1. When to initiate RRT in patients with AKI - Does
timing matter?

2. Review Article
When to initiate RRT in patients with AKI e Does timing
matter?
Saumya Gupta*
Consultant Nephrologist, Apollo Gleneagles Hospital Limited, 58 Canal Circular Road, Kolkata, India
a r t i c l e i n f o
Article history:
Received 5 December 2012
Accepted 31 January 2013
Available online 9 February 2013
Keywords:
Acute kidney injury
Renal replacement therapy
Timing
a b s t r a c t
Acute kidney injury is a serious illness which occurs commonly in the renal units and also
in the ICU setting. It is an independent risk factor of increased mortality and morbidity,
particularly when RRT is needed. The wide variation in utilization of RRT contributes to
a lack of consensus among clinicians regarding the parameters which should guide the
decision to initiate RRT. This problem is confounded by a paucity of high quality evidence
in the current literature. This review examines the role of usual biochemical parameters as
well as conventional clinical indications for commencing RRT. It also discusses the po-
tential role of biomarkers as predictors for the need of RRT in AKI. Initiating dialysis in AKI
should be based on dynamic clinical criteria and not only on specific biochemical values.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Acute kidney injury (AKI) is a serious complication of critical
illness that is associated with substantial morbidity and
mortality. Renal replacement therapy (RRT) has long been
used as supportive treatment of AKI, and has traditionally
focused on averting the life threatening derangements asso-
ciated with kidney failure (i.e. metabolic acidosis, hyper-
kalemia, uraemia, and/or fluid overload) while allowing time
for organ recovery. In patients with AKI, RRT is regarded as
a type of organ support aimed at achieving metabolic ho-
meostasis and preventing fluid overload and new organ fail-
ure. The benefits of RRT must be balanced by potential harm,
including risks related to vascular access, infections and
anticoagulation.1
Whether or not to provide RRT, and when to start, are two
of the fundamental questions facing nephrologists and
intensive-care practitioners in most cases of severe AKI. In
recent publications, the timing of initiation of RRT was listed
as one of the top priorities in research on AKI.2
However, this
dimension has not been included as a factor in any of the
large RCTs in this area. In current practice, the decision to
start RRT is based most often on clinical features of volume
overload and biochemical features of solute imbalance. In
a recently published survey of nephrologists and intensivists
in Canada, serum potassium level and severity of pulmonary
oedema were the most commonly utilized factors for decid-
ing when RRT should be started.3
However, in the absence of
these factors there is generally a tendency to avoid dialysis as
long as possible, a thought process that reflects the decisions
made for patients with CKD Stage 5.4
Clinicians tend to delay
RRT when they suspect that patients may recover on their
own, and because of concern for the well-known risks asso-
ciated with the RRT procedure. There is also some concern
that RRT may compromise recovery of renal function, and
increase the progression of CKD.5
Whether these risks out-
weigh the potential benefits of earlier initiation of RRT is still
unclear.
* Flat No. 3G, Orbit Heights, 33 Gariahat Road South, Kolkata 700031, West Bengal, India. Tel.: þ91 9163262325.
E-mail address: sgupta36@hotmail.com.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 6
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.01.016

3. In ICU patients, AKI is often observed at an early stage
before traditional measures of renal function are deranged.
Many specialists regard AKI as a systemic disease, rather than
a single organ failure in isolation characterised by a systemic
inflammatory response with distant organ injury.6
The cause
of the acute kidney injury (AKI) requiring RRT is also relevant.
Without an underlying cause, clinicians do not have much
information other than an observed disturbance in conven-
tionally measured biochemical parameters of kidney function
combined with oliguria or anuria. The outcome from AKI in
a young patient secondary to a crush syndrome is very dif-
ferent from that of an elderly diabetic developing AKI fol-
lowing systemic infection from an ischaemic limb. It may be
that the aetiology of the underlying condition is also of great
importance with regard to timing of treatment. This high-
lights the differences between ‘single organ AKI’ and ‘multi-
organ AKI’ in that timing of RRT on a renal unit may differ
significantly from ICU patients in terms of both dose delivered
and duration of treatment.7
The timing of initiation of RRT remains a topic of discus-
sion for some years in both groups of patients suffering from
chronic kidney disease8
and AKI9
respectively. A recently
published systematic review and meta-analysis concluded
that earlier initiation of RRT in critically ill AKI patients may
have a beneficial effect on survival but that, in the absence of
new evidence from suitably designed randomized trials,
a definitive treatment recommendation cannot be made.9
2. Where do we stand now regarding current
evidence?
Studies looking at the timing of initiation of RRT need to
address the criteria used for commencing therapy; but this is
hampered by the lack of any universally accepted criteria for
initiation. They have evaluated various arbitrary cut-offs for
serum creatinine, serum urea or urine output, fluid balance,
time from admission or duration of AKI and often differ-
entiated between ‘early’ and ‘late’ RRT (Table 1).10e26
In the current literature, there are 2 RCTs,17,19
2
prospective cohort studies,10,14
13 retrospective cohort
studies11e13,15,16,18,20e26
and 3 meta-analyses/systematic re-
views.9,27,28
Significant heterogeneity still remains regarding
the potential parameters which are monitored by clinicians to
decide that the time has come to commence RRT. Most clinical
trials used serum creatinine, serum urea and/or urine output
to define timing of RRT but the exact cut-offs were variable
between studies.
2.1. Serum creatinine
Five studies contained data on the role of serum creatinine as
a trigger for RRT (Table 1).10,11,22e24
The results are conflicting.
Shiao et al11
retrospectively analysed the data of 98 patients
with AKI post-abdominal surgery and showed that patients
who were started on CVVH at RIFLE stage Risk (i.e. after rise in
serum creatinine by 150e200%) had a significantly lower
hospital mortality than patients who started RRT with either
RIFLE-Injury or RIFLE-Failure (i.e. after serum creatinine rise
by >200%). In contrast, Chou et al12
showed no difference in
hospital mortality in 370 AKI patients between the group who
started RRT with RIFLE-Risk or even before they fulfilled the
RIFLE criteria and patients in whom AKI had progressed to
RIFLE-Injury or RIFLE-Failure when RRT was started. Two
larger studies concluded that mortality was significantly
higher in patients who had a serum creatinine < 309 mmol/L
when RRT was started compared to those with higher crea-
tinine values.10,23
2.2. Serum urea
Different levels of serum urea were used as triggers for RRT in
eight studies.10,13e17,23,26
Liu et al14
reported a significantly
lower mortality in 122 patients who had a serum ure-
a < 27.1 mmol/L at the time of initiation of RRT compared to
121 patients with a higher value. When adjusted for age, he-
patic failure, sepsis, thrombocytopaenia and serum crea-
tinine, the relative risk of death with a higher urea level at the
time of RRT was 1.85 [95% confidence interval (CI) 1.2e3.2].
Improved mortality was also reported in retrospective studies
when RRT was instituted at a serum urea < 21 mmol/L,26
<29 mmol/L13
or <35.7 mmol/L,15
suggesting that RRT at
lower serum urea levels is better than late RRT. In contrast,
two larger studies did not find a correlation between serum
urea at the time of RRT and outcome.10,23
2.3. Urine output
Data on the role of specific urine volumes as triggers for
RRT were included in eight studies12,16e19,23e25
often com-
bined with serum urea or creatinine criteria. The majority of
studies showed better outcomes; when oliguria was used as
the trigger for RRT instead of serum creatinine or urea
values.12,16,18,24,25
However, the definitions for oliguria varied
from urine output < 100 ml/h in 8 h16,24
to <400 ml/24 h23
and
<30 ml/h for 6 h.17
2.4. Fluid overload
There is increasing evidence that fluid overload in patients
with AKI is associated with poor outcome.21,29
Bouchard et al29
showed that ICU mortality was significantly higher in patients
whose body weight on the first day of RRT was 1e20% above
that on ICU admission compared to patients without weight
gain during this period. There was a direct correlation be-
tween the degree of fluid gain and ICU mortality. Similar re-
sults were reported by Payen et al21
who performed
a subgroup analysis of the multicentre ‘Sepsis Occurrence in
Acutely Ill Patients (SOAP) study’. Two hundred and thirteen
patients were treated with RRT within 2 days of ICU admission
compared to 65 patients who had RRT after 2 days in ICU.
Although patients in the early RRT group had higher severity
of illness scores, their ICU and 60-day mortality was lower. A
potential explanation for this difference was the higher cu-
mulative fluid balance and greater need for mechanical ven-
tilation in the late RRT group. Consequently, it may be
appropriate to consider starting RRT in patients with AKI prior
to fluid accumulation of 10% of body weight.30
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 642

4. Table 1 e Parameters at the time of RRT and subsequent outcome.
Study RRT mode Patient population Parameters at the time of RRT Outcome (early vs late
RRT)
Early Late
Bagshaw et al10
prospective
study
CRRT; IHD 1238 mixed ICU patients Serum Cr 3.5 mg/dl serum
urea 136 mg/dl
Serum Cr 3.5 mg/dl serum
urea 136 mg/dl
Hospital mortality 71 vs 53.4%
P 0.0001 P ¼ 0.48
Shiao et al11
retrospective
study
CVVH; IH 98 patients post-abdominal
surgery
AKI as per RIFLE classification;
no AKI or RIFLE-Risk
AKI as per RIFLE classification
RIFLE Injury or Failure
Hospital mortality 43 vs 75%
P ¼ 0.002
Chou et al12
retrospective CVVH; SLED;
SLED-f; IHD
370 patients with AKI and
sepsis
RIFLE-0 or RIFLE-Risk RIFLE-Injury or RIFLE-Failure Hospital mortality 70.8 vs
69.7% P 0.05
Wu et al13
retrospective study CRRT; IHD 80 patients with AKI and acute
liver failure
Serum urea 160 mg/dl Serum urea 160 mg/dl ICU mortality 57 vs 85%
P ¼ 0.02
Liu et al14
prospective study CRRT; IHD 243 mixed ICU patients Serum urea 152 mg/dl Serum urea 152 mg/dl Hospital mortality RR 1.85
with higher urea (95% CI 1.2
e3.2)
Carl et al15
retrospective study CRRT 147 patients with AKI and
sepsis
Serum urea 200 mg/dl Serum urea 200 mg/dl 28 day mortality 52.3 vs 68%
P 0.05
Elahi et al16
retrospective
study
CRRT 64 patients post-cardiac
surgery
Urine output 100 ml in 8 h Serum urea 168 mg/dl serum
Cr 2.82 mg/dl or K 6 mmol/
L
Hospital mortality 22 vs 43%
P 0.05
Bouman et al17
RCT CRRT 106 patients with AKI
circulatory and respiratory
failure
Urine output 30 ml/h for 6 h
and Cr Cl 20 ml/min
Serum urea 224 mg/dl or
K 6.5 mmol/L or severe
pulmonary oedema
28 day mortality 29 vs 25%
P ¼ 0.08
Manche et al18
retrospective
study
IHD 71 patients with AKI post-
cardiac surgery
Urine output 0.5 ml/kg
despite fluid challenge and
single dose of diuretic
AKI which failed to respond to
all supportive medical
measures
ICU mortality 25 vs 87%
P ¼ 0.00001
Sugahara et al19
RCT CRRT 28 patients post-cardiac
surgery
Urine output 30 ml/h for 3 h Urine output 20 ml/h for 2 h 14 day mortality 14 vs 86%
P 0.01
Piccinni et al20
retrospective
study
CRRT 80 patients with AKI, ALI and
septic shock
Within 12 h of admission to
ICU
‘Classic’ indications for RRT ICU mortality 30 vs 60%
P ¼ 0.003 28 day mortality 72.5
vs 45%, P ¼ 0.005
Payen et al21
retrospective
study
RRT 278 patients with sepsis and
AKI
Period from admission to ICU
to RRT 2 days
Period from admission to ICU
to RRT 2 days
60 day mortality 44.8 vs 64.6%
P 0.01
Ji et al22
retrospective study CVVHD 58 patients with AKI post-
cardiac surgery
Urine output 0.5 ml/kg/h for
12 h
Urine output 0.5 ml/kg/h for
12 h
Hospital mortality 8.8 vs 37.5%
P ¼ 0.02
Ostermann et al23
retrospective study
CRRT; IHD 1847 mixed ICU patients Serum Cr 3.5 mg/dl serum
pH 7.2
Serum Cr 3.5 mg/dl serum
pH 7.2
ICU mortality 59 vs 48%
P 0.0001 74 vs 48% P 0.0001
Demirkilic et al24
retrospective
study
CRRT 61 patients with AKI post-
cardiac surgery
Urine output 100 ml within
8 h post surgery
Serum Cr 5.0 mg/dl or K 5.5 ICU mortality 18 vs 48%
P ¼ 0.014 hospital mortality
23.5 vs 56% P ¼ 0.016
Iyem et al25
retrospective
study
CVVH 185 patients with AKI post-
cardiac surgery
Urine output 0.5 ml/kg/h
and a 50% increase in pre op
urea and creatinine
48 h after urine
output 0.5 ml/kg/hr and
a 50% increase in pre op urea
and creatinine
Hospital mortality 5.2 vs 6.6%
P 0.05
Gettings et al26
retrospective
study
CRRT 100 trauma patients Serum urea 120 mg/dl Serum urea 120 mg/dl Hospital mortality 61 vs 80%
P ¼ 0.041
CRRT, continuous renal replacement therapy; IHD, intermittent haemodialysis; RR, relative risk; ALI, acute lung injury; RIFLE, Risk Injury Failure Loss of renal function End stage renal disease; SLED,
slow extended dialysis; SLEDf, slow extended dialysis with haemofiltration; CVVHD, continuous veno-venous haemodialysis.
apollomedicine10(2013)41e4643

5. 2.5. Hyperkalemia
Untreated hyperkalemia is universally fatal. 1 RCT17
and 2 ret-
rospective studies16,24
have used serum potassium as a marker
regarding the timing to initiate RRT. It is interesting to note that
the cut-off in each of these studies were different, namely
6.5 mmol/L,17
6 mmol/L16
and 5.5 mmol/L24
respectively.
2.6. Metabolic acidosis
A retrospective study conducted by Ostermann et al23
found
that ICU mortality was significantly high (48% vs 74%,
P 0.0001) in the late group as defined by serum pH 7.2.
2.7. Non-renal factors
A large retrospective analysis of 1847 ICU patients treated with
RRT for AKI highlighted that the most important independent
risk factors for ICU mortality were need for mechanical ven-
tilation, associated organ failure, pre-existing chronic health
problems, acidosis, oliguria and age.23
Patients who were oli-
guric (urine output 400 ml/24 h) and acidotic with serum
pH 7.2 at the time of RRT had an ICU mortality of 79.1%.
Serum urea and creatinine were not found to be independ-
ently associated with outcome. The results of this study sug-
gest that the decision to start RRT should depend less on
specific serum creatinine or urea values but more on degree of
acidosis, urine output and associated organ failure.
3. Discussion
The idea that earlier initiation of treatment should be bene-
ficial stems from our belief that sometimes complex in-
terventions may change the course of a serious disease
process. Recently published KDIGO guidelines regarding this
question mention to initiate RRT emergently when life
threatening changes in fluid, electrolyte and acid-base bal-
ance exist. It also mentions that consideration needs to be
given to the broader clinical context, modifiable conditions
with relation to RRT and trends of biochemical parameters
rather than their thresholds alone.4
In the common clinical scenario of AKI and sepsis, many
clinicians believe that initiating RRT early in sepsis can remove
circulating levels of inflammatory cytotoxins and may there-
fore have a beneficial effect on the pathophysiologic mecha-
nisms. Unfortunately, the validity of this hypothesis has never
been proven, and existing evidence rather points to the con-
trary.31
In patients with septic AKI, RRT should not be seen as
a curative therapy, but rather as a supportive intervention,
preventing the patient from dying due to hyperkalemia or fluid
overload during the time period when AKI was present.
Whatever criteria are used to define ‘early’ vs ‘late’ RRT, it
is clear that what may be ‘early’ for one patient could be ‘late’
for another patient depending on the patient’s comorbidity
and clinical course.30
Since the course of patients with AKI can
be very variable, it is essential that clinicians assess these
patients regularly to ensure that RRT is started at the ‘right’
time. As mentioned before, there are only 2 RCT’s17,19
in the
literature, which have tried to address this issue. Bouman
et al17
randomized 106 severely ill patients into three groups;
35 patients were treated with early high volume hemofiltra-
tion, 35 patients with early low volume hemofiltration and 36
patients with late low volume hemofiltration. Median ultra-
filtrate rate was 48.2 ml/kg/h, 20.1 ml/kg/h and 19 ml/kg/h
respectively in the 3 groups. There was no statistically sig-
nificant difference in survival rates among the 3 groups
(P ¼ 0.8). Median duration of renal failure in hospital survivors
also did not reach statistical significance (P ¼ 0.25) in the 3
groups. Another RCT by Sugahara et al19
conducted in 28 post-
cardiac surgery patients showed significant improvement in
14 day mortality (P 0.01) in the early group.
Three meta-analyses9,27,28
concluded that earlier initiation
of RRT in critically ill AKI patients might be associated with
a survival benefit though the studies were heterogenous, of
variable quality with a paucity of RCTs. Of studies reporting
secondary outcomes in the meta-analysis by Karvellas et al,9
majority reported greater renal recovery, decreased duration
of RRT and decreased ICU length of stay in the early RRT group.
Currentlythere islittledata to accurately distinguish inadvance
between the injured kidney that will need dialytic support and
theonethatwill recoverspontaneously.Studies inthe literature
most commonly used serum creatinine, serum urea and urine
output as the parameters to trigger RRT with varying cut-off
values. However, their value is limited due to the fact that
they are not always renal specific. In the early stages of AKI, GFR
can decrease significantly without any major shift in serum
creatinine measurements.32
Serum urea concentrations may
also vary as a result of changes in urea production and tubular
reabsorption without changes in GFR.33
The usefulness of urine
criteria for the definition of AKI has also been discussed
widely.34
Proponents argue that a fall in urine output often
precedes renal dysfunction in patients before changes in serum
creatinine. In contrast, critics argue that urine output is affected
by volume status, intrinsic levels of anti-diuretic hormone,
presence of obstruction and use of diuretics. Despite this, there
is increasing evidence that urine output of 500e600 ml/24 h
should be viewed as an ominous sign and trigger an evaluation
of the indications for RRT. Furthermore, oliguria is closely cor-
related with fluid accumulation. Recent data suggest that fluid
overload of 10% of body weight is an independent risk factor
for mortality in AKI.29
Consequently, it may be appropriate to
consider starting RRT prior to fluid accumulation reaching
a threshold of 10% of body weight.
The current literature shows that individual stages of AKI
are not adequate in identifying the optimal time for RRT
either. The RIFLE and AKIN classifications are scoring systems
which were developed to grade prognosis of AKI.35,36
Although
they correlate with mortality, they were never intended to
predict the need for RRT. Two retrospective studies11,12
con-
ducted amongst patients after abdominal surgery and pa-
tients with AKI and sepsis in a surgical ICU utilized the RIFLE
criteria while separating the groups who underwent ‘early’ or
‘late’ RRT. Unfortunately they showed conflicting results.
Shiao et al11
showed that the hospital mortality was sig-
nificantly lower (43% vs 75%, P ¼ 0.002) in the group who
commenced RRT ‘early’ when in the RIFLE-Risk stage. The
other study by Chou et al12
showed that there was no signifi-
cant difference in the hospital mortality (70.8% vs 69.7%,
P 0.05) between the ‘early’ and ‘late’ groups.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 644

6. The recent literature has seen an expansion in studies
examining potential ‘biomarkers’ for the early detection of
AKI. Candidate molecules include neutrophil gelatinase
associated lipocalin (NGAL), kidney injury molecule (KIM)-1
and cystatin C, and the list continues to grow, although the
quest for the renal ‘troponin’ has been hampered by a desire
for one biomarker to be seen as superior over others. A meta-
analysis including 1948 patients from nine studies confirmed
that urinary or plasma NGAL indeed predicted the need for
RRT.37
Cystatin C has been shown to predict AKI, but its su-
periority over serum creatinine has not been observed uni-
versally in conducted studies.38
Currently available data are
insufficient to conclude that timing of RRT should be based on
these new biomarkers but results of future clinical trials are
awaited.
4. Conclusion
There is no doubt that RRT should be initiated in the case
where life threatening conditions such as refractory
hyperkalemia, severe acidosis and fluid overload is evident.
There is also a broad consensus among clinicians that RRT
should be started, if possible, before frank uraemic symptoms
develop. Ostermann et al33
recently proposed an algorithm
(Fig. 1) for initiation of RRT, incorporating the AKIN criteria
and also including the non-renal indications. The message is
that the criteria for initiating RRT should be individualized
based on the existing dynamic parameters rather than abso-
lute values with the aim to support organ function and pre-
vent complications.
The question whether RRT in AKI should be started ‘early’
or ‘late’ remains unanswered with the current available evi-
dence. May be we cannot answer this question now because it
may be the wrong question; as dialysis is a supportive rather
than a curative therapy. Future research in this very impor-
tant field is desperately needed and should include a combi-
nation of clinical and emerging biomarkers. What we need, is
to look forward to doing away with comparisons of ‘early’ vs
‘late’ dialysis and focus on improving outcomes with timely
interventions of renal support tailored to individual patient
need.
Fig. 1 e Algorithm to guide decision regarding the timing of initiating RRT. MAP [ mean arterial blood pressure. Diagnosis
of AKI based on the AKIN classification.35
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 6 45

7. Conflicts of interest
The author has none to declare.
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