Review Article

Cardiorenal Med 2023;13:1–8 Received: July 29, 2022

Accepted: September 13, 2022
DOI: 10.1159/000527204 Published online: November 2, 2022

Extracorporeal Ultrafiltration for Acute

Heart Failure

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Amir Kazory a Luca Sgarabotto b Claudio Ronco b, c
aDivision
of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, FL, USA;
bDepartment
of Nephrology, San Bortolo Hospital and International Renal Research Institute of Vicenza (IRRIV),
Vicenza, Italy; cDepartment of Medicine, University of Padova, Padova, Italy

Keywords den associated with the care of these patients. While isolated
Heart failure · Cardiorenal syndrome · Congestion · ultrafiltration can be performed by conventional machines
Ultrafiltration used for renal replacement therapy, the advent of simplified,
portable, and user-friendly devices that are specifically de-
signed for extracorporeal ultrafiltration therapy has further
Abstract enhanced the interest in this therapeutic modality and in-
Acute decompensated heart failure (ADHF) has the highest creased the potential for its more widespread use. Further,
rate of hospital readmission among all medical conditions development in this direction through device miniaturiza-
and portends a significant financial burden on healthcare tion may extend the horizons of indications and the applica-
systems worldwide. Hospitalization for ADHF is primarily bility of this therapy even in the ambulatory settings.
driven by congestion, with intravenous loop diuretics repre- © 2022 The Author(s).
senting the cornerstone of therapy. However, it is well de- Published by S. Karger AG, Basel

scribed that a significant subset of patients is discharged

with residual fluid overload. While the cause of the incom- Background
plete decongestion is multifactorial, the development of di-
uretic resistance is a well-characterized contributing factor Heart failure represents a major public healthcare
with consequent poor outcomes. Moreover, the therapeutic problem due to its high prevalence, morbidity, mortality,
response to diuretics is known to lack predictability. Extra- and significant financial burden on the healthcare system.
corporeal ultrafiltration (a mechanical pump-driven thera- Approximately 6.5 million adults in the USA have heart
py) has emerged as an option to overcome shortcomings of failure, and one in eight deaths includes it as a contribut-
the diuretics. It allows clinicians to customize the volume ing cause of mortality [1]. Nearly, 40–45% of patients who
and the rate of fluid removal to the needs and clinical char- develop heart failure die within 5 years of diagnosis [1].
acteristics of the patients. The results of the currently avail- The course of chronic heart failure is highlighted by epi-
able studies indicate that this therapy is associated with sodes of exacerbation. Acute decompensated heart failure
more efficient fluid and sodium removal compared to medi- remains among the leading causes of hospital admission
cal therapy, hence leading to reduction in the rate of read- in older patients exceeding one million in both the USA
missions and a potential salutary impact on the financial bur- and Europe with more than one million hospitalizations

[email protected] © 2022 The Author(s). Correspondence to:

www.karger.com/crm Published by S. Karger AG, Basel Amir Kazory, amir.kazory @ medicine.ufl.edu
This is an Open Access article licensed under the Creative Commons
Attribution-NonCommercial-4.0 International License (CC BY-NC)
(http://www.karger.com/Services/OpenAccessLicense), applicable to
the online version of the article only. Usage and distribution for com-
mercial purposes requires written permission.
annually [2]. It has the highest rehospitalization rate stimulation of renin-angiotensin-aldosterone and sym-
among all medical conditions; one in 4 patients (24%) are pathetic nervous systems [13–15]. Post hoc analysis of
readmitted within 30 days, and one in 2 patients (50%) ADHERE database showed that patients receiving high
are readmitted within 6 months [2, 3]. The annual cost of dose of diuretics had poor outcomes in comparison to
the care for patients with heart failure is estimated at 60 patients receiving lower doses [14]. Similar results were
billion dollars in the USA with expenses related to the seen with ESCAPE trial in which high-dose diuretics in-
hospital care accounting for almost 70 percent of the total creased mortality especially when the daily dose of furo-
expenditure [4]. As the population ages, healthcare ex- semide exceeded 300 mg [15]. These studies could be con-
penditures are expected to increase substantially [5]. founded by the fact that patients with more severe disease
Congestion is the primary reason for hospitalization of are likely to receive higher doses of diuretics; the diuretic
patients with heart failure [2, 6]. Venous congestion can dose may possibly be a marker of severity of the disease
cause endothelial activation and upregulation of inflam- rather than a cause for adverse outcomes.

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matory mediators with systemic effects that include im- Patients with ADHF frequently experience suboptimal
pairment of renal function, intestinal villi ischemia, and decongestion, and nearly 50% of them leave the hospital
hepatic dysfunction [7]. Removal of excess fluid consti- with inadequate or minimal weight loss [16]. Therefore,
tutes a major goal in the management of patients with in recent years, there has been a renewed interest in iden-
ADHF. tifying the pathways underlying diuretic resistance.
Moreover, there has been a proposal for shifting of the
patient’s monitoring of responsiveness to diuretics from
Pharmacological Decongestion conventional metrics, such as weight change and urine
output, to measurement of urinary excretion of sodium.
Loop diuretics remain the cornerstone of therapy for flu- Some authors have proposed algorithms for diuretic ther-
id overload in patients with heart failure due to their favor- apy in patients with ADHF that are based on measure-
able diuretic profile of achieving urinary sodium excretion ments of spot urine sodium after administration of a loop
without excessive potassium wasting at lower doses. While diuretic [17]. However, it has been shown that natriuret-
effective early in the course of heart failure, the efficacy of ic response is highly variable in patients who are admitted
diuretics gradually decreases as the disease progresses in a to the hospital for ADHF [18] and emerging reports have
significance subset of patients [8]. As such, diuretic resis- challenged the supposition that urinary sodium concen-
tance (i.e., persistent fluid overload despite an adequate and tration remains constant throughout the course of hospi-
escalating dose of loop diuretics) has been a well-known talization [19]. In parallel, there have been attempts to
challenge in the care of these patients, and not surprisingly develop clinical tools and calculators to predict the pa-
is tied to worse prognosis [8, 9]. Impaired intestinal absorp- tient’s response to diuretics and guide the dosing in order
tion, decreased renal blood flow, nephron remodeling, re- to increase the efficiency of these agents and overcome
nal venous congestion, and neurohormonal activation are the challenge of diuretic resistance [20, 21]. While these
among the underlying pathophysiological mechanisms methods do seem promising, it should be noted that they
leading to reduced responsiveness of these patients to di- are at their infancy, and the investigations are mostly sin-
uretics [9]. The clinical hallmarks of loop diuretic resistance gle-center pilot studies performed in academic centers
are inadequate relief of congestion, increased risk of inhos- primarily as proof of concept. Therefore, it remains un-
pital worsening of heart failure, and a significant increase in clear whether they can be applicable to real-time clinical
rehospitalization rates [10]. practice of centers with limited resources where a signifi-
Sequential blockade of the renal tubules through com- cant number of such patients are being admitted. Table 1
bination of diuretics with different mechanisms of action, summarizes some of the proposed shortcomings of di-
replacing oral agents by intravenous medications during uretic use in the setting of heart failure.
admission to the hospital, infusion of intravenous diuret-
ics instead of bolus administration, and gradual escala-
tion of the dose of the diuretics are among the common Ultrafiltration Process
strategies that clinicians have used for decades to over-
come apparent diuretic resistance [11, 12]. Several obser- Ultrafiltration is an extracorporeal process in which
vational studies have shown poor outcomes with use of plasma water devoid of cells and colloids is forced by hy-
high-dose loop diuretics which has been attributed to drostatic pressure across a biosynthetic, semipermeable

2 Cardiorenal Med 2023;13:1–8 Kazory/Sgarabotto/Ronco

DOI: 10.1159/000527204
Table 1. Potential shortcomings of diuretic use in treatment of Table 2. Proposed advantages of ultrafiltration in treatment of
heart failure heart failure

Direct activation of renin-angiotensin-aldosterone system Reduction in renal venous congestion and improvement in renal
Deterioration in renal function hemodynamics
Electrolyte abnormalities (e.g., hypokalemia and Rapid and adjustable removal of fluid and improvement in
hypomagnesemia) symptoms of congestion
Suboptimal natriuresis (production of hypotonic urine) Higher mass clearance of sodium
Development of diuretic resistance Decreased risk of electrolyte abnormalities (e.g., hypokalemia)
Unpredictability of the therapeutic response Lack of neurohormonal activation (SNS, RAAS, and AVP)
Lack of clarity on the practical aspects of use (e.g., optimal dosing Sustainability of the beneficial effects (e.g., impact on
strategy) neurohormonal axis)
Nonrenal adverse effects (e.g., ototoxicity and hypersensitivity) Improvement in diuretic resistance, natriuresis, and urine output
Decreased rate of heart failure-related rehospitalizations

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Adapted with permission from reference 22. Decreased hospital length of stay
Availability of dedicated ultrafiltration devices that are portable,
user-friendly, with minimal extracorporeal volume (33 mL), and
have the ability of functioning with low blood flow rates (10–40
filter, resulting in the removal of water, electrolytes, small mL/min)
solutes (e.g., water-soluble vitamins). During this pro-
SNS, sympathetic nervous system; RAAS, renin-angiotensin-
cess, blood exits the body through a venous catheter in aldosterone system; AVP, arginine vasopressin. Adapted with
order to reach the hemofilter. Hydrostatic pressure is ex- permission from reference 22.
erted across the filter (i.e., a semipermeable membrane)
and results in the production of ultrafiltrate which is basi-
cally composed of water and smaller solutes such as so-
dium and potassium that have been dragged out along
with the water. The concentration of these solutes will be lack of diffusion of solutes across the hemofilter (and
similar between the ultrafiltrate and serum, hence lack of therefore no clearance of solutes) which is the basis of he-
any impact of ultrafiltration on the serum levels of these modialysis modality.
solutes (i.e., the ultrafiltrate produced is almost isotonic Although isolated ultrafiltration can be performed
compared with the plasma). The ultrafiltration rate is ad- with conventional hemodialysis machines to solely ex-
justed by modifying the positive pressure that is applied tract fluid without providing clearance, there have been
to the blood side of the membrane or the negative pres- dedicated devices marketed exclusively for management
sure that is exerted on the ultrafiltrate side. This rate will of fluid overload. These devices with newer technology
be determined by the amount of fluid that needs to be are simplified user-friendly machines that have the ad-
extracted as well as clinical characteristics of the patient vantages of small size, portability, blood flow rates of as
such as hemodynamics status. The hemoconcentrated low as 40 mL/min (as compared to 300–450 mL/min in
blood is then returned back to the patient via the venous conventional dialysis machines), and an extracorporeal
access. The progressive reduction in intravascular vol- blood volume of less than 50 mL. They can provide ultra-
ume and concomitant increase in the oncotic pressure of filtration rates within a large spectrum (0–500 mL/h), do
serum will lead to shift of fluid from interstitial to replen- not mandate admission to intensive care unit, and have
ish intravascular compartment. Therefore, while fluid re- been marketed with the ability of even using peripheral
moval in ultrafiltration is directly from intravascular sec- veins [22]. Table 2 summarizes some of the proposed ad-
tor, it will ultimately lead to removal of excess fluid from vantages of ultrafiltration therapy in the setting of heart
extravascular and interstitial compartments. It is impor- failure.
tant to note that this process relies on adequate shift of
fluid from interstitium to refill plasma water; hence, the
importance of carefully setting the rate of ultrafiltration Clinical Trials
in order to avoid overzealous fluid extraction with poten-
tial adverse impact on the hemodynamics or perfusion of Earlier trials of ultrafiltration for heart failure have
vital organs such as the kidney. The process of ultrafiltra- been instrumental as proof of concept for feasibility of
tion is fundamentally different from hemodialysis in that this therapeutic option and have been quite successful in
there is no dialysate used in this form of therapy, hence generating the interest for consideration of mechanical

Ultrafiltration for Heart Failure Cardiorenal Med 2023;13:1–8 3

DOI: 10.1159/000527204
fluid extraction as an alternative to medical therapy. RESS-HF) trial included patients with ADHF who also
However, not all their results might be reproducible in the presented with cardiorenal syndrome and persistent con-
current era due to the fact that both medical management gestion despite conventional treatment [30]. The patients
and the technology and practice of extracorporeal thera- were randomized to receive either an algorithm-based
py have changed dramatically over the last two decades. pharmacological regimen or ultrafiltration as a rescue
In one of the largest earlier studies, Canaud et al. [23] used therapy. Surprisingly, not only did patients in the ultrafil-
slow ultrafiltration therapy (continuous or daily) in 52 tration group fail to have greater weight loss, but they also
patients with severe congestive heart failure and showed presented with an increase in serum creatinine level. The
that the patients could tolerate significant fluid removal main concern about the design of this trial was that while
(i.e., an average weight loss of 9.2 kg). These studies also dosing of the diuretics was adjusted in the pharmacolog-
suggested that the salutary effects of ultrafiltration in this ical therapy arm based on patients’ therapeutic response,
setting might be sustainable beyond the duration of ther- the rate of ultrafiltration was delivered uniformly at 200

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apy. In a study of 36 patients with heart failure, Agostoni mL/h. We have previously discussed the importance of
et al. [24] reported an improvement in several respiratory customization of ultrafiltration rate based on plasma refill
parameters (e.g., tidal volume and peak exercise ventila- and patient’s clinical characteristics to avoid adverse ef-
tion) that lasted over the next 6 months following one fects [31]. Nevertheless, the investigators did not observe
single session of ultrafiltration. In a similar study, those a difference in the mortality of the two groups during the
patients with heart failure who underwent one session of 2-month follow-up [30]. Several years later, a per-proto-
ultrafiltration showed improvement in cardiorespiratory col analysis of CARRESS-HF (i.e., inclusion only of sub-
parameters (e.g., exercise tolerance time) that persisted at jects who received their randomized treatment) found
1- and 3-month follow-up assessments; these effects were that ultrafiltration was indeed associated with higher cu-
not observed in the control group [25]. mulative fluid loss, net fluid loss, and relative reduction
Following a clinical study in 2003 where the feasibility in weight compared to stepped, urine output-guided
of using peripherally inserted venous catheters for fluid pharmacological therapy [32]. Regarding the increase in
overloaded patients with heart failure was successfully serum creatinine that was observed in the ultrafiltration
tested [26], Costanzo et al. [27] performed a study of ul- arm, accumulating evidence suggests that transient in-
trafiltration on patients with ADHF who also presented creases in serum creatinine may not represent the renal
with diuretic resistance or renal dysfunction. They re- injury and instead signify a hemodynamically driven re-
ported favorable results with successful decongestion, duction in glomerular filtration rate, indicative of effec-
significant shorter length of stay, and lower readmission tive decongestion with improved outcomes [33, 34].
rates. In 2007, the long expected first large-scale random- The negative results of CARRESS-HF contrasted those
ized controlled trial in this field was published. In Ultra- of UNLOAD and several previous uncontrolled trials.
filtration versus Intravenous Diuretics for Patients Hos- Due to the differences in the design and delivery of the
pitalized for Acute Decompensated Heart Failure (UN- interventions, there was a need for a fair comparison be-
LOAD) trial, patients who were treated with ultrafiltration tween a protocolized diuretic regimen with a well-done
experienced significantly greater weight loss (i.e., decon- algorithm-based ultrafiltration therapy. The Aquapher-
gestion) compared to those who received diuretics [28]. esis Versus Intravenous Diuretics and Hospitalization for
Interestingly, the ultrafiltration group demonstrated a Heart Failure (AVOID-HF) trial was designed to address
greater freedom from rehospitalization during the this knowledge gap [35]. It compared early adjustable ul-
3-month follow-up period as well; ultrafiltration was as- trafiltration therapy with a carefully designed medical
sociated with >50% reduction in the risk of rehospitaliza- treatment protocol that had similarities with the algo-
tion for ADHF. In line with previous studies suggesting rithm used in the CARRESS-HF. The total and net fluid
that the beneficial effects of ultrafiltration are sustainable, losses were again found to be greater in the ultrafiltration
a secondary analysis of the UNLOAD trial found that, group than in the diuretic arm without an adverse impact
with comparable fluid volume removal for ultrafiltration on renal function. The patients in the ultrafiltration arm
and diuretic infusion, still fewer heart failure rehospital- showed a nonsignificant trend toward better outcomes
ization equivalents occurred with ultrafiltration [29]. In such as higher estimated number of days to the first HF
2012, a second large randomized controlled trial was pub- event within 3 months after discharge.
lished. In contrast to UNLOAD, the Cardiorenal Rescue To consolidate data across several studies, a number
Study in Acute Decompensated Heart Failure (CAR- of meta-analyses have been performed. Jain et al. [36]

4 Cardiorenal Med 2023;13:1–8 Kazory/Sgarabotto/Ronco

DOI: 10.1159/000527204
 Table 3. Selected studies of ultrafiltration in heart failure

UNLOAD [28] ULTRA DISCO [38] Hanna et al., [39] CARRESS-HF [30] CUORE [40] AVOID-HF [35]

Year of 2007 2011 2012 2012 2014 2016

publication
Centers, n 28 1 1 22 2 30
Patients, n 200 (100 UF, 100 PT) 30 (15 UF, 15 PT) 36 (17 UF, 19 PT) 188 (94 UF, 94 PT) 56 (27 UF, 29 PT) 224 (110 UF, 114 PT)
Study design RCT, single session early RCT, slow continuous UF, RCT, slow continuous UF RCT, rescue therapy RCT, one or two early UF RCT, single session early UF
and protocol UF therapy for ADHF hemodynamic changes for ADHF, patients were for patients with both treatments for ADHF (within therapy for ADHF (within 24
(within 24 h) were monitored by randomized within two ADHF and WRF 24 h) h)

Ultrafiltration for Heart Failure

pressure recording strata based on baseline
analytical method GFR
Primary Weight loss and dyspnea Change in clinical, Time for PCWP to be kept The changes in Scr and Rehospitalization rate for HF at Time to first HF event within
endpoint at 48 h (efficacy), changes biohumoral, and at ≤18 mm Hg for at least 4 weight at 96 h 1 year 90 days after discharge
in renal function and hemodynamic parameters consecutive hours (bivariate)
hypotension (safety)
Ultrafiltration Duration and rate of UF Blood flow rate of 150 Blood flow rate of 200–300 Fixed UF rate 200 Duration and rate of UF Duration and rate of UF
regimen flexible, maximum UF rate mL/h, adjustable UF rate of mL/min, UF rate of 400 mL/h, median flexible, maximum UF rate 500 flexible, Maximum UF rate
500 mL/h, Average UF rate 100–300 mL/h mL/h for 6 h and then 200 duration of UF 40 h, mL/h, average duration 19±10 500 mL/h, average UF rate
241 mL/h for 12.3±12 h mL/h Median duration 40 h h 138 mL/h for 80±53 h
Medical therapy Conventional Conventional Conventional Stepped Conventional pharmacologic Adjustable intravenous loop
pharmacologic therapy pharmacologic therapy (no pharmacologic therapy pharmacologic therapy (no pre-planned diuretics (algorithm-based)
(no pre-planned pre-planned algorithm) (no pre-planned therapy (algorithm- algorithm)
algorithm) algorithm) based)
Age, years 62 UF, 63 PT 72 UF, 66 PT 60 UF, 59 PT 69 UF, 66 PT 75 UF, 73 PT 67 UF, 67 PT
Male gender, % 70 UF, 68 PT 87 UF, 87 PT 84 UF, 76 PT 78 UF, 72 PT 81 UF, 83 PT 69 UF, 73 PT
Weight, kg 101 UF, 96 PT 74 UF, 83 PT 93 UF, 98 PT 94 UF, 106 PT 83 UF, 89 PT 110 UF, 111 PT
LVEF, % 71 UFa, 70 PTa 34 UF, 30 PT 19 UF, 18 PT 30 UF, 35 PT 32 UF, 32 PT 36 UF, 37 PT
Baseline SCr, 1.5 UF, 1.5 PT (Scr >3 mg/ 2.2 UF, 1.9 PT (Scr >3.0 mg/ 55 UF, 51 PT b (eGFR <15 1.9 UF, 2.09 PT (Scr 1.7 UF, 1.9 PT (Scr >3 mg/dL 1.5 UF, 1.6 PT (Scr ≥3 mg/dL
mg/dL dL excluded) dL excluded) excluded) >3.5 mg/dL excluded) excluded) excluded)
Impact on renal No significant difference in No significant difference in No significant difference in Significant increase in Higher Scr and BUN in the PT No significant difference in
function renal function between UF renal function between UF renal function between UF Scr level with UF, no group at 6 months, No eGFR, Scr, BUN, and BUN/
and PT and PT and PT change in Scr for PT difference in eGFR, Scr, and Scr ratio during treatment
BUN between UF and PT at 1 and up to 90 days between

DOI: 10.1159/000527204
year UF and PT

Cardiorenal Med 2023;13:1–8

Impact on Greater weight loss with Weight loss and total Similar total volume Weight loss and total Weight loss similar for both Higher total amount of fluid
congestion UF, Greater net fluid loss amount of fluid removal extraction for UF and PT, amount of fluid groups at discharge, Lower removed with UF, No
with UF similar for both groups Significantly higher fluid removal similar for body weight for UF at 1 year difference in weight loss
removal rate with UF both groups between UF and PT
Impact of UF Improved NR Similar Improved Improved Improved
versus PT on
readmission
Follow-up, 3 [36 h] 3 2 12 3
months

UF, ultrafiltration; PT, pharmacologic therapy; HF, heart failure; Scr, serum creatinine; LVEF, left ventricular ejection fraction; CAD, coronary artery disease; NR, not reported; PCWP, pulmonary
capillary wedge pressure; eGFR, estimated glomerular filtration rate; BUN, blood urea nitrogen; Scr, serum creatinine; WRF, worsening renal function; RCT, randomized controlled trial; AVOID-HF,
Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure; CARRESS-HF, Cardiorenal Rescue Study in Acute Decompensated Heart Failure; CUORE, Continuous Ultrafiltration
for Congestive Heart Failure; ULTRADISCO, Effects of Ultrafiltration versus Diuretics on Clinical, Biohumoral and Hemodynamic Variables in Patients with Decompensated Heart Failure; UNLOAD,
Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure. Adapted with permission from reference 36. aPercentage of patients with
LVEF ≤40%. bEstimated glomerular filtration rate (eGFR).

5
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pooled data from 7 randomized controlled trials of ultra- failure. There are certain concerns that need to be ad-
filtration including a total of 771 patients. They found dressed with regard to the use of ultrafiltration therapy in
that, based on the available data, ultrafiltration therapy is this setting. Lack of protective effect on renal function,
indeed associated with more efficient decongestion as need for additional training for staff and physicians, need
measured by weight loss and net fluid removal compared for anticoagulation, complications related to extracorpo-
with medical treatment. Although there were similar real circuit (e.g., air embolism and infection), and lack of
changes in renal function for both groups, ultrafiltration knowledge on the long-term outcomes are among the
was shown to be more efficient at reducing the rate of HF proposed limitation of this therapy [22]. Identifying the
rehospitalization, possibly by virtue of more efficient de- subset of patients who benefit the most from ultrafiltra-
congestion. There was no difference in mortality rate or tion therapy could be achievable using these principles.
incidence of adverse events. These results lend support Timing of initiation and ending of therapy can also be
to the previously mentioned notion that the high rate of determined through this process. Similar to other thera-

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heart failure rehospitalization could in part be related to peutic interventions in heart failure, in order to explore
suboptimal decongestion during index hospital admis- the efficacy of ultrafiltration therapy using the precision
sion; the therapy with better decongestive properties medicine approach, there would be a need to use end-
would lead to improved rate of readmission. It also im- points besides mortality (e.g., resolution of congestive
plies that ultrafiltration could potentially have a role in symptoms and increase in the time interval between hos-
reduction of heart failure-related cost as the majority of pital admissions). Furthermore, advances in technology
the expenditure is related to the inpatient care of these should allow development of small portable or wearable
patients. In line with this observation, a recent hospital devices that, while sophisticated, are simple to use (e.g.,
cost analysis revealed that while initial hospitalization through miniaturized filters and circuits). Ultrafiltration
costs are higher for patients with ADHF who receive ul- versus IV Diuretics in Worsening Heart Failure (RE-
trafiltration therapy, this therapeutic modality is cost- VERSE-HF) is a multicenter open-label randomized con-
saving (by more than 14%) at 90-day timeframe due to trolled trial (NCT 05318105) that is designed to compare
reduction in hospital readmission days [37]. Table 3 adjustable ultrafiltration therapy with an adjustable di-
summarizes selected studies of ultrafiltration therapy in uretic regimen, and explore their impact on outcomes
the setting of heart failure. (e.g., first heart failure event and mortality).

Future Research Conclusion

Prediction of outcomes in patients with heart failure Based on the findings of the available trials, ultrafiltra-
has been a topic of much investigation. The functional tion represents an efficacious and safe therapeutic option
decline related to repeated episodes of acute decompen- for selected patients with ADHF, such as those with resis-
sation followed by partial recovery makes it challenging tance to diuretics or a history of multiple hospitalizations
to reliably predict the effectiveness of the medications and for congestion. This pump-driven technique of decon-
devices in this setting. The heterogeneity of heart failure, gestion provides predictable, adjustable, and more effi-
with multiple etiologies, distinct phenotypes, and the cient fluid removal compared to diuretics without clini-
presence of a multitude of comorbidities makes it unlike- cally significant adverse impact on renal function. It can
ly for every subset of patients to benefit from population- be considered early after admission to the hospital, and
based approaches (i.e., one-size-fits-all). Future signifi- the volume and rate of fluid removal need to be custom-
cant improvements in clinical outcomes of patients with ized to the clinical characteristics and specific needs of
heart failure could be achieved when therapy is individu- each patient (e.g., weight gain, blood pressure, and the
alized and tailored to a patient’s biological profile and presence of right ventricular dysfunction). It will be pru-
clinical characteristics (i.e., personalized medicine). This dent to avoid overzealous fluid extraction in order to pre-
practice can be further promoted by integrating a signifi- vent imbalance in plasma refill rate, induce intravascular
cant amount of biological information (e.g., genomes and contraction, and exacerbate neurohormonal activation.
proteomes) to large-scale clinical data (i.e., precision While there has been no head-to-head comparison for
medicine), which will enable the selection of the optimal rate or volume of fluid removal in this setting, some au-
treatment option(s) for individual patients with heart thors have used less aggressive fluid removal in patients

6 Cardiorenal Med 2023;13:1–8 Kazory/Sgarabotto/Ronco

DOI: 10.1159/000527204
with right-sided heart failure and those with tenuous he- that allows ambulatory ultrafiltration to be performed
modynamic status [30, 35]. slowly and continuously could eliminate clinically signif-
Due to the significant adverse impact of persistent icant hemodynamic changes and obviate the need for
congestion on the outcomes, in cases where the patient spending several hours attached to a stationary ultrafil-
shows slight deterioration in renal function while still flu- tration device.
id overloaded, it might be reasonable to favor complete
decongestion over preservation of renal function, espe-
cially if the increase in serum creatinine is not significant Conflict of Interest Statement
and urine output is preserved. With the advent of newer
Amir Kazory has the following potential conflicts of interest:
devices that are dedicated to ultrafiltration therapy and
Baxter, Inc. (Cardiology Advisory Board and consultancy fee), Nu-
are user- friendly and portable, it is conceivable that the Wellis, Inc. (Medical Advisory Board and consultancy fee), Re-
use of this modality will expand over the next few years lypsa, Inc. (consultancy fee), and W.L.Gore Inc. (consultancy fee),

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as the data on its various practical aspects, such as optimal Elsevier (consultancy fee). Luca Sgarabotto has no conflicts. Clau-
timing of initiation and termination of therapy, continues dio Ronco in the last 3 years has been consulting or part of advi-
sory boards for Astute, Baxter, Biomerieux, B.Braun, Cytosor-
to emerge. Moreover, ultrafiltration therapy might prove
bents, ESTOR, FMC, GE, Jafron, Medtronic, and Toray.
useful in other clinical settings where active and prompt
volume management is of utmost importance (e.g., post
cardiac surgery, burn units, right-sided heart failure after Funding Sources
left ventricular assist device implantation). Currently,
some centers that are specialized in the care of patients No specific financial support was obtained for preparation of
with heart failure provide transition units where the pa- this article.
tients with progressive fluid overload can be treated with
intravenous diuretics without the need for admission to
the hospital. If future studies confirm the safety of ultra- Author Contributions
filtration therapy in the ambulatory setting, it can be used
Amir Kazory: conceptualization, gathering the data, and pre-
in transition units for efficient fluid removal and preven- paring the draft. Luca Sgarabotto: critical review of the manuscript.
tion of hospital admission for patients with persistent or Claudio Ronco: conceptualization and critical review of the manu-
worsening fluid overload despite treatment with diuret- script.
ics. Similar to current home-based renal replacement
therapies, with recent advances in telemedicine technol-
ogy and simplified devices, the application of ultrafiltra- Data Availability Statement
tion can potentially expand beyond in-center therapy in
the future and be safely performed by patients in the com- Not applicable (review article).
fort of their home. Furthermore, a small wearable device

References
1 Benjamin EJ, Blaha MJ, Chiuve SE, Cushman 4 Fang J, Mensah GA, Croft JB, Keenan NL. congestion causes inflammation, neurohor-
M, Das SR, Deo R, et al. Heart disease and Heart failure-related hospitalization in the monal, and endothelial cell activation. Eur
stroke statistics-2017 update: a report from U.S., 1979 to 2004. J Am Coll Cardiol. 2008; Heart J. 2014;35(7):448–54.
the American Heart Association. Circulation. 52(6):428–34. 8 Gupta R, Testani J, Collins S. Diuretic resis-
2017;135(10):e146–603. 5 Heidenreich PA, Albert NM, Allen LA, tance in heart failure. Curr Heart Fail Rep.
2 Ambrosy AP, Fonarow GC, Butler J, Chioncel Bluemke DA, Butler J, Fonarow GC, et al. 2019;16(2):57–66.
O, Greene SJ, Vaduganathan M, et al. The Forecasting the impact of heart failure in the 9 ter Maaten JM, Valente MAE, Damman K,
global health and economic burden of hospi- United States: a policy statement from the Hillege HL, Navis G, Voors AA. Diuretic re-
talizations for heart failure: lessons learned American Heart Association. Circ Heart Fail. sponse in acute heart failure-pathophysiolo-
from hospitalized heart failure registries. J 2013 May;6(3):606–19. gy, evaluation, and therapy. Nat Rev Cardiol.
Am Coll Cardiol. 2014;63(12):1123–33. 6 Munir MB, Sharbaugh MS, Thoma FW, 2015 Mar;12(3):184–92.
3 Crespo-Leiro MG, Anker SD, Maggioni AP, Nisar MU, Kamran AS, Althouse AD, et al. 10 Voors AA, Davison BA, Teerlink JR, Felker
Coats AJ, Filippatos G, Ruschitzka F, et al. Eu- Trends in hospitalization for congestive heart GM, Cotter G, Filippatos G, et al. Diuretic re-
ropean society of cardiology heart failure failure, 1996–2009. Clin Cardiol. 2017;40(2): sponse in patients with acute decompensated
long-term registry (ESC-HF-LT): 1-year fol- 109–19. heart failure: characteristics and clinical out-
low-up outcomes and differences across re- 7 Colombo PC, Onat D, Harxhi A, Demmer come: an analysis from RELAX-AHF. Eur J
gions. Eur J Heart Fail. 2016;18(6):613–25. RT, Hayashi Y, Jelic S, et al. Peripheral venous Heart Fail. 2014;16(11):1230–40.

Ultrafiltration for Heart Failure Cardiorenal Med 2023;13:1–8 7

DOI: 10.1159/000527204
11 Kazory A, Elkayam U. Cardiorenal interac- 21 Rao VS, Ivey-Miranda JB, Cox ZL, Riello R, 31 Ross EA, Kazory A. Ultrafiltration therapy for
tions in acute decompensated heart failure: Griffin M, Fleming J, et al. Natriuretic equa- cardiorenal syndrome: physiologic basis and
contemporary concepts facing emerging con- tion to predict loop diuretic response in pa- contemporary options. Blood Purif. 2012;
troversies. J Card Fail. 2014;20(12):1004–11. tients with heart failure. J Am Coll Cardiol. 34(2):149–57.
12 Kazory A, Ronco C. Emergence of chloride as 2021 Feb 16;77(6):695–708. 32 Grodin JL, Carter S, Bart BA, Goldsmith SR,
an overlooked cardiorenal connector in heart 22 Kazory A. Cardiorenal syndrome: ultrafiltra- Drazner MH, Tang WHW. Direct compari-
failure. Blood Purif. 2020;49(1–2):219–21, tion therapy for heart failure: trials and tribu- son of ultrafiltration to pharmacological de-
13 Eshaghian S, Horwich TB, Fonarow GC. Rela- lations. Clin J Am Soc Nephrol. 2013; 8(10): congestion in heart failure: a per-protocol
tion of loop diuretic dose to mortality in ad- 1816–28. analysis of CARRESS-HF. Eur J Heart Fail.
vanced heart failure. Am J Cardiol. 2006 Jun 23 Canaud B, Leblanc M, Leray-Moragues H, 2018;20(7):1148–56.
15;97(12):1759–64. Delmas S, Klouche K, Beraud JJ. Slow con- 33 Kazory A, Costanzo MR. The never-ending
14 Peacock WF, Costanzo MR, De Marco T, tinuous and daily ultrafiltration for refractory quest for the appropriate role of ultrafiltra-
Lopatin M, Wynne J, Mills RM, et al. Impact congestive heart failure. Nephrol Dial Trans- tion. Eur J Heart Fail. 2019;21(7):949.
of intravenous loop diuretics on outcomes of plant. 1998;13(Suppl 4):51–5. 34 Ahmad T, Jackson K, Rao VS, Tang WHW,
patients hospitalized with acute decompen- 24 Agostoni PG, Marenzi GC, Pepi M, Doria E, Brisco-Bacik MA, Chen HH, et al. Worsening
sated heart failure: insights from the AD- Salvioni A, Perego G, et al. Isolated ultrafiltra- renal function in patients with acute heart

Downloaded from http://karger.com/crm/article-pdf/13/1/1/4115678/000527204.pdf by Universidad Peruana Cayetano user on 04 October 2024

HERE registry. Cardiology. 2009; 113(1): 12– tion in moderate congestive heart failure. J failure undergoing aggressive diuresis is not
9. Am Coll Cardiol. 1993;21(2):424–31. associated with tubular injury. Circulation.
15 Hasselblad V, Stough WG, Shah MR, Lokh- 25 Pepi M, Marenzi GC, Agostoni PG, Doria E, 2018;137(19):2016–28.
nygina Y, O’Connor CM, Califf RM, et al. Re- Barbier P, Muratori M, et al. Sustained car- 35 Costanzo MR, Negoianu D, Jaski BE, Bart BA,
lation between dose of loop diuretics and out- diac diastolic changes elicited by ultrafiltra- Heywood JT, Anand IS, et al. Aquapheresis
comes in a heart failure population: results of tion in patients with moderate congestive versus intravenous diuretics and hospitaliza-
the ESCAPE trial. Eur J Heart Fail. 2007;9(10): heart failure: pathophysiological correlates. tions for heart failure. JACC Heart Fail. 2016;
1064–9. Heart. 1993;70(2):135–40. 4(2):95–105.
16 Gheorghiade M, Filippatos G. Reassessing 26 Jaski BE, Ha J, Denys BG, Lamba S, Trupp RJ, 36 Jain A, Agrawal N, Kazory A. Defining the
treatment of acute heart failure syndromes: Abraham WT. Peripherally inserted veno-ve- role of ultrafiltration therapy in acute heart
the ADHERE registry. Eur Heart J Suppl. nous ultrafiltration for rapid treatment of vol- failure: a systematic review and meta-analy-
2005;7(Suppl l_B):813–B19. ume overloaded patients. J Card Fail. 2003; sis. Heart Fail Rev. 2016 Sep;21(5):611–9.
17 Felker GM, Ellison DH, Mullens W, Cox ZL, 9(3):227–31. 37 Costanzo MR, Fonarow GC, Rizzo JA. Ultra-
Testani JM. Diuretic therapy for patients with 27 Costanzo MR, Saltzberg M, O’Sullivan J, So- filtration versus diuretics for the treatment of
heart failure: JACC state-of-the-art review. J botka P. Early ultrafiltration in patients with fluid overload in patients with heart failure: a
Am Coll Cardiol. 2020;75(10):1178–95. decompensated heart failure and diuretic re- hospital cost analysis. J Med Econ. 2019;22(6):
18 Hodson DZ, Griffin M, Mahoney D, Raghav- sistance. J Am Coll Cardiol. 2005; 46(11): 577–83.
endra P, Ahmad T, Turner J, et al. Natriuretic 2047–51. 38 Giglioli C, Landi D, Cecchi E, Chiostri M,
response is highly variable and associated 28 Costanzo MR, Guglin ME, Saltzberg MT, Jes- Gensini GF, Valente S, et al. Effects of UL-
with 6-month survival: insights from the sup ML, Bart BA, Teerlink JR, et al. Ultrafil- TRAfiltration vs. DIureticS on clinical, biohu-
ROSE-AHF trial. JACC Heart Fail. 2019;7(5): tration versus intravenous diuretics for pa- moral and haemodynamic variables in pa-
383–91. tients hospitalized for acute decompensated tients with deCOmpensated heart failure: the
19 Verbrugge FH, Nijst P, Dupont M, Penders J, heart failure. J Am Coll Cardiol. 2007; 49(6): ULTRADISCO study. Eur J Heart Fail. 2011;
Tang WW, Mullens W. Urinary composition 675–83. 13(3):337–46.
during decongestive treatment in heart failure 29 Costanzo MR, Saltzberg MT, Jessup M, Teer- 39 Hanna MA, Wilson Tang W, Teo BW, O’Neill
with reduced ejection fraction. Circ Heart link JR, Sobotka PA. Ultrafiltration is associ- JO, Weinstein DM, Lau SM, et al. Extracorpo-
Fail. 2014;7(5):766–72. ated with fewer rehospitalizations than con- real ultrafiltration vs. conventional diuretic
20 Testani JM, Hanberg JS, Cheng S, Rao V, On- tinuous diuretic infusion in patients with de- therapy in advanced decompensated heart
yebeke C, Laur O, et al. Rapid and highly ac- compensated heart failure: results from failure. Congest Heart Fail. 2012;18(1):54–63.
curate prediction of poor loop diuretic natri- UNLOAD. J Card Fail. 2010;16(4):277–84. 40 Marenzi G, Muratori M, Cosentino ER, Rin-
uretic response in patients with heart failure. 30 Bart BA, Goldsmith SR, Lee KL, Givertz MM, aldi ER, Donghi V, Milazzo V, et al. Continu-
Circ Heart Fail. 2016;9(1):e002370. O’Connor CM, Bull DA, et al. Ultrafiltration ous ultrafiltration for congestive heart failure:
in decompensated heart failure with cardiore- the CUORE trial. J Card Fail. 2014; 20(1): 9–
nal syndrome. N Engl J Med. 2012; 367(24): 17.
2296–304.

8 Cardiorenal Med 2023;13:1–8 Kazory/Sgarabotto/Ronco

DOI: 10.1159/000527204