diuretic response and renal function in heart failure
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University of Groningen
Diuretic response and renal function in heart failureter Maaten, Jozine Magdalena
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2 Diuretic response in acute heart failure – pathophysiology, evaluation and therapy
Jozine M. ter Maaten, Mattia A.E. Valente, Kevin Damman, Hans L. Hillege, Gerjan Navis, and Adriaan A. Voors
Nature Reviews Cardiology 2015;12(3):184-192
20 Chapter 2
absTracT
The administration of loop diuretics to achieve decongestion is the cornerstone of therapy
for acute heart failure. Unfortunately, impaired response to diuretics is common in these
patients and associated with adverse outcomes. Diuretic resistance is thought to result from
a complex interplay between cardiac and renal dysfunction and specific renal adaptation
and escape mechanisms, such as neurohormonal activation and the braking phenomenon.
However, our understanding of diuretic response in patients with acute heart failure is still
limited and a uniform definition is lacking. Three objective methods to evaluate diuretic
response have been introduced, which all suggest that diuretic response should be de-
termined based on the effect of diuretic dose administered. Several strategies have been
proposed to overcome diuretic resistance, including combination therapy and ultrafiltra-
tion, but prospective studies in patients who are truly unresponsive to diuretics are lacking.
An enhanced understanding of diuretic response should ultimately lead to an improved,
individualized approach to treating patients with acute heart failure.
Diuretic response in acute heart failure 21
2
inTroDucTion
Acute heart failure is one of the leading causes of hospital admission worldwide, and is
associated with high morbidity, mortality, and rehospitalization.1,2 Most of the symptoms as-
sociated with acute heart failure are the result of excessive fluid retention, and loop diuretics
are the treatment of choice to combat them. Loop diuretics are administered in up to 90%
of patients hospitalized for acute heart failure, despite the lack of evidence for outcome
benefit.2,3 Poor response to diuretic therapy (that is, persistent signs and symptoms despite
increasing doses of diuretic drug, known as diuretic resistance) frequently occurs in patients
during hospitalization for acute heart failure, although the exact frequency is unknown
owing to the lack of a standard definition.4 In two studies from 2014, a poor response to
diuretics was more frequently found in patients with diabetes mellitus, reduced glomerular
filtration rate (GFR) and high blood urea nitrogen levels, or low systolic blood pressure.5,6
Importantly, a poor diuretic response was independently associated with impaired symp-
tom relief, a higher risk of in-hospital worsening of heart failure, increased mortality after
discharge from hospital, and a threefold higher rate of rehospitalization, compared with
patients with a good diuretic response. Moreover, an improved definition and quantification
of diuretic response to loop diuretics has been called for by some clinicians.7 However, the
pathophysiology behind diuretic resistance is not completely understood, and thought to
result from the complex interplay between cardiac and renal dysfunction, specific renal
adaptation, and escape mechanisms, such as the braking phenomenon.4 In this Review,
we describe the pathophysiological background of diuretic resistance, the evaluation and
definition of diuretic response, as well as current and future strategies to improve diuretic
response in patients with acute heart failure.
PaThoPhysiology
The cardiorenal systemThe heart and kidney function together to regulate circulatory homeostasis via several
mechanisms and feedback loops. In healthy individuals, glomerular filtration remains stable
despite changes in volume and blood pressure. When triggered by sodium and volume
overload, a rise in atrial pressure and release of natriuretic peptides facilitates renal sodium
excretion via direct tubular effects and an increase in glomerular filtration rate.8–10 Con-
comitant suppression of the renin–angiotensin–aldosterone system (RAAS) contributes to
stable blood pressure via systemic vasodilatation and renal sodium excretion by inhibiting
the tubular effects of angiotensin II and aldosterone.11 Conversely, in a volume depleted
state, increased RAAS activity contributes to the maintenance of blood pressure and renal
sodium retention.11 Furthermore, angiotensin II induces renal efferent vasoconstriction,
22 Chapter 2
helping to maintain renal filtration pressure and filtration rate despite decreasing arterial
pressure.12 Activation of the sympathetic nervous system has a similar effect as, and is in
part stimulated by, the RAAS.12 Moreover, the interaction of the cardiorenal system affects
osmoregulation via effects on water diuresis. Under normal physiological conditions, the
release of arginine vasopressin (an antidiuretic hormone) is stimulated by a high plasma
osmolarity, which leads to renal water retention and restores normal osmolarity.13 However,
during pronounced water volume disturbances, responses to volume depletion or overload
can overcome the osmotic triggers, contributing to restoration of volume status at the
expense of osmoregulation.11
In patients with acute heart failure, a decrease in cardiac function causes reduced cardiac
output and arterial underfilling, leading to decreased activation of arterial stretch recep-
tors and resulting in compensatory systemic and intrarenal vasoconstriction.12 Decreased
stretch of the glomerular afferent arteriole stimulates renin release, which leads to angio-
tensin II production. Angiotensin II release leads to afferent and efferent vasoconstriction,
stimulation of sodium retention in the proximal tubule, and release of aldosterone.14 In turn,
aldosterone increases sodium reabsorption in the collecting duct, resulting in extracellular
fluid expansion and systemic congestion.15 In healthy individuals sodium delivery to distal
renal tubules by increased vascular volume overcomes the sodium retaining effect of
aldosterone (known as an aldosterone escape mechanism).16 This mechanism is impaired
in patients with acute heart failure, in whom reduced renal blood flow forces continued
sodium retention in response to aldosterone.12,16
Heart failure also results in baroreceptor-mediated sympathetic nervous system activa-
tion that promotes vasoconstriction and contributes to further RAAS activation and renal
sodium and water retention.17 The release of antidiuretic hormone exacerbates these ef-
fects.18 Furthermore, the protective effect of natriuretic peptides is diminished in patients
with acute heart failure due to renal vasoconstriction, reduced sodium delivery, fewer active
forms of natriuretic peptides, and downregulation of their receptors.19,20 In addition, adenos-
ine (released in response to increased renal work load and high sodium concentration in the
distal tubule) further reduces renal blood flow, stimulates proximal sodium reabsorption
and through tubuloglomerular feedback further decreases GFR via the adenosine A1 recep-
tor.21 In contrast to the adenosine A1 receptor, activation of the adenosine A2 receptor can
increase renin secretion.21 The combination of these pathways creates a vicious circle that
leads to further congestion and worsening heart failure.
A major symptom of heart failure is decreased organ perfusion.1 The kidney can com-
pensate for a drop in renal blood flow by increasing the filtration fraction via angioten-
sin II-mediated efferent vasoconstriction and thereby preserve GFR.22 The combination
of pump failure, neurohormonal activation, and therapies for heart failure, particularly
angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers, can eventu-
ally overcome the kidney’s capacity to compensate for reduced perfusion.23,24 Additionally,
Diuretic response in acute heart failure 23
2
increased venous filling and abdominal pressures owing to ascites can increase renal af-
terload and intrarenal pressure, reduce the transrenal perfusion gradient (and thus renal
perfusion pressure), increase renal interstitial pressure (directly opposing filtration pressure),
and further contribute to renal insufficiency.25–27
Mechanisms of diuretic resistanceDiuretics are the first-line therapy for volume overload and aim to establish a negative
sodium and consequently fluid balance. Poor response to diuretics is an important clinical
problem in patients with acute heart failure and its underlying pathophysiological mecha-
nisms are diverse.2,4
Regulation of renal sodium excretion involves several sequential transport mechanisms in
the renal tubule.28 Diuretics act on specific sodium transport mechanisms, and are classified
based on their tubular site of action (Figure 1). Acetazolamide and mannitol act on the
proximal tubule, where up to two-thirds of the sodium load is filtered under physiological
Figure 1. Diuretic therapy(1) Acetazolamide function in the proximal tubule by blocking carbonic anhydrase an decreasing NaHCO3 ex-cretion. (2) Mannitol functions in both the proximal tubule and the loop of Henle by increasing H2O excretion. (3) Loop diuretics function in thick ascending limb of the loop of Henle by blocking the sodium-chloride-potas-sium cotransporter and increasing sodium, potassium, and chloride excretion. (4) Thiazide functions in the distal convoluted tubule by blocking the sodium-chloride transporter and increasing sodium chloride excretion. (5) Mineralocorticoid-receptor antagonists function in the collecting duct of the distal tubule and antagonize the aldosterone receptor, hence increasing sodium excretion and potassium retention.
24 Chapter 2
conditions.29,30 Acetazolamide stimulates alkaline diuresis via bicarbonate excretion with
sodium and potassium by inhibiting carbonic anhydrase in the proximal tubule.29 Mannitol
is an osmotic diuretic that acts primarily on the loop of Henle and the proximal tubule by
increasing the osmotic pressure of glomerular filtrate, thus inhibiting tubular reabsorption.30
Loop diuretics inhibit solute carrier family 12 member 1 (a sodium–chloride–potassium co-
transporter) in the thick ascending limb of the loop of Henle, leading to decreased sodium
and chloride reabsorption from the urine.28 Thiazide diuretics act on the distal convoluted
tubule by blocking the sodium–chloride transporter in the distal tubule.28 Metolazone is a
thiazide-like diuretic that exerts its effect in the distal tubule by inhibiting the reabsorption
of sodium and chloride ions.31 Mineralocorticoid-receptor antagonists (MRAs; also known
as aldosterone antagonists) act on the collecting duct by competitively antagonizing the
mineralocorticoid receptor, thereby reducing sodium reabsorption.28
Delivery of diuretics to the site of action relies on several mechanisms (Figure 2). First,
orally administered diuretics first must be absorbed in the gut to enter the bloodstream. In
the presence of gastrointestinal oedema or gut hypoperfusion, absorption of orally admin-
istered diuretics is impaired, and might differ substantially between diuretics.32 For example,
Figure 2. Mechanisms of loop diuretic resistancePatients who are resistant to loop diuretics might have reduced absorption of the drug in the intestine, reduced filtration, or increased proximal or distal sodium reabsorption in the kidney, or reduced drug availability in the tubule. Abbreviations: CO, cardiac output; CVP, central venous pressure; GFR, glomerular filtration rate; OAT, organic anion transporter; RAAS, renin-angiotensin-aldosterone system; RBF, renal blood flow; SNS, sympathetic nervous system.
Diuretic response in acute heart failure 25
2
absorption of bumetanide and torsamide is likely to be better than that of furosemide under
these conditions.32,33 Intravenous administration can overcome impaired absorption of orally
administered diuretics. In patients with renal insufficiency or heart failure, a higher diuretic
dose is required to achieve the same effects and, over time, increasing diuretic doses will
become less effective.4
Second, most loop diuretics (although interestingly bumetanide less so, because it can
bind to plasma globulins), thiazide diuretics, metolazone, and acetazolamide are bound
to plasma albumin.34,35 These diuretics act on their molecular target from the luminal side.
Consequently, these drugs must be filtered by the glomerulus and actively secreted into
the tubular lumen by the proximal tubule’s organic anion transporter in order to function.34
Hypoalbuminaemia, which is common in patients with heart failure, impairs the uptake
and secretion of active furosemide and enhances conversion to its inactive form.36,37 Ad-
ditionally, albumin lost into the tubule might bind furosemide and prevent it from acting
on the sodium–chloride–potassium co-transporter.38,39 Coadministration of albumin and
furosemide improves diuretic response in patients with cirrhosis, nephrotic syndrome, or
chronic kidney disease, but no data are available in individuals with heart failure.40–42
Third, patients with heart failure and chronic renal dysfunction have elevated levels of
circulating organic acids, such as blood urea nitrogen, which competitively inhibit the or-
ganic anion transporter and further reduce diuretic availability at the site of action.43,44 RAAS
and sympathetic nervous system activation lead to flow-dependent passive resorption of
urea in the distal tubule; a concentration gradient created by increased sodium and water
resorption in the proximal tubule results in diminished distal flow and increased reabsorp-
tion.45,46 High circulating blood urea nitrogen levels, therefore, not only contribute directly
to diuretic resistance, but also reflect a kidney that is actively working to retain sodium and
water. Consequently, in patients with heart failure, impaired absorption, decreased renal
blood flow, azotaemia, hypoalbuminaemia, and proteinuria (resulting in reduced levels of
active diuretics in the tubular lumen) might affect diuretic effectiveness.
At the onset of diuretic treatment, the natriuretic effect results in the intended nega-
tive sodium balance. The resulting decrease in extracellular volume triggers a homeostatic
response, mediated by activation of the RAAS and sympathetic nervous system, leading to
increased sodium retention at tubular sites not targeted by the specific diuretic.47,48 After
several days, this homeostatic response counterbalances the diuretic effect of the drug,
balancing sodium excretion and intake, and creating a new steady state with a lower
extracellular volume.47 This braking phenomenon is an appropriate homeostatic response
that prevents excessive volume depletion during continued diuretic therapy. However, in
patients with pre-existent secondary hyperaldosteronism, such as those with heart failure,
this phenomenon can be pronounced, causing rapid and abundant sodium reabsorption
and contributing to diuretic resistance.49 Furthermore, persistent delivery of sodium or di-
uretics to the distal tubule leads to hypertrophy of the distal tubular cells,50 which bypasses
26 Chapter 2
the proximal effect of the loop diuretic and results in enhanced sodium retention. Other
noncardiac mechanisms resulting in a diminished response to diuretics, including reduced
renal blood flow caused by renal artery stenosis or drug interactions, should also be consid-
ered when administering loop diuretics to patients.28
evaluaTing DiureTic resPonse
No single accepted definition of diuretic resistance has been described. Of the several
definitions proposed, the most frequently cited is ‘failure to decongest despite adequate
and escalating doses of diuretics’.4 Less clinically applicable definitions that include variables
not routinely obtained by clinicians have also been suggested (Box 1).
Box 1: Definitions of diuretic resistance
Persistent congestion despite adequate and escalating doses of diuretic with >80 mg furosemide per day107
Amount of sodium excreted as a percentage of filtered load <0.2%108
Failure to excrete at least 90 mmol of sodium within 72 h of a 160 mg oral furosemide dose given twice daily109
In our experience, unresponsiveness to diuretic therapy leading to persistent signs and
symptoms of congestion is usually considered diuretic resistance. Three objective methods
to evaluate diuretic response have been introduced (Box 2).
Box 2: Metrics of diuretic response
Weight loss per unit of 40 mg furosemide (or equivalent)5,51
Net fluid loss per milligram of loop diuretic (40 mg of furosemide or equivalent) during hospitalization6
Natriuretic response to furosemide as the ratio of urinary sodium to urinary furosemide52
These measures suggest that diuretic response should be determined based on the effect
of diuretic dose administered.
Some investigators have tried to determine a quantitative measure of diuretic response,
combining decongestive effect and diuretic dose.5 In this study, diuretic response was de-
fined as weight loss from admission to day 4 per 40 mg furosemide (or equivalent). A poor
diuretic response independently predicted heart failure rehospitalization (HR 1.58, 95% CI
1.24–2.01, P <0.001) and mortality (HR 1.73, 95% CI 1.40–2.12, P <0.001).5 This metric was
investigated in the RELAX-AHF trial,51 which confirmed these findings (60-day cardiovas-
cular death or heart failure rehospitalization: HR 1.86, 95% CI 1.20–2.88, P <0.001). Using
weight change per unit of furosemide might provide an applicable metric to confirm that
a patient is resistant to diuretics. Other investigators have used a similar metric to define
diuretic response (termed ‘diuretic efficiency’) defined as net fluid loss per milligram of loop
diuretic (40 mg of furosemide or equivalent) during hospitalization for acute heart failure,
Diuretic response in acute heart failure 27
2
dichotomizing above and below the median.6 Consistent with the results of other inves-
tigators, low diuretic efficiency was associated with worse long-term outcomes (HR 1.39,
95% CI 1.08–1.77, P = 0.007; HR 2.86, 95% CI 1.52–5.36, P <0.0016). In both studies, poor
diuretic response or efficiency was associated with renal impairment and higher blood urea
nitrogen levels.5,6 However, diuretic response is not only a reflection of renal impairment,
and poor diuretic response was also associated with more advanced heart failure, diabetes,
and atherosclerotic disease.
Finally, a ratio of urinary sodium to urinary furosemide measured in spot urine samples
was also examined.52 A poor response (<2 mmol/mg) was associated with impaired clinical
outcomes (including death, cardiac transplantation, or rehospitalization owing to heart fail-
ure), which were independent of renal function, in patients with acute heart failure (HR 1.62,
95% CI 1.13–2.39, P = 0.008).52 Haemoconcentration has also been suggested as a practical
and readily applicable strategy to assess diuretic response.53 The use of urinary sodium and
chloride in patients with heart failure to assess decongestion has also been investigated.54
Decongestion was associated with reduced urinary sodium and chloride excretion per
bumetanide dose. Given that urine measurements are not common practice in cardiology,
this metric might be less applicable than other metrics, which are easier to obtain and so far
have provided similar results to urine measurements. Ultimately, after extensive validation
and investigation, the use of such metrics of diuretic response could be used to help to
identify patients who might benefit from alternative decongestive therapies and to guide
treatment selection.
TreaTmenT of PaTienTs
Several treatment strategies have been proposed to overcome diuretic resistance. An ap-
proach to treat patients with acute heart failure who are also diuretic resistant is shown in
Figure 3. Overall, we believe in an integrated, patient-tailored approach to improving bio-
logical availability of the drugs and counteracting maladaptive responses in patients who
are diuretic resistant, which can be attempted using stepped pharmacological therapies,
novel drugs, or mechanical fluid removal. Recommendations and scientific evidence for all
the treatment options described below are presented in Table 1. Firstly, patient noncompli-
ance to therapy should be ruled out by verifying mediation intake and sodium restriction.4
Secondly, nonsteroidal inflammatory drugs should be discontinued, because they poten-
tially lead to diuretic resistance by inhibiting prostaglandin G/H synthase 2 (also known as
cyclo-oxygenase) and thereby interfere with prostaglandin synthesis, which antagonizes
the natriuretic response to loop diuretics.55 Thirdly, switching to an alternative loop diuretic
might be useful to achieve adequate absorption. For example, bumetanide and torasemide
both have higher biological absorption than furosemide in patients with chronic heart
28 Chapter 2
failure.32,49 In the TORIC study,56 which included outpatients with heart failure, torasemide
treatment was associated with a significant improvement in NYHA class compared with
furosemide or other diuretics (improvement of one grade in NYHA class 45.8% versus 37.2%;
P <0.001). In a small meta-analysis of 2,025 patients, these findings were confirmed, sug-
gesting a trend toward improvement in NYHA class with torasemide treatment.57 Adequate
increasing doses of loop diuretics have to be prescribed to establish whether a patient truly
has diuretic resistance. Finally, efficacy of diuretic therapy can be improved by switching
from oral to intravenous administration to circumvent impaired enteral drug uptake in
congested patients.4 The investigators of several small studies have suggested that continu-
ous infusion improves diuresis, renal function, and leads to fewer adverse events compared
with bolus injections.58–60 However, in the Diuretic Optimization Strategies Evaluation61 no
differences in either treatment response or outcome in patients randomized to bolus versus
continuous infusion were found, although diuretic doses and the incidence of worsening
renal function were higher for patients in the bolus group. However, bolus dosing will not
always be carried out as carefully in clinical practice as it was in the study, because this
dosing strategy is usually driven by signs and symptoms and not by protocols.
Figure 3. An approach to treating patients with acute heart failure who are diuretic resistant.If a patient with acute heart failure is diuretic resistant, switch to an alternative loop diuretic. If symptoms persist, intravenously administer the drug before attempting a combination of diuretic therapies. In patients who are still diuretic resistant after these steps, alternative therapies might achieve decongestion.
Diuretic response in acute heart failure 29
2
Table 1. Treating diuretic resistant patients with acute heart failure
Treatment strategy Author recommendations References
Loop diuretic Increasing doses of loop diuretics are considered a first step
Felker et al.61
Switch loop diuretic Switching to bumetanide or torasemide can improve bioavailability of loop diuretic
Vargo et al.,32 Brater et al.,33,49 Cosin et al.,56 Bikdeli et al.57
Intravenous administration
Intravenous administration of loop diuretic strongly recommended to circumvent impaired enteral uptake
Dormans et al.,58 Thomson et al.,59 van Meyelet al.,60 Felker et al.61
Combination therapy
Add thiazide Improves sodium excretion by inhibiting distal sodium reabsorption, can be considered when increasing doses of intravenous loop diuretic are insufficient
Ellison,28 Kunau et al.,62 Channer et al.63
Add metalozone Provides marked diuresis and can produce diuresis despite a low glomerular filtration rate
Ng et al.,64 Tilstone et al.65
Add acetazolamide Increases diuresis; caution is recommended in patients with advanced renal failure owing to risk of concentration-dependent adverse effects
Brater et al.,66 Khan,67
Kassamali & Sica,68
Add mannitol In one study, mannitol improved diuresis Turagam et al.,69
Add MRA at natriuretic doses
Associated with increased diuresis; can be considered in addition to combination therapy of loop and thiazide diuretics
RALES Investigators,75 van Vliet et al.,76 Ferreira et al.,77 Sigurd et al.,80 Olesen & Sigurd81
Dopamine Does not seem to improve diuretic response in acute heart failure and, therefore, has limited additive value in treating patients who are diuretic resistant
Elkayam et al.,84 Chen et al.,85
Triposkiadis et al.,86 Giamouzis et al.87
Hypertonic saline Improves diuresis and seems to be a safe alternative strategy in patients who are diuretic resistant
Paterna et al.,88 Licata et al.,89
Paterna et al.,90 Paterna et al.91
Ultrafiltration Studies on ultrafiltration have not demonstrated consistent improvement; ultrafiltration a last resort when other strategies have failed
Bart et al.,93 Costanzo et al.,94 Bart et al. 95
Alternative therapies
Tolvaptan Can increase urine output and might have additive value
Schrier et al.,83 Udelson et al.99
Nesiritide Does not increase urine output and is unlikely to have additive value
Gottlieb et al.101
Ularitide Induces natriuresis and diuresis; the TRUE-AHF trial is ongoing
Valentin et al.102
Levosimendan Associated with symptom relief Packer et al.104
Glucocorticoids Addition of prednisone can result in marked diuresis; an alternative strategy that needs to be studied further
Liu et al.105
Rolofylline Significant predictor of diuretic response and could help to overcome diuretic resistance
Valente et al.5
Serelaxin No significant effect on diuretic response Voors et al.,51 Metra et al.106
Abbreviation: MRA, mineralocorticoid-receptor antagonist.
30 Chapter 2
Combined diuretic therapyIf escalating intravenous doses of loop diuretics are insufficient, combination therapy with
two classes of diuretic drugs might improve diuretic efficacy. The addition of a thiazide di-
uretic enhances sodium excretion by inhibition of distal sodium reabsorption,62 and prevent
post-diuretic sodium retention after cessation of loop diuretic activity because thiazides
have a longer half-life than loop diuretics.28 Potential adverse effects of combination therapy
include hypokalaemia, hyponatraemia, dehydration, worsening renal function and meta-
bolic acidosis; careful monitoring of patients receiving these drugs is, therefore, required.63
Addition of metozalone to a loop diuretic results in marked diuresis and is especially useful in
patients with renal failure, because metozalone can produce diuresis despite a low GFR.64,65
Given that a large amount of sodium is reabsorbed in the proximal tubule, adding a
diuretic that functions in this location might be beneficial to patients. In healthy volunteers,
addition of acetazolamide to furosemide showed a minor additive effect on diuresis.66 In one
study, an additional effect of acetazolamide in correcting metabolic acidosis and increased
diuresis when used intermittently in combination with furosemide and spironolactone
therapy in patients with congestive heart failure was reported.67 Given that acetazolamide is
cleared by the kidney, caution is recommended in patients with advanced renal failure ow-
ing to the risk of concentration-dependent adverse effects.68 Another option for combined
therapy is mannitol. Investigators reported effective diuresis in 80.3% of 122 patients with
acute heart failure treated with furosemide–mannitol infusion, although the study had no
control group.69 To date, studies to evaluate combination therapy in patients with heart
failure and who are diuretic resistant are scarce, and evidence remains inconclusive. Two
trials (DIURESIS-CHF70 and CLOROTIC71) to investigate combination therapy in patients with
acute heart failure are ongoing and planned, respectively. However, diuretic resistance is not
explicitly defined as an inclusion criterion in either study.
Adding a natriuretic dose of an MRA to diuretics might also help to overcome diuretic
resistance by blocking the mineralocorticoid receptor and thereby prevent excess sodium
reabsorption in the collecting duct caused by secondary hyperaldosteronism.72 MRAs at low
doses are guideline-recommended therapy in heart failure and significantly improve sur-
vival.1,73,74 The dose-finding Randomized Aldactone Evaluation Study75 revealed that higher
doses of spironolactone (50–75 mg daily) had natriuretic effects, compared with doses of
12.5 mg or 25 mg daily, which had no natriuretic effect. In two small, single-centre studies of
100 and 21 patients, respectively, high-dose spironolactone was associated with increased
diuresis or earlier resolution of symptoms and signs of congestion.76,77 A common adverse
effect of high-dose MRAs is hyperkalaemia; new MRA drugs with a reduced risk of causing
electrolyte disturbances are currently being investigated.78,79 Addition of high-dose MRAs can
be considered even in addition to combination therapy with loop and thiazide diuretics.80,81
In clinical practice, no clear consensus on combination therapy exists and implementa-
tion is mostly determined by personal experience. We do not intend to use combination
Diuretic response in acute heart failure 31
2
therapy for outpatients based on the potential complications, which mean that daily
monitoring of laboratory values and hydration status is required. Several strategies can be
used to prevent or overcome electrolyte disturbances. Hypokalaemia can be avoided by the
co-administration of a low-dose potassium-sparing MRA or potassium sparing diuretic.80,82
Tolvaptan, a vasopressin V2 receptor blocker, has a potential role in the prevention of
hyponatraemia.83 Overall, combination treatment requires careful follow-up and a tailored
approach for each patient.
DopamineAddition of low-dose dopamine (<3 μg/kg/min) to diuretic therapy has been suggested as
a method to improve renal blood flow, thereby preserving renal function and improving
diuresis.84 Investigators in the Renal Optimization Strategies Evaluation85 tested whether
addition of low-dose dopamine (2 μg/kg/min), low-dose nesiritide (a synthetic B-type
natriuretic peptide; 0.005 μg/kg/min), or placebo, to diuretic therapy enhanced deconges-
tion and preserved renal function in patients with acute heart failure and renal dysfunction.
However, neither dopamine nor nesiritide had a significant effect on urine volume (placebo:
8,296 ml; dopamine: 8,524 ml; nesiritide: 8,574 ml) or level of cystatin C (placebo: 0.11 mg/l;
dopamine: 0.12 mg/l; nesiritide: 0.07 mg/l), suggesting no added benefit to diuretic therapy.
In a subsequent study, investigators in the prematurely discontinued, small-scale Dopamine
in Acute Decompensated Heart Failure II trial confirmed these findings, despite promising
results from the previous Dopamine in Acute Decompensated Heart Failure I study.86,87
The results of these studies suggest that dopamine does not improve diuretic response in
patients with acute heart failure. Despite the lack of evidence, low-dose dopamine is still
often used in clinical practice because this drug is thought to stimulate diuretic response
by improving renal function, and might be beneficial in patients for whom other strategies
have failed.
Hypertonic salineIntravenous hypertonic saline, co-administered with diuretics, has been suggested as a way
to improve diuresis, by mobilizing extravascular fluid into the intravascular space resulting in
increased cardiac output, renal blood flow, and quick excretion of excess volume. In several
small studies of no more than 107 patients, increased diuresis and clinical improvement
in patients with acute heart failure was observed with addition of hypertonic saline.88–90
In the largest study to date (the SMAC-HF trial91), including 1,771 patients, increased di-
uresis and natriuresis, and reduced rehospitalization rates (18.5% versus 34.2%; P <0.001),
were observed in the patients treated with intravenous furosemide and hypertonic saline,
compared with those who received furosemide alone. These promising results suggest that
hypertonic saline is a safe alternative strategy to improve diuretic response in patients with
acute heart failure. However, most experience comes from only a limited number of studies
32 Chapter 2
and, therefore, prospective trials in patients who are truly diuretic resistant are needed to
establish the role of hypertonic saline.
UltrafiltrationUltrafiltration is an effective method for fluid removal that filters plasma water directly
across a semipermeable membrane using a pressure gradient, which yields an ultrafil-
trate that is iso-osmotic compared with plasma.92 In two randomized, controlled trials
(RAPID-CHF93 and UNLOAD94) to compare diuretic therapy and ultrafiltration, greater fluid
removal was observed in the ultrafiltration groups, although weight loss after 24 h did not
differ in RAPID-CHF (P = 0.24), and dyspnoea scores were similar in UNLOAD (P = 0.35).
Interestingly, ultrafiltration was associated with significant reductions in rehospitalization
for heart failure (18% versus 32%; P = 0.037) and fewer unscheduled hospital visits (21%
versus 44%; P = 0.009); unfortunately these results were not adjudicated. In the CARRESS-HF
study,95 the investigators examined the use of ultrafiltration in 188 patients with acute heart
failure and cardiorenal syndrome. Patients were randomly assigned to receive stepped di-
uretic therapy or fixed-rate ultrafiltration in a 1:1 ratio (n = 94 per group). Ultrafiltration was
inferior to pharmacological therapy, primarily owing to an increase in the creatinine level in
the ultrafiltration group (+0.23 ± 0.70 versus –0.04 ± 0.53 mg/dl; P = 0.003), along with more
adverse events (72% versus 57%; P = 0.03). However, not all patients in the ultrafiltration
group received ultrafiltration therapy, and the fixed rate of fluid removal in the ultrafiltration
arm has been questioned. So far, ultrafiltration has not been studied specifically in patients
with diuretic resistance. In our opinion, ultrafiltration is a last resort when increasing doses
of intravenous loop diuretics, combination therapy or hypertonic saline strategies have
failed to overcome diuretic resistance and, even then, only in selected patients who are
truly diuretic resistant. Multiple studies on ultrafiltration in heart failure are ongoing, but
a phase III outcome trial (AVOID-HF96) was terminated owing to recruitment problems.96–98
Unfortunately, none of the studies explicitly addresses diuretic resistance in patients.
Alternative therapiesVarious intravenous agents have been investigated in acute heart failure, and although
none has shown convincing survival benefits to date, several have mechanisms of action
that might be helpful in overcoming diuretic resistance. The vasopressin V2 receptor blocker,
tolvaptan, is effective at increasing sodium concentrations in patients with hyponatraemia,
increases urine output in patients with symptomatic heart failure and might, therefore, have
additive value in patients who are diuretic resistant.83,99 Synthetic natriuretic peptides have
also been developed and investigated in patients with heart failure. Nesiritide, approved by
the FDA in the USA for relief of heart failure symptoms (class IIa, level of evidence C), but
not by European regulators owing to a lack of efficacy,100 did not increase urine output in
patients with acute heart failure, and is, therefore, unlikely to have additive value in patients
Diuretic response in acute heart failure 33
2
with diuretic resistance.101 Ularitide is a synthetic form of the hormone urodilatin, a human
endogenous natriuretic peptide expressed in the kidney, and induces natriuresis and diure-
sis by binding to specific natriuretic peptide receptors.102 Ularitide might have therapeutic
advantages in acute heart failure and specifically in patients who are diuretic resistant, and is
being investigated in the ongoing TRUE-AHF trial.103 Levosimendan is a phosphodiesterase
inhibitor with vasodilator and positive inotropic properties, which enables rapid and durable
symptom relief in acute heart failure and has positive effects on renal function, and which
could help to treat symptoms in patients who are diuretic resistant.104
In a small study of 13 patients with acute heart failure, addition of prednisone in individu-
als with diuretic resistance led to marked diuresis, significant weight loss (9.39 ± 3.09 kg;
P <0.01), and improved renal function (GFR 33.63 ± 15.87 ml/min/1.73m2; P <0.01).105 Further
studies are needed to confirm these findings.
Finally, treatment with the adenosine A1 antagonist rolofylline was a significant predictor
of diuretic response (t-statistic = –3.091; P = 0.002 in multivariate models) due to greater
weight loss, possibly owing to improved renal perfusion or direct diuretic effects.5 In some
patients with poor diuretic response, inhibition of adenosine A1 might help to overcome
diuretic resistance, although the adverse effect profile of rolofylline, in addition to lack of
efficacy, has led to discontinuation of its development. Serelaxin is a human recombinant
of the vasodilator relaxin-2, with systemic and renal effects.106 Although no significant ef-
fect of serelaxin on diuretic response has been observed, this drug might have beneficial
effects that can prevent organ damage in patients with acute heart failure who are diuretic
resistant.51,106
conclusions
Impaired diuretic response is a common problem in patients with acute heart failure and
strongly associated with poor in-hospital and post-discharge clinical outcomes. Quantita-
tive measures for diuretic response have been proposed, but need to be validated in other
populations of patients with acute heart failure. In addition to establishing the value of
diuretic response metrics as prognostic markers, early identification of patients at risk of
a poor diuretic response might allow the initiation of therapies to modify their response.
Prospective studies using a validated metric of diuretic response to identify patients who
are diuretic resistant are a necessary first step towards determining the best strategies for
overcoming diuretic resistance, and consequently determining whether such metrics lead
to improved outcomes. Such strategies could ultimately result in a better, individualized ap-
proach to treating patients with acute decompensated heart failure, for whom no evidence-
based therapies currently exist.
34 Chapter 2
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