Oncotarget

Meta-Analysis:

This article has been corrected. Correction in: Oncotarget. 2018; 9:6657.

The optimal time of initiation of renal replacement therapy in acute kidney injury: A meta-analysis

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Oncotarget. 2017; 8:68795-68808. https://doi.org/10.18632/oncotarget.17946

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Kaiping Luo, Shufang Fu, Weidong Fang and Gaosi Xu _

Abstract

Kaiping Luo1,*, Shufang Fu1,*, Weidong Fang2 and Gaosi Xu1

1Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang, China

2Department of Nephrology, People's Hospital of Ganzhou, Ganzhou, China

*These authors have contributed equally to this work

Correspondence to:

Gaosi Xu, email: gaosixu@163.com

Keywords: acute kidney injury, renal replacement therapy, mortality, meta-analysis

Received: January 09, 2017     Accepted: March 30, 2017     Published: May 16, 2017

ABSTRACT

Background: The impact on the timing of renal replacement therapy (RRT) initiation on clinical outcomes for patients with acute kidney injury (AKI) remains controversial.

Materials and methods: We searched the Cochrane Library, EMBASE, Global Health, MEDLINE, PubMed, the International Clinical Trials Registry Platform, and Web of Science.

Results: We included 49 studies involving 9698 patients. Pooled analysis of 5408 critically ill patients with AKI showed that early RRT was significantly associated with reduced mortality compared to late RRT [odds ratio (OR), 0.40; 95% confidential intervals (CI), 0.32 - 0.48; I2, 50.2%]. For 4290 non-critically ill patients with AKI, there was no statistically significant difference in the risk of mortality between early and late RRT (OR, 1.07; 95% CI, 0.79 - 1.45; I2, 73.0%). Early RRT was markedly associated with shortened intensive care units (ICU) length of stay (LOS) and hospital LOS compared to late RRT in both critically ill and non-critically ill patients with AKI.

Conclusions: Early RRT probably reduce the mortality, ICU and hospital LOS in critically ill patients with AKI. Inversely, early RRT in non-critically ill patients with AKI did not decrease the mortality, but shortened the ICU and hospital LOS.


The optimal time of initiation of renal replacement therapy in acute kidney injury: A meta-analysis | Luo | Oncotarget

INTRODUCTION

Acute kidney injury (AKI) is increasingly common and associated with adverse clinical outcomes, including excess mortality and morbidity, and prolonged hospital length of stay (LOS) [14]. Renal replacement therapy (RRT) is the cornerstone for the treatment of severe AKI. Although RRT provokes a considerable escalation in the complexity of therapy, the optimal timing of initiation of RRT in patients with AKI has been the focus of those debates [5, 6]. Conflicting results from clinical trials and systematic reviews have not resolved the debates, leaving clinicians to select the timing of initiation of RRT based on suboptimal evidence.

Studies aimed at determining the optimal time for starting RRT have evaluated the various arbitrary cut-offs for time from Intensive Care Unit (ICU) admission [79] or development of a biochemical “start time” [10, 11], AKI stage [12, 13], serum urea [14, 15], urine output [16, 17], fluid balance [18], and serum creatinine [15, 19, 20]. However, the arbitrary cut-offs often differentiated between early and late RRT. Some data suggested that early compared with late RRT reduced the mortality with better renal recovery. Early initiation of RRT may produce benefits by avoiding hypervolemia, eliminating of uremic toxins, establishing acid-base homeostasis, and preventing other complications such as gastric hemorrhage and metabolic encephalopathy [7, 13, 16]. Late RRT may allow time for the stabilization of a patient’s condition before RRT and may even avoid the RRT [12, 2123]. Gaudry et al. showed that the mortality was lower in patients who never received RRT than those received RRT early or late (37.1% vs. 48.5% or 61.8%), and the patients with late RRT were the most severely ill at baseline [13]. Thus, we hypothesized that the different severity of illness for patients with AKI who received early RRT may produce distinct effects on mortality. Therefore, we firstly performed a meta-analysis according to the severity of illness for patients with AKI to investigate the opportunity of RRT initiation.

3 earlier meta-analyses (Seabra et al. [24] identified 23 studies, Karvellas et al. [25] identified 15 studies and Wang et al. [26] included 51 trials) showed that early RRT could confer a survival benefit. 11 trials performed before 1985 in Seabra et al. and Wang et al. were excluded, and the addition of 10 recently published studies have been included in the present meta-analysis. However, a recent meta-analysis found no significant difference in mortality between early and late RRT [27], but included only nine “high-quality” studies. Furthermore, the included studies were limited with high heterogeneity. In the present study, we firstly made a definition of early RRT based on time-based cutoffs for patients with AKI to investigate the optimal timing of initiation of RRT.

RESULTS

Study enrolment and characteristics

Figure 1 outlines the process for study selection. 49 studies including 9 RCTs [10, 12, 13, 15, 16, 19, 21-23] and 40 observational studies [7-9, 11, 14, 17, 18, 20, 28-59] were included in our meta-analysis. The eligible studies were conducted from 1985 to 2016 with 9698 patients evaluated the timing of initiation of RRT in patients with AKI. The characteristics of the articles were listed in Table 1, and the details of risk of bias for RCTs were showed in Figure 2.

Flow diagram for the selection of studies inclusion in the meta-analysis.

Figure 1: Flow diagram for the selection of studies inclusion in the meta-analysis.

Table 1: The fundamental characteristics and patient demographic data of included studies reporting data on early RRT versus late RRT

Auther,
Year

Country

Study Design

Population

Early
Mortality

Late Mortality

Severity of
Illness

Early RRT Criteria

Late RRT Criteria

Quality

Early time to RRT <12 h

Bouman
2002

Netherlands

RCT

Multisystem

20/70

9/36

Early: SOFA 10.3;
Late: SOFA 10.6

Time to RRT<12 h

Time to RRT>12h

M

Piccinni
2006

Italy

Retrospective

Sepsis; ICU

18/40

29/40

Early: APACHE2=27.2;
Late: APACHE2=27.8

Time to RRT <12 h

No RRT

7

Andrade
2007

Brazil

Retrospective

Multisystem;
Leptospirosis

3/18

10/15

Early: APACHE2=24.5;
Late: APACHE2=26

Mean time to RRT = 4.4hrs

Mean time to RRT = 27.3hrs

5

Wu VC
2007

China

Retrospective

Acute Liver
Failure;
Surgical ICU

34/54

22/26

Early: APACHE2=18;
Late: APACHE2=19

Mean time from ICU admit to RRT =4.4hrs; BUN<80 mg/dL AND
traditional indications present

Mean time from ICU admit to RRT =11.1hrs; BUN>80 mg/dL AND
traditional indications present

6

Manche
2008

Malta

Retrospective

Post Cardiac
Surgery

14/56

13/15

NR

Mean RRT start 8.6hrs post-op; Oliguria unresponsive to med mgmt

Mean RRT start 41.2hrs post-op; Oliguria refractory to med mgmt

6

Ji
2011

China

Retrospective

Post Cardiac
Surgery

3/34

9/24

Early: APACHE3= 69;
Late: APACHE3= 88.2
p<0.001

Time from urine output <0.5ml/kg/h to RRT <12h; Mean oliguria to start of RRT 8.4hrs

Time from urine output <0.5ml/kg/h to RRT >12h; Mean oliguria to start of RRT21.5hrs

6

Shum
2013

China

Retrospective

Multisystem;
Sepsis

43/89

15/31

Early: SOFA 13;
Late: SOFA 12
P=0.011

Mean time from ICU admit to RRT
= 10.8hrs (RIFLE criteria:
‘Injury’ or ‘Failure’ criteria)

Mean time from ICU admit to RRT =20.7hrs (RIFLE criteria:
‘pre- Risk’ or ‘Risk’ criteria)

6

Serpytis
2014

Lithuania

Retrospective

Multisystem;
Sepsis

30/42

39/43

NR

Time from anuria to RRT <12hrs

Time from anuria to RRT >12hrs

5

Wald
2015

Canada

RCT

Multisystem

16/48

19/52

Early: SOFA 13.3;
Late: SOFA 12.8

Mean time to RRT = 9.7hrs

Meantime to RRT = 32hrs;
Classic indications for RRT

H

Crescenzi
2015

Italy

Prospective

Post Cardiac
Surgery

28/46

10/13

NR

Time from urine output <0.5ml/kg/h
to RRT <12h

Time from urine output <0.5ml/kg/h to RRT >12h

6

Zarbock
2015

Germany

RCT

Multisystem

44/112

65/119

Early: SOFA 15.6;
Late: SOFA 16.0

Time to RRT <8h; KDIGO stage 2

Time to RRT <12h; Stage 3 AKI
or no initiation

H

Gaudry
2015

France

RCT

Multisystem

150/311

153/308

Early: SOFA 10.9;
Late: SOFA 10.8

Time to RRT <6h; Stage 3 AKI

Classic indications for RRT; Oliguria or anuria >72hrs after randomization

H

Early time to RRT <24 h

Elahi
2004

UK

Retrospective

Post Cardiac
surgery

8/36

12/28

NR

Mean RRT start 0.78 days;
Low urine output <100ml within 8h after surgery

Mean RRT start 2.5 days; Traditional indications: Urea≥30mmol/L,
Cr ≥250mmol/L, K >6.0mEq/L

6

Demirkilic
2004

Turkey

Retrospective

Post Cardiac
Surgery

8/34

15/27

NR

Mean RRT start 0.88 days;
Low urine output <100ml within 8hrs post-op;

Mean RRT start 2.56 days;
Cr ≥5mg/dL, or K >5.5 mEq/L

6

Boussekey
2012

France

Retrospective

Multisystem

28/67

28/43

Early: SOFA: 11.1;
Late: SOFA 8.8;
p=0.002

Time from RIFLE- ‘Injury’ to RRT
< 16hrs; Mean time to RRT=6hrs

Time from RIFLE- ‘Injury’ to RRT > 16hrs; Mean time to RRT=64hrs

7

Chon
2012

Korea

Retrospective

Multisystem;
Sepsis

7/36

9/19

Early: SOFA 13.5;
Late: SOFA 12

Time to RIFLE ‘Injury’/‘Failure’
< 24hrs; Mean time to RRT=12.5hrs

Time to RIFLE ‘Injury’/‘Failure’
> 24hrs; Mean time to RRT= 42.2hrs

7

Leite
2013

Brazil

Retrospective

Multisystem

33/64

67/86

Early: APACHE2=19.2;
Late: APACHE2=18.7

Time from AKIN 3 diagnosis to RRT <24hrs

Time from AKIN 3 diagnosis to RRT >24hrs

7

Jun
2014

Australia

Prospective

Multisystem;
Sepsis

82/219

84/220

Early: SOFA: 2.0;
Late: SOFA 2.1

Time from AKI diagnosis to RRT <17.6hrs

Time from AKI diagnosis to RRT>17.6hrs

6

Combes
2015

France

RCT

Post Cardiac
Surgery

40/112

40/112

Early: SOFA 11.5;
Late: SOFA 12.0

RRT initiated <24hrs and continued
for min of 48hrs

Traditional indications for RRT

H

Yang
2016

China

Retrospective

Post Cardiac
Surgery

20/59

80/154

Early: APACHE2=21.4.;
Late: APACHE2=23.1

AKI in absence of traditional indications for RRT; persistence of hypotension (for more than 6 h) despite preload optimization;

Traditional indications for RRT

7

Early time to RRT <48 h

Durmaz
2003

Turkey

RCT

Post Cardiac
Surgery

1/21

7/23

NR

Cr rise >10% from pre-op level
within 48hrsof surgery

Cr rise >50%from pre-op level;
or Urine output <400ml/24hrs

L

Lyem
2009

Turkey

Prospective

Post Cardiac
Surgery

5/95

6/90

NR

Low urine output triggering RRT started <48hrs; Evidence of 50% increase in BUN,

Time >48hrs to start of RRT for similar markers of renal failure managed medically for minimum 48hrs

7

Bagshaw
2009

Multi
countries

Prospective

Multisystem

462/785

304/442

Early: SOFA 10.9;
Late: SOFA 10.7
p=0.04

RRT started <2d from ICU admission

RRT started >2d from ICU admission

7

Perez
2012

Spain

Prospective

Multisystem
Sepsis

71/135

78/109

Early: SOFA 12;
Late: SOFA 11

Time from ICU admission to RRT < 48h

Time from ICU admission to RRT > 48h

5

Lim
2014

Singapore

Prospective

Multisystem

37/56

36/84

Early: SOFA 11;
Late: SOFA 7;
p=0.001

RRT started < 2d from admission;
Traditional indications for RRT

RRT started > 2d from admission; AKIN stage 1 or 2 with indication or AKIN stage3

6

Hyung
2016

Korea

Retrospective

Multisystem
Sepsis

9/30

17/30

Early: APACHE2=22.9;
Late: APACHE2=21.1

Time to RRT <26.4 h

Time to RRT >26.4 h

6

Early time to RRT <72 h

Sugahara
2004

Japan

RCT

Post Cardiac
Surgery

12/14

2/14

Early: APACHE2=18;
Late: APACHE2=19

Mean time to RRT start 1.7d±0.8 post op; UOP <20ml/hrs ×2hrs + OR UOP <500ml/day

Mean time to RRT start 18d±0.9 post op; UOP <30ml/hrs ×3hrs OR
UOP <750ml/day

L

Sabater
2009

Spain

Prospective

Multisystem

21/44

68/104

Early: APACHE2=26;
Late: APACHE2=24

Mean RRT start 2.2d post ICU admit (RIFLE criteria: RISK & INJURY)

Mean RRT start 6.4d post ICU admit (RIFLE criteria: FAILURE)

7

Fernandez
2011

Spain

Retrospective

Post Cardiac
Surgery

59/111

74/92

NR

RRT started <3d after cardiac surgery

RRT started >3d after cardiac surgery

5

Shiao
2012

China

Retrospective

Surgical

236/436

143/212

Early: SOFA 11.4;
Late: SOFA 11.3

Time to development of traditional RRT indications <3d; Mean time to start of RRT 1.4d

Traditional RRT indications AND start of RRT >3 d; Mean time to start of RRT 18d

6

Early time to RRT >72 h

Gettings
1999

USA

Retrospective

Multisystem;
Trauma

25/41

47/59

Early ISS = 33.0;
Late ISS = 37.2

Mean RRT start post admission10d; BUN <60mg/dl AND Oliguria,
Vol overload, Electrolytes, Uremia;

Mean RRT start post admission 19d; BUN >60 mg/dL AND Oliguria, Electrolytes, Uremia;

5

Shiao
2009

China

Prospective

Major
Abdominal
Surgery

22/51

34/47

Early: SOFA 8.3;
Late: SOFA 8.5

Mean Time to RRT from ICU Admit =7.3d (RIFLE criteria:
RISK or pre-RISK criteria)

Mean Time to RRT from ICU Admit = 8.4d (RIFLE criteria:
INJURY or FAILURE criteria)

7

Chung
2009

US

Retrospective

Severe Burned
Patients

9/29

24/28

Early: SOFA 13;
Late: SOFA 13

Mean time from admit to RRT =
17 days; AKIN stage2(+shock)/3

Mean time from admit to AKIN stage 2(+shock)/3 but not dialyzed = 23 days

6

Carl
2010

US

Retrospective

Multisystem;
Sepsis

44/85

42/62

Early: APACHE2=24.8;
Late: APACHE2=24.7

Mean ICU stay prior to RRT = 6.3d;
BUN <100mg/dL + AKIN stage >2;

Mean ICU stay prior to RRT = 12.3d; BUN > 100mg/dL + AKIN stage >2;

7

Hyung
2012

Korea

Retrospective

Multisystem

75/105

81/105

Early: SOFA 14.4;
Late: SOFA 14.4

Time from ICU admission to RRT =4.7d

Time from ICU admission to RRT =4.8d

7

RRT initiated base on biochemical indicators; Meantime to initiation of RRT not specified

Kresse
1999

Germany

Retrospective

Multisystem

83/141

102/128

NR

BUN≤34mmol/L, sCr 380umol/L, and urine output 924 ml/24h

BUN >34mmol/L, sCr 477umol/L, and urine output 525 ml/24h

7

Splendiani
2001

Italy

Retrospective

Multisystem

6/14

3/13

NR

BUN≤ 33mmol/L

BUN> 59 mmol/L and/or severe electrolyte disturbances

5

Tsai
2005

China

Retrospective

Multisystem

42/67

30/31

NR

BUN< 29 mmol/L

BUN> 29 mmol/L

5

Liu
2006

Multi
countries

Prospective

Multisystem

43/122

50/121

NR

Azotemia defined by BUN < 76mg/dL

Azotemia defined by BUN > 76mg/dL

6

Payen
2009

France

RCT

Multisystem

20/37

17/39

Early: SOFA 11.6;
Late: SOFA 10.4

RRT × 96hrs w/diagnosis of ‘sepsis’

No RRT; unless metabolic renal failure & classic indications for RRT present

M

Elsevivrs
2010

Belgium

Prospective

Multisystem

379/653

280/650

Early: SOFA 9.9;
Late: SOFA 8.5
p=0.001

Serum Cr >2mg/dL

No RRT

5

Konopka
2011

Poland

Retrospective

Multisystem

17/25

11/12

NR

As soon as AKI was diagnosed

After full treatment for HF and unsuccessful pharmacological treatment of complicating AKI

5

Chou
2011

China

Retrospective

Sepsis;
Surgery ICU

135/192

124/178

Early: SOFA 10.8;
Late: SOFA 11.6

RIFLE criteria: RISK or pre-RISK

RIFLE criteria: INJURY or FAILURE

6

Nascimento2012

Brazil

Retrospective

Multisystem

9/23

43/63

Early: APACHE 2= 21;
Late: APACHE 2= 28

BUN ≤26.7 mmol/L

BUN>26.7 mmol/L

6

Wu SC
2012

China

Retrospective

Multisystem
Surgery

10/20

45/53

Early: SOFA 9.5;
Late: SOFA 10.0

RIFLE criteria: RISK

RIFLE criteria: INJURY or FAILURE

5

Hu
2013

China

Retrospective

Multisystem

20//36

8/13

Early: SOFA 9.3;
Late: SOFA 11.5

AKIN 1and 2 (Cr >200-300%baseline &
Urine<0.5cc/kg/h for >12h)

AKIN 3 (Cr ≥354μmol/L or Cr >300% baseline & urine <0.3cc/kg/h for 24h or anuria >12h)

5

Jamle
2013

India

RCT

Multisystem

21/102

13/106

Early: SOFA 7.3;
Late: SOFA 8.2

Cr >618μmol/L

Traditional indications for RRT

M

Gaudry
2014

France

Retrospective

Multisystem;
Sepsis

44/91

29/112

Early: SOFA 9;
Late: SOFA 8
P<0.01

RRT criteria: Cr ≥300μmol/L,
Urea >25mmol/L,K >6.5mmol/L,
pH <7.2, Oliguria, Vol overload,

No RRT

5

Tian(461)
2014

China

Retrospective

Multisystem;
Sepsis

5/23

11/26

Early: SOFA 7.6;
Late: SOFA 8.4

AKIN 1 (Cr ≥26.4μmol/L or >150- 200% baseline & urine < 0.5cc/kg/h for >6h)

No RRT

6

Tian(462)
2014

China

Retrospective

Multisystem;
Sepsis

12/31

14/21

Early: SOFA 9.3;
Late: SOFA 9.6

AKIN 2 (Cr >200-300% baseline &
Urine <0.5cc/kg/h for >12h)

No RRT

6

Tian(463)
2014

China

Retrospective

Multisystem;
Sepsis

31/46

11/13

Early: SOFA 10;
Late: SOFA 11.2

AKIN 3 (Cr ≥354μmol/L or Cr >300% baseline & urine < 0.3cc/kg/h for 24h or anuria >12h)

No RRT

6

LEGEN: AKI Acute kidney injury, RRT renal replacement therapy, Cr Creatinine, UOP Urine output, ICU Intensive Care Unit, AKIN Acute Kidney Injury Network, RIFLE Risk, Injury, Failure, Loss and End-stage, KDIGO Kidney Disease: Improving Global Outcomes, RCTs randomized clinical trials, Quality Score: The Cochrane Collaboration Risk of Bias tool for RCTs and Newcastle-Ottawa Scale for observational studies, H High quality: low risk of bias, M Medium quality: unclear risk of bias, L Low quality: high risk of bias, APACHE Acute Physiology and Chronic Health Evaluation, SOFA Sequential Organ Failure Assessment, NR Not reported.

Risk of bias summary of early versus late RRT initiation on mortality in patients with AKI on randomized controlled trial.

Figure 2: Risk of bias summary of early versus late RRT initiation on mortality in patients with AKI on randomized controlled trial.

Meta-analysis results

Primary outcomes

Pooled analysis of 5408 critically ill patients with AKI showed that early RRT was markedly associated with reduced mortality compared to late RRT (OR, 0.40; 95% CI, 0.32 - 0.48; I2, 50.2%, Figure 3). For 4290 non-critically ill patients with AKI, there was no statistically significant difference in the risk of mortality between early and late RRT (OR, 1.07; 95% CI, 0.79 - 1.45; I2, 73.0%, Figure 3).

Figure 3:

Figure 3: Forest plot shows the effect of early versus late RRT on mortality in critically ill (A) and non-critically ill patients with AKI (B).

Subgroup analysis of critically ill patients was firstly conducted in the present study by using the definition of early according to time criteria versus biochemical indicators. The significant association between early RRT and reduced mortality was also found under the studies that defined early by time criteria [early RRT within 12 hours (OR, 0.28; 95% CI, 0.16 - 0.49; I2, 44.8%), within 24 hours (OR, 0.37; 95% CI, 0.25 - 0.54; I2, 0.0%), within 48 hours (OR, 0.55; 95% CI, 0.39 - 0.77; I2, 30.8%), within 72 hours (OR, 0.45; 95% CI, 0.29 - 0.69; I2, 48.2%), and after 72 hours (OR, 0.32; 95% CI, 0.14 - 0.74; I2, 71.4%)], and by biochemical parameters (OR, 0.40; 95% CI, 0.25 - 0.64; I2, 58.9%). Subgroup analysis of non-critically ill patients depending on the definition of early showed no significant subgroup survival benefits from early RRT.

Subgroup analysis of critically ill patients was based on the type of ICU admission. Early RRT was significantly associated with reduced mortality compared to late RRT among surgical group (OR, 0.33; 95% CI, 0.22 - 0.48; I2, 47.9%) and mixed group (OR, 0.43; 95% CI, 0.34 - 0.54; I2, 49.8%). Subgroup analysis of non-critically ill patients based on ICU admission type showed no evidence of survival advantage in early RRT.

Subgroup analysis of critically ill patients was also performed according to RRT modality [continuous renal replacement therapy (CRRT), intermittent hemodialysis (IHD) or Mixed]. We found a markedly significant reduce in mortality in critically ill patients assigned to early RRT in the CRRT group (OR, 0.40; 95% CI, 0.30 - 0.54; I2, 28.4%), IHD group (OR, 0.11; 95% CI, 0.03 - 0.43; I2, 56.9%) and Mixed group (OR, 0.45; 95% CI, 0.35 - 0.57; I2, 53.6%) when compared to late RRT. Subgroup analysis of non-critically ill patients according to RRT modality showed that early RRT could not confer a survival benefit (Table 2).

Table 2: Outcomes measures of early versus late RRT initiation

Outcome or Subgroup

Group A: critically ill patients with AKI

Group B: non-critically ill patients with AKI

Studies

No. of Patients

Study Reference No

Effect Estimate (95% CI)

p

Studies

No. of Patients

Study Reference No

Effect Estimate (95% CI)

p

Primary Outcomes: early versus late RRT initiation on mortality

All studies

31

5408

7-9,12,18,28-30,32,34,35,38-
41,43,44, 462,463,47,48,50-59

OR, 0.40 (0.32 to 0.48)

0.001

20

4290

10,11,13-17,19-23,31,
33,36,37,42,45,461,49

OR, 1.07 (0.79 to 1.45)

0.000

Subgroup stratified by the definition of early according to time criteria and biochemical indicators on mortality

Time: Early RRT <12h

7

639

9,12,28-30,32,56

OR, 0.28 (0.16 to 0.49)

0.093

5

1003

10,13,21,31,42

OR, 0.86 (0.58 to 1.29)

0.201

Time: Early RRT <24h

4

534

34,35,53,54

OR, 0.37 (0.25 to 0.54)

0.691

4

782

11,22,33,36

OR, 0.72 (0.43 to 1.19)

0.097

Time: Early RRT <48h

3

1531

7,55,57

OR, 0.55 (0.39 to 0.77)

0.236

3

368

17,19,37

OR, 0.82 (0.18 to 3.79)

0.012

Time: Early RRT <72h

3

999

18,38,58

OR, 0.45 (0.29 to 0.69)

0.145

1

28

16

OR, 36.0 (4.33 to 299.02)

NE

Time: Early RRT >72h

4

465

8,39,40,52

OR, 0.32 (0.14 to 0.74)

0.015

0

NE

NE

NE

NE

Biochemicl indicators

10

1240

41,43,44, 462,463-48,50,51,59

OR, 0.40 (0.25 to 0.64)

0.009

7

2109

14,15,20,23,45, 461,49

OR, 1.46 (0.96 to 2.23)

0.008

Subgroup stratified by surgical versus mixed medical admissions on mortality

Surgical

9

1506

8,9,18,30,32,34,38,44,54

OR, 0.33 (0.22 to 0.48)

0.053

6

602

16,17,19,22,31,33

OR, 0.71 (0.24 to 2.07)

0.000

Mixed medical

22

3902

7,12,28,29,35,39,41,43,
462,463-48,50-53,55-59

OR, 0.43 (0.34 to 0.54)

0.004

14

3688

10,11,13-15,20,21,23,
36,37,42,45,461,49

OR, 1.22 (0.91 to 1.63)

0.000

Subgroup stratified by RRT modality on mortality

Mixed

14

3442

7,9,12,28,29,35,38,41,
43,48,53,54,55,57

OR, 0.45 (0.35 to 0.57)

0.009

6

2495

13,14,20,21,45,49

OR, 1.32 (0.86 to 2.03)

0.000

CRRT

14

1771

8,18,32,34,39,40,44,462,
463,47,50,52,55,58

OR, 0.40 (0.30 to 0.54)

0.152

12

1544

10,11,15-17,22,31,
33,36,37,42, 461

OR, 0.92 (0.58 to 1.46)

0.017

IHD

3

255

30,51,59

OR, 0.11 (0.03 to 0.43)

0.098

2

251

19,23

OR, 0.56 (0.04 to 8.73)

0.000

Secondary outcomes: ICU and Hospital LOS

ICU LOS

8

862

28,34,35,38,41, 462,463,53

MD, -0.41 (-0.55 to -0.27)

0.000

4

336

17,19,31, 461

MD, -1.47 (-1.71 to -1.22)

0.000

Hospital LOS

6

755

8,28,34,38,39,54

MD, -0.36 (-0.51 to -0.21)

0.000

3

287

17,19,31

MD, -1.07 (-1.31 to -0.82)

0.415

LEGEN: OR odds ratio, 95% CI confidence interval, P Test for Heterogeneity, MD mean difference, RRT renal replacement therapy, ICU Intensive Care Unit, CRRT continuous renal replacement therapy, IHD intermittent hemodialysis, Mixed CRRT and/or IHD and/or other RRT modality, LOS length of stay, NE not evaluable.

Secondary outcomes

For critically ill patients with AKI, as showed in Table 2, early RRT significantly shortened ICU (MD, -0.41; 95% CI, -0.55 to -0.27; I2, 87.0%) and hospital LOS (MD, -0.36; 95% CI, -0.51 to -0.20; I2, 94.7%) compared to late RRT. Similar results were obtained in non-critically ill patients with AKI in ICU (MD, -1.47; 95% CI, -1.71 to -1.22; I2, 89.3%) and hospital LOS (MD, -1.07; 95% CI, -1.31 to -0.82; I2, 0%).

Sensitivity, meta-regression analyses

Statistically similar results were obtained after omitting each study of critically ill patients with AKI, and the results of the sensitivity analyses were robust. Sensitivity analyses showed that Elsevivrs et al. [20] was the main source of heterogeneity for the studies of non-critically ill patients with AKI, and the heterogeneity was significantly decreased by omitting the study. For non-critically ill patients with AKI, there was no statistically significant difference in the risk of mortality between early and late RRT with the study (OR, 1.07; 95% CI, 0.79 - 1.45; I2, 73.0%) or without the study (OR, 1.02; 95% CI, 0.74-1.40; I2, 66.8%). Elsevivrs et al. was a large sample trial with 1303 patients when compared to other articles including not more than 619 subjects (Figure 4).

Figure 4:

Figure 4: Sensitivity analyses of early versus late RRT on mortality in critically ill (A) and non-critically ill patients with AKI (B).

With the meta-regression, we did not find a correlation between patient mortality and study design (RCT vs. observational), RRT modality (CRRT, IHD vs. Mixed), study quality score, severity of illness [Sequential Organ Failure Assessment (SOFA) score], ICU admission type (surgical vs. mixed medical admissions). However, we find a correlation between patient mortality and sample size (n ≥ 100 vs. n < 100, P = 0.001) in critically ill patients with AKI.

Publication bias

No potential publication bias was observed in non-critically ill patients with AKI (P = 0.347 for the Begg test, and P = 0.169 for the Egger test). Publication bias was seen in critically ill patients with AKI (P = 0.001 for the Begg test, and P = 0.000 for the Egger test, Figure 5).

Figure 5:

Figure 5: Begg’s funnel plots of early versus late RRT on mortality in critically ill (A) and non-critically ill patients with AKI (B).

DISCUSSION

We identified 49 studies reported data on the timing of RRT initiation among 9698 patients with AKI, and we found that early RRT significantly reduced the mortality compared to late RRT in critically ill patients with AKI. In addition, no significant survival benefits associated with early RRT were seen in non-critically ill patients with AKI. Early RRT was markedly associated with shortened ICU and hospital LOS compared to late RRT in both critically ill and non-critically ill patients with AKI.

Regardless of the definition of early RRT (according to time criteria or biochemical indicators), ICU admission type (surgical vs. mixed) or RRT modality (CRRT, IHD vs. Mixed), subgroup analyses of critically ill patients with AKI did reveal survival benefits from early RRT. Furthermore, subgroup analyses of non-critically ill patients with AKI showed that no evidence of survival advantage in early RRT.

In the present study, we firstly performed the meta-analysis according to the severity of illness and definition of early RRT based on time-based cutoffs for patients with AKI to investigate the time of RRT initiation. We accepted a broad definition of “critically ill patients with AKI” based on AKI with multiple-organ dysfunction syndrome [60], septic shock [40], RIFLE criteria (failure, loss of function, and end-stage kidney disease) [37, 43, 44], AKIN stages 3 [41, 42, 46] or Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 [12, 61].

By the meta-regression, we found sample size was one of the sources of heterogeneity. In contrast to previous meta-analyses, we found a lower heterogeneity among studies on this topic, especially in the subgroup. We noted those critically ill patients in early RRT within 12 hours (I2, 44.8%), 24 hours (I2, 0.0%), 48 hours (I2, 30.8%), and 72 hours (I2, 48.2%) showed the lower heterogeneities, indicating that the heterogeneity may be partially explained by the definition of early RRT timing. However, we could not account for the observed heterogeneity by meta-regression according to study design, RRT modality, the study quality score, severity of the illness, and ICU admission type. Thereby, the heterogeneity observed is most likely explained by the differences in definitions for early RRT timing, the inability to account for heterogeneity in clinical practice and critical care patterns, many confounding factors that affect the mortality, publication bias, sample size and the inclusion of retrospective, prospective and RCTs.

The present systematic review has some limitations. Firstly, definitions for AKI are to some extent different in the included studies. Secondly, the definition of early RRT based on various arbitrary cut-offs for time, which ultimately downgraded the strength of evidence. Thirdly, there were publication bias and significant heterogeneity in the present study. Many confounding factors affect the mortality, and meta-regression may not be enough to verify this issue. Lastly, the association with mortality is largely dependent on observational studies and might have been affected by allocation or selection bias. Thus, further high-quality RCTs focused on mortality according to the optimal time for starting RRT are necessary to fully understand the effects of early RRT for patients with AKI.

MATERIALS AND METHODS

Participants, interventions and outcome measures

We included studies that evaluated the timing of initiation of RRT in patients with AKI. For the review, early and late RRT were defined based on criteria used by the authors in their studies. early and late RRT were defined as extended time-based cutoffs (arbitrary cut-offs for time from ICU admission or development of a biochemical “start time”), or biochemical indicators [serum creatinine, serum urea, RIFLE (risk, injury, failure, loss of function, and end-stage kidney disease) classifications, Acute Kidney Injury Network (AKIN) stages, urine output, and fluid balance]. Late RRT criteria also included conventional RRT indications (hyperkalemia, acidosis or fluid overload) and expectant care (no RRT initiated). The primary outcome was mortality, and the secondary outcomes were ICU and hospital LOS.

Searching strategies

We searched the Cochrane Library, EMBASE, Global Health, MEDLINE, PubMed, the International Clinical Trials Registry Platform, and Web of Science from January 1985 to November 2016. Owing to a low likelihood of relevance to modern RRT and critical care practices, studies published before 1985 were excluded in the present study. Keywords include acute renal failure/acute kidney injury/renal insufficiency, mortality, renal replacement therapy/renal dialysis/hemodialysis/dialysis. The related research references were also reviewed.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (1) randomized clinical trials (RCTs) and/or observational cohort studies; (2) studies evaluating the timing of initiation of RRT in patients with AKI with direct effect on mortality; (3) complete data available to calculate odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI); (4) clear definitions of AKI stated. Exclusion criteria were as follows: (1) data from the studies could not be extracted and analyzed; (2) duplicate publications; (3) non-human experimental studies.

Study selection and data extraction

Two investigators (Kaiping Luo and Shufang Fu) independently performed the study selection. All the disagreements were resolved by discussion. Data extraction included first author, year of publication, country, study design, sample size, age, sex, RRT modality, mortality, ICU LOS, hospital LOS, and definitions of early and late RRT.

Dr. Gaudry and colleagues [13] showed that the mortality was lower in the patients who never received RRT than those received RRT early or late. Patients who received RRT late were the most severely ill at baseline, and patients who never received it were less ill at baseline. More than 50% mortality in critically ill patients with AKI received RRT was confirmed by many randomized controlled trials [1, 3, 4, 60]]. Thus, we hypothesized that critically ill patients with AKI who receive early RRT may decrease mortality, non-critically ill patients with AKI may confer survival benefits without early RRT. Subjects were identified as being of “critically ill patients” if the late RRT group with high mortality rates (≥ 50%), or “non-critically ill patients” if the late RRT group with low mortality rates (< 50%).

Quality assessment

The Cochrane Collaboration Risk of Bias tool was used to assess RCTs [62]. This tool consists of 6 domains and assesses 5 specific biases. A judgment of low risk, unclear risk, or high risk was provided for each domain. The Newcastle-Ottawa Scale (NOS) was used in the assessment of quality of cohort studies [63]. NOS quality assessment scale ranges from 0 to 9 stars. The star evaluates 3 main categories: selection, comparability, and outcome.

Statistical analysis

Statistical analysis was performed using Review Manager (version 5.3) and STATA statistical software (version 12.0). We calculated OR with 95% CI for dichotomous data and MD with 95% CI for continuous data. Statistical heterogeneity of the data was quantified using the I2 test, and the I2> 50% indicated significant statistical heterogeneity. Sensitivity analysis, meta-regression analyses and subgroup analysis were conducted to investigate the potential sources of heterogeneity. Publication bias was assessed by constructing a funnel plot and using the Egger regression test and the Begg rank correlation test. A P value less than 0.05 was considered statistically significant.

CONCLUSIONS

Our data suggest that early RRT probably reduce the mortality, ICU and hospital LOS in critically ill patients with AKI. Inversely, early RRT in non-critically ill patients with AKI did not decrease the mortality, but shorted the ICU and hospital LOS.

Abbreviations

renal replacement therapy (RRT); acute kidney injury (AKI); odds ratio (OR); confidential intervals (CI); intensive care units (ICU); length of stay (LOS); risk, injury, failure, loss of function, and end-stage kidney disease (RIFLE); Acute Kidney Injury Network (AKIN); randomized clinical trials (RCTs); mean difference (MD); Newcastle-Ottawa Scale (NOS); continuous renal replacement therapy (CRRT); intermittent hemodialysis (IHD); Sequential Organ Failure Assessment (SOFA); Kidney Disease: Improving Global Outcomes (KDIGO).

CONFLICTS OF INTEREST

The authors have no competing interests to declare.

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