CJASN ePress. Published on October 28, 2020 as doi: 10.2215/CJN.

09670620

Intravenous Albumin for Mitigating Hypotension and

Augmenting Ultrafiltration during Kidney
Replacement Therapy
Nicole Hryciw,1 Michael Joannidis,2 Swapnil Hiremath ,3 Jeannie Callum,4,5 and Edward G. Clark 3

Abstract 1
Department of
Among its many functions, owing to its oversized effect on colloid oncotic pressure, intravascular albumin helps Medicine, University
preserve the effective circulatory volume. Hypoalbuminemia is common in hospitalized patients and is found of Ottawa, Ottawa,
Ontario, Canada
especially frequently in patients who require KRT either for AKI or as maintenance hemodialysis. In such patients, 2
Division of Intensive
hypoalbuminemia is strongly associated with morbidity, intradialytic hypotension, and mortality. Intravenous Care and Emergency
albumin may be administered in an effort to prevent or treat hypotension or to augment fluid removal, but this Medicine, Department
practice is controversial. Theoretically, intravenous albumin administration might prevent or treat hypotension by of Internal Medicine,
promoting plasma refilling in response to ultrafiltration. However, clinical trials have demonstrated that albumin Medical University
Innsbruck, Innsbruck,
administration is not nearly as effective a volume expander as might be assumed according to its oncotic properties. Austria
Although intravenous albumin is generally considered to be safe, it is also very expensive. In addition, there are 3
Division of
potential risks to using it to prevent or treat intradialytic hypotension. Some recent studies have suggested that Nephrology,
hyperoncotic albumin solutions may precipitate or worsen AKI in patients with sepsis or shock; however, the overall Department of
Medicine, University
evidence supporting this effect is weak. In this review, we explore the theoretical benefits and risks of using
of Ottawa and the
intravenous albumin to mitigate intradialytic hypotension and/or enhance ultrafiltration and summarize the Ottawa Hospital
current evidence relating to this practice. This includes studies relevant to its use in patients on maintenance Research Institute,
hemodialysis and critically ill patients with AKI who require KRT in the intensive care unit. Despite evidence of its Ottawa, Ontario,
frequent use and high costs, at present, there are minimal data that support the routine use of intravenous albumin Canada
4
Department of
during KRT. As such, adequately powered trials to evaluate the efficacy of intravenous albumin in this setting are Laboratory Medicine
clearly needed. and Molecular
CJASN 16: ccc–ccc, 2021. doi: https://doi.org/10.2215/CJN.09670620 Diagnostics,
Sunnybrook Health
Sciences Centre,
Toronto, Ontario,
Introduction Management of hypotension specifically during KRT Canada
5
Albumin is an important 66-kD protein that is syn- (i.e., intradialytic hypotension [IDH]) can be challenging Department of
thesized solely in the liver and serves many roles in both critically ill patients on KRT and in patients on Laboratory Medicine
and Pathobiology,
within the human body (1,2). The metabolism of maintenance hemodialysis (HD). Prompt identification University of Toronto,
albumin is summarized in Figure 1. Although and reversal of IDH during treatment are important, Toronto, Ontario,
accounting for only approximately half of the plasma not only for symptomatic relief but also to mitigate the Canada
protein content, albumin is responsible for generating potential consequences of hypoperfusion (9). Both
an even greater proportion (approximately 70%–80%) hyperoncotic (20%–25%) and iso-oncotic (4%–5%) in- Correspondence:
of intravascular colloid oncotic pressure due to its Dr. Edward G. Clark,
travenous albumin have been used in place of saline Division of
capacity to attract water (1–3). Beyond that, endog-
for volume resuscitation in this setting, but this Nephrology,
enous albumin serves many other important functions Department of
practice is controversial. In the context of hemody-
in the human body. These include maintenance of the Medicine, The Ottawa
namic instability due to intravascular hypovolemia, Hospital–Riverside
redox state as well as molecular and drug transport
hyperoncotic albumin can theoretically be expected Campus, 1967
(4,5). Given albumin’s many functions and that its
to shift water into the vasculature, which may in Riverside Drive,
synthesis is dependent on adequate dietary protein Ottawa, ON K1H
intake, it is not surprising that poor outcomes are turn improve hemodynamic stability and then permit
7W9, Canada. Email:
associated with hypoalbuminemia across a range of greater overall fluid removal via ultrafiltration. There edclark@toh.ca
medical conditions (6,7). The corollary to this is that are several other properties of albumin that could
administering intravenous albumin could theoreti- theoretically be helpful in the settings of dialysis-
cally be beneficial to patients who are hypoalbumi- requiring AKI and maintenance HD, such as its anti-
nemic or hypotensive due to intravascular volume inflammatory action, antioxidant properties, and role
depletion. To that end, exogenous human albumin in promoting microvascular circulation (10–12).
products have been used as therapeutic agents Nonetheless, not all IDH episodes are due to hypovo-
since their introduction into the medical field in lemia (13,14), and few studies have specifically ad-
the 1940s (8). dressed the role of intravenous albumin in preventing

www.cjasn.org Vol 16 May, 2021 Copyright © 2021 by the American Society of Nephrology 1
2 CJASN
Figure 1. | Metabolism of albumin and causes of hypoalbuminemia. Overview of albumin metabolism and selected mechanisms for the
development of hypovolemia. Not shown is the normal breakdown of albumin, which has a t1/2 of approximately 3 weeks. Hypoalbuminemia
results from some combination of decreased production, increased losses, acute dilution (not shown), or increased shift out of the vascular space.
*Increased skin and gastrointestinal losses typically occur in the context of concurrent, increased capillary leak.
or treating IDH. The objective of this narrative review is to
highlight knowledge gaps in the use of intravenous albumin
to prevent or treat IDH and/or facilitate ultrafiltration. In
this article, we will summarize the physiology of albumin,
explore the implications of hypoalbuminemia, and discuss
the potential risks and benefits of intravenous albumin use
for these indications.
Incidence and Implications of Hypoalbuminemia
The etiology of hypoalbuminemia in most patients is
likely multifactorial. As detailed in Figure 1, several
mechanisms are implicated, including increased capillary
permeability, exudative losses, breakdown, occult protein
wasting enteropathy in critical illness and decreased liver
production (4,15). In patients with AKI, the extent to which
proteinuria due to tubular damage contributes to hypo-
albuminemia is unclear.
Marked hypoalbuminemia (when defined as serum
albumin ,25 g/L) correlates with a 34% in-hospital mor-
tality rate compared with a 2% mortality rate for hospital-
ized patients with normal albumin levels of 35–45 g/L
(6).The prevalence of hypoalbuminemia in patients on
maintenance HD is even greater than in hospitalized
patients, reported to be as high as 33% in a study that
defined hypoalbuminemia as serum albumin ,35 g/L (16).
In both patients on incident HD and patients on mainte-
nance HD, hypoalbuminemia is strongly associated with
morbidity and mortality (16–18). To a large extent, the
correlation between hypoalbuminemia and worse outcomes
may simply be due to hypoalbuminemia serving as a
marker for poor nutrition and/or inflammation in chronic
or severe illness. Notably, the correlation between hypo-
albuminemia and increased mortality in patients on main-
tenance HD is markedly less in those with normal
C-reactive protein levels (19). Similarly, hypoalbuminemia
is independently associated with IDH (20,21), theoretically
due to its effect on oncotic pressure in the circulation;
however, residual confounding on the basis of concurrent
chronic or severe illness is very likely.
Physiology Relevant to Intravenous Albumin
Administration for Intradialytic Hypotension
Endogenous albumin is distributed between the intra-
vascular (40%) and extravascular (60%) space, where it is
the most abundant protein in both compartments (3). Serum
albumin is responsible for approximately 80% of the colloid
oncotic pressure within the vasculature (2). Regarding
intravenous albumin, 5% albumin is iso-oncotic with
human plasma, whereas 25% albumin is approximately
five times more osmotically active.
From a physiologic standpoint, the oncotic action of
albumin infusion, which is calculated to attract a total of
18 ml of water per 1 g of protein, would be expected to
expand plasma volume to a greater degree than the same
volume of normal saline (2). Theoretically, this would be
helpful in a setting where a physician desires to minimize
volume overload, retaining fluid intravascularly to reduce
third spacing. On the basis of its oncotic properties, one
would expect that intravenous albumin administration
would expand intravascular plasma by a volume that is
several times greater than crystalloid alone (3). In intensive
care unit (ICU) studies involving critically ill patients, this
ratio was found to be much lower than expected, with only
approximately 1.4 L saline necessary to result in an
equivalent volume of intravascular expansion as 1 L of
human albumin product (22,23). Notably, in a trial
involving 321 critically ill patients requiring fluid re-
suscitation, the cumulative volume of resuscitation fluid
was reduced by 600 ml over 48 hours through the use of
CJASN 16: ccc–ccc, May, 2021
20% versus 4%–5% albumin fluids, indicating that volume
effects depend on the albumin concentration applied (24).
Despite classic teaching, recent studies indicate that fluid
movement across the capillary bed into the interstitial
space and subsequent reabsorption are not influenced by
Starling forces, such as oncotic pressure, in the same
manner as previously thought (25). This issue and the
role of the endothelial glycocalyx in regulating albumin
distribution are detailed in Figure 2 and in Supplemental
Material. Supplemental Material also includes additional
information regarding the antioxidant and anti-
inflammatory roles of albumin in patients with dialysis-
requiring AKI or those on maintenance HD.
Albumin Usage for Intradialytic Hypotension
Currently, there are few generally agreed upon indica-
tions for intravenous albumin (3). These indications include
spontaneous bacterial peritonitis, large volume paracent-
esis, and hepatorenal syndrome (3). Despite the apparent
effectiveness of albumin in the setting of end stage liver
disease, it is unclear the extent to which that hinges on
pharmacologic cointerventions or other disease-specific
factors. Newly reported data from a randomized controlled
trial (n5828) that assessed albumin normalization using
20% intravenous albumin in hospitalized patients with
cirrhosis and serum albumin ,30 g/L indicates that this
strategy did not significantly improve 28-day mortality
(China et al., abstract). Furthermore, the utility of intrave-
nous albumin products is widely debated for primary
volume expansion and specific to nephrology, nephrotic
syndrome, enhancement of ultrafiltration/prevention of
IDH, or treatment of refractory IDH.
IDH is multifactorial (i.e., not always due to volume
depletion) (14), and thus, fluid administration often may
not be the most appropriate response. The initial clinical
response to IDH is usually to place the patient in Trende-
lenburg position, pause ultrafiltration, or stop treatment
altogether, prior to administering any type of fluid
(9,15,26). In a study that included 2559 inpatient HD
sessions, of the 433 sessions complicated by IDH, a
protocolized approach that used albumin administration
as the last line of treatment resulted in reversal of
hypotension for 91% of patients who did not receive
albumin and in another 2% overall who did get it (27).
Currently, normal saline is generally advised as first line if
fluid resuscitation is required to restore BP in this setting
(28). The potential benefits and risks of using intravenous
albumin to enhance ultrafiltration and/or prevent or treat
IDH are detailed in Table 1. One unique consideration of
the use of albumin in this setting is that its use runs counter
to the usual overall goal of net fluid removal with KRT.
This is especially the case when considering the use of
albumin for prevention of IDH (or to facilitate overall fluid
removal) where the alternative would be to not give any
fluid. One must also consider that there is an accompany-
ing sodium load as albumin formulations typically have a
sodium concentration similar to that of normal saline (as
detailed in Table 2). This is a particularly relevant concern
given that worse outcomes are found in both critically ill
patients and patients on maintenance HD with more fluid
overload (29–32). The basis for intravenous albumin use in
Intravenous Albumin during Kidney Replacement Therapy, Hryciw et al. 3
the setting of KRT (including maintenance HD) is generally
extrapolated from the results of studies in critical care but,
as further discussed below, is not backed by high-quality
trials designed specifically to assess its effect on KRT-
related outcomes. Nonetheless, recent data from three large
academic medical centers in Ontario, Canada provide
ancillary evidence that albumin is frequently used for
patients for the prevention or treatment of IDH: approx-
imately 30% of all inpatients who received any form of KRT
while hospitalized were also administered albumin (25%)
on at least 1 day that they underwent KRT treatment (33).
Safety of Intravenous Albumin Administration
The safety and efficacy of intravenous albumin admin-
istration have been scrutinized heavily in the past due to its
cost in comparison with crystalloid solutions and concerns
raised by a flawed 1998 metanalysis (34) that included
studies done prior to significant quality improvements in
the production of albumin (35). Table 1 includes additional
details regarding albumin safety. The issue of intravenous
iso-osmolar albumin safety, specifically in the setting of
fluid resuscitation, was largely resolved with the publica-
tion of the Saline versus Albumin Fluid Evaluation (SAFE)
study in 2004 (36). A heterogenous group of 6997 patients
in the ICU were randomized to receive either 4% albumin
or normal saline for intravascular fluid resuscitation, with
the primary outcome being all-cause mortality. There was
no significant difference in death at 28 days between the two
groups. Furthermore, there was no difference in mechanical
ventilation, need for KRT, or length of ICU stay. Subgroup
and post hoc analyses of 460 patients suggested possible
increased risk of death with albumin administration in
patients with traumatic brain injury (Relative Risk, 1.63;
95% confidence interval [95% CI], 1.17 to 2.26; P50.003), as
well as increased intracranial pressure in those with intracra-
nial pressure monitoring (36–38).
Some recent studies have suggested a risk of AKI asso-
ciated with the use of hyperoncotic albumin. A cohort
study of 984 patients in the postoperative cardiac surgery
period found a dose-dependent increase in AKI with
hyperoncotic albumin administration according to a pro-
pensity score analysis (39). Similarly, a retrospective cohort
study of 11,512 patients in postoperative shock, the majority
of whom had undergone cardiac surgery, found a greater
risk of AKI (odds ratio [OR], 1.10; 95% CI, 1.04 to 1.17;
P50.002) in those exposed to hyperoncotic albumin (40).
Generally, observational studies that have assessed the
relationship between hyperoncotic albumin and AKI are
significantly limited by the potential for residual confound-
ing according to the indication for hyperoncotic albumin
administration. In contrast to the observational data re-
viewed above, a recent randomized control trial of 220
patients undergoing off-pump coronary artery bypass
surgery revealed that preoperative treatment with 20%
hyperoncotic albumin for patients with albumin ,40 g/L
was associated with significantly less postoperative AKI
than occurred in patients given the same volume of normal
saline (13.7% versus 25.7%, respectively; P50.05) (41).
Furthermore, a 2010 metanalysis evaluating the use of
seven trials utilizing hyperoncotic albumin found that
albumin was protective against kidney insult (OR, 0.24;
4 CJASN

Figure 2. | Albumin movement across the capillary endothelium in health and disease. (A) In the historical model of capillary fluid exchange on
the basis of Starlings forces, net plasma filtration was believed to occur at the arteriolar end of the capillary due to predominant hydrostatic force
(blue arrows), which then transitioned to net reabsorption as plasma reached the venular end due to increasing oncotic drive from the interstitium,
back into the capillary lumen (green arrows) (additional details are in Supplemental Material). Some research now suggests that there is, in fact,
little to no reabsorption at the level of the capillary in the steady state (but it still may occur during acute hypovolemia). (B and C) A simplified
version of the endothelial glycocalyx in its role as a selectively permeable barrier for fluid resorption. Hydrostatic pressure is the predominant
force in this new model regulated by the glycocalyx, with little to no effect from osmotic forces between the vascular lumen and the interstitium.
Instead, the endothelial glycocalyx functions to create an osmotic gradient (orange arrow) between the capillary lumen and the subglycocalyx
space that opposes outward shift of fluid but does not reverse the direction of fluid flow. Both the interstitium and the subglycocalyx space have
low oncotic content, resulting in negligible oncotic forces between the two spaces and overall net ultrafiltration throughout plasma transit in
capillary microcirculation. Fluid that has shifted into the interstitium is resorbed solely through the lymphatic system, with exceptions (including
the kidneys). (D) Fluid shift in the setting of a damaged endothelial glycocalyx from stressors, including inflammation, uremia, arteriosclerosis,
hyperglycemia, and hypovolemia, among many others. With a damaged endothelial glycocalyx, capillaries have increased permeability to both
serum proteins and fluid, leading to increased net fluid movement into the interstitium and interstitial edema when the lymphatic drainage
capacity is exceeded.
CJASN 16: ccc–ccc, May, 2021 Intravenous Albumin during Kidney Replacement Therapy, Hryciw et al. 5

Table 1. Potential benefits and risks of intravenous albumin for patients on KRT

Benefits/Risks Related Evidence Comments

Potential benefits
Reduced No data support use of iso-oncotic albumin. ,150 patients included across all trials
hypotension, Hyperoncotic albumin trials report hemodynamic
enhanced benefits (Table 3)
ultrafiltration
Anti- Patients on maintenance treated with 20% albumin Potential effect on patient outcomes is unclear
inflammatory have reduced markers of inflammation
effects (Supplemental Table 1)
Potential risks
Unnecessary fluid Observational data: less net fluid removal reported This finding likely confounded according to
accumulation for inpatient HD sessions when 25% albumin indication for albumin use
was given
AKI due to Finding of recent observational studies but Implications for kidney recovery in AKI,
hyperoncotic hyperoncotic albumin never found to cause AKI preservation of residual function in HD. Trial
albumin across multiple trials data are very reassuring
administration
Aluminum toxicity Historically, trace metals were introduced during Very unlikely given manufacturing improvements
manufacturing
Infection Theoretical risk of transmission of viruses, prions No cases have been reported
Other Anaphylaxis and hypotension have been reported Extremely rare relative to other blood products

HD, hemodialysis.

95% CI, 0.12 to 0.48; P,0.001) and mortality (OR, 0.52; 95%
CI, 0.28 to 0.95; P50.05), but the indication for albumin
administration in the included studies was quite variable,
with many patients with liver cirrhosis included (42). The
potential occurrence of renal tubular damage in response to
administration of other hyperosmolar fluids is well estab-
lished (43); however, albumin is not an exogenous colloid
and was not found to have accumulated in early kidney
autopsy studies of a small number of patients who had
received very high volumes of 25% albumin (44). More
broadly, a recent network metanalysis including ten studies
(6664 patients) with direct comparison could not establish
an increased risk for KRT when comparing albumin with
crystalloids with moderate certainty (although this included
studies of iso-oncotic albumin) (45). In a trial of patients
with severe sepsis (n51818), those randomized to 20%
albumin plus crystalloid (targeting albumin .30 g/L) were
not at increased risk of severe AKI as a predefined
secondary outcome (serum creatinine .300 mmol/L) com-
pared with those randomized to crystalloid alone (21). A
post hoc analysis also found no difference between the
groups when AKI was defined according to RIFLE criteria.
On balance, we conclude that hyperoncotic intravenous
albumin is very unlikely to be directly harmful to the
kidneys. This is reassuring with respect to the potential
effect on kidney recovery in albumin-treated patients with
AKI and preservation of residual kidney function in those
on maintenance HD.
Effectiveness of Intravenous Albumin for Patients
Receiving Kidney Replacement Therapy
A recent large observational study assessed the use of
intravenous 25% albumin for improving ultrafiltration in
238 inpatients (973 HD sessions) at a single large US center
(46). Contrary to what might be expected, albumin use
(compared with no albumin use) was associated with less
ultrafiltration achieved (1242 versus 1899 ml, respectively;
P,0.001). Despite adjustment, this result may have been
confounded by additional factors related to the indication
for which albumin was given, as this study sought to
specifically assess instances when albumin had been given
to enhance ultrafiltration.
As summarized in Table 3, clinical trials that have
specifically assessed the use of intravenous albumin for
mitigating hypotension and/or augmenting ultrafiltration
(47–51) have generally been small (with all having been
conducted at single centers) and are heterogeneous with

Table 2. Fluids used in the treatment or prevention of intradialytic hypotension

Fluid Sodium Content, mEq/L Protein Content, g/L pH Cost per 100 ml, US Dollars

Iso-oncotic albumina 140–145 4–5 7 15.91

Hyperoncotic albumina 140–145 20–25 7 108.75
Normal saline 154 0 5.5 0.10
Hydroxyethyl starch Contraindicated in AKI and maintenance HD

HD, hemodialysis.
a
Average values are reported for albumin products (57). Specific manufacturer-reported details for albumin brands available in the
United States and Canada are reported in Supplemental Table 1.
 6
CJASN
Table 3. Summary of trials assessing intravenous albumin for intradialytic hypotension

Author
Study Designa Study Size Population Intervention Main Results Study Conclusions
[Year]

Macedo et al. Randomized, n565 (249 Inpatients (maintenance 25% albumin (100 ml) versus NS Albumin resulted in significantly less IDH Pretreatment with 25%
[2018 crossover HD HD or for AKI) with (100 ml) prior to start of (defined according to SBP decrease $30 or albumin resulted in less
abstract] sessions) serum albumin HD session $20 mm Hg or nadir SBP ,90 mm Hg frequent IDH
,30 g/L
Rostoker et al. Randomized, n510 (HD Outpatients on 20% albumin (200 ml) versus 4% Fewer episodes of SBP,100 mm Hg in six 20% albumin improved
[2011] (49) single- sessions maintenance HD gelatin (200 ml) given patients (60%) with albumin hemodynamic
blind, not “prone to IDH” throughout HD parameters
crossover specified)
study
Knoll et al. Randomized, n545 (135 Outpatients on 5% albumin (250 ml) versus NS No significant differences in primary 5% albumin was not
[2004] (48) blinded, HD maintenance HD (250-ml) boluses (up to 33 per outcome (percentage of target UF superior to NS for
crossover sessions) session) for symptomatic IDH achieved) or other treatment of
study hemodynamic measures symptomatic IDH
van der Randomized, n59 (27 Outpatients on 20% albumin (100 ml) versus 3% 20% albumin (and HES) sessions: lower drop 20% albumin was superior
Sande et al. nonblinded, HD maintenance HD with saline (33 ml) versus 10% HES in BV and lower drop in end treatment to 3% saline for
[2000] (50) crossover sessions) recurrent IDH (100 ml) for BP drop SBP versus 3% saline preventing IDH
study and CHF
van der Randomized, n510 (30 Outpatients on 20% albumin (100 ml) versus NS Albumin and HES both maintained a 20% albumin was superior
Sande et al. nonblinded, HD maintenance HD; (100 ml) versus 10% HES (100 significantly smaller change in BV than to NS for preserving BV
[1999] (51) crossover sessions) CHF excluded ml) for 10% BV decline NS (P50.05). No significant differences during HD
study in SBP
Jardin et al. Nonblinded, n58 (53 Inpatients with sepsis HD circuit primed with either Albumin sessions: more UF achieved and Priming HD circuit with
[1982] (47) crossover HD and anuric AKI 300 ml 17.5% albumin or higher MAP during treatment versus NS 17.5% albumin limited
study sessions) 300 ml NS IDH, facilitated
ultrafiltration

n, number of patients; HD, hemodialysis; NS, normal saline; IDH, intradialytic hypotension; SBP, systolic BP; UF, ultrafiltration; CHF, congestive heart failure; HES, hydroxyethyl starch; BV,
blood volume; MAP, mean arterial pressure.
a
All single-center studies.
CJASN 16: ccc–ccc, May, 2021
respect to the intervention (iso- or hyperoncotic albumin,
volume, and timing/indications for administration) and
outcomes assessed. In the largest trial involving mainte-
nance HD, Knoll et al. (48) sought to assess the use of iso-
oncotic (5%) albumin infusion versus normal saline for the
acute management of IDH during maintenance HD. Par-
ticipants were randomized to one of two possible se-
quences in a crossover study design following three
dialysis sessions affected by IDH in a given patient.
Individuals in one sequence were treated with 5% albumin
infusion for the first dialysis session complicated by IDH,
followed by the use of normal saline for the remaining two
dialysis sessions where IDH occurred. In the other se-
quence, treatment was reversed, and patients were treated
with normal saline during the first dialysis session com-
plicated by IDH and subsequently, 5% albumin in the
remaining sessions. Patients were placed in Trendelenberg
position, and ultrafiltration was stopped prior to the
administration of study fluid; however, the number of
patients whose hypotension resolved prior to any fluid
administration was not reported. The primary outcome of
the study was percentage of target ultrafiltration achieved
on the basis of pre- and postdialysis weights. Approxi-
mately 84% and 80% ultrafiltration values were achieved in
the albumin and normal saline treatment groups, respec-
tively, with no significant difference detected between the
two groups (P50.14). Secondary outcomes, including
postdialysis BP, volume of fluid used in the resuscitation
effort, time required to restore BP, or frequency of recurrent
hypotensive episodes, were also not significantly different.
When the Cochrane Group performed a meta-analysis in
2010 to evaluate the use of albumin for IDH in maintenance
HD, the study by Knoll et al. (48) in 2004 was the only study
to meet inclusion criteria for the analysis (28). No random-
ized control trials or other randomized crossover studies of
sufficient quality were identified, and they concluded that
the evidence to support albumin use over normal saline in
the setting of IDH was insufficient (28).
In theory, the use of hyperoncotic albumin has a stronger
theoretical foundation for use in KRT than iso-oncotic
albumin given its potential to result in greater fluid shifts
from the interstitium to the intravascular space. In general,
the small studies that assessed the use of hyperoncotic
albumin did suggest that it led to significant hemodynamic
improvements (47,49–51) (Macedo et al., abstract). The
largest trial that assessed the effect of hyperoncotic albumin
for prevention (rather than treatment) of IDH (reported as
an abstract in 2018) included 65 patients starting HD for
either AKI or as maintenance HD who were randomized to
100 ml of normal saline versus 25% albumin prior to HD
and then alternated between the two fluids for up to six
subsequent HD sessions (249 sessions were included)
(Macedo et al., abstract). According to some of the IDH
definitions assessed (including drop in systolic BP to min-
imum BP during treatment of .20 mm Hg or nadir systolic
BP during treatment ,90 mm Hg), albumin administration
resulted in significantly fewer episodes of IDH (Macedo
et al., abstract).
There is almost no evidence regarding administration
of intravenous albumin for IDH (hemodynamic instability
during KRT [14]) in critically ill patients. The only trial
in critically ill patients was a study that included eight
Intravenous Albumin during Kidney Replacement Therapy, Hryciw et al. 7
patients who were septic (47) (Table 3). A 2018 systematic
review of interventions to prevent hemodynamic instabil-
ity during KRT in critically ill patients did not uncover any
new studies assessing the use of albumin for IDH (52). The
saline versus albumin for extracorporeal fluid removal in
slow low-efficiency dialysis pilot study (53) recently com-
pleted enrollment of 60 critically ill patients randomized to
receive 100 ml of 25% albumin versus normal saline twice
during slow low-efficiency dialysis treatments; however,
the results have not yet been reported.
Costs of Intravenous Albumin Treatment
Establishing evidence-based indications for intravenous
albumin is important given the potential clinical and
societal implications, including the high cost of intravenous
albumin preparations (Table 2) relative to crystalloid fluids
(or relative to not giving anything, if considering its use for
prevention of IDH/augmenting ultrafiltration). Analysis
over a 3-month period at a single center revealed that the
cost associated with albumin use for nonevidence-based
indications was US $48,900 (54). In the SAFE trial (de-
scribed in more detail above), the difference in the cost of
treatment was 75-fold higher for patients randomized to
4% albumin versus crystalloid (36), highlighting the need to
establish whether the theoretical benefits of albumin use
translate into real-world benefits with respect to patient
outcomes. One review from 2004 reported that the base cost
of a single liter of 5% albumin was $232 compared with
,$2.32 for the same volume of normal saline (55). A study
published in 2020 estimated that the median cost per
patient in the ICU for 25% albumin is $417 (56). Another
recently published study evaluated the costs of resuscita-
tion fluids internationally and reported that, after taking
into account the greater volume required to achieve an
equally effective volume challenge, the cost of normal
saline was approximately 27-fold less than for albumin
(57). In our opinion, albumin should be thought of as an
expensive medication whose routine use should be re-
stricted to evidence-based indications, which do not cur-
rently include the prevention or treatment of IDH or
facilitation of ultrafiltration during KRT.
Conclusion
More rigorous studies are needed to determine whether
there is a role for the routine use of intravenous albumin
during KRT. It is possible that hyperoncotic intravenous
albumin use during KRT can improve patient outcomes by
minimizing fluid overload and limiting cardiac, kidney,
and other organ damage potentiated by IDH. Studies to
definitively establish if this is true are not only needed, but
also, they are readily justifiable on the following basis:
there are well-grounded theoretical benefits, and, although
generally safe, there are also potential risks. Beyond that,
intravenous albumin is very expensive, and there is good
evidence that this intervention, tested in fewer than 150
patients in all trials combined, is likely already being given
to tens of thousands of patients for these indications on an
annual basis. If shown to be ineffective in improving
clinically meaningful outcomes, significant resources could
be saved, but if shown to be effective, intravenous albumin
8 CJASN
is widely available, and its use could immediately be more
broadly implemented.
Disclosures
J. Callum reports employment at Sunnybrook Health Sciences
Centre and has received program support funding from Canadian
Blood Services and a clinical trial grant from Octapharma. E. Clark
reports receiving research salary support from the University of
Ottawa, outside the submitted work. S. Hiremath reports receiving
research salary support from the University of Ottawa and serving
on the boards for Hypertension Canada and NephJC, outside the
submitted work. M. Joannidis reports receiving grants and personal
fees from Baxter Healthcare, grants from Fresenius Kabi, and
speakers’ fees from CLS Behring, outside the submitted work. All
remaining authors have nothing to disclose.
Funding
None.
Supplemental Material
This article contains the following supplemental material online at
http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.
09670620/-/DCSupplemental.
Supplemental Material. Additional details regarding albumin
physiology in patients on KRT.
Supplemental Table 1. Albumin formulations available in the
United States and Canada.
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