Intensive Care Med (2022) 48:1368–1381

https://doi.org/10.1007/s00134-022-06851-6

REVIEW

Delivering optimal renal replacement

therapy to critically ill patients with acute
kidney injury
Ron Wald1,2*  , William Beaubien‑Souligny3, Rahul Chanchlani4, Edward G. Clark5, Javier A. Neyra6,
Marlies Ostermann7, Samuel A. Silver8, Suvi Vaara9, Alexander Zarbock10 and Sean M. Bagshaw11

© 2022 Springer-Verlag GmbH Germany, part of Springer Nature

Abstract 
Critical illness is often complicated by acute kidney injury (AKI). In patients with severe AKI, renal replacement therapy
(RRT) is deployed to address metabolic dysfunction and volume excess until kidney function recovers. This review is
intended to provide a comprehensive update on key aspects of RRT prescription and delivery to critically ill patients.
Recently completed trials have enhanced the evidence base regarding several RRT practices, most notably the timing
of RRT initiation and anticoagulation for continuous therapies. Better evidence is still needed to clarify several aspects
of care including optimal targets for ultrafiltration and effective strategies for RRT weaning and discontinuation.
Keywords:  Acute kidney injury, Renal replacement therapy, Intensive care unit, Clinical trials

Introduction Timing of RRT initiation

One of the most controversial and clinically uncertain
Acute kidney injury (AKI) is a frequent complication of
aspects of RRT delivery in the setting of AKI pertains
critical illness and a significant minority of patients with
to patient selection and the optimal circumstances for
AKI receive extracorporeal renal replacement therapy
its initiation. In patients with objective AKI-associated
(RRT) [1]. As a result, it is incumbent on clinicians prac-
complications that are readily controlled by RRT (e.g.,
ticing in the intensive care unit (ICU) to have a robust
medically refractory hyperkalemia, metabolic acidosis
understanding of when to deploy RRT and appreciate the
or volume overload), the decision to commence RRT is
nuances of its prescription. This paper will provide an
unambiguous, assuming RRT is consistent with the over-
updated review of the key considerations germane to the
all goals of care. However, when severe AKI is unaccom-
prescription and delivery of RRT to critically ill patients
panied by such urgency, the role of RRT is less clear. Two
with AKI. Where possible, the focus will be on knowl-
clinical trials published in 2016 provided new knowledge
edge that has emerged since this topic was last reviewed
yet differing answers regarding this question [3, 4]. The
in Intensive Care Medicine [2].
Initiation of Dialysis Early Versus Delayed in the Inten-
sive Care Unit (IDEAL-ICU) trial recruited 488 patients
with severe AKI associated with septic shock and no
urgent indications for RRT initiation. A strategy of early
*Correspondence: Ron.wald@unityhealth.to
1
RRT initiation, as compared to delaying RRT initiation by
Division of Nephrology, St. Michael’s Hospital and the University
of Toronto, 61 Queen Street East, 9‑140, Toronto, ON M5C 2T2, Canada
48  hours, did not reduce mortality at 90  days nor did it
Full author information is available at the end of the article impact on other important clinical outcomes [5].
The multinational Standard versus Accelerated
Renal Replacement Therapy in Acute Kidney Injury

(STARRT-AKI) trial enrolled 3019 participants to test
whether immediate RRT initiation conferred improved
patient outcomes in critically ill patients with Stage 2–3
AKI and no urgent indications for RRT initiation [6].
STARRT-AKI also required clinicians to exclude patients
for whom they lacked clinical equipoise. Practically, this
meant that a clinician who strongly believed that imme-
diate RRT was mandated or that kidney recovery was
imminent, and hence deferral of RRT was necessary,
could trigger exclusion of the patient. The accelerated
strategy entailed RRT initiation within 12  h of meeting
full eligibility. In the standard strategy, RRT was discour-
aged unless an urgent indication emerged (i.e., severe
AKI complications including hyperkalemia, metabolic
acidosis, and severe hypoxia attributed to volume over-
load); or if AKI persisted at 72  h after randomization.
Patients allocated to accelerated RRT initiation com-
menced RRT a median of 6  h from meeting eligibility
criteria whereas those in the standard strategy who initi-
ated RRT did so a median of 31 h from meeting eligibility
criteria; 38% of patients in the standard strategy did not
receive RRT mostly due to recovery of kidney function.
The accelerated strategy did not confer any advantage
with respect to the primary outcome of 90-day all-cause
mortality; however, patients allocated to the accelerated
strategy experienced a higher likelihood of persistent
RRT dependence at 90 days from randomization. Table 1
provides a detailed summary of recent clinical trials that
compared early vs delayed RRT initiation strategies.
Whereas STARRT-AKI demonstrated that early or pre-
emptive RRT initiation did not confer any clear clinical
advantage, it did not address how long RRT could safely
be deferred in the setting of unremitting AKI [7]. The
Artificial Kidney Initiation for Kidney Injury 2 (AKIKI-
2) was a multicenter trial conducted in France that rand-
omized individuals with > 72 h of unresolved Stage 3 AKI
to RRT initiation vs further deferral of RRT until emer-
gence of a clinical urgency or the serum urea surpassed
50  mmol/L. Prolonged delay of RRT initiation did not
increase the number of RRT-free days (the primary out-
come) and in a pre-planned adjusted analysis, this strat-
egy conferred an increased risk for mortality. Figure  1
provides a suggested algorithm for RRT initiation based
on current evidence.
The potential role of biomarkers to predict RRT initiation
The relatively high frequency of spontaneous kidney
recovery in patients with even the most severe degrees of
AKI was highlighted in the delayed arms of the AKIKI,
IDEAL-ICU and STARRT-AKI trials [4–6]. Ideally, all
patients recruited into these trials would have had a
virtual certainty of progressing to RRT with prognosti-
cation enhanced by a variety of readily accessible tools.
1369
Take‑home message 
The evidence base for the delivery of renal replacement therapy to
critically ill patients with acute kidney injury has expanded in recent
years. Several trials have shown no benefit of earlier RRT initiation in
patients with severe AKI. Key persisting areas of uncertainty include
the optimal approach to fluid removal and renal replacement ther‑
apy discontinuation.
Novel AKI biomarkers have the theoretical potential to
anticipate the course of AKI, particularly the probability
of persistent severe AKI and the likelihood for receipt of
RRT.
A meta-analysis of 63 studies including 13 different
biomarkers and over 15,000 patients concluded that sev-
eral biomarkers showed reasonable prediction of future
RRT initiation in critically ill patients with AKI but the
strength of evidence was inadequate to guide decision-
making in routine clinical practice [8]. The pooled areas
under the receiver operating curve (AUROCs) for urine
and blood neutrophil gelatinase-associated lipocalin
(NGAL) were 0.720 (95% confidence interval (CI) 0.638–
0.803) and 0.755 (0.706–0.803), respectively, while serum
creatinine and cystatin  C had pooled AUROCs of 0.764
(0.732–0.796) and 0.768 (0.729–0.807), respectively.
Urine biomarkers interleukin (IL) −  18, cystatin  C, and
the product of tissue inhibitor of metalloproteinases-2
(TIMP-2) and insulin-like growth factor-binding protein
7 (IGFBP7) showed pooled AUROCs of 0.668 (0.606–
0.729), 0.722 (0.575–0.868), and 0.857 (0.789–0.925),
respectively. Some of the limiting factors were uncer-
tainty regarding optimal cut-offs, the reliance on single
measurements, differences in timing of measurement
and confounding by underlying comorbidities. Further-
more, several studies failed to show better predictive per-
formance than clinical models.
A more recent study identified urinary C–C motif
chemokine ligand 14 (CCL14) as a promising prognos-
tic marker in patients with advanced AKI. Among 331
patients with AKI Stage 2 or 3, CCL14 anticipated the
development persistent severe AKI, defined as Stage 3
AKI for 72 h or the receipt of RRT or death after achiev-
ing Stage 3 AKI, with an area under the receiver operating
curve of 0.83 (95% CI 0.78–0.87) [9] Higher CCL14 con-
centrations were also associated with an increased risk of
the composite endpoint of RRT initiation or death within
90  days. These findings have been externally validated
in an another cohort [10]. In a recent meta-analysis, the
response to a fixed dose of furosemide, also known as
the furosemide stress test (FST), has shown comparable
performance characteristics to CCL14 in anticipating the
future receipt of RRT in patients with AKI [11]. Though
the precise role of CCL14 and the FST in guiding clinical
1370

Table 1  Summary of  recent randomized controlled trials examining the timing of  RRT initiation in  critically ill patients
with AKI
ELAIN (n = 231) AKIKI (n = 620) IDEAL-ICU (n = 488) STARRT-AKI (n = 3019)

Setting and population
Key inclusion criteria
Key exclusion criteria
SOFA score (early vs
delayed)
Window for RRT initiation
in early arm
Triggers for RRT initiation
in delayed arm
Proportion of patients in
the delayed arm that
received RRT​
Serum creatinine at
RRT initiation (early vs
delayed), mcmol/L (SD)
Serum urea at RRT initia‑
tion (early vs delayed),
mmol/L (SD)
Time to RRT initiation in
the delayed arm
Initial RRT modality
Primary outcome (early vs 90-day mortality:
delayed) 39% vs 54% (p = 0.03)
Single center in Germany; 31 centers in France; 80% 24 centers in France 168 centers in 15 countries. 67% with a
95% with a primary with a primary medical primary medical diagnosis
surgical diagnosis (47% diagnosis
cardiac surgery)
KDIGO stage 2 AKI, plus KDIGO stage 3 AKI plus RIFLE stage F, AKI within KDIGO stage 2–3 AKI
NGAL > 150 ng/ml and mechanical ventilation 48 h of vasopressor
sepsis, vasopressors, and/or catecholamines initiation; septic shock
volume overload use
Emergency indications Emergency indications Emergency indications Emergency indications for RRT. Previ‑
for RRT. Pre-existing for RRT. Pre-existing for RRT. Receipt of RRT ous RRT, pre-existing eGFR < 20 ml/
eGFR < 30 ml/ CrCl < 30 ml/min for end-stage kidney min/1.73m2. Clinician perception of
min/1.73 ­m2 disease mandated need for RRT or imminent
kidney recovery
15.6 vs 16.0 10.9 vs 10.8 12.2 vs 12.4 11.6 vs 11.8
Within 8 h of stage 2 AKI Within 6 h of stage 3 AKI Within 12 h of stage F AKI Within 12 h of full trial eligibility
Within 12 h of pro‑ Serum urea > 40 mmol/L, 48 h after inclusion, if RRT discouraged 
gression to stage K > 6 mmol/L, pH < 7.1, K > 6 mmol/L, pH < 7.1, unless K ≥ 6.0 mmol/L, pH ≤ 7.20
3 AKI, serum oliguria > 72 h, acute fluid overload with HCO3 ≤ 12 mmol/L, severe
urea > 36 mmol/L, pulmonary edema respiratory failure ­(PaO2/FiO2 ≤ 200)
K > 6 mmol/L, or edema due to volume overload, or persistent
resistant to diuretics AKI ≥ 72 h
91% 51% 62% 62%
 167 (53) vs  212 (88)  289 (124) vs 469 (203)  283 (133) vs 407 (150)  327 (150) vs 433 (186)
  13.9 (5.7) vs 17.1 (7.9)  18.6 (8.6) vs 32.1 (12.1)  21.1 (10.0) vs 31.1 (12.5)  22.8 (17.9) vs 30.3 (18.2)
25 h post-randomization 57 h post-randomization 51 h from AKI diagnosis 31 h following full eligibility
CRRT (CVVHDF) Mixed (CRRT 45%) Mixed (CRRT 56%) Mixed (CRRT 70%)
60-day mortality: 90-day mortality: 90-day mortality:
49% vs 50% (p = 0.79) 58% vs 54% (p = 0.38) 44% vs 44% () (p=0.92)h

NGAL Neutrophil gelatinase-associated lipocalin, SOFA Sequential Organ Failure Assessment, eGFR estimated glomerular filtration rate, CrCl creatinine clearance, RRT​
renal replacement therapy, AKI acute kidney injury, CRRT​ continuous renal replacement therapy, CVVHDF continuous veno-venous hemodiafiltration, RIFLE Risk Injury
Failure Loss End-stage Renal Disease, KDIGO, Kidney Disease: Improving Global Outcomes

decision-making remain to be established, they hold
promise as new tools that may be integrated into future
RCTs that test RRT initiation strategies (as well as other
candidate therapies for patients with AKI) by enriching
the trial cohort with patients who are more likely to expe-
rience an adverse outcome.
RRT modality selection
Extracorporeal RRT modalities commonly used in the
ICU include intermittent hemodialysis (IHD), continu-
ous RRT (CRRT) and various hybrid therapies broadly
classified as sustained low efficiency dialysis (SLED).
SLED is typically performed using a conventional dialysis
machine. There is no uniform approach to delivery of
SLED and it varies at different centers with respect to
duration and frequency of treatments, blood flow rate,
dialysate flow rate, filter size and characteristics, and
modes of solute clearance [12]. Acute peritoneal dialy-
sis (PD) is also used in some ICU settings. While a 2002
single-center trial (N = 70) found increased mortality
in patients with septic AKI treated with PD compared
to CRRT [13], more recent evidence suggests that PD-
treated critically ill patients with AKI have similar sur-
vival to patients treated with CRRT or IHD [14–17].
Table  2 summarizes the characteristics of the different
RRT modalities used in the ICU.
 1371

Fig. 1  A proposed algorithm for the initiation of renal replacement therapy

There is no clear evidence that any particular RRT recovery of kidney function in critically ill patients with
modality confers benefit with respect to survival and AKI [2, 18–22]. Thus, RRT modalities should continue

Table 2  Characteristics of renal replacement therapy modalities used to treat acute kidney injury in the ICU
Characteristic RRT modality
IHD SLED CRRT​ PD

Treatment duration (h) 3–6 6–18 24 24

Frequency 3 times per week plus additional 3 times per week plus additional Daily Daily
treatments as indicated treatments as indicated
Mode of solute transport Diffusion/convection/both Diffusion/convection/both Diffusion/convection/both Diffusion
Blood flow (ml/min) 200–350 100–300 100–250 N/A
Dialysate flow (ml/min) 300–800 100–300 0–50 N/A
Filter size ­(m2) 1.7–2 0.4–1.7 0.6–1.5 N/A
Urea clearance (ml/min) 150–180 90–140 20–45 15–35
Need for anticoagulation Can be readily delivered without Can be readily delivered without Generally required No
anticoagulation anticoagulation
RRT​ renal replacement therapy, IHD intermittent hemodialysis, SLED sustained low efficiency dialysis, PD peritoneal dialysis, h hours, N/A not applicable, m2 square-
meters, ICP intracranial pressure, DDS dialysis disequilibrium syndrome, CVC central venous catheter, PDC peritoneal dialysis catheter, CKD chronic kidney disease Rx
prescription, ICU intensive care unit, RO reverse osmosis, HD hemodialysis
1372
to be considered complementary therapies with modal-
ity selection based on patient-specific considerations and
in accordance with local resources, expertise and training
[23]. A central argument in favor of CRRT over IHD is
that, in hemodynamically unstable patients, it delivers a
lower ultrafiltration rate and a lower rate of osmotic shift,
theoretically reducing the likelihood of hemodynamic
instability related to RRT (HIRRT) [18]. For patients ini-
tiating RRT with increased intracranial pressure or fulmi-
nant hepatic failure, rapid osmotic shifts precipitated by
IHD can worsen brain edema and further increase intrac-
ranial pressure making CRRT a potentially safer choice
in these settings. CRRT may also be preferred when
large volumes of ultrafiltration are required in patients
with severe fluid overload or within the context of ongo-
ing high fluid intake. It should be noted that local avail-
ability will invariably influence RRT modality selection.
For example, IHD may be the only available modality
at some hospitals and is thus delivered even to patients
with hemodynamic instability. There are situations in
which conventional IHD may be favored even in patients
with hemodynamic compromise. This is particularly rel-
evant  when rapid clearance is needed, for example in
the setting of severe hyperkalemia or intoxication with
a dialyzable toxin. Intermittent modalities such as IHD
and SLED may be favored when the patient is ready for
mobilization which can be facilitated by less time being
spent receiving RRT [2].
The recent Kidney Disease: Improving Global Out-
comes (KDIGO) Controversy Conference on Acute Kid-
ney Injury suggested that switching from CRRT to an
intermittent modality could be considered once vaso-
pressor support has been weaned, intracranial hyper-
tension resolved, and fluid balance controlled [24]. This
approach aims to minimize the risk of intradialytic hypo-
tension and its adverse sequelae after patients transition
to intermittent RRT. In a single-center study in Canada,
50% of initial intermittent RRT sessions following transi-
tion from CRRT were complicated by intradialytic hypo-
tension [25]. The most potent risk factor for intradialytic
hypotension was the persistent need for vasopressor sup-
port at the time of CRRT discontinuation.  These obser-
vations support the rationale for waiting for sustained
hemodynamic stability before considering a transition
from CRRT to an intermittent modality.
Hemodynamic instability related to RRT​
The relative impact of different RRT modalities on
HIRRT and its consequences have not been well estab-
lished. HIRRT is reported to occur commonly in criti-
cally ill patients across all extracorporeal RRT modalities
used in the ICU (i.e., 10–70% of IHD treatments; 19–43%
of CRRT treatments) [26]. HIRRT has been associated
with increased mortality [25, 27] and may disrupt kidney
repair and hinder kidney recovery [26].
Hypovolemia and consequent pre-load reduction due
to ultrafiltration and rapid osmotic shifts are the predom-
inant mechanisms for HIRRT [26]. Myocardial stunning
that occurs independent of ultrafiltration is common in
the outpatient HD population and more recently, it has
also been shown to occur during IHD [28] and CRRT
[29] in patients with AKI. A 2018 systematic review of
interventions to mitigate HIRRT in critically ill patients
found some evidence to support the use of low dialysate
temperature and higher dialysate sodium concentration
or sodium profiling for patients treated with intermittent
RRT modalities [30]. Two small trials have shown the
hemodynamic benefits of pre-emptive administration of
hyperoncotic albumin to patients receiving IHD [31] and
SLED [32]. Adequately powered trials are now needed to
establish the efficacy of interventions to mitigate HIRRT.
Potential interventions to mitigate HIRRT across the
various modalities of extracorporeal RRT are reported in
Table 3.
Modes of solute clearance
Extracorporeal solute clearance can be delivered with
diffusion (dialysis), convection (filtration), adsorption
or some combination of these. Diffusive clearance is
proportional to the concentration gradient between the
blood and dialysate and is inversely proportional to the
molecular size of substances. In contrast, convective
clearance is achieved through the movement of water
which drags molecules across the hemofilter membrane
provided they do not exceed the size of the pores or are
significantly protein- bound. Adsorption involves the
binding of molecules to a solid media for the purpose of
removal from the bloodstream.
As compared to diffusive clearance, convective clear-
ance enables the removal of uremic toxins of middle-
range molecular weight such as b ­ eta2-microglobulin that
accumulate and mediate complications in end-stage kid-
ney disease. The pathophysiological implications related
to the accumulation of these hmolecules in the setting
of AKI are unknown although some might impact the
innate immune system [33]. Beyond removal of sub-
stances that accumulate as a direct consequence of AKI,
extracorporeal clearance has been explored as a strategy
to mitigate the severity of acute illness by the modulation
of the inflammatory response, or through the elimination
of noxious products such as bacterial endotoxins. How-
ever, contradictory data exist on the capacity of high-
volume hemofiltration (> 35  mL/kg/h) to significantly
reduce circulating levels of inflammatory mediators
[34, 35]. While some trials reported lower vasopressor
requirements with the use of hemofiltration [35, 36], it is
 1373

Table 3  Potential interventions to mitigate hemodynamic instability related to renal replacement therapy in critically ill
patients receiving RRT​
Intervention Proposed Mechanism Comments

Lower dialysate temperature, e.g., 0.5 °C less
than body temperature (to a minimum of
35–35.5 °C)
High ­[Na+] dialysate/dialysate ­[Na+] profiling,
e.g., increase dialysate ­[Na+] to 145 mmol/L
Isolated ultrafiltration
High ­[Ca++] dialysate,
e.g., increase dialysate ­[Ca++] to 1.50–
1.75 mmol/L
Pre- or intra-RRT administration of intravenous
hyperoncotic (20–25%) albumin
Improve cardiac contractility (less myo‑
cardial stunning) ± increase/prevent
loss of vascular tone
Increase plasma [­ Na+] to prevent rapid
osmotic shifts
Eliminate hemodynamic effects of
rapid solute removal that occurs with
dialysis
Improve cardiac contractility
Increase vascular tone
Increase oncotic pressure to promote
vascular refilling in response to ultra‑
filtration and osmotic-shift-mediated
hypovolemia
Good evidence from maintenance HD studies that using
lower temperature dialysate prevents myocardial stun‑
ning. Some evidence of effectiveness in the critically ill
population
Some evidence of effectiveness in the critically ill popula‑
tion
Helpful when volume overload is the primary indication
for RRT​
Limited evidence to support this as a routine practice
Small trials showed less hypotension & increased UF in
hospitalized HD patients with serum albumin < 30 g/L;
less hypotension in critically ill treated with SLED.
Expensive intervention with unknown impact on survival,
kidney recovery

IHD intermittent hemodialysis, SLED sustained low efficiency dialysis, HD hemodialysis, [Na+] sodium concentration, Qd dialysate flow rate, [Ca++] calcium
concentration, Qb blood flow rate, HIRRT​ hemodynamic instability related to renal replacement therapy, UF ultrafiltration

unclear if this is mediated through immunomodulation Intensity of renal replacement therapy

or through other mechanisms such as the thermal effect
of infusing a high volume of room temperature replace-
ment fluid. Although the body of evidence in limited,
available trials have not shown significant differences in
patient outcomes with the use of hemofiltration, as com-
pared to hemodialysis, either in the form of continuous
[37, 38] or intermittent [39] RRT.
For patients with AKI receiving CRRT, it is possible
to combine adsorption with diffusion and convection.
CRRT hemofilters equipped with membranes that have
adsorptive properties that preferentially adsorb cytokines
and endotoxin (Oxiris, Baxter, Deerfield, IL) have been
developed. Exploratory trials suggested reductions in
cytokines and endotoxin levels similar to those achieved
with stand-alone cartridges although no adequately pow-
ered trials that focused on patient outcomes have been
performed [40, 41]. Another form of combined therapy
is coupled plasma filtration adsorption (CPFA) which
first involves filtering the plasma using a large-pore fil-
ter before it comes into contact with a cartridge for non-
selective adsorption. In the multicenter COMPACT-2
trial in patients with septic shock, the use of CPFA was
associated with a trend toward increased mortality which
led early termination of the trial [42]. Overall, the body
of evidence for dedicated adsorption devices as well
as modified CRRT filters with adsorptive proprieties
remains low [43].
The non-superiority of intensive small-solute clear-
ance, as compared to less-intensive clearance, was
demonstrated by the VA-NIH ATN and RENAL trials
[44, 45]. Guided by the less-intensive arms of these tri-
als, an effluent flow of 20–25  mL/kg/hr has become the
standard of care for the delivery of CRRT. For patients
receiving intermittent modalities, a Kt/V (K represents
dialyzer urea clearance, t is the duration of dialysis, and
V is the volume of distribution of urea) of > 1.2 delivered
on alternating days is the standard. It is unclear if these
recommended doses are the optimal set-points for RRT
dosing. Lower intensity RRT, prescribed from the outset
of therapy or after metabolic control has been achieved,
could yield similarly acceptable outcomes. Moreover,
adequacy in the setting of acute RRT extends well beyond
urea clearance and is also reflected by other dimensions
including achievement of electrolyte and acid–base
homeostasis. In addition, close attention needs to be paid
to the unintended consequences of blood purification,
namely removal of vital medications, the depletion of
essential vitamins and trace elements and excessive clear-
ance of key electrolytes (e.g., phosphate).
Dialysate/replacement fluid composition
Intermittent RRT​
The dialysate composition for intermittent RRT modali-
ties can be finely tailored to address the dynamic needs
of the patient with a variety of concentration options
for sodium, potassium, calcium and bicarbonate. For
example, the utilization of a grelatively higher dialysate
1374
sodium (> 140  mmol/L) and calcium (> 1.25  mmol/L)
concentrations can promote hemodynamic stability.
Patients receiving frequent or prolonged RRT sessions
may become hypophosphatemic which can be addressed
by the addition of phosphate solutions to the acid con-
centrate. The capability of modern dialysis machines to
generate on-line infusion-grade replacement solutions
has presented the opportunity to incorporate convective
clearance into intermittent RRT.
CRRT​
There are numerous commercially available options with
a range of concentrations of constituents as depicted in
Table  S1. Commercially available solutions are typically
manufactured in dual-chamber bags, with one small
and one large compartment connected by a frangible
pin or peel seal for subsequent mixing. This distribu-
tion prevents precipitation of components (i.e., calcium
and bicarbonate) during storage. Once components are
mixed, the solution is stable for 24 h.
Customization of CRRT solutions
Some of the specific clinical scenarios that may benefit
from customization of CRRT solutions are described
below.
1. Management of severe hyponatremia.
If a patient has indications for CRRT and the serum
sodium concentration is < 120  mmol/L, the use of
standard CRRT solutions with a sodium concentra-
tion of 140  mmol/L may increase the risk of exces-
sively rapid correction of the serum sodium con-
centration and cause osmotic demyelination. In this
context, one could customize the CRRT circuit to
provide a desired rate of 5% dextrose as post-filter
replacement fluid (i.e., CVVH or CVVHDF) [46]
or customize the CRRT solutions by diluting the
sodium concentration to desired levels using sterile
water [47–49]. By doing the latter, one should con-
sider that the addition of sterile water to dilute the
sodium concentration in the bag also dilutes the con-
centration of other constituents.
2. Management of severe hypernatremia or induced
hypernatremia to manage intracranial hypertension.
The customization of CRRT solutions (dialysate
and/or replacement fluid) by the addition of 5 to
20  ml of 23.4% or 30% hypertonic saline increases
sodium concentration in 5 L bags up to 160 mmol/L
[47]. This can help prevent overly rapid correction
of hypernatremia and risk of cerebral edema by the
use of standard solutions that contain 140  mmol/L
of sodium. Alternatively, delivery of hypertonic
solutions through the CRRT circuit (i.e., post-filter
replacement fluid) or external to CRRT can attain the
same goal.
3. Prevention of hypophosphatemia by the use of phos-
phate-containing CRRT solutions.
Evolving observational data suggest that the addition
of 1–1.2  mmol/L of phosphate to CRRT solutions
(dialysate and/or replacement fluid) can significantly
mitigate incident hypophosphatemia during CRRT
(Table  S2). Though some observational studies have
suggested a potential impact of phosphate-contain-
ing CRRT solutions (or their effect on attenuating
hypophosphatemia) on clinical outcomes such as the
need of tracheostomy or days on ventilator, rand-
omized clinical trials are needed to better interrogate
the role of preventing hypophosphatemia on skeletal
muscle function and respiratory failure in critically ill
patients requiring both CRRT and mechanical venti-
lation [50–52].
Risk of euglycemic ketoacidosis with the use
of glucose‑free CRRT solutions
In recent years, there have been multiple case reports
of diabetic patients developing euglycemic ketoacidosis
while receiving CRRT using glucose-free solutions [53–
55]. Although its incidence and risk factors have not yet
been well characterized, clinicians should remain alert
to the possibility that euglycemic ketoacidosis is respon-
sible for an otherwise unexplained anion gap metabolic
acidosis that develops during CRRT using glucose-free
solutions.
Anticoagulation
Clotting of the extracorporeal circuit is a common com-
plication in all forms of acute RRT but this is  particu-
larly challenging in the setting of CRRT due to lower
blood flows than those utilized in intermittent modali-
ties. Moreover, failure of the extracorporeal circuit due to
clotting has greater implications in CRRT, as compared
to IHD, due to the higher costs of filter set replacement
and the associated CRRT downtime. Though CRRT may
be theoretically performed without anticoagulation,
anticoagulation is generally recommended to minimize
treatment interruptions and maximize the quality of
clearance.
Unfractionated heparin (UFH) is usually administered
as an initial bolus followed by a continuous infusion
with a target activated partial thromboplastin time 1.5–2
times the normal range. Whether injected into the extra-
corporeal circuit or intravenously, the effects of UFH are
systemic which subjects patients to the risk of bleeding.
Regional citrate anticoagulation (RCA) creates a hypoc-
alcemic environment in the extracorporeal circuit while

Fig. 2  Decision-making strategy for anticoagulation in patients receiving CRRT​
maintaining normocalcemia systemically. Practically, cit-
rate is infused into the arterial limb of the circuit thereby
chelating calcium, a key cofactor of multiple steps of the
clotting cascade. Coagulation is inhibited when ionized
calcium levels are < 0.45  mmol/L in the extracorpor-
eal circuit [56]. This is coupled with a calcium infusion
to maintain systemic normocalcemia. In a recent meta-
analysis, RCA conferred a lower risk of bleeding with a
higher risk of hypocalcemia compared to UFH [57]. In
the largest trial evaluating anticoagulation strategies to
date, the Regional Citrate vs Systemic Heparin Anticoag-
ulation for Continuous Kidney Replacement Therapy in
Critically Ill Patients With Acute Kidney Injury (RICH)
trial confirmed that RCA, compared with UFH, medi-
ated a lower risk of bleeding (OR 0.27 (95% CI 0.15–0.49)
while extending filter life span (44.9 (SD 26.9) vs 33.3 (SD
25.1) hours) [58]. However, the risk of culture-proven
infection was significantly increased in the RCA arm, a
finding not observed in previous trials. Figure 2 provides
a suggested algorithm to help guide anticoagulant choice
for patients receiving CRRT. RCA must be used with cau-
tion in patients with impaired citrate metabolism due
to liver failure, with or without hyperlactatemia, though
there are several reports on the safe use of RCA with
close metabolic monitoring [59], 60. In the face of cit-
rate accumulation, as reflected by a total/ionized calcium
1375
ratio of > 2.5,  the citrate infusion rate can be lowered
and/or the dialysate rate increased. 
Fluid management in patients receiving RRT
for AKI
Fluid accumulation, driven by administered fluid cou-
pled with reductions in urine output, is common in criti-
cally ill patients with severe AKI and may be a potent
mediator of multi-organ toxicity [61]. Furthermore, fluid
accumulation is associated with a higher risk of mortal-
ity [62] and kidney non-recovery [63]. For these reasons,
the achievement and maintenance of euvolemia is a key
objective of any acute RRT regimen.
The ideal ultrafiltration prescription in acute RRT
remains elusive. In a secondary analysis of the RENAL
trial, sustained achievement of a net negative cumu-
lative fluid balance was associated with a lower risk
of death and more RRT-free days [64]. However, in a
more recent re-analysis of the same trial, receipt of a
net ultrafiltration rate exceeding 1.75  mL/kg/h was
associated with a higher risk of death as compared to
a rate of < 1.01  mL/kg/h [65]. These seemingly con-
tradictory findings may be reconciled by highlighting
the importance of decongestion but the concomitant
hazards of doing so with high ultrafiltration rates due
to the possible induction of iatrogenic organ injury.
1376
Fig. 3  Proposed strategy for RRT weaning and discontinuation
Reverse causality is also possible: patients whose
course of critical illness was more favorable achieved
more effective diuresis, hence a more negative fluid
balance, and thus required less aggressive extracor-
poreal fluid removal. The methodologic challenges in
the interpretation of observational data in this area
highlight the urgency of a well-designed RCT that will
compare the effect of different fluid removal strate-
gies in critically ill patients with AKI who are receiving
RRT.
Discontinuation of RRT​
As highlighted in a recent systematic review, it is
challenging to objectively determine when sufficient
kidney recovery has occurred in order to safely dis-
continue RRT [66]. Two risk scores to anticipate the
successful discontinuation of CRRT were derived and
internally validated at single centers and achieved
reasonable discrimination [67, 68]. Major AKI tri-
als have generally used measures of urine output,
metabolic parameters, and creatinine clearance to
guide decision-making (Table  S3). Two ongoing pilot
randomized trials, RECOVER-AKI (ClinicalTrials.
gov NCT04948476) and LIBERATE-D (ClinicalTrials.
gov NCT04218370) will test the feasibility of applying
objective criteria that must be satisfied to stop or con-
tinue RRT. Figure  3 presents a proposed approach to
RRT discontinuation.
Pediatric considerations
AKI is common among hospitalized neonates and chil-
dren and is associated with adverse outcomes including
increased health care utilization [69–72]. AKI occurs in
20–45% of critically ill neonates and children and 40–60%
of those undergoing cardiac surgery, of whom 1.5–9%
receive RRT [73–77]. Recent technological advancements
have enabled the provision of safe and effective RRT in
neonates and children [77, 78].

Fig. 4  Key practice points and areas of persisting uncertainty in the delivery of RRT to critically ill patients with acute kidney injury
Peritoneal dialysis
PD is a safe, effective, and inexpensive modality [79, 80].
It is commonly utilized for AKI in low and low–middle-
income countries and in specific patient populations such
as cardiac surgery, extremely low-birthweight neonates,
and where extracorporeal therapy is not feasible [81–84].
New automated PD systems are now available with lower
fill volumes aptly suited for the neonatal population [85].
In critical care settings, several strategies are employed
to optimize clearance and improve PD efficiency, such as
continuous equilibration PD (CEPD), high-volume PD
(HVPD), tidal PD, and continuous flow PD (CFPD), each
with its strengths and limitations [86–90]. There has been
a renewed interest in using CFPD for AKI. In this tech-
nique, continuous circulation of peritoneal fluid is main-
tained at a high flow rate of 100–300  ml/min/1.73  ­m2
using either two peritoneal catheters or a double lumen
PD catheter, thereby maximizing the transport potential
across the peritoneal membrane [91]. A few studies have
shown that CFPD is safe and effective in infants and chil-
dren, but more data in larger cohorts are needed [90, 92].
1377
Hemodialysis and continuous renal replacement therapy
New technology has made extracorporeal therapies more
feasible and safer in neonates and small infants. The
introduction of a dedicated miniaturized filter such as
the Prismaflex HF20 (polyarylethersulfone membrane),
with a priming volume of 65 ml for infants (BSA 0.2 ­m2),
has reduced the need for blood priming [93–95]. Neo-
natal-specific CRRT machines have been developed and
approved for clinical use [78, 96–100]. The key features of
these devices are highlighted in Table S4.
Conclusions
The evidence base for guiding the prescription and deliv-
ery of RRT for AKI has expanded in recent years (Fig. 4).
There is now greater clarity about the circumstances for
RRT initiation with definitive evidence to show that ini-
tiation of RRT without an urgent indication is not ben-
eficial to patients. It is hoped that persistent areas of
uncertainty, most notably in the areas of fluid manage-
ment and RRT discontinuation, will be subjected to rig-
orous examination in RCTs that will generate definitive
evidence to inform clinical practice.
1378
Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1007/​s00134-​022-​06851-6.
Author details
1
 Division of Nephrology, St. Michael’s Hospital and the University of Toronto,
61 Queen Street East, 9‑140, Toronto, ON M5C 2T2, Canada. 2 Li Ka Shing
Knowledge Institute of St. Michael’s Hospital, Toronto, ON, Canada. 3 Division
of Nephrology, Centre Hospitalier de L’Université de Montréal, Montréal, QC,
Canada. 4 Division of Pediatric Nephrology, Department of Pediatrics, McMas‑
ter University, Hamilton, ON, Canada. 5 Division of Nephrology, Department
of Medicine, University of Ottawa, Ottawa, ON, Canada. 6 Division of Nephrol‑
ogy, University of Alabama at Birmingham, Birmingham, AL, USA. 7 Depart‑
ment of Critical Care Medicine, Guys and St. Thomas Hospital, London, UK.
8
 Division of Nephrology, Kingston Health Sciences Center, Queen’s University,
Kingston, ON, Canada. 9 Division of Intensive Care Medicine, Department
of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki
and Helsinki University Hospital, Helsinki, Finland. 10 Department of Anesthe‑
siology, Intensive Care and Pain Medicine, Muenster, Germany. 11 Department
of Critical Care Medicine, University of Alberta and Alberta Health Services,
Edmonton, AB, Canada.
Acknowledgements
SMB is supported by a Canada Research Chair in Critical Care Outcomes and
Systems Evaluation.
Declarations
Conflicts of interest
RW has received unrestricted research support and speaker fees from Baxter
and consulting fees from Lilly. JAN has received consulting fees from Baxter.
SAS has received speaking fees from Baxter. SMB has received unrestricted
research support and fees for speaking and scientific advisory from Baxter, fees
for scientific advisory from Novartis, fees for data safety monitoring for I-SPY-
COVID, and fees for scientific advisory and clinical adjudication from BioPorto.
MO has received speaker honoraria and research funding from Baxter, Frese‑
nius Medical and Biomerieux. AZ has received unrestricted research support
and speaker fees from Baxter, Fresenius, and BioMerieux.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Springer Nature or its licensor holds exclusive rights to this article under a
publishing agreement with the author(s) or other rightsholder(s); author self-
archiving of the accepted manuscript version of this article is solely governed
by the terms of such publishing agreement and applicable law.
Received: 4 May 2022 Accepted: 29 July 2022
Published: 6 September 2022
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