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Extended Daily Dialysis Versus Continuous Renal Replacement Therapy for Acute Kidney Injury: A Meta-analysis
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, PhD2 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; P 5 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 5 0.05). There was no evidence of heterogeneity in RCTs (I 2 5 0%) or observational studies (I 2 5 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). 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 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. Am J Kidney Dis. 66(2):322-330. ª 2015 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.
A
cute 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), first performed for a patient with AKI in 1945 as an alternative modality of RRT to CRRT, is a special form of intermittent dialysis with low dialysate and blood flow 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 significant difference in mortality 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 1Division of Nephrology, West China Hospital of Sichuan University, Sichuan, Chengdu, China; 2Division of Intensive Care Unit, Austin Health, Heidelberg, VIC, Australia; 3 West China School of Medicine, Sichuan University, Sichuan, Chengdu; and 4Division 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, Heidelberg, VIC 3084, Australia. E-mail: [email protected] 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.02.328
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Extended Dialysis for Acute Kidney Injury
METHODS Overview We performed this systematic review using the guidelines proposed 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 defined as extended (sessions . 6 but ,24 hours) hemodialysis or hemodiafiltration using a conventional hemodialysis machine, including extended daily dialysis/diafiltration, sustained low-efficiency dialysis/diafiltration, or prolonged intermittent dialysis/diafiltration. We specifically excluded intermittent hemofiltration in our analysis. We used the term CRRT to describe continuous hemofiltration and/or continuous hemodialysis and/or continuous hemodiafiltration, 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 Identification of Studies Study Selection We used the PRISMA (Preferred Reporting Items for Systematic 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 language 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 failure” and “dialysis or hemodialysis or renal replacement therapy or blood purification.” 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 identified 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) sufficient data available to calculate a relative risk (RR) or mean difference with 95% confidence interval (CI). The following exclusion criteria were used: (1) studies comparing standard with intensified extended dialysis; (2) studies comparing EDD with other modalities of dialysis, such as standard intermittent dialysis or peritoneal dialysis; and (3) nonhuman studies. For studies with the same or overlapping data by the same authors, the Am J Kidney Dis. 2015;66(2):322-330
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 independently and recorded eligibility, quality, and outcomes. Disagreements regarding eligibility arose with 7% of the articles (k 5 0.87), which were resolved by consensus, with a third investigator (G.M.E.) providing arbitration. We extracted the following study features: first author, publication year, country, funding source, number of participants, RRT modalities, mortality, kidney recovery, fluid 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 “low” risk of bias was provided for each of the following domains: adequate random sequence generation, allocation sequence concealment, 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 “low” risk of bias was provided for each domains, and a “low” risk of bias was scored 1 and a “high” or “unclear” risk 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 defined 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 fluid removal, mean difference and 95% CI were calculated for each study. Heterogeneity was evaluated using the Cochrane Q test and I2 statistic to assess the degree of interstudy variation. I2 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 significant 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 influence of an individual 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 comparison with other modalities of RRT (n 5 8), no comparison between RRTs (n 5 7), not all patients with AKI (n 5 2), and overlapping data (n 5 1). 323
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607 Potentially relevant studies identified by research MEDLINE (n = 206) EMBASE (n = 267) Cochrane (n = 89) Others (n = 45)
249 excluded (duplicate studies) 358 Potentially relevant articles screened based on abstracts 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
bias, one study18 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 studies6,8,19 generated adequate randomized sequence and reported appropriate allocation concealment. Among all RCTs, none was double blinded. However, blinding of patients and clinicians was impossible in studies comparing EDD with CRRT, and the authors judged that the primary outcome (mortality) is not likely to be influenced 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 studies23,25-27,30 was unclear reporting of dropout rates or uncompleted follow-ups.
35 full-text articles selected for full review
Mortality 18 excluded 8 Comparison with other modalities of RRT 7 No comparison between RRT 2 Not all patients with AKI 1 Overlapping data 17 studies included in the meta-analysis 7 RCTs 10 Observational
Figure 1. Flow chart of selection of studies. Abbreviations: AKI, acute kidney injury; RCT, randomized controlled trial; RRT, renal replacement therapy.
Finally, 7 RCTs6-8,18-21 and 10 observational studies9,22-30 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 fluid 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 (18.023.5 hours per day). Characteristics of the RCTs and observational studies fulfilling 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 studies8,19 were judged to be at low risk of 324
In 6 RCTs (617 patients) and 10 observational studies (675 patients), data for mortality were reported. Within RCTs (Fig 3), there was no statistically significant difference in the risk of mortality rate between EDD and CRRT (RR, 0.90; 95% CI, 0.74-1.11; P 5 0.3). There was no evidence for heterogeneity (I2 5 0). 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; P 5 0.05). No evidence was detected for heterogeneity (I2 5 15%). Kidney Recovery A total of 3 RCTs (174 patients) and 5 observational studies (238 patients) provided information on kidney recovery. Within RCTs, as shown in Fig 3, there was no significant difference in kidney recovery rate with EDD in comparison to CRRT (RR, 1.12; 95% CI, 0.83-1.76; P 5 0.4), with moderate heterogeneity (I2 5 65%). Similar results were obtained in observational studies (RR, 1.14; 95% CI, 0.90-1.46; P 5 0.3; I2 5 0%). Fluid Removal Overall, 4 RCTs (367 patients) and 3 observational studies (140 patients) reported data for fluid 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 (I2 5 73%), indicating a similar effect on fluid removal between EDD and CRRT (Fig 3). On analysis of observational studies, there were also no significant differences in fluid removal between EDD and CRRT (mean difference, 20.06 [95% CI, 21.03 to 0.91] L/d), with significant heterogeneity (I2 5 79%). Two RCTs (120 patients; 864 sessions) reported data for fluid removal rate during treatment (Table 2); Am J Kidney Dis. 2015;66(2):322-330
Mean Therapy Duration (h/d) Study
Country
Kielstein6 (2004) Baldwin18 (2007) Abe7 (2010) Abe19 (2011) Shin20 (2011) Schwenger8 (2012) Badawy21 (2012) Kumar22 (2000) Kumar23 (2004) Berbece24 (2006) Marcelino25 (2006) Lu29 (2008) Birne30 (2009) Fieghen26 (2010) Wu9 (2010) Khanal27 (2012) Chen28 (2014)
DE AU JP JP KR DE EG US US CA PT CN PT CA TW NZ CN
Design of Study
RCT RCT RCT RCT RCT RCT RCT Retrospective Prospective Prospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective
Modality
N
Mean Age (y)
Male Sex (%)
EDD
CRRT
Main Outcomes
Funding
EDD vs CVVH EDD vs CVVH EDDF vs CVVHDF EDDF vs CVVHDF SLED vs CVVH SLED vs CVVH EDD vs CVVHDF EDD vs CVVH EDD vs CVVHD SLED vs CVVHDF SLED vs CVVHDF SLED vs CVVH SLED vs CVVHDF SLED vs CVVHDF SLED vs CVVH SLEDF vs CVVHDF SLEDF vs CVVH
39 16 60 50 46 232 80 42 54 34 53 12 63 43 101 166 107
50.5 69.5 68.7 65.9 63 66.2 47.5 50 52 58.4 59.1 49.7 63.3 62.1 67.4 58.5 59.5
62.9 56.3 65.0 66.0 63.0 67.7 65.0 64.3 63.0 61.8 NR 66.7 49.2 76.7 65.3 62.0 NR
11.7 7.3 6.5 6.0 10 14.9 6-8 7.5 6.7 7.5 6.8 10 6-12 6.8 8.0 7.2 8.8
23.3 18.4 20.3 15.2 NR 19.9 NR 19.5 16.8 21.3 22.1 18 NR 19.7 NR NR 23.5
Mortality, fluid removal Fluid removal Mortality, kidney recovery, ICU days Mortality, kidney recovery, ICU days Mortality Mortality, fluid removal, ICU days Mortality, fluid removal, ICU days Mortality Mortality, kidney recovery Mortality, fluid removal Mortality Mortality, kidney recovery Mortality, fluid removal Mortality, fluid removal Mortality, kidney recovery Mortality, ICU days Mortality, kidney recovery
Industry NR NR NR NR NR NR NR NR NR NR Public NR NR NR NR NR
Abbreviations: AU, Australia; CA, Canada; CN, China; CRRT, continuous renal replacement therapy; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; 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.
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Table 1. Characteristics of Studies Fulfilling the Inclusion Criteria
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Figure 2. Risk of bias summary. Abbreviation: RCT, randomized controlled trial.
EDD was associated with a higher fluid removal rate compared to CRRT (202.23 [95% CI, 151.27-253.19] mL/h; I2 5 98%). Length of ICU Stay A total of 4 RCTs7,8,19,21 (422 patients) and one observational study27 (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 significant heterogeneity (I2 5 80%). 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 RCTs6,8,21 (351 patients) and 5 observational studies23,24,27-29 (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 significant heterogeneity (I2 5 98%). Similar results were obtained in observational studies (mean difference, 0.40 [95% CI, 20.36 to 1.15] mg/dL; I2 5 91%). A total of 3 RCTs6,8,21 (351 patients) and 4 observational studies23,27-29 (690 patients) reported plasma urea levels (Table 2). There was no significant difference in urea levels between EDD and CRRT in RCTs (mean difference, 28.56 [95% CI, 237.17 to 326
20.04] mg/dL; I2 5 99%) or observational studies (mean difference, 14.90 [95% CI, 28.20 to 38.0] mg/ dL; I2 5 95%). Two RCTs6,8 (271 patients) and one observational study23 (54 patients) reported on serum phosphate levels. As shown in Table 2, there was no significant 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; I2 5 98%) or observational studies (mean difference, 0.31 [95% CI, 20.38 to 1.0] mg/dL). Heparin Dose Two RCTs6,8 (351 patients) and one observational study28 (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 significant (mean difference, 24.49 [95% CI, 212.09 to 3.10] kU/d; I2 5 99%). However, the difference was significant in observational studies (mean difference, 28.91 [95% CI, 29.32 to 28.50] kU/d). Episodes of Vasopressor Escalation Two RCTs6,19 (89 patients; 412 sessions) and 1 observational study26 (43 patients; 125 sessions) described episodes of vasopressor escalation during RRT. There was no significant difference between EDD and CRRT in RCTs (P 5 0.8; I2 5 0%) and observational studies (P 5 0.2). The outcome might be different if it were expressed as hourly rates Am J Kidney Dis. 2015;66(2):322-330
Extended Dialysis for Acute Kidney Injury Mortality (Observational Studies)
Mortality (RCTs) Berbece, 2008
Abe, 2010
Birne, 2009 Abe, 2011
Chen, 2014 Fieghen, 2010
Badawy, 2012
Khanal, 2012 Kumar, 2000
Kielstein, 2004
Kumar, 2004 Schwenger, 2012
Lu, 2008 Marcelino, 2006
Shin, 2011
Wu, 2010 Overall Effect (reml)
Overall Effect (reml)
Kidney Recovery (Observational Studies)
Kidney Recovery (RCTs) Chen, 2014
Abe, 2010
Kumar, 2004 Abe, 2011
Lu, 2008
Badawy, 2012 Wu, 2010
Overall Effect (reml)
Overall Effect (reml)
Fluid Removal (RCTs) Badawy, 2012
Fluid Removal (Observational Studies) Berbece, 2006
Baldwin, 2007 Birne, 2009
Kielstein, 2004
Fieghen, 2010 Schwenger, 2012
Overall Effect (reml)
Overall Effect (reml)
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.
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.
were lower with EDD compared to CRRT. Metaanalysis could not be estimated due to absence of a standard deviation.
Costs
Sensitivity Analysis
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 hospitalization in 1 study.28 All results indicated that costs
In order to assess the stability of results of the current meta-analysis, we performed sensitivity analysis for mortality by omitting a single study. Statistically similar results were obtained after omitting
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Fluid removal rate (in mL/h) ICU days Serum creatinine (in mg/dL) Serum urea (in mg/dL) Serum phosphate (in mg/dL) Heparin dose (I kU/d) Episodes of vasopressor escalation
Study Type
No. of Studies
RCT RCT Observational RCT Observational RCT Observational RCT Observational RCT Observational RCT Observational
2 3 1 3 5 3 4 2 1 2 1 2 1
EDD vs CRRTa
202.23 21.51 22.30 0.37 0.40 28.56 14.90 20.31 0.31 24.49 28.91 0.85 0.65
(151.27 to 253.19) (27.84 to 4.83) (25.61 to 1.01) (20.43 to 1.17) (20.36 to 1.15) (237.17 to 20.04) (28.20 to 38.00) (21.50 to 0.89) (20.38 to 1.0) (212.09 to 3.10) (29.32 to 28.50) (0.52 to 1.40) (0.36 to 1.18)
I2
98% 80%
—
98% 91% 99% 95% 98%
—
99%
—
0%
—
Abbreviations: CRRT, continuous renal replacement therapy; EDD, extended daily dialysis; ICU, intensive care unit; RCT, randomized 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.
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 quality7,18,19 or funding bias6 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 identified 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 modality 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 significant differences in kidney recovery, fluid removal, and episodes of vasopressor escalation with EDD in comparison to CRRT. Also, EDD showed similar efficacy to CRRT in laboratory results (serum urea, serum creatinine, and serum phosphate) during RRT and was associated with lower costs. Several meta-analyses31-34 have compared conventional intermittent RRT and CRRT and found no significant difference in mortality, and a recent RCT confirmed 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 properties 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-analysis32 in 2008 compared EDD (in the form of sustained low-efficiency dialysis [SLED]) with CRRT 328
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 efficacy of EDD for patients with AKI. In this meta-analysis, there was a mild trend toward improved survival in favor of EDDtreated patients with AKI, although the evidence was weak because of a lack of significant difference in RCTs. There might be some reasons for this trend. First, heparin was the main anticoagulant in included studies (table b of 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 significant 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 frequency, although some evidence shows that intensified 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. Am J Kidney Dis. 2015;66(2):322-330
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To our knowledge, this study is the first to systematically 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 Portuguese25 languages. It included data from more than 1,200 patients, 17 studies, and 10 countries; from different regions of Asia, North America, Europe, Oceania, and Africa; and from both large observational studies and RCTs. Furthermore, 2 independent investigators thoroughly evaluated methodological 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 specific outcomes were limited. No sufficient data were obtained to evaluate adverse outcomes such as bleeding, infection, and hypotension. In addition, although a similar effect on fluid removal was found for EDD and CRRT, data regarding fluid 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 study6 to 30 days in 6 studies7,9,19-21,28 to 90 days in 2 studies,8,27 or to ICU mortality in 1 study30 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 unavailability of unreported outcomes possibly could result in reporting bias. For instance, 2 studies reported insufficient data for mortality.6,18 Regardless of these limitations, we have minimized bias throughout the process by our methods of study identification, data selection, and statistical 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 difference 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 allocation or selection bias, further high-quality RCTs focused on mortality according to different RRT modalities are necessary to fully understand the effects of EDD for patients with AKI. Am J Kidney Dis. 2015;66(2):322-330
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial 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 investigated 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 fulfilling 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
REFERENCES 1. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813-818. 2. Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368: 379-385. 3. Kielstein JT, Schiffer M, Hafer C. Back to the future: extended dialysis for treatment of acute kidney injury in the intensive care unit. J Nephrol. 2010;23:494-501. 4. Kumar N, Ahlawat RS. Extended daily dialysis in acute renal failure: a new therapeutic approach. Iran J Kidney Dis. 2007;1:63-72. 5. Cornelis T, van der Sande FM, Eloot S, et al. Acute hemodynamic response and uremic toxin removal in conventional and extended hemodialysis and hemodiafiltration: a randomized crossover study. Am J Kidney Dis. 2014;64:247-256. 6. Kielstein JT, Kretschmer U, Ernst T, et al. Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study. Am J Kidney Dis. 2004;43:342-349. 7. Abe M, Okada K, Suzuki M, et al. Comparison of sustained hemodiafiltration with continuous venovenous hemodiafiltration for the treatment of critically ill patients with acute kidney injury. Artif Organs. 2010;34:331-338. 8. Schwenger V, Weigand MA, Hoffmann O, et al. Correction: Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury—a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts. Crit Care. 2012;16:451. 9. Wu VC, Wang CH, Wang WJ, et al. Sustained lowefficiency dialysis versus continuous veno-venous hemofiltration for postsurgical acute renal failure. Am J Surg. 2010;199:466-476. 10. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. BMJ. 2009;339:b2535. 11. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283:2008-2012. 329
Zhang et al 12. Higgins J, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 13. Wells G, Shea B, O’Connell D, et al. The NewcastleOttawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_ epidemiology/oxford.asp. Accessed February 26, 2015. 14. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558. 15. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327: 557-560. 16. Kontopantelis E, Reeves D. metaan: random-effects metaanalysis. Stata J. 2010;10:395. 17. Cornell JE, Mulrow CD, Localio R, et al. Random-effects meta-analysis of inconsistent effects: a time for change. Ann Intern Med. 2014;160:267-270. 18. Baldwin I, Bellomo R, Naka T, Koch B, Fealy N. A pilot randomized controlled comparison of extended daily dialysis with filtration and continuous veno-venous hemofiltration: fluid removal and hemodynamics. Int J Artif Organs. 2007;30:10831089. 19. Abe M, Maruyama N, Matsumoto S, et al. Comparison of sustained hemodiafiltration with acetate-free dialysate and continuous venovenous hemodiafiltration for the treatment of critically ill patients with acute kidney injury. Int J Nephrol. 2011;2011:432094. 20. Shin YB, Cho JH, Park JY, et al. Sustained low-efficiency dialysis as an alternative therapy to continuous renal replacement therapy in critically ill patients with acute kidney injury. Korean J Nephrol. 2011;30:516-522. 21. Badawy SS, Hassan AR, Samir EM. A prospective randomized comparative pilot trial on extended daily dialysis versus continuous venovenous hemodiafiltration in acute kidney injury after cardiac surgery. Egypt J Cardiothorac Anesth. 2013;7:69-73. 22. Kumar VA, Craig M, Depner TA, Yeun JY. Extended daily dialysis: a new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis. 2000;36:294300. 23. Kumar VA, Yeun JY, Depner TA, Don BR. Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal failure: a two-year single center report. Int J Artif Organs. 2004;27:371-379. 24. Berbece AN, Richardson RM. Sustained low-efficiency dialysis in the ICU: cost, anticoagulation, and solute removal. Kidney Int. 2006;70:963-968. 25. Marcelino P, Marum S, Fernandes AP, Ribeiro JP. Hybrid or continuous renal replacement techniques for unstable haemodynamic patients in the intensive care unit. Acta Med Port. 2006;19:275-280. 26. Fieghen HE, Friedrich JO, Burns KE, et al. The hemodynamic tolerability and feasibility of sustained low efficiency dialysis in the management of critically ill patients with acute kidney injury. BMC Nephrol. 2010;11:32.
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27. Khanal N, Marshall MR, Ma TM, Pridmore PJ, Williams AB, Rankin AP. Comparison of outcomes by modality for critically ill patients requiring renal replacement therapy: a singlecentre cohort study adjusting for time-varying illness severity and modality exposure. Anaesth Intensive Care. 2012;40:260-268. 28. Chen X, Ma T. Sustained low-efficiency daily diafiltration for diabetic nephropathy patients with acute kidney injury. Med Princ Pract. 2014;23:119-124. 29. Lu R-h, Yan Y-c, Gu Y, et al. Effects of CVVH and SLED in patients with acute renal failure after liver transplantation. J Shanghai Jiaotong University (Medical Science)(China). 2008;8: 1010-1014. 30. Birne R, Branco P, Marcelino P, et al. A comparative study of cardiovascular tolerability with slow extended dialysis versus continuous haemodiafiltration in the critical patient. Port J Nephrol Hypertens. 2009;23:323-330. 31. Schneider AG, Bellomo R, Bagshaw SM, et al. Choice of renal replacement therapy modality and dialysis dependence after acute kidney injury: a systematic review and meta-analysis. Intensive Care Med. 2013;39:987-997. 32. Pannu N, Klarenbach S, Wiebe N, Manns B, Tonelli M; Alberta Kidney Disease Network. Renal replacement therapy in patients with acute renal failure: a systematic review. JAMA. 2008;299:793-805. 33. Rabindranath K, Adams J, Macleod AM, Muirhead N. Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev. 2007;3: CD003773. 34. Bagshaw SM, Berthiaume LR, Delaney A, Bellomo R. Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: a meta-analysis. Crit Care Med. 2008;36:610-617. 35. Schefold JC, Haehling S, Pschowski R, et al. The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial. Crit Care. 2014;18:R11. 36. Moore I, Bhat R, Hoenich NA, et al. A microbiological survey of bicarbonate-based replacement circuits in continuous veno-venous hemofiltration. Crit Care Med. 2009;37:496-500. 37. Kanagasundaram NS, Moore I, Hoenich NA. Biofilm in bicarbonate-based replacement fluid circuits in CVVH. Kidney Int. 2009;76:682. 38. Fliser D, Kielstein JT. Technology insight: treatment of renal failure in the intensive care unit with extended dialysis. Nat Clin Pract Nephrol. 2006;2:32-39. 39. VA/NIH Acute Renal Failure Trial Network; Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359:7-20. 40. Faulhaber-Walter R, Hafer C, Jahr N, et al. The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit. Nephrol Dial Transplant. 2009;24:21792186.
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A
cute 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), first performed for a patient with AKI in 1945 as an alternative modality of RRT to CRRT, is a special form of intermittent dialysis with low dialysate and blood flow 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 significant difference in mortality 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 1Division of Nephrology, West China Hospital of Sichuan University, Sichuan, Chengdu, China; 2Division of Intensive Care Unit, Austin Health, Heidelberg, VIC, Australia; 3 West China School of Medicine, Sichuan University, Sichuan, Chengdu; and 4Division 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, Heidelberg, VIC 3084, Australia. E-mail: [email protected] 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.02.328
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Extended Dialysis for Acute Kidney Injury
METHODS Overview We performed this systematic review using the guidelines proposed 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 defined as extended (sessions . 6 but ,24 hours) hemodialysis or hemodiafiltration using a conventional hemodialysis machine, including extended daily dialysis/diafiltration, sustained low-efficiency dialysis/diafiltration, or prolonged intermittent dialysis/diafiltration. We specifically excluded intermittent hemofiltration in our analysis. We used the term CRRT to describe continuous hemofiltration and/or continuous hemodialysis and/or continuous hemodiafiltration, 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 Identification of Studies Study Selection We used the PRISMA (Preferred Reporting Items for Systematic 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 language 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 failure” and “dialysis or hemodialysis or renal replacement therapy or blood purification.” 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 identified 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) sufficient data available to calculate a relative risk (RR) or mean difference with 95% confidence interval (CI). The following exclusion criteria were used: (1) studies comparing standard with intensified extended dialysis; (2) studies comparing EDD with other modalities of dialysis, such as standard intermittent dialysis or peritoneal dialysis; and (3) nonhuman studies. For studies with the same or overlapping data by the same authors, the Am J Kidney Dis. 2015;66(2):322-330
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 independently and recorded eligibility, quality, and outcomes. Disagreements regarding eligibility arose with 7% of the articles (k 5 0.87), which were resolved by consensus, with a third investigator (G.M.E.) providing arbitration. We extracted the following study features: first author, publication year, country, funding source, number of participants, RRT modalities, mortality, kidney recovery, fluid 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 “low” risk of bias was provided for each of the following domains: adequate random sequence generation, allocation sequence concealment, 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 “low” risk of bias was provided for each domains, and a “low” risk of bias was scored 1 and a “high” or “unclear” risk 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 defined 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 fluid removal, mean difference and 95% CI were calculated for each study. Heterogeneity was evaluated using the Cochrane Q test and I2 statistic to assess the degree of interstudy variation. I2 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 significant 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 influence of an individual 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 comparison with other modalities of RRT (n 5 8), no comparison between RRTs (n 5 7), not all patients with AKI (n 5 2), and overlapping data (n 5 1). 323
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607 Potentially relevant studies identified by research MEDLINE (n = 206) EMBASE (n = 267) Cochrane (n = 89) Others (n = 45)
249 excluded (duplicate studies) 358 Potentially relevant articles screened based on abstracts 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
bias, one study18 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 studies6,8,19 generated adequate randomized sequence and reported appropriate allocation concealment. Among all RCTs, none was double blinded. However, blinding of patients and clinicians was impossible in studies comparing EDD with CRRT, and the authors judged that the primary outcome (mortality) is not likely to be influenced 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 studies23,25-27,30 was unclear reporting of dropout rates or uncompleted follow-ups.
35 full-text articles selected for full review
Mortality 18 excluded 8 Comparison with other modalities of RRT 7 No comparison between RRT 2 Not all patients with AKI 1 Overlapping data 17 studies included in the meta-analysis 7 RCTs 10 Observational
Figure 1. Flow chart of selection of studies. Abbreviations: AKI, acute kidney injury; RCT, randomized controlled trial; RRT, renal replacement therapy.
Finally, 7 RCTs6-8,18-21 and 10 observational studies9,22-30 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 fluid 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 (18.023.5 hours per day). Characteristics of the RCTs and observational studies fulfilling 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 studies8,19 were judged to be at low risk of 324
In 6 RCTs (617 patients) and 10 observational studies (675 patients), data for mortality were reported. Within RCTs (Fig 3), there was no statistically significant difference in the risk of mortality rate between EDD and CRRT (RR, 0.90; 95% CI, 0.74-1.11; P 5 0.3). There was no evidence for heterogeneity (I2 5 0). 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; P 5 0.05). No evidence was detected for heterogeneity (I2 5 15%). Kidney Recovery A total of 3 RCTs (174 patients) and 5 observational studies (238 patients) provided information on kidney recovery. Within RCTs, as shown in Fig 3, there was no significant difference in kidney recovery rate with EDD in comparison to CRRT (RR, 1.12; 95% CI, 0.83-1.76; P 5 0.4), with moderate heterogeneity (I2 5 65%). Similar results were obtained in observational studies (RR, 1.14; 95% CI, 0.90-1.46; P 5 0.3; I2 5 0%). Fluid Removal Overall, 4 RCTs (367 patients) and 3 observational studies (140 patients) reported data for fluid 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 (I2 5 73%), indicating a similar effect on fluid removal between EDD and CRRT (Fig 3). On analysis of observational studies, there were also no significant differences in fluid removal between EDD and CRRT (mean difference, 20.06 [95% CI, 21.03 to 0.91] L/d), with significant heterogeneity (I2 5 79%). Two RCTs (120 patients; 864 sessions) reported data for fluid removal rate during treatment (Table 2); Am J Kidney Dis. 2015;66(2):322-330
Mean Therapy Duration (h/d) Study
Country
Kielstein6 (2004) Baldwin18 (2007) Abe7 (2010) Abe19 (2011) Shin20 (2011) Schwenger8 (2012) Badawy21 (2012) Kumar22 (2000) Kumar23 (2004) Berbece24 (2006) Marcelino25 (2006) Lu29 (2008) Birne30 (2009) Fieghen26 (2010) Wu9 (2010) Khanal27 (2012) Chen28 (2014)
DE AU JP JP KR DE EG US US CA PT CN PT CA TW NZ CN
Design of Study
RCT RCT RCT RCT RCT RCT RCT Retrospective Prospective Prospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective
Modality
N
Mean Age (y)
Male Sex (%)
EDD
CRRT
Main Outcomes
Funding
EDD vs CVVH EDD vs CVVH EDDF vs CVVHDF EDDF vs CVVHDF SLED vs CVVH SLED vs CVVH EDD vs CVVHDF EDD vs CVVH EDD vs CVVHD SLED vs CVVHDF SLED vs CVVHDF SLED vs CVVH SLED vs CVVHDF SLED vs CVVHDF SLED vs CVVH SLEDF vs CVVHDF SLEDF vs CVVH
39 16 60 50 46 232 80 42 54 34 53 12 63 43 101 166 107
50.5 69.5 68.7 65.9 63 66.2 47.5 50 52 58.4 59.1 49.7 63.3 62.1 67.4 58.5 59.5
62.9 56.3 65.0 66.0 63.0 67.7 65.0 64.3 63.0 61.8 NR 66.7 49.2 76.7 65.3 62.0 NR
11.7 7.3 6.5 6.0 10 14.9 6-8 7.5 6.7 7.5 6.8 10 6-12 6.8 8.0 7.2 8.8
23.3 18.4 20.3 15.2 NR 19.9 NR 19.5 16.8 21.3 22.1 18 NR 19.7 NR NR 23.5
Mortality, fluid removal Fluid removal Mortality, kidney recovery, ICU days Mortality, kidney recovery, ICU days Mortality Mortality, fluid removal, ICU days Mortality, fluid removal, ICU days Mortality Mortality, kidney recovery Mortality, fluid removal Mortality Mortality, kidney recovery Mortality, fluid removal Mortality, fluid removal Mortality, kidney recovery Mortality, ICU days Mortality, kidney recovery
Industry NR NR NR NR NR NR NR NR NR NR Public NR NR NR NR NR
Abbreviations: AU, Australia; CA, Canada; CN, China; CRRT, continuous renal replacement therapy; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; 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.
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Table 1. Characteristics of Studies Fulfilling the Inclusion Criteria
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Figure 2. Risk of bias summary. Abbreviation: RCT, randomized controlled trial.
EDD was associated with a higher fluid removal rate compared to CRRT (202.23 [95% CI, 151.27-253.19] mL/h; I2 5 98%). Length of ICU Stay A total of 4 RCTs7,8,19,21 (422 patients) and one observational study27 (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 significant heterogeneity (I2 5 80%). 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 RCTs6,8,21 (351 patients) and 5 observational studies23,24,27-29 (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 significant heterogeneity (I2 5 98%). Similar results were obtained in observational studies (mean difference, 0.40 [95% CI, 20.36 to 1.15] mg/dL; I2 5 91%). A total of 3 RCTs6,8,21 (351 patients) and 4 observational studies23,27-29 (690 patients) reported plasma urea levels (Table 2). There was no significant difference in urea levels between EDD and CRRT in RCTs (mean difference, 28.56 [95% CI, 237.17 to 326
20.04] mg/dL; I2 5 99%) or observational studies (mean difference, 14.90 [95% CI, 28.20 to 38.0] mg/ dL; I2 5 95%). Two RCTs6,8 (271 patients) and one observational study23 (54 patients) reported on serum phosphate levels. As shown in Table 2, there was no significant 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; I2 5 98%) or observational studies (mean difference, 0.31 [95% CI, 20.38 to 1.0] mg/dL). Heparin Dose Two RCTs6,8 (351 patients) and one observational study28 (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 significant (mean difference, 24.49 [95% CI, 212.09 to 3.10] kU/d; I2 5 99%). However, the difference was significant in observational studies (mean difference, 28.91 [95% CI, 29.32 to 28.50] kU/d). Episodes of Vasopressor Escalation Two RCTs6,19 (89 patients; 412 sessions) and 1 observational study26 (43 patients; 125 sessions) described episodes of vasopressor escalation during RRT. There was no significant difference between EDD and CRRT in RCTs (P 5 0.8; I2 5 0%) and observational studies (P 5 0.2). The outcome might be different if it were expressed as hourly rates Am J Kidney Dis. 2015;66(2):322-330
Extended Dialysis for Acute Kidney Injury Mortality (Observational Studies)
Mortality (RCTs) Berbece, 2008
Abe, 2010
Birne, 2009 Abe, 2011
Chen, 2014 Fieghen, 2010
Badawy, 2012
Khanal, 2012 Kumar, 2000
Kielstein, 2004
Kumar, 2004 Schwenger, 2012
Lu, 2008 Marcelino, 2006
Shin, 2011
Wu, 2010 Overall Effect (reml)
Overall Effect (reml)
Kidney Recovery (Observational Studies)
Kidney Recovery (RCTs) Chen, 2014
Abe, 2010
Kumar, 2004 Abe, 2011
Lu, 2008
Badawy, 2012 Wu, 2010
Overall Effect (reml)
Overall Effect (reml)
Fluid Removal (RCTs) Badawy, 2012
Fluid Removal (Observational Studies) Berbece, 2006
Baldwin, 2007 Birne, 2009
Kielstein, 2004
Fieghen, 2010 Schwenger, 2012
Overall Effect (reml)
Overall Effect (reml)
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.
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.
were lower with EDD compared to CRRT. Metaanalysis could not be estimated due to absence of a standard deviation.
Costs
Sensitivity Analysis
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 hospitalization in 1 study.28 All results indicated that costs
In order to assess the stability of results of the current meta-analysis, we performed sensitivity analysis for mortality by omitting a single study. Statistically similar results were obtained after omitting
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Fluid removal rate (in mL/h) ICU days Serum creatinine (in mg/dL) Serum urea (in mg/dL) Serum phosphate (in mg/dL) Heparin dose (I kU/d) Episodes of vasopressor escalation
Study Type
No. of Studies
RCT RCT Observational RCT Observational RCT Observational RCT Observational RCT Observational RCT Observational
2 3 1 3 5 3 4 2 1 2 1 2 1
EDD vs CRRTa
202.23 21.51 22.30 0.37 0.40 28.56 14.90 20.31 0.31 24.49 28.91 0.85 0.65
(151.27 to 253.19) (27.84 to 4.83) (25.61 to 1.01) (20.43 to 1.17) (20.36 to 1.15) (237.17 to 20.04) (28.20 to 38.00) (21.50 to 0.89) (20.38 to 1.0) (212.09 to 3.10) (29.32 to 28.50) (0.52 to 1.40) (0.36 to 1.18)
I2
98% 80%
—
98% 91% 99% 95% 98%
—
99%
—
0%
—
Abbreviations: CRRT, continuous renal replacement therapy; EDD, extended daily dialysis; ICU, intensive care unit; RCT, randomized 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.
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 quality7,18,19 or funding bias6 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 identified 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 modality 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 significant differences in kidney recovery, fluid removal, and episodes of vasopressor escalation with EDD in comparison to CRRT. Also, EDD showed similar efficacy to CRRT in laboratory results (serum urea, serum creatinine, and serum phosphate) during RRT and was associated with lower costs. Several meta-analyses31-34 have compared conventional intermittent RRT and CRRT and found no significant difference in mortality, and a recent RCT confirmed 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 properties 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-analysis32 in 2008 compared EDD (in the form of sustained low-efficiency dialysis [SLED]) with CRRT 328
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 efficacy of EDD for patients with AKI. In this meta-analysis, there was a mild trend toward improved survival in favor of EDDtreated patients with AKI, although the evidence was weak because of a lack of significant difference in RCTs. There might be some reasons for this trend. First, heparin was the main anticoagulant in included studies (table b of 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 significant 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 frequency, although some evidence shows that intensified 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. Am J Kidney Dis. 2015;66(2):322-330
Extended Dialysis for Acute Kidney Injury
To our knowledge, this study is the first to systematically 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 Portuguese25 languages. It included data from more than 1,200 patients, 17 studies, and 10 countries; from different regions of Asia, North America, Europe, Oceania, and Africa; and from both large observational studies and RCTs. Furthermore, 2 independent investigators thoroughly evaluated methodological 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 specific outcomes were limited. No sufficient data were obtained to evaluate adverse outcomes such as bleeding, infection, and hypotension. In addition, although a similar effect on fluid removal was found for EDD and CRRT, data regarding fluid 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 study6 to 30 days in 6 studies7,9,19-21,28 to 90 days in 2 studies,8,27 or to ICU mortality in 1 study30 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 unavailability of unreported outcomes possibly could result in reporting bias. For instance, 2 studies reported insufficient data for mortality.6,18 Regardless of these limitations, we have minimized bias throughout the process by our methods of study identification, data selection, and statistical 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 difference 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 allocation or selection bias, further high-quality RCTs focused on mortality according to different RRT modalities are necessary to fully understand the effects of EDD for patients with AKI. Am J Kidney Dis. 2015;66(2):322-330
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial 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 investigated 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 fulfilling 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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