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New Drugs and Technologies
Contemporary Trends in the Pharmacological and
Extracorporeal Management of Heart Failure
A Nephrologic Perspective
Amir Kazory, MD; Edward A. Ross, MD
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Abstract—Heart failure and chronic kidney disease share a number of risk factors and pathophysiological pathways. These
2 pathological processes coexist in large numbers of patients. Whereas the presence of chronic kidney disease in patients
with heart failure adversely influences their survival, cardiovascular disease is the major cause of mortality in
individuals with chronic kidney disease. The management of heart failure by cardiologists has recently expanded from
pharmacological treatment to extracorporeal strategies; the interaction between (and concurrent use of) these approaches
traditionally has been part of nephrology care and training. The purpose of this review is to explore these management
strategies from a nephrologic standpoint and cover the pathophysiology of diuretic resistance, new pharmaceutical
strategies to induce natriuresis or aquaresis, and the physiological basis and theoretical advantages of fluid removal by
nontraditional peritoneal or hemofiltration approaches. This review also focuses on the technical features, safety, and
potential risks of dedicated ultrafiltration devices that do not require dialysis staff or facilities and that are now readily
available to nonnephrologists. (Circulation. 2008;117:975-983.)
Key Words: diuretics 䡲 extracorporeal circulation 䡲 heart failure 䡲 natriuretic peptides 䡲 pharmacology
O
isolated ultrafiltration, and PD) are to be considered different
steps of a strategy in which they have complementary or
sequential, rather than competitive, roles in the care of this
large patient population. The principal sites of action of these
therapeutic options are summarized in Table 1.
HF remains the single most common reason for admission
among patients aged ⬎65 years, and its direct and indirect costs
were estimated at $30 billion in 2006.1,2 Most patients are
admitted with fluid overload, often diuretic resistant and typically in the setting of cardiomyopathy. CKD and ischemic
cardiomyopathy share a number of major risk factors, including
hypertension and diabetes mellitus.3 Moreover, it has been
shown that kidney dysfunction per se is a risk factor for
developing HF both in middle-aged adults and in the elderly,4,5
and thus they are comorbidities present in a large portion of
patients. The term cardiorenal syndrome has been applied to the
presence or development of renal dysfunction in patients with
HF.6 In a study by de Silva et al7 of 1216 patients with chronic
stable HF, only 7% of the patients had an estimated glomerular
filtration rate of ⱖ90 mL/min, with 83% of the patients presenting with stage 2 or 3 CKD (glomerular filtration rate of 60 to
89 or 30 to 59 mL/min per 1.73 m2, respectively). CKD carries
a poor prognosis in these patients. It has been shown that the
glomerular filtration rate in patients with HF is the most
powerful predictor of mortality, exceeding functional status and
ejection fraction.8 Finally, as described below, many patients
admitted to the hospital for decompensated HF develop either de
ur understanding of the pathophysiology of heart failure
(HF) and the development of new therapeutic strategies
are rapidly evolving. It is now appreciated that HF and
chronic kidney disease (CKD) share a number of risk factors
and pathophysiological pathways (eg, activation of the reninangiotensin-aldosterone system [RAAS]) and have a causal
relationship (ie, the role of CKD as an independent cardiovascular risk factor). Indeed, by necessity, cardiologists have
become adept at the management of refractory volume
overload, complex diuretic regimens, dysnatremias, and hemodynamic causes of acute renal failure. In addition to
pharmacology advances, technology for extracorporeal ultrafiltration has been newly introduced and is advocated for use
by nonnephrologists. This represents a major paradigm shift
away from the traditional hemodialysis or peritoneal dialysis
(PD) modalities for fluid removal.
Despite practical and theoretical advantages of some of
these newer treatment strategies, some can potentially be
harmful to the patient. This is especially true in the case of the
mechanical pumped blood ultrafiltration devices that can
worsen renal function or be subject to potentially serious or
lethal complications. It is the purpose of this article to address
these concerns from a nephrologic perspective, highlighting
the pathophysiology and benefits of recent pharmacological
approaches, as well as detailing practical aspects and pitfalls
related to use of these extracorporeal ultrafiltration devices.
The different therapeutic tools (eg, aquaretics, diuretics,
From the Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville.
Correspondence to Edward A. Ross, MD, Division of Nephrology, Hypertension, and Transplantation, University of Florida, Box 100224, 1600 SW
Archer Rd, Room CG-98, Gainesville, FL 32610-0224. E-mail [email protected]
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.107.742270
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Circulation
February 19, 2008
Table 1. Principal Sites of Action for Potential Therapeutic
Options of HF
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Antidiuretic hormone receptor
antagonists
Nephron; V2 receptors at the inner
medullary collecting duct
Loop diuretics
Nephron; NaK2Cl cotransporter at
the luminal thick ascending limb
of the loop of Henle
Adenosine A1 receptor
antagonists*
Nephron; afferent arteriole,
glomerulus, proximal tubule, and
collecting ducts
Thiazides
Nephron; NaCl cotransporter at the
apical surface of distal convoluted
tubule
Aldosterone receptor blockers
Nephron; mineralocorticoid
receptor at the distal convoluted
tubule and cortical collecting duct
Natriuretic peptides
Nephron; multiple Locations
including
collecting duct
Extracorporeal ultrafiltration
Extracellular fluid; intravascular
compartment accessed via
peripheral or central venous
system
Peritoneal ultrafiltration
Extracellular fluid; intravascular
sector accessed via peritoneal
membrane capillaries
*Under development.
novo kidney dysfunction or worsening of their CKD secondary
to aggressive removal of fluid.9
Aquaretics
Release of antidiuretic hormone (ADH) increases in patients
with HF because of reduced activation of mechanoreceptors
located on the high-pressure side of the circulation.10 Two
types of ADH (or vasopressin) receptors have been identified:
V1 (V1a, V1b) and V2.11 ADH increases blood volume by
promoting free water retention through the V2 receptors in
renal cortical collecting ducts. It can also lead to vasoconstriction and possibly cardiac hypertrophy via V1a receptors.12 This
nonosmotic release of ADH, concurrent with activation of the
sympathetic nervous system (SNS) and RAAS, is thought to
represent a maladaptive response that is central to the pathophysiology of HF.10 ADH receptor antagonists (“aquaretics”)
were originally used for the correction of hyponatremia in the
context of syndromes of inappropriate ADH secretion or cirrhosis13,14 and are potentially capable of ameliorating fluid overload
in HF patients through excretion of electrolyte-free water.15
Compared with diuretics, ADH antagonists have the theoretical
advantage of correcting hyponatremia, an independent predictor
of mortality in patients with HF.15–17
The 2 most extensively investigated ADH antagonists are
conivaptan (a dual V1a/V2 receptor antagonist) and tolvaptan
(an oral, selective antagonist of the V2 receptor). Recently,
the results of the Efficacy of Vasopressin Antagonism in
Heart Failure Outcome Study With Tolvaptan (EVEREST)
trials in acute decompensated HF were published.18,19 These
large, randomized, double-blind, placebo-controlled studies
tested the benefit of tolvaptan in 3 clinical trials: 2 identical
short-term and 1 longer-term safety and outcome protocols.
The aggregate findings demonstrated that tolvaptan, used in
addition to standard therapy (including diuretics), relieved
certain symptoms without adverse affect on renal function19;
however, it did not decrease mortality or HF-related morbidity at 1 year.18 Hyponatremia, when present, was also improved.20 Although these studies showed modest symptomatic
relief with no major adverse effect, lack of a beneficial long-term
impact on mortality and morbidity makes it unlikely that ADH
antagonists will become a major or primary part of treatment
strategies in patients with decompensated HF in the near future.
Currently, only the intravenous formulation is available outside
the research setting, and hypotension is potentially problematic
because of blockade of the V1 receptor. If the V2-selective oral
forms of these medications become available in the United
States, it is possible that they will have a role as part of broader
treatment strategies.
Diuretics
Even though diuretics are the traditional mainstay of treatment for both chronic and acutely decompensated patients,
they are one of the few therapies for HF that have not been
subjected to a randomized, placebo-controlled trial.21 The optimal diuretic dose in either of these clinical situations has been
controversial. Although furosemide was reported to be safe at
doses as high as 4000 mg/d by some investigators in the past,
more recent studies recommend much lower ceiling doses
because of potential adverse effects.22,23 Practice patterns vary
substantially worldwide, and these drugs are being used by
clinicians at the upper dose ranges only when their benefits are
thought to outweigh the concern for ototoxicity.22 In general,
compared with normal individuals, patients with HF need higher
doses of loop diuretics to achieve a similar sodium excretion,
and the magnitude of the “maximal” response is attenuated.24
Resistance to diuretics is a potentially devastating phenomenon
and an independent predictor of mortality that can develop as HF
progresses.25 The definition of diuretic resistance has been
problematic and hinders interpretation of the older literature: The
natriuretic response to a loop diuretic such as furosemide can
theoretically be defined by relating the amount of the drug in the
urine to the sodium excretion in the same sample.26 However,
most clinical studies have used various diuretic doses (and/or
urine volumes) as indices of resistance.
An understanding of the kidney’s normal mechanisms of
adaptation to sodium losses has provided a physiological
basis for the development of diuretic resistance. The term
braking phenomenon applies to the long-term use of diuretics
and refers to a decline in the magnitude of natriuresis after
administration of sequential doses. The key concept is that the
nephron normally autoregulates to maintain sodium homeostasis. “Tubuloglomerular feedback” mechanisms exist
that attenuate natriuresis when an increase in tubular sodium
load is detected: Sodium clearance is thus reduced back to
baseline, and the person is thereby kept in sodium balance.
Unfortunately, a therapeutic increase in tubular sodium delivery induced by diuretics elicits these same counterbalancing autoregulatory responses, which are considered maladaptive in the case of HF. Specifically, the primary diuretic
response increases sodium delivery to the juxtaglomerular
Kazory and Ross
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apparatus, stimulates renin secretion, enhances the RAAS system, induces hypertrophy and hyperplasia of distal tubular cells,
and stimulates the efferent SNS.24 Consistent with a maladaptive
neurohumoral response to a pharmacological natriuresis, in
Studies of Left Ventricular Dysfunction (SOLVD), Domanski et
al27 found that the rates of hospitalization for HF, cardiovascular
mortality, and all-cause mortality were higher in patients taking
a diuretic than in those who were not. The increased absorption
of sodium by the distal tubules attenuates the effectiveness of the
medication. This can sometimes be overcome by altering the
diuretic regimen by (1) combining thiazide diuretics with loop
diuretics (to block increased distal sodium reabsorption), (2)
using higher (preferably intravenous) doses of loop diuretics,
and (3) using continuous diuretic infusions to avoid the phenomenon of postdiuretic salt retention.28 Importantly, a new class of
agents is under development that block the adenosine A1
receptors mainly in the afferent arteriole, in hopes of attenuating
the tubuloglomerular feedback mechanism and enhancing
diuresis.29,30
The proximal tubules also manifest an autoregulatory
increase in sodium reabsorption that can progressively become a major problem over time: With diminishing sodium
leaving the proximal nephron, loop diuretics lose their effectiveness. Thus, a benefit sometimes results from simultaneously using agents that act proximally even though in
normal situations they are considered weak diuretics. For
example, acetazolamide, a proximal tubule diuretic, might
partially restore the effectiveness of loop diuretics; however,
it should be used cautiously and briefly under close observation because long-term administration can lead to severe
bicarbonate losses and worsening metabolic acidosis.
The concept of proximal sodium avidity leading to decreased delivery to the distal (ie, collecting) tubules also
provides insight into the role of pharmacological mineralocorticoid blockade in the treatment of HF. In other (noncardiac) sodium-retaining, high-aldosterone disease processes,
ultimately a new equilibrium is reached when sodium retention results in an increased filtered load that exceeds the
absorptive capacity of the tubule. Importantly, this physiological “escape” from excess aldosterone does not occur in
patients with HF.10 Therefore, they continue to retain sodium
in response to aldosterone, and, indeed, use of receptor
antagonists (ie, spironolactone) is often followed by a substantial natriuresis in these patients.31 During the last decade,
there has also been a growing understanding of the adverse
effects of aldosterone beyond these tubular phenomena.
Through mechanisms different from its effects on epithelial
cell transport of sodium and potassium, aldosterone may
mediate hypertension and cardiac fibrosis.32,33 In patients
with HF, not only is the activity of the RAAS increased, but
the action of aldosterone is also more persistent.10 Consistent
with this pathophysiological process, evidence for pleiotropic
benefits of mineralocorticoid blockade is rapidly emerging. It
is now well known, for example, that spironolactone has
effects in nonepithelial tissues, including the heart, vasculature, and brain, that are independent of its action on renal
tubular cell ion transport.34 The analysis of SOLVD revealed
a significantly lower risk for hospitalization and/or death
from HF, cardiovascular mortality, and all-cause mortality
Nephrology-Oriented Management of CHF
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when a potassium-sparing diuretic was used alone or in
combination with a non–potassium-sparing diuretic.27 Spironolactone is now considered a mainstay of treatment in HF
patients. In the Randomized Aldactone Evaluation Study
(RALES), Pitt et al35 found that adding spironolactone to
standard therapy for HF led to a reduction in the risk of death,
decrease in the rate of hospitalization, and a significant
improvement of symptoms without increasing the risk of
hyperkalemia. Eplerenone is a novel agent that selectively
blocks the mineralocorticoid receptor and not those for
glucocorticoids, progesterone, or androgens.36 It has also
been shown to reduce morbidity and mortality in patients
with acute myocardial infarctions complicated by left ventricular dysfunction and HF.37 However, serious hyperkalemia (serum potassium ⱖ6.0 mmol/L) was not infrequent.
Although the beneficial effects of aldosterone blockade in HF
go far beyond the diuretic properties, hyperkalemia due to
impaired potassium excretion would be the main concern in
these patients. They frequently have concomitant treatment
using other medications with the potential side effect of
hyperkalemia (eg, angiotensin-converting enzyme inhibitors).
Natriuretic Peptides
The natriuretic peptide family includes atrial natriuretic
peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilantin. ANP and BNP are
secreted by the heart, CNP is secreted by the endothelium,
and urodilantin is synthesized in renal distal tubular
cells.38 – 40 ANP, BNP, and CNP induce vasodilation, increased urinary sodium and chloride excretion, and suppression of the RAAS and SNS.41 After luminal secretion,
urodilantin binds downstream to natriuretic peptide type-A
receptors in the inner medullary collecting duct, regulating
renal sodium and water excretion via intracellular increase in
cyclic guanosine monophosphate.42 Because sodium is the
major determinant of extracellular fluid volume, it was
suggested that these peptides might be useful in the management of acute decompensated HF. Nesiritide, a recombinant
form of human BNP, and ularitide, a synthetic form of
urodilantin, have been used in this setting.
The preliminary studies on nesiritide suggested its efficacy
and safety in the management of decompensated HF,43,44 and
it is the only drug specifically approved for this indication.21
Nesiritide has been shown to be associated with improved
postoperative renal function in the setting of coronary artery
bypass grafting with the use of cardiopulmonary bypass.45
However, other studies, including 2 meta-analyses, did not
confirm its safety46,47 or efficacy with regard to improvement
in renal function or urine output.48,49 Theoretically, nesiritide,
in contrast to loop diuretics, should improve renal hemodynamics through suppression of the RAAS and SNS; thus, no
adverse impact on kidney function was expected in patients
treated with nesiritide. However, worsening renal function
was observed more frequently in the nesiritide group,46 and it
was also associated with an increased mortality rate within 30
days after its administration.47 Additionally, a double-blind,
placebo-controlled, crossover study failed to show any improvement in glomerular filtration rate, effective renal plasma
flow, urine output, or sodium excretion with use of nesiritide.48
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February 19, 2008
Table 2. Proposed Advantages of Slow Ultrafiltration
Compared With Diuretics
More rapid removal of fluid and improvement in symptoms
Higher mass clearance of sodium
Decreased risk of electrolyte abnormality (eg, hypokalemia)
Lack of RAAS activation
Lack of neurohormonal (SNS) activation
Removal of proinflammatory cytokines (with potential restoration of
responsiveness to diuretics)
Shortened length of stay for HF-related hospitalizations
Decreased rate of readmissions for HF-related hospitalizations
Decreased risk of worsening renal function
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The Fusion I trial was the first study to evaluate the potential
clinical utility of outpatient intermittent nesiritide infusions in
patients with HF.50 It did not show any difference in renal
adverse events between 2 different regimens of nesiritide and
usual medical therapy alone.50 Fusion II is a multicenter,
randomized, double-blind, placebo-controlled trial designed to
further assess the safety, efficacy, and optimal dosing frequency
of outpatient nesiritide for patients with advanced HF.51 Published results are expected in late 2007.
In pilot studies, ularitide demonstrated beneficial effects in
decompensated HF with a stimulation of natriuresis and
reduction in the pulmonary capillary wedge pressure.52 A
decrease in blood pressure has been reported to be relatively
common in studies evaluating the safety and efficacy of
short-term infusion of ularitide.42,53 Although the preliminary
results of studies with ularitide are encouraging, because of
its numerous similarities to nesiritide, safety concerns
(mainly renal effects) should be evaluated carefully in a
randomized, double-blind, placebo-controlled study before its
widespread use can be recommended.
Extracorporeal Ultrafiltration
Isolated ultrafiltration is an area of recent great interest in the
nonpharmacological management of HF, especially because
of the marketing of small, relatively simple devices that are
dedicated to this purpose. Ultrafiltration has been used both in
the in-hospital setting of acute decompensated HF and as an
outpatient treatment of refractory HF.54,55 The main rationale
for its use in the acute setting would be rapid correction of
fluid overload when standard management (eg, high-dose
intravenous diuretics with or without inotrope agents) has
been unsuccessful.54
Of paramount importance in determining the role of extracorporeal ultrafiltration (with its attendant risks and expense) is
whether the claim of its superiority over fluid removal by
aggressive diuresis has a physiological basis. Currently, the
rationale for use of extracorporeal methodologies in the chronic
setting centers on 3 aspects: rapidity, avoidance of maladaptive
renal tubular autoregulatory responses, and magnitude of sodium
clearance (Table 2). Indeed, part of the logistical difficulty in
caring for HF patients is the slow pace of fluid removal during
diuretic titrations, which can often greatly prolong hospitalizations. Faster fluid removal might theoretically reduce the risk of
further clinical decompensation, cardiac ischemia, arrhythmias,
or need for intensive care unit monitoring. In addition, a
cost-benefit analysis for hospital resource utilization might in
some cases rationalize the use of expensive ultrafiltration devices by virtue of reducing the hospital length of stay. A more
cogent approach to justifying ultrafiltration would be based on
the underlying physiology: Although not fully investigated,
sodium removal by ultrafiltration may be fundamentally different from, and superior to, diuretic therapies by avoiding enhanced sodium delivery to the distal nephron. Hypothetically,
this would prevent the tubuloglomerular feedback mechanisms
that lead to maladaptive diuretic resistance, stimulation of the
RAAS, and activation of the SNS.24 Furthermore, for similar
volumes of fluid removal, ultrafiltration removes more total
body sodium (the main determinant of extracellular fluid volume) than do diuretics.56 Urine produced by diuretics is hypotonic compared with plasma, whereas ultrafiltrate is isonatremic
and iso-osmolar.57 Finally, by choosing a hemofilter with an
appropriately high sieving coefficient, the extracorporeal device
designed for ultrafiltration can simultaneously clear through
convection (ie, by hemofiltration) large molecules that may be
biologically active and have an adverse role in the pathophysiology of HF. For example, high-flux membranes can clear
moieties in the size range of cytokines, and there could be a
theoretical benefit, for example, from removing certain interleukins or tumor necrosis factors.
Although the concept of using ultrafiltration in the management of HF is supported by the aforementioned hypotheses, the long-term outcome of this therapeutic modality has
not been explored extensively. It is not yet clear if this
therapy can be considered an efficient and safe part of the
standard treatment for refractory HF. Although studies tend to
show beneficial effects of this therapy, the majority of them
have included highly selected small numbers of patients with
a relatively short follow-up of 30 to 90 days without a control
group.54,55,58 – 60 The results of the first large-scale randomized
study designed to assess the benefits and safety of ultrafiltration for the management of HF (the Ultrafiltration Versus IV
Diuretics for Patients Hospitalized for Acute Decompensated
Congestive Heart Failure [UNLOAD] trial) was recently
published.61 In this multicenter study, patients hospitalized
for decompensated HF were randomized to receive standard
care (ie, intravenous diuretics) or ultrafiltration therapy. The
ultrafiltration group showed a greater fluid loss at 48 hours
compared with the diuretic group, without a change in serum
creatinine or blood pressure. During the 90-day follow-up
period, the ultrafiltration patients had reduced rates of rehospitalization and unscheduled visits. We have previously
discussed potential methodological shortcomings of this
study.62 In brief, the study population seemed to be more
stable than typical decompensated HF patients. Because
hemodynamic instability is a potential complication of ultrafiltration therapy, selection of a more stable population might
have acted in favor of this modality. Furthermore, the 2
groups were not controlled for the total amount of volume
loss at the end of treatment. Therefore, the beneficial effects
of ultrafiltration in the reduction of rate of rehospitalization
might, at least in part, be the reflection of a greater volume
loss in this group.
Kazory and Ross
Table 3. Potential Complications of Extracorporeal Pumped
Ultrafiltration Machines
Air embolus
Hemorrhage from venous return disconnection
Hemorrhage from hollow fiber blood leak
Hemorrhage complicating systemic anticoagulation
Nephrology-Oriented Management of CHF
979
in the venous tubing “return” pressure, and this methodology
can be unreliable in these slow-flow low-pressure systems.
Although an added safety margin is present at low blood
pump speeds, undetected hemorrhage remains a real concern
with these machines. We are developing alternative electrically based detection technology to overcome these shortcomings, but it is not yet commercially available.66
Membrane bioincompatibility
Hemolysis and hyperkalemia
Hemolysis
Catheter-related complications (ie, infections, stenoses, thromboses)
Tubing that is defective or mismatched for the rotating pump
head assembly can cause hemolysis and potentially severe
hyperkalemia. The risk of this occurring with improved
technology and low ultrafiltration pump speeds is rare but
never totally eliminated.
Excess ultrafiltration resulting in hypotension, prerenal azotemia, or acute
renal failure
Allergic reactions to the extracorporeal circuit
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Overall, because of lack of strong clinical evidence supporting the advantage of costly ultrafiltration techniques, this
modality has not yet gained widespread use. We believe,
however, that the aforementioned hypothetical advantages of
ultrafiltration will prompt more frequent use of this technique
and that nonnephrologist clinicians need to be aware of the
potential risks inherent to these extracorporeal pumped blood
technologies (Table 3). One obvious potential hazard well
recognized in the renal literature is overly aggressive fluid
removal, which can lead to decreased effective blood volume,
hypotension, renal hypoperfusion, prerenal azotemia, and
possibly acute renal failure necessitating dialysis. Central to
this pathophysiology is whether a mismatch exists between
the ultrafiltration rate and the plasma refill rate. Indeed, it has
been suggested that the plasma refill rate can be used to guide
the rate of volume extraction in patients with HF undergoing
ultrafiltration to avoid inadequate decongestion.63 We have
previously described64 how rapid ultrafiltration can exceed
the plasma refill rate, leading to quantifiable hemoconcentration and acute intravascular volume depletion.
Other than excessively high ultrafiltration rates, a number
of other safety issues with these machines are in part shared
by traditional dialysis and hemofiltration devices, which are
discussed below.65
Air Emboli
Of great concern for any pumped blood technology is the risk
of air embolus. Air typically enters the extracorporeal circuit
on the prepump side of the tubing set because of the negative
(vacuum) pressure at that location. Because even small
amounts of an air embolus can have disastrous or lethal
effects, these machines are required to have air detectors and
circuitry to immediately stop the pump and clamp the tubing.
Nevertheless, despite the sophistication of the sensors, none
are foolproof, and this exceedingly rare complication must
remain an ongoing concern for the nursing staff and any
practitioner offering these treatments.
Bioincompatibility
Compared with older technologies, ultrafiltration devices that
use synthetic polymers have superb biocompatibility and
have virtually eliminated the alternative complement activation problem of cytokine release, fever, bronchospasm, and
hypotension. However, polyacrylonitrile membranes (which
are currently used in hemofilters because of their excellent
ultrafiltration characteristics) can cause profound hypotension due to bradykinin activation in patients on angiotensinconverting enzyme inhibitors. These medications must be
discontinued before the use of ultrafiltration treatments or
alternative membranes (such as polysulfone).65
Allergic Reactions
There can rarely be immunoglobulin E–-related reactions (ie,
hypotension, bronchospasm) to the ethylene oxide sterilant
used in some dialyzers and tubing sets. This problem can be
prevented by extensive rinsing of the extracorporeal circuit,
or it can be totally eliminated by choosing components that
have undergone alternative methods of sterilization (eg,
gamma irradiation).
Blood Leaks Within the Hemofilter
Damage in shipping or handling to the hollow fibers within
the hemofilters can lead to blood leaks into the ultrafiltrate.
The risk of hemorrhage has been minimized by sensitive
blood-leak detectors in the ultrafiltration tubing pathway.
Ultrafiltration Rate Calibration Problems
Inadvertently high ultrafiltration rates have historically been a
major concern in renal replacement and volume-removal technologies, especially with modern high-flux hemofilters that yield
large amounts of ultrafiltration from small pressure gradients.
Machine errors causing excess fluid removal still rarely occur
despite the technological advances of “volumetrically” controlled ultrafiltration (ie, sealed fluid-filled balancing chambers),
redundant scales weighing the ultrafiltrated fluid, and protocols
necessitating manual machine calibration.
Venous Disconnection and Blood Leak
Vascular Access–Related Problems
Even with low blood pump rates, an undetected disconnection
of the return (venous) blood line can cause severe hemorrhage. This is a well-recognized complication65 that can occur
when the venous needle dislodges or tubing connections
loosen. Current technology detects disconnections by a drop
Newer ultrafiltration-dedicated machines are appealing in
that some have blood flow rates low enough (⬍50 mL/min)
to use small-caliber needles in peripheral veins. However, a
substantial portion of these HF patients will not have veins
appropriate or durable for these therapies and will need
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February 19, 2008
dual-lumen central venous catheters. The risk of local or
systemic infections with the use of these devices has been
problematic in chronic hemodialysis patients, and the epidemiology of complications such as bacteremia, endocarditis,
and death has been well described.67
Machine Design Considerations
Most traditional renal replacement devices have limitations
that make them problematic for slow ultrafiltration in HF
patients: high blood flow rates, bulky nonportable enclosures,
and nonintuitive interfaces designed for highly experienced
dialysis staff. Recently marketed machines have great appeal
because of their small size, simplicity of their single-purpose
design, and intentionally restricted flow rates that force slow
therapy, minimize safety concerns, and reduce annoying
false-alarm messages.
Peritoneal Ultrafiltration
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Lessons learned from the use of PD in end-stage renal disease
have been useful in the design of peritoneal ultrafiltration
protocols for the treatment of HF. In the 3-pore model of
peritoneal transport, water can leave plasma and reach the
peritoneal cavity through both ultrasmall transcellular channels (aquaporins) and small pores. This shift of water from
peritoneal capillaries toward peritoneal cavity (transcapillary
ultrafiltration) occurs at a rate dependent on the osmotic
force, which in turn can be modified by dextrose concentration in the instilled dialysate.68 The shift is highest at the
beginning of the dwell and progressively declines as the
osmotic force decreases. Interestingly, sodium sieving occurs
over the first hour after instillation of PD solution in the
peritoneal cavity; the rapid shift of water through aquaporins
(without any solute) results in a decrease in the concentration
of sodium in dialysate.69 High ultrafiltration rates induced by
PD can thereby lead to an increase in serum sodium levels
through this mechanism. However, during the whole period
of dwell, sodium as well as other small solutes also pass
through the small pores and enter the peritoneal cavity.69
Therefore, if peritoneal ultrafiltration is used for removal of
water and sodium, the dwell time should theoretically be
short enough to exploit the high transcapillary ultrafiltration
early on to maximize water removal, but long enough to
allow the removal of a sufficient amount of sodium as well.70
In clinical practice, the feasibility of efficient fluid removal
by peritoneal ultrafiltration has been shown by several studies.71 In a case report by Maxwell et al,72 up to 1063 mL/h of
ultrafiltration was achieved with the use of this technique.
The present data, however, are limited to small observational
studies and cases without a control group. Indeed, no evidence exists to suggest the superiority of inpatient peritoneal
ultrafiltration over high-dose intravenous diuretics or extracorporeal ultrafiltration in the context of decompensated HF
and acute volume overload. Practical considerations also exist
relative to the emergent placement of a PD catheter followed
by its immediate use. Apart from the cost of laparoscopic
catheter positioning, early initiation of PD with either temporary or tunneled devices can be associated with dialysate
leaks and the risk of bacterial peritoneal infection. Thus, at
present, peritoneal ultrafiltration cannot be recommended as
first-line therapy for management of acute volume overload
and decompensated HF.
A similar paucity of evidence exists supporting the use of PD
in the setting of chronic stable HF in patients without end-stage
renal disease, limited to case reports and small studies. Overall,
most of these investigations point to a reduction in rehospitalization rate and improvement in functional capacity.70 For
example, Gotloib et al73 reported 20 patients with severe HF
refractory to optimal pharmacological therapy. They were initially treated by 2 to 5 sessions of venovenous hemofiltration,
followed by the initiation of automated PD (3 sessions per
week). After 1 year, all patients showed improvement in cardiac
index, thoracic fluid content, New York Heart Association
functional class, and rehospitalization rate.
Although the use of PD to treat HF in patients with
end-stage renal disease is conceptually appealing, the data are
insufficient and contradictory. A study by Takane et al74 of 16
patients with HF newly started on PD showed benefits in term
of lowering systolic blood pressure, an increase in ejection
fraction, and improved functional status. However, a retrospective study by Stack et al75 using data from the Center for
Medicare and Medicaid Services found that new end-stage
renal disease patients with a history of HF experienced poorer
survival when treated with PD compared with hemodialysis.
This and other studies that compare hemodialysis and PD
results need to be interpreted cautiously because these investigations are subject to selection bias, may not have the
appropriate control group, and often are retrospective in
design. Clearly, a large-scale randomized trial is needed to
evaluate the efficacy and safety of PD in the setting of chronic
stable diuretic-resistant HF.
Therapeutic Effects Beyond Fluid Removal
Although current therapeutic options discussed in this review for
HF (pharmacological and nonpharmacological) are mainly
aimed at removal of excess water and sodium in these patients,
it has been suggested that nonpharmacological modalities (ie,
ultrafiltration and PD) might also have other beneficial effects
beyond fluid volume removal. Indeed, one of the potential
benefits of these therapies might be a reflection of avoiding
adverse renal effects of high-dose diuretics, namely, increased
RAAS stimulation and activation of SNS.24 It has been shown
that in cirrhotic patients with increased SNS activity, similar to
HF patients, the addition of clonidine, a centrally acting sympatholytic agent, decreases diuretic dose requirements and enhances diuretic responsiveness.76 Ultrafiltration has also been
suggested to partially reverse the pathophysiological process of
HF by removal of inflammatory cytokines and readjustment of
neurohormonal pathways, with subsequent restoration of responsiveness to diuretics (see below).77 In addition, some authors
have stressed the benefits of cytokine removal compared with
the simple removal of fluid. In a recent study by Libetta et al60
on 10 patients with decompensated heart failure, the authors
found a reduction in circulating proinflammatory cytokines
(interleukin-8 and monocyte chemotactic protein-1) only in
patients treated by intermittent hemodiafiltration compared with
intravenous diuretic therapy alone. The authors concluded that
intermittent hemodiafiltration is effective in removal of proinflammatory cytokines and might therefore improve myocardial
Kazory and Ross
function and chronic vascular inflammation. We have previously
described the shortcomings of this study.78 Overall, the mass
clearance of these compounds is low; they have short half-life
periods and can rapidly reappear in the plasma. Convective
clearance is nonspecific in that beneficial cytokines are lost
along with the potentially harmful ones, with no change in the
source of inflammatory process. In regard to PD, the molecular
weight of myocardial depressant factors ranges between 0.5 and
20 to 30 kDa.79 The ANP chain is composed of 17 to 28 amino
acids, and the molecular weight of tumor necrosis factor-␣ is
⬇17 kDa. It has been shown that ANP and tumor necrosis
factor-␣ have transperitoneal clearance.80,81 It seems likely that
myocardial depressant factors are also removed by PD, but this
remains to be proven.
On the basis of these data, although it seems plausible that
extracorporeal ultrafiltration and PD play a therapeutic role in
HF beyond their removal of extracellular fluid, future studies
are clearly needed to further investigate this issue.
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Optimal Hemoglobin Target
Outside the scope of this review are various other diagnostic
and therapeutic considerations typically in the purview of
nephrology consultation. These include issues of renal artery
stenosis inducing either kidney hypoperfusion or episodes of
“flash” pulmonary edema, progression of underlying CKD,
changes in vascular and tissue oncotic pressures due to
protein-losing nephropathies, drug metabolism, and pharmacological approaches to minimize the cardiorenal syndrome.
Anemia management, however, is of cardinal importance and
is a topic that has merited special attention in the fields of
both nephrology and cardiology.
Anemia is prevalent in both HF and CKD82,83 and is
associated with worse outcomes in both diseases. Unlike most
other comorbidities (eg, diabetes mellitus, hypertension, and
obesity), management strategies for correction of anemia are
quite divergent between CKD and HF. Although anemia is
known to be associated with increased mortality and morbidity in HF patients,84 studies that focus on correction of anemia
in these patients have reported contradictory results. Some
authors have found that correction of anemia with erythropoietin improves functional capacity, quality of life, exercise
tolerance, and renal function.85,86 However, a recent randomized, double-blind, placebo-controlled study failed to show
any significant change in exercise tolerance, functional status,
plasma BNP levels, or hospitalization rate.87 On the other
hand, in patients with CKD, no major randomized controlled
trial has thus far shown a significant reduction in cardiovascular events or death by targeting a hemoglobin level of ⬎12
g/dL.88 In fact, a randomized trial in dialysis patients was
stopped early after an interim analysis because of a significantly higher mortality rate in the group with a normal target
hemoglobin level (14 g/dL).89 Furthermore, 2 randomized
controlled trials recently confirmed that CKD patients with
lower hemoglobin levels present a lower mortality rate.90,91
On the basis of currently available data, a target hemoglobin
level of 10 to 12 g/dL for CKD patients has been recommended by the US Food and Drug Administration.92
Because HF and CKD coexist in a great number of
patients, studies on anemia correction in CKD patients have
Nephrology-Oriented Management of CHF
981
inevitably included patients with HF. However, no randomized clinical trial has specifically addressed the optimal
hemoglobin level in CKD patients with HF. Therefore, the
optimal hemoglobin levels in HF patients with CKD are not
known, and it seems prudent, for now, to treat these patients
in a manner similar to that used in the general CKD
population and to avoid complete correction of anemia.
Conclusion
In summary, studies of new pharmacological agents for the
management of refractory HF have thus far been associated with
either limited or controversial results. Further large randomized
controlled trials are clearly needed before these agents can be
recommended for routine use in these patients. In the meantime,
extracorporeal ultrafiltration could be employed cautiously as an
adjunct therapy only in highly selected and hemodynamically
stable patients when other less invasive options have been
ineffective. Although the proposed superiority of fluid removal
by extracorporeal devices has a potential physiological basis,
close follow-up for potential adverse effects, including worsening kidney function, is warranted in these patients. Although
available data are insufficient, PD shows a theoretical and
practical potential in this setting. The extensive experience and
literature in nephrology can be helpful in developing a risk-tobenefit analysis and strategy for implementing these ultrafiltration methods because they are associated with potential adverse
effects.
Disclosures
None.
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Contemporary Trends in the Pharmacological and Extracorporeal Management of Heart
Failure: A Nephrologic Perspective
Amir Kazory and Edward A. Ross
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Circulation. 2008;117:975-983
doi: 10.1161/CIRCULATIONAHA.107.742270
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