Diuretic response and renal function in heart failure

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,


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.


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,


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.


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


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


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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