14, or
initiation of hemofiltration or dialysis or death through day 7).
The latter was primarily driven by a higher number of patients
with persistent serum creatinine increase. More frequent adverse events with rolofylline were seizures and a trend for
increased number of strokes [73].
In a subsequent analysis focusing on renal function, it was
reported that while loop diuretic dose was similar between
placebo and rolofylline groups, the rolofylline group lost
significantly more weight [74]. This may have contributed to
the higher rate of persistent serum creatinine increase.
Interestingly, when the treatment effect was analyzed
according to baseline creatinine clearance, patients with lower
creatinine clearance tended to do better with rolofylline. This
was also true for the combined morbidity and mortality endpoint (hazard ratio 0.64, confindence interval 0.43, 0.95).
While this may be a chance finding, there could be some
benefit in adenosine A1 receptor antagonism in patients with
more severely impaired renal function. It would also be important to test whether adenosine A1 receptor antagonists
other than rolofylline would have fewer adverse effects on
the central nervous system.
Relaxin
Relaxin is a hormone with vasodilating and antifibrotic properties. A recent trial with a 48-h infusion of a recombinant
relaxin, serelaxin, showed some promising effects in HF patients, including improved creatinine and cystatin C [75, 76].
Unlike some recent vasodilator trials with nesiritide, patients
enrolled in this study were required to have a baseline blood
pressure of more than 125 mmHg, thus reducing the risk of
hypotension and its adverse effects on renal function. While
serelaxin reduced dyspnea during the hospital stay, the most
interesting finding was improved survival in the serelaxin
292
Curr Heart Fail Rep (2013) 10:285–295
group at 180 days. A drug given for only a few days that could
affect long-term outcomes would be quite impressive.
in renal function and to refine our therapeutic strategies to be
more renal-protective.
Natriuretic Peptides
Compliance with Ethics Guidelines
The cardiac natriuretic peptides ANP and BNP are secreted in
response to cardiac stress, and have pleiotropic actions such as
vasodilation, natriuresis, antifibrosis, and aldosterone suppression. Carperitide (recombinant ANP) was approved for the
treatment of HF in Japan in 1995. Nesiritide (recombinant
BNP) was approved for the treatment of ADHF in the USA in
2001 [77]. However, after initial enthusiasm for BNP, its use
steeply declined after studies suggested increased renal dysfunction, mortality, and lack of efficacy. A subsequent definitive trial showed a non-significant trend for a small improvement in dyspnea, with no indication that nesiritide worsened
renal function or improved outcomes [78]. The minimum
systolic blood pressure at enrollment was 100 mmHg.
Hypotension occurred more often with nesiritide than with
placebo (26.6 vs 15.3 %), which may have offset potential
beneficial effects of nesiritide. Urodilatin is a renal splice
variant of ANP with four additional N-terminal amino acids
[79, 80]. Ularitide (recombinant urodilatin) is currently being
investigated in patients with ADHF; one inclusion criterion is
systolic blood pressure ≥110 mmHg. While the role of natriuretic peptides in ADHF treatment remains unclear, they have
shown some benefit in renal protection during cardiac surgery
[81–84].
Conflict of Interest Guido Boerrigter declares that he has no conflict of
interest.
Berthold Hocher declares that he has no conflict of interest.
Harald Lapp has received payment for lectures, including service on
speakers bureaus, for scientific talks in the field of heart failure treatment.
LCZ626
Due to their peptide nature, the long-term administration of
natriuretic peptides, while not impossible, is a somewhat unattractive option. Therefore, strategies have been developed to
augment the natriuretic peptide system by other means, such as
inhibitors of neprilysin [14]. This enzyme, also known as
neutral endopeptidase 24.11, is involved in the degradation of
several hormones, including the natriuretic peptides. LCZ626
is a single molecule that, after ingestion, is cleaved into its two
components: valsartan and the neprilysin inhibitor prodrug
AHU377. In patients with hypertension, LCZ626 reduced
blood pressure more than the corresponding dose of valsartan
[85]. It is currently being investigated for the treatment of HF
with reduced and preserved ejection fraction [86].
Conclusion
In summary, the concept of renal dysfunction as an important
independent prognostic factor and disease modifier in HF has
generated much research interest in the last few years. Novel
markers of AKI are in development and will hopefully help us
to distinguish between inconsequential and significant changes
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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