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Extended Daily Dialysis Versus Continuous Renal Replacement Therapy for Acute Kidney Injury: A Meta-analysis

Authors:
  • West China School of Medicine/West China Hospital, Sichuan University

Abstract and Figures

Extended daily dialysis (EDD) has been suggested as an effective renal replacement therapy for acute kidney injury. However, results from studies comparing EDD to continuous renal replacement therapy (CRRT) are inconclusive. A systematic review and meta-analysis was performed by searching in MEDLINE, EMBASE, the Cochrane Library, Google Scholar, and a Chinese database (SinsoMed). Patients with acute kidney injury. Randomized controlled trials (RCTs) and observational studies were included. EDD was defined as extended hemodialysis or hemodiafiltration for more than 6 but less than 24 hours per session using a conventional hemodialysis machine. Renal replacement therapy comparing EDD with CRRT. Mortality, kidney recovery, and fluid removal. We included 17 studies from 2000 to 2014: 7 RCTs and 10 observational studies involving 533 and 675 patients, respectively. Meta-analysis of RCTs showed no difference in mortality rates between EDD and CRRT (relative risk, 0.90; 95% CI, 0.74-1.11; P=0.3). However, EDD was associated with lower mortality risk compared with CRRT in observational studies (relative risk, 0.86; 95% CI, 0.74-1.00; P=0.05). There was no evidence of heterogeneity in RCTs (I(2)=0%) or observational studies (I(2)=15%). In both RCTs and observational studies, there were no significant differences in recovery of kidney function, fluid removal, or days in the intensive care unit, and EDD showed similar biochemical efficacy to CRRT during treatment (serum urea, serum creatinine, and serum phosphate). The survival benefit of EDD is dependent on only observational studies and might have been affected by allocation or selection bias. EDD is associated with similar outcomes to CRRT in RCTs. The finding that EDD is associated with a lower mortality rate relies on data from observational studies, which are potentially subject to allocation or selection bias, making further high-quality RCTs desirable. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Content may be subject to copyright.
Original Investigation
Extended Daily Dialysis Versus Continuous Renal Replacement
Therapy for Acute Kidney Injury: A Meta-analysis
Ling Zhang, MD,
1,2
Jiqiao Yang, MD,
3
Glenn M. Eastwood, MD,
2
Guijun Zhu, MD,
2,4
Aiko Tanaka, MD,
2
and Rinaldo Bellomo, MD, PhD
2
Background: Extended daily dialysis (EDD) has been suggested as an effective renal replacement therapy
for acute kidney injury. However, results from studies comparing EDD to continuous renal replacement therapy
(CRRT) are inconclusive.
Study Design: A systematic review and meta-analysis was performed by searching in MEDLINE, EMBASE,
the Cochrane Library, Google Scholar, and a Chinese database (SinsoMed).
Setting & Population: Patients with acute kidney injury.
Selection Criteria for Studies: Randomized controlled trials (RCTs) and observational studies were
included. EDD was defined as extended hemodialysis or hemodiafiltration for more than 6 but less than 24
hours per session using a conventional hemodialysis machine.
Intervention: Renal replacement therapy comparing EDD with CRRT.
Outcomes: Mortality, kidney recovery, and fluid removal.
Results: We included 17 studies from 2000 to 2014: 7 RCTs and 10 observational studies involving 533 and
675 patients, respectively. Meta-analysis of RCTs showed no difference in mortality rates between EDD and
CRRT (relative risk, 0.90; 95% CI, 0.74-1.11; P50.3). However, EDD was associated with lower mortality risk
compared with CRRT in observational studies (relative risk, 0.86; 95% CI, 0.74-1.00; P50.05). There was no
evidence of heterogeneity in RCTs (I
2
50%) or observational studies (I
2
515%). In both RCTs and
observational studies, there were no significant differences in recovery of kidney function, fluid removal, or
days in the intensive care unit, and EDD showed similar biochemical efficacy to CRRT during treatment
(serum urea, serum creatinine, and serum phosphate).
Limitations: The survival benefit of EDD is dependent on only observational studies and might have been
affected by allocation or selection bias.
Conclusions: EDD is associated with similar outcomes to CRRT in RCTs. The finding that EDD is asso-
ciated with a lower mortality rate relies on data from observational studies, which are potentially subject to
allocation or selection bias, making further high-quality RCTs desirable.
Am J Kidney Dis. 66(2):322-330. ª2015 by the National Kidney Foundation, Inc.
INDEX WORDS: Extended daily dialysis (EDD); continuous renal replacement therapy (CRRT); hemofiltration;
hemodiafiltration; prolonged intermittent dialysis; sustained low-efficiency dialysis/diafiltration (SLED),
hemodialysis; acute kidney injury (AKI); acute renal failure (ARF); mortality; kidney recovery; fluid removal;
meta-analysis.
Acute kidney injury (AKI) is a major problem in
critical illness. When AKI is severe, renal
replacement therapy (RRT) might be required.
1
Continuous RRT (CRRT) is the preferred method in
intensive care unit (ICU) patients, but survival rates
remain low.
2
Extended daily dialysis (EDD), rst per-
formed for a patient with AKI in 1945 as an alternative
modality of RRT to CRRT, is a special form of inter-
mittent dialysis with low dialysate and blood ow rates
and prolonged duration.
3
In recent studies, EDD
appeared better tolerated hemodynamically and showed
faster normalization of deranged metabolic parameters
compared to conventional intermittent hemodialysis.
4,5
Several small randomized controlled trials (RCTs)
have compared EDD to CRRT for the treatment of
AKI. They found no signicant difference in mor-
tality between the 2 groups.
6-8
However, a recent
study reported that EDD might reduce mortality in
patients with AKI in comparison to CRRT.
9
Thus, we
sought to systematically review the current literature
and analyze all studies comparing EDD to CRRT for
the treatment of AKI in critical illness.
From the
1
Division of Nephrology, West China Hospital of
Sichuan University, Sichuan, Chengdu, China;
2
Division of
Intensive Care Unit, Austin Health, Heidelberg, VIC, Australia;
3
West China School of Medicine, Sichuan University, Sichuan,
Chengdu; and
4
Division of Intensive Care Unit, Fourth Hospital
of Hebei Medical University, Shijiazhuang, Hebei, China.
Received November 23, 2014. Accepted in revised form
February 13, 2015. Originally published online April 2, 2015.
Address correspondence to Rinaldo Bellomo, MD, PhD, Division
of Intensive Care Unit, Austin Health, 145 Studley Road, Heidel-
berg, VIC 3084, Australia. E-mail: rinaldo.bellomo@austin.org.au
2015 by the National Kidney Foundation, Inc.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2015.02.328
322 Am J Kidney Dis. 2015;66(2):322-330
METHODS
Overview
We performed this systematic review using the guidelines pro-
posed by the Cochrane Collaboration in the Cochrane Handbook for
Systematic Reviews of Interventions (www.cochrane-handbook.
org). There was no registered protocol for this meta-analysis.
Study Selection Criteria
Participants
This review focused on patients with critical illness who
received EDD or CRRT for AKI.
Interventions
For the purpose of the review, EDD was dened as extended
(sessions .6 but ,24 hours) hemodialysis or hemodialtration
using a conventional hemodialysis machine, including extended
daily dialysis/dialtration, sustained low-efciency dialysis/dia-
ltration, or prolonged intermittent dialysis/dialtration. We spe-
cically excluded intermittent hemoltration in our analysis.
We used the term CRRT to describe continuous hemoltration
and/or continuous hemodialysis and/or continuous hemodialtra-
tion, all intended to run on a continuous basis (24 hours a day).
Types of Outcome Measures
The primary outcomes were mortality and kidney recovery
among patients with AKI. Fluid removal, ICU days, laboratory
results, and other parameters during RRT were also analyzed.
Types of Studies
We included all RCTs and observational studies concerning
EDD versus CRRT for patients with AKI from 2000 to 2014. We
excluded reviews, commentaries, and editorials.
Search Methods for Identication of Studies
Study Selection
We used the PRISMA (Preferred Reporting Items for System-
atic Reviews and Meta-analyses) and MOOSE (Meta-analysis of
Observational Studies in Epidemiology) statement methodologies
to report a systematic review and meta-analysis of RCTs and
observational studies.
10,11
Two independent reviewers (L.Z. and
J.Y.) conducted a search in MEDLINE, EMBASE, the Cochrane
Library, Google Scholar, a Chinese database (SinoMed), and
major nephrology journals. Trials were considered without lan-
guage or date restriction. We performed the last updated search on
August 8, 2014. The following text words and corresponding
heading terms were used as search terms: acute kidney injury or
acute renal failureand dialysis or hemodialysis or renal
replacement therapy or blood purication.The exact search
strategy is provided in Item S1 (available as online supplementary
material). Related articles and reference lists were manually
searched to avoid omissions. After title screening, we evaluated
abstracts for relevance and identied studies as included, excluded,
or requiring further assessment. At this stage, if a paper required
further assessment, we contacted the study lead investigator by
e-mail and/or telephone with a request for further information.
Data Extraction
Inclusion criteria were as follows: (1) studies comparing EDD
with CRRT and (2) sufcient data available to calculate a relative
risk (RR) or mean difference with 95% condence interval (CI).
The following exclusion criteria were used: (1) studies comparing
standard with intensied extended dialysis; (2) studies comparing
EDD with other modalities of dialysis, such as standard intermit-
tent dialysis or peritoneal dialysis; and (3) nonhuman studies. For
studies with the same or overlapping data by the same authors, the
most suitable studies with the largest number of cases or latest
publication dates were selected.
Two investigators (L.Z. and J.Y.) assessed each trial indepen-
dently and recorded eligibility, quality, and outcomes. Disagree-
ments regarding eligibility arose with 7% of the articles (
k
50.87),
which were resolved by consensus, with a third investigator
(G.M.E.) providing arbitration. We extracted the following study
features: rst author, publication year, country, funding source,
number of participants, RRT modalities, mortality, kidney recov-
ery, uid removal, ICU days, and parameters and laboratory results
during RRT. Outcomes reported in 2 or more articles were
extracted for meta-analysis.
Quantitative Data Synthesis
Independently and in duplicate, reviewers assessed risk of bias of
RCTs using the Cochrane collaboration tool.
12
For each RCT, a
description, a comment, and a judgment of high,”“unclear,or
lowrisk of bias was provided for each of the following domains:
adequate random sequence generation, allocation sequence con-
cealment, blinding for objective outcomes, incomplete outcome
data, freedom from selective outcome reporting, and freedom from
other bias. Trials with high risk of bias for 1 or more key domains
were considered at high risk of bias. Trials with low risk of bias for
all key domains were considered at low risk of bias. Otherwise, they
were considered at unclear risk of bias.
The Newcastle-Ottawa Scale was used in the assessment of
quality of observational studies (case-control or cohort studies).
13
A judgment of high,”“unclear,or lowrisk of bias was pro-
vided for each domains, and a lowrisk of bias was scored 1 and
ahighor unclearrisk of bias was scored 0.A quality bar
was plotted for each domain to examine the limitations of the
studies. Studies of high quality were dened as a score .5 points.
Before the analysis, data were standardized into equivalent
units. For dichotomous variables such as mortality, rates in the
experimental (EDD) and control (CRRT) groups were expressed
as RR and 95% CI. For continuous variables such as uid removal,
mean difference and 95% CI were calculated for each study.
Heterogeneity was evaluated using the Cochrane Q test and I
2
statistic to assess the degree of interstudy variation. I
2
values of
0% to 24.9%, 25% to 49.9%, 50% to 74.9%, and 75% to 100%
were considered as having no, mild, moderate, and signicant
thresholds for statistical heterogeneity.
14,15
A random-effects
model using restricted maximum likelihood,
16
which is thought
to be better than the conventional DerSimonian-Laird method,
17
was performed to provide more conservative estimates of effect
in the presence of known or unknown heterogeneity. Sensitivity
analysis was conducted by sequentially omitting each study one at
a time in an attempt to identify the potential inuence of an in-
dividual study. Data analysis was performed using Stata SE,
version 12, software (StataCorp LP).
RESULTS
Eligible Studies
The study selection process is presented in Fig 1.
The literature search yielded 607 potentially relevant
records. By screening the titles, we removed 249
duplicate studies. After evaluating the abstract of
each, 323 studies were excluded because they did not
meet the inclusion criteria. Subsequently, we carefully
read the full text of each of the remaining 35 trials and
excluded 18 trials. Reasons for exclusion were com-
parison with other modalities of RRT (n 58), no
comparison between RRTs (n 57), not all patients
with AKI (n 52), and overlapping data (n 51).
Extended Dialysis for Acute Kidney Injury
Am J Kidney Dis. 2015;66(2):322-330 323
Finally, 7 RCTs
6-8,18-21
and 10 observational
studies
9,22-30
comparing EDD with CRRT for patients
with AKI were included in this systematic review and
meta-analysis.
The eligible studies were conducted from 2000 to
2014 with a total of 634 patients undergoing EDD and
574 patients undergoing CRRT. Six studies were from
Asia; 4, North America; 4, Europe; 2, Oceania; and 1,
Africa. A variety of outcomes were recorded in these
studies, including mortality (16 studies),
6-9,19-30
kidney
recovery (7 studies),
7,9,19,21 ,22,28,29
uid removal (9
studies),
6-8,18,19,21,24, 26,30
ICU days (5 studies),
7,8,19,21 ,27
serum creatinine level (8 studies),
6,8,21,23 ,24,27-29
serum
urea level (7 studies),
6,8,21,23,27-29
serum phosphate level
(3 studies),
6,8,23
total heparin dose (3 studies),
6,8,28
and
events of increasing vasopressors dose (3 studies).
6,19,26
Among these studies, the duration of EDD was 6.0 to
14.9 hours per day, which was lower than CRRT (18.0-
23.5 hours per day). Characteristics of the RCTs and
observational studies fullling the inclusion criteria are
listed in Table 1 and Item S2.
Assessment of Methodological Quality
The details of risk of bias for RCTs are summarized in
Fig 2. Only 2 studies
8,19
were judged to be at low risk of
bias, one study
18
was judged to be at high risk of bias
due to selection bias, and the other 4 were judged to
be at unclear risk of bias. Three studies
6,8,19
generated
adequate randomized sequence and reported appropriate
allocation concealment. Among all RCTs, none was
double blinded. However, blinding of patients and cli-
nicians was impossible in studies comparing EDD with
CRRT, and the authors judged that the primary outcome
(mortality) is not likely to be inuenced by lack of
blinding.
The Newcastle-Ottawa Scale quality assessment of
included observational studies is also listed in Fig 2. All
studies showed comparatively high quality (score .5).
The main limitation observed in 5 studies
23,25-27,30
was
unclear reporting of dropout rates or uncompleted
follow-ups.
Mortality
In 6 RCTs (617 patients) and 10 observational
studies (675 patients), data for mortality were re-
ported. Within RCTs (Fig 3), there was no statisti-
cally signicant difference in the risk of mortality
rate between EDD and CRRT (RR, 0.90; 95% CI,
0.74-1.11; P50.3). There was no evidence for
heterogeneity (I
2
50). When observational studies
comparing EDD with CRRT were pooled, EDD was
associated with lower risk for mortality compared
with CRRT (RR, 0.86; 95% CI, 0.74-1.0;
P50.05). No evidence was detected for heteroge-
neity (I
2
515%).
Kidney Recovery
A total of 3 RCTs (174 patients) and 5 observa-
tional studies (238 patients) provided information on
kidney recovery. Within RCTs, as shown in Fig 3,
there was no signicant difference in kidney recovery
rate with EDD in comparison to CRRT (RR, 1.12;
95% CI, 0.83-1.76; P50.4), with moderate hetero-
geneity (I
2
565%). Similar results were obtained in
observational studies (RR, 1.14; 95% CI, 0.90-1.46;
P50.3; I
2
50%).
Fluid Removal
Overall, 4 RCTs (367 patients) and 3 observational
studies (140 patients) reported data for uid removal.
Within RCTs, the overall summary mean difference
using the random-effects model was 20.10 (95%
CI, 20.39 to 0.19) L/d (I
2
573%), indicating a
similar effect on uid removal between EDD and
CRRT (Fig 3). On analysis of observational studies,
there were also no signicant differences in uid
removal between EDD and CRRT (mean
difference, 20.06 [95% CI, 21.03 to 0.91] L/d), with
signicant heterogeneity (I
2
579%).
Two RCTs (120 patients; 864 sessions) reported
data for uid removal rate during treatment (Table 2);
607 Potentially relevant studies identified by
research
MEDLINE (n = 206)
EMBASE (n = 267)
Cochrane (n = 89)
Others (n = 45)
358 Potentially relevant articles screened based on
abstracts
249 excluded (duplicate studies)
35 full-text articles selected for full review
17 studies included in the meta-analysis
7RCTs
10 Observational
323 excluded
231 Reviews, comments, and editorials
45 Other modalities of RRT
21 Patients with other diagnosis
15 Studied other treatment
11 No relevant events data
18 excluded
8 Comparison with other modalities of
RRT
7 No comparison between RRT
2 Not all patients with AKI
1Overlapping data
Figure 1. Flow chart of selection of studies. Abbreviations:
AKI, acute kidney injury; RCT, randomized controlled trial;
RRT, renal replacement therapy.
324 Am J Kidney Dis. 2015;66(2):322-330
Zhang et al
Table 1. Characteristics of Studies Fulfilling the Inclusion Criteria
Study Country Design of Study Modality N Mean Age (y) Male Sex (%)
Mean Therapy
Duration (h/d)
Main Outcomes FundingEDD CRRT
Kielstein
6
(2004) DE RCT EDD vs CVVH 39 50.5 62.9 11.7 23.3 Mortality, fluid removal Industry
Baldwin
18
(2007) AU RCT EDD vs CVVH 16 69.5 56.3 7.3 18.4 Fluid removal NR
Abe
7
(2010) JP RCT EDDF vs CVVHDF 60 68.7 65.0 6.5 20.3 Mortality, kidney recovery, ICU days NR
Abe
19
(2011) JP RCT EDDF vs CVVHDF 50 65.9 66.0 6.0 15.2 Mortality, kidney recovery, ICU days NR
Shin
20
(2011) KR RCT SLED vs CVVH 46 63 63.0 10 NR Mortality NR
Schwenger
8
(2012) DE RCT SLED vs CVVH 232 66.2 67.7 14.9 19.9 Mortality, fluid removal, ICU days NR
Badawy
21
(2012) EG RCT EDD vs CVVHDF 80 47.5 65.0 6-8 NR Mortality, fluid removal, ICU days NR
Kumar
22
(2000) US Retrospective EDD vs CVVH 42 50 64.3 7.5 19.5 Mortality NR
Kumar
23
(2004) US Prospective EDD vs CVVHD 54 52 63.0 6.7 16.8 Mortality, kidney recovery NR
Berbece
24
(2006) CA Prospective SLED vs CVVHDF 34 58.4 61.8 7.5 21.3 Mortality, fluid removal NR
Marcelino
25
(2006) PT Retrospective SLED vs CVVHDF 53 59.1 NR 6.8 22.1 Mortality NR
Lu
29
(2008) CN Prospective SLED vs CVVH 12 49.7 66.7 10 18 Mortality, kidney recovery Public
Birne
30
(2009) PT Retrospective SLED vs CVVHDF 63 63.3 49.2 6-12 NR Mortality, fluid removal NR
Fieghen
26
(2010) CA Retrospective SLED vs CVVHDF 43 62.1 76.7 6.8 19.7 Mortality, fluid removal NR
Wu
9
(2010) TW Retrospective SLED vs CVVH 101 67.4 65.3 8.0 NR Mortality, kidney recovery NR
Khanal
27
(2012) NZ Retrospective SLEDF vs CVVHDF 166 58.5 62.0 7.2 NR Mortality, ICU days NR
Chen
28
(2014) CN Retrospective SLEDF vs CVVH 107 59.5 NR 8.8 23.5 Mortality, kidney recovery NR
Abbreviations: AU, Australia; CA, Canada; CN, China; CRRT, continuous renal replacement therapy; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous he-
modialysis; CVVHDF, continuous venovenous hemodiafiltration; DE, Germany; EDD, extended daily dialysis; EDDF, extended daily diafiltration; EG, Egypt; ICU, intensive care unit; JP, Japan;
KR, Korea; NR, not reported; NZ, New Zealand; PT, Portugal; RCT, randomized controlled trial; SLED, sustained low-efficiency dialysis; SLEDF, sustained low-efficiency diafiltration; TW,
Taiwan; US, United States.
Am J Kidney Dis. 2015;66(2):322-330 325
Extended Dialysis for Acute Kidney Injury
EDD was associated with a higher uid removal rate
compared to CRRT (202.23 [95% CI, 151.27-253.19]
mL/h; I
2
598%).
Length of ICU Stay
A total of 4 RCTs
7,8,19,21
(422 patients) and one
observational study
27
(166 patients) described length
of ICU stay. Within RCTs, as shown in Table 2, there
was similar duration of ICU stay between EDD and
CRRT (mean difference, 21.51 [95% CI, 27.84 to
4.3] days), with signicant heterogeneity (I
2
580%).
Similar results were obtained in observational studies
(mean difference, 22.30 [95% CI, 25.61 to 1.01]
days).
Laboratory Results During RRT
Overall, 3 RCTs
6,8,21
(351 patients) and 5 observa-
tional studies
23,24,27-29
(724 patients) reported on
serum creatinine. Within RCTs, as shown in Table 2,
the overall summary mean difference using the
random-effects model was 0.37 (95% CI, 20.43 to
1.17) mg/dL, indicating there was no difference in
serum creatinine levels between CRRT and EDD, with
signicant heterogeneity (I
2
598%). Similar results
were obtained in observational studies (mean differ-
ence, 0.40 [95% CI, 20.36 to 1.15] mg/dL; I
2
591%).
A total of 3 RCTs
6,8,21
(351 patients) and 4
observational studies
23,27-29
(690 patients) reported
plasma urea levels (Table 2). There was no signicant
difference in urea levels between EDD and CRRT in
RCTs (mean difference, 28.56 [95% CI, 237.17 to
20.04] mg/dL; I
2
599%) or observational studies
(mean difference, 14.90 [95% CI, 28.20 to 38.0] mg/
dL; I
2
595%).
Two RCTs
6,8
(271 patients) and one observational
study
23
(54 patients) reported on serum phosphate
levels. As shown in Table 2, there was no signicant
difference in serum phosphate levels with EDD in
comparison to CRRT in RCTs (mean difference,
20.31 [95% CI, 21.50 to 0.89] mg/dL; I
2
598%) or
observational studies (mean difference, 0.31 [95%
CI, 20.38 to 1.0] mg/dL).
Heparin Dose
Two RCTs
6,8
(351 patients) and one observational
study
28
(724 patients) reported on heparin dose
(Table 2). Within RCTs, there was nominally lower use
of heparin per session with EDD than with CRRT, but
the difference was not statistically signicant (mean
difference, 24.49 [95% CI, 212.09 to 3.10] kU/d;
I
2
599%). However, the difference was signicant
in observational studies (mean difference, 28.91 [95%
CI, 29.32 to 28.50] kU/d).
Episodes of Vasopressor Escalation
Two RCTs
6,19
(89 patients; 412 sessions) and 1
observational study
26
(43 patients; 125 sessions)
described episodes of vasopressor escalation during
RRT. There was no signicant difference between
EDD and CRRT in RCTs (P50.8; I
2
50%) and
observational studies (P50.2). The outcome might
be different if it were expressed as hourly rates
Figure 2. Risk of bias summary.
Abbreviation: RCT, randomized con-
trolled trial.
326 Am J Kidney Dis. 2015;66(2):322-330
Zhang et al
because the duration of CRRT in these studies was
about twice as long as EDD; however, no relevant
data could be obtained for any of the included studies.
Costs
Three studies reported costs in different ways,
including total RRT costs in 2 studies,
24,28
RRT cost
per day in 2 studies,
8,24
and total costs of hospitali-
zation in 1 study.
28
All results indicated that costs
were lower with EDD compared to CRRT. Meta-
analysis could not be estimated due to absence of a
standard deviation.
Sensitivity Analysis
In order to assess the stability of results of the
current meta-analysis, we performed sensitivity anal-
ysis for mortality by omitting a single study. Statis-
tically similar results were obtained after omitting
Mortality ( Observat ional Stud ies)
Mortality (R CTs)
Kidney Recovery (RCTs)
Fluid Removal (RCTs) Fluid Removal (Observational Studies)
Abe, 2010
Abe, 2011
Badawy, 2012
Kielstein, 2004
Schwenger, 2012
Shin, 2011
Overall
Effect (rem l)
Berbece, 2008
Birne, 2009
Chen, 2014
Fieghen, 2010
Khanal, 2012
Kumar, 2000
Kumar, 2004
Lu, 2008
Marcelino, 2006
Wu, 2010
Overall
Effect (reml)
Abe, 2010
Abe, 2011
Badawy, 2012
Overall
Effect (rem l)
Chen, 2014
Kumar, 2004
Lu, 2008
Wu, 2010
Overall
Effect (reml)
Kidney Recovery (Observational Studies)
Badawy, 2012
Baldwin, 2007
Kielstein, 2004
Schwenger, 2012
Overall
Effect (reml)
Berbece, 2006
Birne, 2009
Fieghen, 2010
Overall
Effect (rem l)
Figure 3. Forest plot for mortality, kidney recovery, and fluid removal. The analysis was stratified by study design. Original weights
(squares) displayed; largest to smallest ratios are 13.64, 11.30, 1.51, 3.83, 10.35, and 1.11, respectively, for randomized controlled trial
(RCT) mortality, observational mortality, RTC kidney recovery, observational kidney recovery, RCT fluid removal, RCT fluid removal.
Abbreviations: CI, confidence interval; MD, mean difference; RR, risk ratio.
Am J Kidney Dis. 2015;66(2):322-330 327
Extended Dialysis for Acute Kidney Injury
each of the studies (RR range in RCTs, 0.82-0.93; RR
range in observational studies, 0.81-0.90). We also
evaluated the effect on overall mortality of removing
studies with unclear methodological quality
7,18,19
or
funding bias
6
and found similar RRs (0.89 and 0.86,
respectively; P.0.05) in RCTs.
DISCUSSION
We performed a systematic review of the literature
and identied 17 original studies reporting data on
EDD versus CRRT among more than 1,200 patients
with AKI. When we analyzed RCTs, we found that
patients who received EDD as an initial RRT mo-
dality for AKI had a similar risk of death compared
with those who initially received CRRT. However, a
difference in favor of EDD was seen in observational
studies. In both RCTs and observational studies, there
were no signicant differences in kidney recovery,
uid removal, and episodes of vasopressor escalation
with EDD in comparison to CRRT. Also, EDD
showed similar efcacy to CRRT in laboratory results
(serum urea, serum creatinine, and serum phosphate)
during RRT and was associated with lower costs.
Several meta-analyses
31-34
have compared con-
ventional intermittent RRT and CRRT and found no
signicant difference in mortality, and a recent RCT
conrmed this result.
35
A meta-analysis found that conventional intermittent
RRT may be associated with higher rates of dialysis
dependence compared with CRRT.
31
However,
because EDD is a hybrid technology combining prop-
erties from both intermittent RRT and CRRT, EDD
should not be considered a conventional form of
intermittent RRT. To date, to our knowledge, only 1
meta-analysis
32
in 2008 compared EDD (in the form of
sustained low-efciency dialysis [SLED]) with CRRT
for AKI, but it included just 1 trial with 54 patients. In
contrast, the present review includes data from 7 RCTs
and 10 observational studies with more than 1,200
patients with AKI. Such studies, although subject to
bias, involve a large number of patients and might be
more likely to accurately represent the efcacy of EDD
for patients with AKI. In this meta-analysis, there was a
mild trend toward improved survival in favor of EDD-
treated patients with AKI, although the evidence was
weak because of a lack of signicant difference in
RCTs. There might be some reasons for this trend. First,
heparin was the main anticoagulant in included studies
(table bof Item S2), and CRRT used a relatively high
dose of heparin, which might be associated with higher
risk of bleeding. Second, a higher rate of clotting was
found in CRRT from included studies,
22,23
which
might contribute to inadequate treatment and increased
blood loss.
8
Third, long duration of treatment might be
associated with a higher rate of biofilm formation and
circuit contamination.
36,37
Many studies and meta-analyses have focused on
conventional intermittent RRT in comparison to CRRT
for critically ill patients with AKI and found no sig-
nicant difference in mortality. However, there might
be some advantages and disadvantages with both
modalities.
38
In this regard, EDD to some extent
combines several advantages of both modalities.
However, there are only a few high-quality studies to
compare EDD with other modalities for patients with
AKI. In addition, much more attention should be
focused on the intensity of EDD, such as dose or fre-
quency, although some evidence shows that intensied
EDD is not associated with better outcomes.
39,40
Thus, future studies comparing RRT modalities
should focus on studying EDD as a therapeutic option
in severe AKI.
Table 2. Meta-analysis of Secondary Outcomes
Outcome Study Type No. of Studies EDD vs CRRT
a
I
2
Fluid removal rate (in mL/h) RCT 2 202.23 (151.27 to 253.19) 98%
ICU days RCT 3 21.51 (27.84 to 4.83) 80%
Observational 1 22.30 (25.61 to 1.01)
Serum creatinine (in mg/dL) RCT 3 0.37 (20.43 to 1.17) 98%
Observational 5 0.40 (20.36 to 1.15) 91%
Serum urea (in mg/dL) RCT 3 28.56 (237.17 to 20.04) 99%
Observational 4 14.90 (28.20 to 38.00) 95%
Serum phosphate (in mg/dL) RCT 2 20.31 (21.50 to 0.89) 98%
Observational 1 0.31 (20.38 to 1.0)
Heparin dose (I kU/d) RCT 2 24.49 (212.09 to 3.10) 99%
Observational 1 28.91 (29.32 to 28.50)
Episodes of vasopressor escalation RCT 2 0.85 (0.52 to 1.40) 0%
Observational 1 0.65 (0.36 to 1.18)
Abbreviations: CRRT, continuous renal replacement therapy; EDD, extended daily dialysis; ICU, intensive care unit; RCT, ran-
domized controlled trial.
a
Values shown are mean difference (EDD CRRT), except episodes of vasopressor escalation, which give relative risk for EDD
versus CRRT. Values in parentheses are 95% confidence intervals.
328 Am J Kidney Dis. 2015;66(2):322-330
Zhang et al
To our knowledge, this study is the rst to sys-
tematically evaluate the effect of EDD versus CRRT
on patients with AKI. Our search strategy was broad
and included studies in English, Chinese,
29
Korean,
20
and Portuguese
25
languages. It included data from
more than 1,200 patients, 17 studies, and 10 coun-
tries; from different regions of Asia, North America,
Europe, Oceania, and Africa; and from both large
observational studies and RCTs. Furthermore, 2 in-
dependent investigators thoroughly evaluated meth-
odological quality.
However, our study also has several limitations.
First, this association with mortality is largely
dependent on observational studies and might have
been affected by allocation or selection bias.
Second, despite a total of 17 studies, eligible studies
comparing specic outcomes were limited. No suf-
cient data were obtained to evaluate adverse outcomes
such as bleeding, infection, and hypotension. In
addition, although a similar effect on uid removal
was found for EDD and CRRT, data regarding uid
intake and volume balance were lacking. Furthermore,
the evidence on secondary outcomes might be at
high risk of reporting bias because only a few
included studies (#50%) reported these outcomes
and did so with high heterogeneity. Thus, in our
opinion, these results do not warrant changing clinical
practice, but rather support the need for additional
research.
Third, although we extracted data for mortality at
the end of follow-up, the duration of each study
varied from 10 days in 1 study
6
to 30 days in 6
studies
7,9,19-21,28
to 90 days in 2 studies,
8,27
or to ICU
mortality in 1 study
30
and in-hospital mortality in 6
studies.
22-26,29
Even so, although end points of
different follow-up periods could modify the absolute
risk, they should not bias the overall RR.
Last, but not least, only published studies with selective
databases were included for data analysis. The unavail-
ability of unreported outcomes possibly could result in
reporting bias. For instance, 2 studies reported insufcient
data for mortality.
6,18
Regardless of these limitations, we
have minimized bias throughout the process by our
methods of study identication, data selection, and sta-
tistical analysis and in our controlling publication bias and
sensitivity. These steps should strengthen the stability and
accuracy of the meta-analysis.
In conclusion, available RCTs do not show a dif-
ference in mortality between EDD and CRRT.
However, observational studies suggest that EDD
may be associated with a greater survival rate.
Because these studies might be associated with allo-
cation or selection bias, further high-quality RCTs
focused on mortality according to different RRT
modalities are necessary to fully understand the ef-
fects of EDD for patients with AKI.
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: The authors declare that they have no
relevant nancial interests.
Contributions: Research idea and study design: LZ, RB; data
acquisition: LZ, JY; data analysis/interpretation: LZ, JY, AT;
statistical analysis: LZ, GZ; supervision or mentorship: RB, GME.
Each author contributed important intellectual content during
manuscript drafting or revision and accepts accountability for the
overall work by ensuring that questions pertaining to the accuracy
or integrity of any portion of the work are appropriately investi-
gated and resolved. LZ and RB take responsibility that this study
has been reported honestly, accurately, and transparently; that no
important aspects of the study have been omitted, and that any
discrepancies from the study as planned have been explained.
SUPPLEMENTARY MATERIAL
Item S1: Electronic search strategies.
Item S2: Additional characteristics of studies fullling inclusion
criteria.
Note: The supplementary material accompanying this article
(http://dx.doi.org/10.1053/j.ajkd.2015.02.328) is available at
www.ajkd.org
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Zhang et al
... Schneider et al [19] reviewed the rate of dialysis dependence among patients on intermittent RRT modalities collectively. Zhang et al [24] review compared CRRT and SLED in 2015, but in their analysis they separated the results of randomized controlled trials (RCTs) and observational studies resulting in inconclusive findings. Also, there was evidence of publication bias from the selected studies as many of the included studies were not available online and were from China. ...
... Also, there was evidence of publication bias from the selected studies as many of the included studies were not available online and were from China. [24] Furthermore, the review by Nash et al [25] in 2017 compared all the existing 3 modalities of RRT but they limited their study selection to RCTs only and very few outcome parameters were assessed. ...
... Our study builds on previous published meta-analyses by Zhang et al, [24] Nash et al, [25] and Tonelli et al. [30] We found 4 and 9 studies that reported on in-hospital mortality and ICU mortality rate, respectively. The analyses indicate that there were no statistically significant differences for the pooled results of inhospital mortality and ICU mortality rates comparing patients who received CRRT compared with SLED. ...
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... A 2015 meta-analysis (Zhang et al) 40 of 17 studies comparing PIRRT and CRRT, 16 of which are included in the Table 3, 15,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] showed no difference in mortality rates between the 2 modalities. In the observational studies, 15,41,42,[44][45][46][47][48][49]55 PIRRT was associated with a lower mortality risk, although these studies are potentially subject of selection bias. ...
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A primary goal of meta-analysis is to improve the estimation of treatment effects by pooling results of similar studies. This article explains how the most widely used method for pooling heterogeneous studies-the DerSimonian-Laird (DL) estimator-can produce biased estimates with falsely high precision. A classic example is presented to show that use of the DL estimator can lead to erroneous conclusions. Particular problems with the DL estimator are discussed, and several alternative methods for summarizing heterogeneous evidence are presented. The authors support replacing universal use of the DL estimator with analyses based on a critical synthesis that recognizes the uncertainty in the evidence, focuses on describing and explaining the probable sources of variation in the evidence, and uses random-effects estimates that provide more accurate confidence limits than the DL estimator.
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Prolonged intermittent renal replacement therapy (PIRRT) is a recently defined acute modality for critically ill patients, and in theory combines the superior detoxification and haemodynamic stability of continuous renal replacement therapy (CRRT) with the operational convenience and low cost of intermittent haemodialysis (iHD). We performed a retrospective cohort study for all critically ill adults treated with renal replacement therapy at our centre in Auckland, New Zealand from 1 January 2002 to 31 December 2008. The exposure of interest was modality (PIRRT, CRRT, iHD). Primary and secondary outcomes were patient mortality determined at hospital discharge and 90 days post renal replacement therapy inception, respectively. Co-variates included co-morbidity and baseline illness severity measured by Acute Physiology and Chronic Health Evaluation IV and Sepsis-Related Organ Failure Assessment (SOFA) and time-varying illness severity measured by daily SOFA scores. We used Marginal Structural Modelling to estimate mortality risk adjusting for both time-varying illness severity and modality exposure. A total of 146 patients with 633 treatment-days had sufficient data for modelling. With PIRRT as the reference, the adjusted hazard ratios for patient hospital mortality were 1.31 (0.60 to 2.90) for CRRT and 1.22 (0.21 to 2.29) for iHD. Corresponding estimates for mortality at 90 days were 0.96 (0.39 to 2.36) and 2.22 (0.49 to 10.11), respectively, reflecting the poorer longer-term prognosis of patients still on iHD at hospital discharge with delayed or non-recovery of acute kidney injury. Our study supports the recent increased use of PIRRT, which within limits can be regarded as safe and effective.
Article
Background and objectives Acute kidney injury (AKI) requiring dialysis after cardiac surgery is accompanied by high mortality. Continuous venovenous hemodiafiltration (CVVHDF) and extended daily dialysis (EDD) are commonly used for critically ill patients with AKI. The aim of this prospective randomized comparative pilot trial was to compare the efficacy of CVVHDF and EDD in patients with AKI after cardiac surgery. Patients and methods A total of 80 patients who developed AKI and who needed renal replacement therapy (RRT) after cardiac surgery were included in this prospective randomized comparative trial. Patients were randomized to receive either CVVHDF or EDD. The outcomes assessed were renal recovery, mortality rate at day 30, and cost of RRT in the ICU. Results Both groups were comparable with respect to demographic data and APACHE II score. The frequencies of renal recovery and mortalities were comparable in both groups. The cost of RRT was significantly lower in the EDD group compared with the CVVHDF group ( P Conclusion Both CVVHDF and EDD are effective in patients with AKI after cardiac surgery, with EDD having the advantage of lower cost.
Article
Background Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal. Study Design Randomized crossover trial. Settings & Participants Stable patients with end-stage renal disease undergoing conventional HD. Intervention 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments. Outcomes Acute hemodynamic effects and uremic toxin clearance. Measurements Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied. Results Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, −21.7 ± 15.6 mm Hg; during HDF4, −23.3 ± 20.8 mm Hg; during HD8, −6.7 ± 15.2 mm Hg [P = 0.04 vs HD4; P = 0.08 vs HDF4]; and during HDF8, −0.5 ± 14.4 mm Hg [P = 0.004 vs HD4; P = 0.008 vs HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, −1.4 ± 1.5 L/min; during HDF4, −1.6 ± 1.0 L/min; during HD8, −0.4 ± 0.9 L/min [P = 0.02 vs HDF4]; and during HDF8, −0.5 ± 0.8 L/min [P = 0.06 vs HD4; P = 0.03 vs HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3 ± 4.7 W; HDF4, 16.2 ± 5.6 W; HD8, 14.2 ± 6.0 W; and HDF8, 14.5 ± 4.3 W). Small-molecule and phosphate removal were superior during long treatments. β2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8. Limitations Small sample size, only acute effects were studied. Conclusions Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF.