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Prevention of Acute Kidney Injury and Protection of Renal Function in the Intensive Care Unit: Update 2017.

ESM_2: Summary Tables

Table S2: Large randomized controlled trials investigating the effect of crystalloids in critically ill patients.AuthorYear

Study DesignLevel (A=C)

Clinical setting Intervention Nr trials or patients

Endpoints Results Comments

Young P 2015 SPLIT [1]

RCTA

ICU patients PlasmalyteNS

11621116

AKIHospital mortalityRRT

9.6% vs 9.2%, p=0.777.6% vs 8.6%, p=0.403.3% vs 3.4%, p=0.91

Double-blind, cluster randomized, double-crossover trialMedian of 1.5 l fluids received

Semler MW 2016 SALT [2]

RCTA

ICU patients Balanced crystalloidsNS

520

454

MAKE 30d (death, dialysis, persistent renal dysfunction)

24.7% vs 24.6%, p=0.98 Median of 1.5 l fluids received

Incidence of MAKE 30d was increasing with total amount of infusion volume in the NS but not in the balanced crystalloids group (p=0.026)

RCT = randomised controlled trial, HA = Human serum albumin, AKI = acute kidney injury, RRT = renal replacement therapy, RL = ringer´s lactate, NS= normal saline


Table S3: Large randomised controlled trials and meta-analyses investigating colloids in critically ill patients.

AuthorYear

Study DesignLevel (A-C)

Clinical setting

Time of study/search

Intervention Nr trials or patients


Stockwell MA 1992 [3]

RCTA

ICU patients 4.5% HA 3.5% gelatine

226249

AKI 1.3% vs. 2.0%, NS no

Schortgen F 2001 [4]

RCTB

Severe sepsis, septic shock

1998-199 6% HES 200/0.63% gelatine

6565

AKI (twofold increase in s-crea or RRT)Oliguria

42% vs 23%, p=0.028OR 2.57 (95%CI 1.13-5.83)

56% vs. 37%, p=0.025

differences in serum creatinine at baseline

Finfer S 2004 SAFE [5]

RCTA

ICU patients requiring fluid resuscitation

2001-2003 4% HANS

34973500

28 day mortalityDuration RRT

20.9% vs 21.1%, p=0.870.5+2.3 vs. 0.4+2.0, p=0.41

Brunkhorst FM 2008 [6]

RCTA

Severe sepsis 2003-2005 10% HES 200/0.5modified RL

262275

28 day mortalityAKI (twofold increase in s-crea or RRT)RRT

26.7% vs. 24.1%, p=0.4834.9% vs. 22.8%, p=0.002

31.0% vs. 18.8%, p=0.001

harm by HES

Guidet B 2012CRYSTMAS [7]

RCTB

Severe sepsis 2007-2010 6% HESNS

10096

Amount to reach hemodynamic stabilisationMortalityAKI (AKIN)

1.37 vs. 1.71 P=0.019

31% vs. 25.3% P=0.5948% vs. 45,8% p=0.37

Perner A 2012 6S [8]

RCT A

Severe sepsis 2009-2011 6% HES Ringer´s Acetate

398400

90 d mortalityAKI (twofold increase in s-crea)RRT

51% vs 43%, p=0.0341% vs 35%, p=0.08

22% vs 16% p=0.04

harm by HES (mortality, AKI,RRT)

Myburg, J.A. 2012 CHEST [9]

RCT A

ICU patients, fluid resuscitation

2009-2012 6% HES NS

33363315

90 d mortalityAKI (RIFLE F)RRT

18% vs 17%, p=0.2610.4% vs 9.2%, p=0.127% vs 5.8%, p=0.26

harm by HES (RRT)increased rates of itching


Caironi P 2014 ALBIOS [10]

RCTA

Severe sepsis 2008-2012 20% HAcrystalloid

903907

28d mortalityAKIRRT

31.8% vs. 32 % p=0.9421.9% vs.22.7 % p=0.7124.6% vs. 21.4 % p=0.11

decreased mortality in subgroup with septic shock (n=1121), RR=0.87, 95%CI 0.77-0.99, less positive fluid balance

Zarychanski R 2013[11]

Meta-analysis A

ICU , surgical patients

1966-2012 HEScrystalloids, albumin or gelatine

31 RCTs including10290 patients

mortalityAKI RRT

RR 1.09 (95% CI 1.02-1.17)RR 1.27 (95% CI 1.09-1.47)RR 1.32 (95% CI 1.15-1.50)

retracted studies by J. Boldt excludedharm by HES (mortality, AKI,RRT)

Haase N 2013 [12]

Meta-analysis A

Sepsis 1966-2012 HEScrystalloids, or albumin


mortalityAKI RRT

RR 1.04 (95% CI 0.89-1.22)RR 1.18 (95% CI 0.99-1.40)RR 1.36 (95% CI 1.08-1.72)

mortality in 4 trials with low risk of bias, 3016 patients RR 1.11 (95% CI 1.00-1.23)

Gattas DJ 2013 [13]

Meta-analysis A

ICU patients 1966-2012 6% HES resuscitation fluids


mortalityRRT

RR 1.08 (95% CI 1.00-1.17)RR 1.25 (95% CI 1.08-1.44)

harm by HES (mortality RRT)

Rochwerg B 2015 [14]

Network meta-analysis A

Sepsis 1966-2014 HESalbumincrystalloidbalanced crystalloids


RRT Starch vs. crystalloidsRR 1.39 (95% CI 1.17-1.66)Albumin vs. crystalloidsRR 1.04 (95% CI 0.78-1.38)

harm by HES (RRT)

Moeller C 2016 [15]

Meta-analysis C

Acutely ill patients

1966-2015 gelatine crystalloid or albumin

60 Studies30 RCTs8 non-randomised studies22 animal studies

MortalityAKI

RR 1.15 (95% CI 0.96-1.38)RR 1.35 (95% CI 0.58-3.14)

Increased risk of anaphylaxis by gelatine

RCT= randomised controlled trial, HA = Human serum albumin, AKI = acute kidney injury, RRT =renal replacement therapy, RL = ringer´s lactate, NS = normal saline


Table S4: Meta-analyses and randomised controlled trial s not included in the meta-analyses evaluating the effects of loop diuretics on renal function and/or mortality

Authoryear

Study designEvidence (A-C)

Clinical setting Intervention Number of patients included

Endpoints Results Renal protection

Comments

Sampath S et al. 2007 [16]

Meta-analysisA

Patients with or at risk of AKI

Loop diuretics versus placebo

5 RCTs Mortality RRT

RR 1.12 (95% CI 0.92-1.35)RR 0.76 (95% CI 0.53-1.00)

No

Bagshaw SM et al. 2007 [17]

Meta-analysisA

Critically ill and non-critically ill patients with AKI

Frusemide versus placebo

5 RCTs including 555 patients

renal recovery hospital mortality

OR 0.88 (95% CI 0.59-1.31)OR 1.28 (95% CI 0.89-1.84)

No

Ho KM et al. 2010 [18]

Meta-analysis A

Adults with or at risk of AKI

Frusemide versus placebo


RRT hospital mortality

RR 1.02 (95% CI 0.90-1.16)RR 1.12 (95% CI 0.93–1.34)

No more side effects

Wu MY et al. 2014 [19]

Meta-analysisA

Patients with acutely decompensated heart failure

Continuous loop diuretic infusion versus bolus treatment


change in creatinine

mortality

No significant difference

RR 1.13 (95% CI 0.61-2.10)

No

Hager B et al. 1996 [20]

RCT B

Patients post major thoraco-abdominal or vascular surgery

Frusemide infusion versus placebo

121 patients creatinine clearance

Decrease of creatinine clearance by 83% in frusemide group and by 81% in placebo group

No more hypokalaemia in frusemide group

Lassnigg A et al. 2000 [21]

RCTB

Patients with normal renal function having cardiac surgery

Dopamine versus frusemide infusion versus placebo

n=42 (dopamine)n=41 (frusemide_n=40 placebo


Significant rise in creatinine in frusemide group

No

Sirivella S et al. 2000 [22]

RCTC

Patients with oliguric or anuric AKI after cardiac surgery

Intermittent diuretics versus continuous infusion of mannitol, frusemide and dopamine

n=40 (intermittent)n=60 (continuous)

RRT 90% vs 6.7% Yes


Smith MN et al. 2008 [23]

RCTC

Patients with creatinine 130 – 250 μmol/L having cardiac surgery

Mannitol versus Hartmann’s solution

n=25 (mannitol)n=25 (Hartmann’s)


RRT

No difference in creatinine changesNo difference

No

Kunt AT et al. 2009 [24]

RCTB

Elective CABG surgery patients with creatinine <1.4mg/dl

Continuous frusemide infusion versus bolus treatment

n=50 (infusion)n=50 (bolus)

RRT creatinine

clearance 30-day mortality

0 vs 5% ; p=0.028significant fall in bolus group

0 vs 5% ; p=0.028

Yes (infusion)

Majumdar SR et al. 2009 [25]

RCTB

Adults with creatinine >1.7mg/dl undergoing coronary angiography

Saline + frusemide + mannitol versus saline hydration

n=46 (combination)n=46 (saline)

contrast induced nephropathy (≥25% or ≥0.5mg/dL rise in creatinine)

mortality

50% vs 28% ; p=0.03

no difference

No

Marenzi G et al. 2012 [26]

RCTB

Patients with CKD undergoing contrast coronary procedures

Frusemide with matched hydrationversus isotonic saline hydration

n=87 (furosemide)n=83 (saline)

Contrast induced nephropathy (≥25% or ≥0.5mg/dL rise in creatinine)

4.6% vs 18% ; p=0.005 Yes less in-hospital complications

Palazzuoli A et al. 2014 [27]

RCTB

Patients with acutely decompensated heart failure

Continuous frusemide infusion versus frusemide boluses

n=43 (infusion)n=39 (boluses)

AKIestimated GFR

22% vs 15% ; p=0.3 -9 vs +5 ; p<0.05

No

AKI = acute kidney injury; CABG = coronary artery bypass graft; CCF = congestive cardiac failure; CKD = chronic kidney disease; GFR = glomerular filtration rate; RCT = randomised controlled trial; RRT = renal replacement therapy; RR = relative risk; OR = odds ratio; CI = confidence interval;


Table S5: Randomised controlled trials evaluating the renal protective effects of vasopressors

AuthorYear publication

Study DesignEvidence (A-C)

Clinical setting

Year of study Intervention Nr trialspatients

Endpoints Results Comment

Arterial pressure targetAsfar P2014 [28]

RCTA

Sepsis 2010-2011 MAP 65-70 mm HgMAP 80-85 mmHg

388388

AKIN II Renal SOFA RRT RRT free days Mortality 90-d

41.6% vs. 38.6%, p=0.421.0±1.4 vs. 0.8±1.3, p=0.07635.8% vs. 33.5%, p=0.521±11 vs. 19±11, p=0.3642.3% vs. 43.8%, p=0.74

High target: more new atrial fibrillation

Chron. hypertension subgroup

MAP 65-70 mm HgMAP 80-85 mmHg

173167

AKIN II Renal SOFA RRT

52.3% vs. 38.9%, p=0.021.1±1.4 vs. 0.7±1.2, p=0.00542.2% vs. 31.7%, p=0.046

Quereshi AI2016 [29]

RCTA

Acute Cerebral Hemorrhage

2011-2015 Systolic Pressure 110-139 mmHgSystolic Pressure 140-179 mmHg

500500

Renal adverse events c

9.0%4.0% p=0.002

VasopressorsRussell JA2008VASST [30]

RCTA

Septic shock b 2001-2006 vasopressin (0.01 to 0.03 U/min)noradrenaline(5 to15 μg/min)

besides open label vasopressors

396382

Mortality 90-d

RRT

44.2 vs. 49.5, p=0.11In less severe septic shock

26.5% vs. 35.7%, p = 0.05

Gordon AC2010PosthocVASST [31]

PosthocRCTB

Septic shock b

+ AKI RIFLE risk

2001-2006 vasopressin (0.01 to 0.03 U/min)noradrenaline(5 to15 μg/min) besides open label vasopressors

53 53

Worsening renal function

RRT mortality

20.8 vs. 39.6%, p=0.03

17.0 vs. 37.7%, p=0.0230.8 vs. 54.7%, p=0.01

De Backer D2010 [32]

RCTA

Shock 2003-2007 DopamineNorepinephrine

858821

Mortality RRT free days

arrhythmia

52.5% vs. 48.5%, p=0.1012.8±12.4 vs. 14.0±12.3, p=0.0124.1% vs. 12.4%, p<0.01


Subgroup Cardiogenic shock

135145

Mortality Higher in the dopamine group, P=0.03

Gordon ACVANISH2016 [33]

RCTA

Septic shock 2013-2015 vasopressina norepinephrine

205204

Kidney failure free days

% patient without kidney failure

RRT

RRT in survivors

Mortality

V vs. N: 9 (1-24) vs 13 (1-25)Diff -4 (-11 to 5)

V vs. N: 57.0% vs. 59.2%Diff: -2.3% (-13.0 to 8.5%)

V vs. N: 25.4% v. 35.3%Diff:-9.9% (-19.3 to -0.6%)*

V vs. 19.9% vs. 22.3% Diff: -2.4 (-12.5 to 7.7)

V vs.N:10.7% vs.8.3%Diff: 2.5% (-3.3 to 8.2%)

Hajjar LAVANCS2017 [34]

RCTBd

Vasoplegic shock after Cardiac Surgery

2012-2014 vasopressin (0.01 to 0.06 U/min

noradrenalin 10 to 60 μg/min

149

151

mortality orseverecomplications e

within 30 days AKIN 1

AKIN 2

AKIN 3

RRT

Mortality 90d

.V vs., N: 32% vs. 49%HR 0.55 (0.38 to 0.80)

V vs. N: 20.0% vs. 18.5% OR 1.64 (0.889 to 3.03)

V vs. N: 6.2% vs. 11.9% OR 3.39 (1.43 to 8.06)

V vs. N: 8.3% vs. 32.5%6.93 (3.4 to 14.12)

V vs N: 2.7% vs. 13.9%OR 0.17 (0.06 to 0.51)

V vs N: 16.1% vs. 17.2%OR 0.92 (0.5-1.69)..

No difference in mortality

Single-centre studyhigh mortalityhigh incidence of RRT, possibly related to the inclusion criteria

a titrated up to 0.06 U/min, RRT renal replacement therapy, ND not differentb patients with septic shock needing s minimum of 5 μg of norepinephrine per minute .c Renal adverse events according to Medical Dictionary for Regulatory Activities (MEDDRA) definitionsd Monocenter study, high mortality and high incidence of AKIN and RRT possibly related to the inclusion criteria e stroke, requirement for mechanical ventilation for longer than 48h, deep sternal wound infection, reoperation, or acute renal failure


Table S6: Meta-analysis evaluating the renal protective effect of low dose dopamine


Study DesignEvidence (A-D)

Clinical setting



Meta-analysisFriedrich2005 [35]

Meta-analysisA

Major surgeryCritically ill

1966-2005 Low dose dopamine 613359

Need for RRT

Urine Output d-1Urine Output d 2Urine Output d 3

Creat Clearance d1Creat Clearance d2Creat Clearance d3

Mortality

RR 0.96 (0.78-1.19)

RM 1.24 (1.14-1.35), , p<0.01RM 1.09 (0.99-1.20)RM 1.02 (0.87-1.20)

RM 1.06 (1.01-1.11) , p=0.02RM 1.02 (0.90-1.15)RM 1.09 (0.96-1.24

RR 0.96 (0.78-1.19)RR = relative risk, RM = ratio of means


Table S7. Meta-analyses and RCT not included in the meta-analyses evaluating the renal protective effect of fenoldopam Authoryear

Study DesignLevel (A-C)

Clinical settingInclusion

Time of study/search

Intervention Nr trials or patients


Meta-analysesLandoni G a

2007 [36]Meta-analysisB *

Critically ill andCardiovascular surgery

Up to 2005 fenoldopam placebo/dopamine

or dobutamine /control

16 a

1290Risk for AKINeed for RRTHosp. mortality

OR 0.44 (CI0.32-0.59)OR 0.54 (0.34-0.84)OR 0.64 (0.45-0.91)

Small and non-RCT

Landoni G b


Cardiovascular surgery

Up to 2006 fenoldopam placebo/

dopamine/control

13 b

1059Need for RRTHosp. mortality

OR 0.37 (0.23-0.59)OR 0.46 (0.29-0.75)

Small and biased trials

Zangrillo A c


Cardiac surgery Up to 2012 fenoldopam placebo

6 c

440Risk for AKINeed for RRTHosp. mortality

OR 0.41 (0.23-0.74)No effectNo effect

SmallMore hypotension

Gillies MA c


Major surgery NR fenoldopam placebo

6 c

507New AKINeed for RRTHosp. mortality

OR 0.46 (0.27-0.79)OR 0.27 (0.06-1.19)OR 1.0 (0.14-7.37)

SmallHigh risk of biasMore hypotension

RCTBove T2014 [40]

RCTA

Post cardiac surgeryAKI RIFLE Risk

2008-2013 fenoldopam0.1μg/kg/min (0.025-0.3μg).

Placeboup to 4-days

338

329

Need for RRT

Mortality

69/338 (20%)60/329 (18%), p=0.8678/338 (23%)74/329 (22%), p=0.47

No protectionMore hypotension

AKI = acute kidney injury, RRT= renal replacement therapy, RCT = randomised controlled trial, CrCl = creatinine clearance, SCr = serum creatinine, * Small studies, some heterogeneity, different definitions of AKI, outcome reported bias

a In this meta-analysis, all included studies were RCTs; 5 RCTs included ICU patients, 5 cardiac surgery, 3 vascular surgery, 2 liver and 1 renal transplantationb In this meta-analysis, 4/13 studies including 386/1059 patients were non-randomised (case control, propensity matched)c The included RCTs in the meta-analysis of Gilles et al. differ from those in the meta-analysis of Zangrillo et al.. Gilles at al. also included a RCT in patients with a solitary kidney undergoing partial nephrectomy and in patients undergoing liver transplantation , but did not include a RCT in critically ill patient with early acute tubular necrosis and a RCT in cardiac surgery comparing fenoldopam to dopexamine


Table S8: Meta-analysis and RCT not included in the meta-analyses evaluating the renal protective and or mortality effects of natriuretic peptides

Authoryear

Study DesignEvidence

Clinical setting Time of study/search

Intervention Nr trialspatients

Endpoints Results Renal protection

Comments

Meta-analysesNigwekar SU2009 [41]

Meta analysisB

Prevention AKI 1966-2007 ANPPlacebo

11818

Need for RRT

Mortality

OR 0.45 (0.21-0.99)P=0.05OR 0.67 (0.19-2.35)

Yes LOS

Treatment AKI 8 1043

Need for RRT Mortality

OR 0.59 (0.32-1.08)OR 0.34 (0.12-0.96) b

OR 1.01 (0.72-1.43)Yes b

Hypotension b

Arrhythmias b

Subgroup major surgery a

14817

Need for RRTMortality

OR 0.49 (0.27-0.88)NS

Subgroup CV surgery

8 Need for RRT OR 0.24 (0.10-0.58) Yes

Oliguric AKI Need for RRTMortality

OR 0.46 (0.19-1.12)OR 0.94 (0.62-1.43)

No

Mitaka C2011[42]

MetaAnalysisB

Cardiac and CV surgery

1994-2011 ANP or BNPPlacebo

6 ANP1041

Peak seCr

RRT

Mortality

-0.13 (-0.130-0.126) p<0.00016/280 vs. 18/283OR 0.261 (0.090-0.761)OR 0.62 (0.22 – 1.75)

Yes LOS Arrhythmias

3 BNP425

seCr / RRTMortality

NSOR 0.72 (0.24 - 2.12)

No LOS

Xiong B2015 [43]

Meta-analysisB

Acute decompensated heart failure

1999-2014 BNP nesiritide)Control or placebo

Subgroup high dose> 0.01 μg/kg/minSubgroup standard dose< 0.1 + bolus 2 μg/kg Subgroup low dose

159623

1269

7698

503

Worsening renal function

RR 1.08 (1.01–1.15) p=0.023

RR 1.54,9 (1.19-2.00 p=0.001RR 1.04 (0.98–1.12) p=0.213 RR 1.01 (0.74–1.37)


< 0.01 μg/kg/min Subgroup non-CKD

Subgroup CKD

Subgroup 1030 Weighted mean SeCreat

p=0.968RR 1.08 (1.02–1.16) p=0.016RR 0.94 (0.70–1.27) p=0.680-2.54 (-5.76–0.67) p=0.121

Randomised controlled trialsMori Y2014 [44]

RCTC

Aortic arch surgery

ANP 0.0125 μg/kg/min Placebo

2022

AKI

RRTmortality

6/20 (30%) vs. 16/22(72%), p=0.0140/20 vs. 0/22, NS0/20 vs. 1/22, NS

Yes

Sezai A2013 [45]

RCTB

High risk CABG+CPBEuroscore ≥ 6

hANP (carperitide) placeboduring CPB until oral intake

183184

RRT

Mortality

0/183 vs. 7/184 (p=0.015)14/183 vs. 22/184 (p=0.22)

Yes less MACCE Fragility 1

OR = odds ratio; CV = cardiovascular; RCT = randomised controlled trial; ANP = atrial natriuretic factor; seCr = serum creatinine; RRT = renal replacement therapy; LOS = length of stay; CPB = cardiopulmonary bypass; MACCE = major adverse cardiovascular and cerebrovascular events. CKD = chronic kidney diseasea including 3 RCT in liver transplantation and 1 RCT in heart transplantationb low dose ANP; no benefit for high dose ANP ; c non inotrope control; d any control; e low dose


Table S9: Meta-analysis and RCT not included in the meta-analyses evaluating the renal protective effects of levosimendanAuthorYear


Clinical setting Time of study/search

Intervention Nr trialspatients


Bove T 2015 [46]

Meta-analysisB**

Critically ill with or at risk for AKI

High quality studies

1999-2013 levosimendanplacebo/dobutamine/

PGE2milrinone/ fur-osemide/ standard inotrop-ics

333867

6

AKI

RRT

RRT

L: 7.3% vs. C: 9.3%RR 0.79 (0.63 to 0.99) L: 3.5% vs. C: 8.7%RR 0.52 (0.32 to 0.86)

RR 0.41 ( 0.15 to 1.12) p=0.08

Zhou C 2016 [47]

Meta-analysisB**

Cardiac Surgeryperioperatively

1990-2015 levosimendanplacebo (9)/other inotropic

(4)

131345

AKI

RRT

Mortality

L: 8.7% vs. C: 15.1%OR 0.51 (0.24-0.79)L: 4.5% vs. C: 10%OR 0.43 (0.25-0.76)L: 5.3% vs. C: 14.3%OR 0.41 (0.27 -0.62)

Randomised controlled trialsGordon AC2016 [48]

RCTdouble blindA

Sepsis 2014-2015 levosimendan0.1 g/kg/min (0.5-2) for 24h

placebo

258

257

Renal SOFA

Need of RRT

Mortality 28-d

Mean diff0.61 (−0.07 to 1.29)L: 24.1% vs. C: 24.1% OR 0.99 (0.66 – 1.49)L: 34.5% vs. P: 30.9% OR 1.19 (0.82 – 1.72)

Trend to worse outcome,no renal protection,longer weaning,more arrhythmia

Mehta RH2017 [49]

MulticentreRCTnon-blindedA

Cardiac surgeryLV ejection fraction < 35%

2014-2016 levosimendan 0.2 μg/kg/min for 1 hour,

followed by 0.1 μg/kg/min for 23 hours

placebo

Per protocol428

421

Composite: 30-d mortality, RRT, MI, 5-d mechanical assist RRT at 30-d

24.3% vs. 24.4%OR 1.00 (0.66–1.54)

2.1% vs. 3.8%OR 0.54 (0.24–1.24)


Landoni G2017 [50]

MulticentreRCTdouble-blindA

Cardiac surgeryNeeding HD support

2009-2016 levosimendan 0.025 to 0.2 μg/kg/min for 48-h

placebo

248

258

30-day mortality

AKI risk

AKI injury

AKI failure

RRT

12.9% vs. 12.8%OR 0.1 (−5.7 to 5)16.6% vs. 21.3% OR −4.7 (−11.5 to 2.1)10.5% vs. 10.5%OR 0.1 (−5.3 to 5.4)6.9% vs. 8.5%OR −1.6 (−6.3 to 3.0)9.7% vs. 12.8%OR −3.1 (−8.6 to 2.4)

RCT = randomised controlled trial, CABG = coronary artery bypass grafting, PCI = percutaneous coronary intervention, RRT = renal replacement therapy, SOFA = Sequential Organ Failure Assessment, GFR = glomerular filtration rate; * cardiac surgery OR 0.52 (0.35-0.75), cardiology OR 0.75 (0.63-0.91), LV left ventricular, MI myocardial infaction, HD hemodynamic** Small studies, some heterogeneity, AKI was not always a predefined endpoint, different definitions of AKI, outcome reported bias


Table S10: Randomised controlled trials evaluating the renal protective effects of dexmedetomidine



Clinical setting



Leino 2011[51]

RCT B

Coronary Artery Bypass Surgey

1994-1997 -dexmedetomidine-placebo

4443

Diuresis in the first 4 hours after insertion of urinary catheterPeri-operative serum creatinine

74 % increase in diuresis in the dexmedetomidine group (P < 0.001)

No differences between the two groups (P> 0.05) regarding creatinine

Balkanay2015 [52]

RCTB

Coronary Artery Bypass Surgey

2009-2011-dexmedetomidine < 8 mcg/kg-dexmedetomidine > 8 mcg/kg-placebo

312928

NGAL at 24 h

serum creatinine, diuresis

NGAL 24h [ng/ml]97.767.3176.8(P < 00.1)

no differences in serum creatinine or diuresis

Cho 2016 [53]

RCTA

Valvular Hart Surgery Patients

2013-2015 Groups- placebo - dexmedetomidine 0.4 mcg/kg

100100

AKI at 48h

ICU length of Stay in days

AKI at 48 h 33%14 %P < 0.05

placebo: 2.4 ddexmedetomidine: 2.3 dP < 0.05

RCT = randomised controlled trial, AKI = acute kidney injury, NGAL= Neutrophil gelatinase-associated lipocalin


Table S11: Randomised controlled studies evaluating the renal protective effect of tight glycaemic control

Author

Year [ref]

Design

Evidence

(A-C)

Clinical

setting

Year of

study

Intervention Targets

(mg/dL)

N patients

(N trials)

endpoints Results

(TGC vs control)

RR Comments

Van den Berghe G

2001 [54]

RCT

A

Surgical ICU 2000-

2001

TGC

control

80-110R/ if >215Stop if <180

765

783

mortality

RRT

AKI1

7.2% vs 10.9% (p=0.01)

4.8% vs 8.2% (p=0.007)

9.0% vs 12.3% (p=0.04)

0.66 (0.48-0.92)

0.59 (0.4-0.88)

Van den Berghe G

2006 [55]

RCT

A

Medical ICU 2002-

2005

TGC

control

80-110R/ if >215Stop if <180

595

605

mortality

RRT

AKI2

37.3% vs 40% (p=0.33)

19.8 vs 19.8% (NS)

5.9 vs 8.9% (p=0.04)

0.93 (0.81-1.08)

0.92 (0.74-1.14)

Brunkhorst F

2008 [6]

RCT

A

Severe sepsis/

septic shock

2003-

2005

TGC

control

80-110

180-200

247

290

mortality

RRT

AKI4

24.7% vs 26% (p=0.74)

27.5% vs 22.5% (p=0.19)

31.1% vs 26.6% (p=0.25)

0.95 (0.71-1.27)

1.21 (0.9-1.63)

Arabi YM

2008 [56]

RCT

A

Mixed ICU 204-

2006

TGC

control

80-110

180-200

266

257

mortality

RRT

27.1% vs 32.3% (p=0.19)

11.7% vs 12.4% (p=0.54)

0.84 (0.64-1.09)

0.97 (0.61-1.54)

De Le Rosa G

2008 [57]

RCT

A

Mixed ICU 2003-

2005

TGC

control

80-110

180-200

254

250

mortality

RRT

AKI

40% vs 38.4% (NS)

10.8 vs 13% (p=0.45)

12.6 vs 10% (p0.36)

1.13 (0.89-1.44)

0.81 (0.50-1.3)

Large overlap achieved blood

glucose levels

Preiser

2009 [58]

RCT

A

Mixed ICU 2004-

2006

TGC

control

80-110

140-180

536

542

mortality

Days of RRT

23.3% vs 19.4% (p=0.11)

519 vs 523 (p=0.75)

1.21 (0.93-1.57) Stopped early

Large overlap achieved blood

glucose levels

Finfer S

2009 [59]

RCT

A

Mixed ICU 2004-

2008

TGC

control

81-108

<180

3010

3012

mortality3

mortality6

RRT

22.3% vs 20.8% (p=0.17)

27.5% vs 24.9% (p=0.02)

15.4% vs 14.5% (p=0.34)

1.07 (0.97-1.18)

1.14 (1.02-1.28)

1.06 (0.94-1.2)

Strict vs. intermediate level

Unreliable glucose meters


Arabi YM

2011 [60]

RCT

A

Mixed ICU ?? TGC

control

80-110

180-200

120

120

mortality

RRT

35% vs 37.5%

16.7% vs 15% (p=0.72) 1.11 (0.62-1.91)

Wiener

2008 [61]

Meta-

analysis

A

TGC

Control

1790

1839 (9)

mortality

RRT

0.93 (0.85-1.03)

0.96 (0.76-1.2)

Ling Y

2012 [62]

Meta-

analysis

A

TGC

control

5368

5417 (8)

mortality

RRT

1.02 (0.95-1.10)

0.96 (0.83-1.11)

RCT = randomised controlled trial, TGC = tight glycemic control, RRT = need for renal replacement therapy, AKI = acute kidney injury mortality = hospital mortality unless otherwise reported1 peak Screat <2.5mg/dL, 2 doubling of admission Screat or peak >2.5mg/dL 3 28-day mortality, 4 doubling of Screat or RRT, 5 30d mortality, 6 90d mortality


Table S12: Randomised controlled studies evaluating the renal protective effect of erythropoietin

AuthorYear [ref]

DesignEvidence (A-C)

Clinical setting Interventionin U rHuEPO

N patients(N trials)

endpoints ResultsEPO vs placebo

RR for AKI Comments

Endre 2010 [63]

RCTC

ICU + increased biomarker

500U/kgplacebo

8479

RRT in 30dAKI in 7d

6% vs 3.8% (p=0.72)48.8% vs 48.7% (p=1)

Shema-Didi2016 [64]

RCTC

Contrast in diabetics

50,000IUcontrol

7266

Scr increase of 0.5mg/dL in 48h

9.7% vs 7.6% (p=0.65)

Song2009 [65]

RCTC

Elective CABG 300U/kgplacebo

3635

AKI in 5d 8% vs 29% (p=0.035) Fragility index 1

Yoo2011 [66]

RCTC

Valvular heart surgery

500U/kgplacebo

3737

AKI in 48h 24.3% vs 54.3% (p=0.017) Fragility index 3

De Seigneux2012 [67]

RCTC

Cardiac surgery 20000U40000Uplacebo

202040

AKI in 7d 25% vs 30% vs 17.5% (NS)

Tasanarong2013 [68]

RCTC

Cardiac surgery 200U/kgplacebo

5050

AKI in 48h 14% vs 38% (p<0.01) Fragility index 4

Kim2013 [69]

RCTC


4949

AKI in 48h 33% vs 35% (p=0.83)

Dardashti2014 [70]

RCTC


3535

AKI in 48h 34% vs 29% (p?)

Kim2016 [71]

RCTC

Aortic surgery 500U/kgplacebo

3030

AKI in 7dStage 3 AKI

58% vs 62% (p=0.75)16% vs 14% (p>0.99)

Tie2015 [72]

Meta-analysisB

Cardiac surgery All patientsLow AKI riskHigh AKI risk

321 (5)143 (3)178 (2)

AKI 0.64 (0.35-1.16)0.38 (0.24-0.61)1.22 (0.77-1.94)

heterogeneity

Penny-Dimri2016 [73]

Meta-analysisB

Cardiac surgery All patientsLow AKI riskPre anaesthetic administration

531 (6)171 (2)172 (2)

AKI 0.69 (0.35-1.36)0.25 (0.11-0.56)0.27 (0.13-0.54)

heterogeneity


Zhao2015 [74]

Meta-analysisC

ICU or peri-operative care

All patients 13911368 (10)

mortalityRRTAKI

0.96 (0.78-1.18)0.72 (0.31-1.70)0.97 (0.79-1.19)

EPO = erythropoietin, RCT = randomised controlled trial, RRT = need for renal replacement therapy, AKI = acute kidney injury. The fragility index refers to the numbers of events that is required to change a statistically significant result into a non-significant result.


Table S13. Randomised controlled studies evaluating the renal protective effect of N-acetyl cysteine in ICU patients

Authoryear


Clinical setting Intervention Nr of patients


Burns KE2005 [75]

RCTB

At risk patients (CRF, ≥70 yrs, DM, poor LV) undergoingcardiopulmonary bypass

IV NAC (600mg x 4 doses)

placebo or control

295 Increase in SCr > 44μmol/l or > 25% baseline

29.7 vs. 29% (OR 1.03 (0.72-1.46) p = 0.89

Macedo E2006 [76]

RCTC

Elective AAA repairStable renal function

NAC 2x1200mg po starting day before surgery , then Iv NaC 600mg x 4placebo

42 Increase in SCr > 44μmol/l or > 25% baselineICU MortalityICU LOS

50% vs. 27.3% p = 0.16

p = 0.29p = 0.4

Komisarof JA2007 [77]

RCTB

> 30 minutes new onset hypotension

oral/NG NAC 3.0g bolus, then 1.5g x 8 doses, then 1.2g x 8 doses

placebo

142 Increase in SCr > 0.5mg/dl

ICU MortalityNeed for RRT

15.5 vs 16.9% p = 0.82

NoneNone

Sisillo E2008 [78]

RCTB

Patients with CrCl < 60 ml/min undergoingcardiopulmonary bypass

IV NAC 1.2 g x 4 doses

placebo

254 Increase in SCr > 44μmol/l or > 25% baseline


40 vs 52% p = 0.06

NoneNone

Decreased need for prolonged MV in NAC group ( 3 vs. 18% p = 0.001)ICU stay > 4 days reduced (13 vs. 33% p = 0.001)

Adabag AS2008 [79]

RCTB

Patients with chronic kidney disease undergoing cardiac surgery

IV NAC 600mg bd for 7 days

placebo

102 Maximum change in SCr from baseline


0.45 +/- 0.7 mg/dL (NAC) vs. 0.55 +/- 0.9 mg/dL (placebo) p = 0.53p = 1.0p = 0.68


Wijeysundera DN 2007 [80]

RCTB

Patients with CrCl < 60 ml/min undergoingCardiopulmonary bypass

IV NAC 100mg/kg bolus followed by 20mg/kg/hr for 4 hours

placebo

177 %age change in GFR during first 72 hours

Increase in SCr > 44μmol/l or > 25% baselineNeed for RRTICU Mortality

5.2% improved in NAC group (CI 2.4-12.1%)

28 vs. 32% p = 0.59OR 0.84 (0.42-1.68)p = 0.370 vs 8%, p = 0.007

Song JW2015 [81]

RCTB

At risk patients undergoing off-pump coronary bypass surgery (i) preoperative serum creatinine >1.4 mg/dL; (ii) left ventricular ejection fraction <35% or congestive heart failure (iii) age >70 years (iv) diabetes (v) re-operation

IV NAC 150 mg/kg bolus followed by 24 hours of 150 mg/kg NAC

placebo

117 AKI (AKIN)

Urine output

35% (NAC) vs 32% (placebo) (p = 0.695)4982 ± 1185 mL (NAC) vs. 5528 ± 1247 mL (placebo) (p=0.017)

Fraga CM 2016 [82]

RCTC

General ICU , new onset hypotension (MAP < 60 mmHg)

IV NAC 50 mg/kg over 4h followed by 48h of 100 mg/kg/d NAC + deferoxamine (DFX) 1000mg

placebo

80 AKI

AKI duration

RRT

Mortality

NAC/DFX vs. placebo: 65% vs. 67%; adjusted RR 1.1 (95% CI: 0.37-3.2) 1d (NAC(DFX) vs. 0.5d (p=0.04)15% vs. 15%; adjusted RR 1.1 (95% CI: 0.3-4.2) 60% vs. 57% adjusted RR 1.3 (95% CI: 0.51-3.7)

NAC effect indistinguishable from DFX effect, thus level of evidence downgraded

RCT = randomised controlled trial, NAG = Urine N-acetyl-β-D-glucosaminidase, SCr = serum creatinine, NAC = N-acetylcysteine, DFX= deferoxamine, MV = mechanical ventilation, LOS = length of stay, ICU = intensive care unit.


Table S14: Recent meta-analyses evaluating the renoprotective effect of statins following coronary angiography / interventionsAuthorYear




Navarese EP 2017

[83]

Network Meta-

analysis

A

Patients undergoing

cardiovascular

procedures with

contrast

Statin versus

Saline / sodium

bicacarbonate /

saline + NAC /

prostaglandin

2951 patients AKI RR 0.36 – 0.51

Su X 2016 [84] Bayesian network

meta-analysis

A

Patients undergoing

procedures with

contrast

High dose statins

Placebo / control

Low dose statin

Placebo / control

13 RCTs including

2612 patients

AKI OR 0.37 (95% CI 0.17-0.72)

OR 0.98 (95% CI 0.41 – 2.07) low dose statins

not effective

Li H 2016 [85] Meta-analysis

A

Patients undergoing

procedures with

contrast

Statin

Placebo

21 RCTs including

7746 patients

AKI RR 0.57 (95% CI 0.47-0.69)

Wang N 2016 [86] Meta-analysis

A

Patients undergoing

coronary

catheterisation

Statin

Placebo

14 RCTs including

6033 patients

AKI 3.7% vs 8.3% ; p<0.00001

Thompson K 2016

[87]

Meta-analysis

A

Patients undergoing

angiography

Statin

Placebo

19 RCTs including

7161 patients

AKI RR 0.52 (95% CI 0.40-0.67)

Yang Y 2015 [88] Meta-analysis

A

Patients undergoing

coronary

Statin

Placebo

5 RCTs including

4045 patients

AKI OR 0.49 (95% CI 0.37-0.66)


catheterisation

Marenzi G 2015

[89]

Meta-analysis

A

Patients undergoing

coronary

catheterisation

Statin

Placebo

9 RCTs including

5212 patients

AKI RR 0.50 (95% CI 0.39-0.64)

Wu H 2015 [90] Meta-analysis

A

Patients undergoing

coronary angiography

High dose statin

versus low dose

statin

14 RCTs including

1689 patients

AKI RR 0.41 (95% CI 0.29-0.56)

Liu YH 2015 [91] Meta-analysis

A

Patients undergoing

coronary

catheterisation

Statin versus

placebo

9 RCTs including

5143 patients

AKI

RRT

mortality

RR 0.47 (95% CI 0.37-0.60)

OR 0.14 (95% CI 0.03-0.60)

RR 0.77 (95% CI 0.28-2.12)

Briasoulis A 2015

[92]

Meta-analysis

A

Patients undergoing

interventions which

require contrast

Statin versus

placebo/control

9 RCTs including

4984 patients

AKI OR 0.45 (95% CI 0.34-0.58)

Ukaigwe A 2014

[93]

Meta-analysis

A

Patients undergoing


High dose statin

versus low dose

statin or placebo

12 RCTs including

5564 patients

AKI OR 0.43 (95% CI 0.33-0.55)

Lee JM 2014 [94] Meta-analysis

A

Patients undergoing


Statin

Placebo

13 RCTs including

5825 patients

AKI High dose statins:

RR 0.45 (95% CI 0.35-0.57)

Singh N 2014 [95] Meta-analysis

A

Patients exposed to

contrast

Statin

Placebo

9 RCTs including

5143 patients

AKI RR 0.47 (95% CI 0.34-0.64)

Peruzzi M 2014

[96]

Network

Meta-analysis

A

Patients exposed to

contrast

Statin

Placebo

14 RCTs including

6160 patients AKI

RRT

High dose statins:

OR 0.47 (95% CI 0.37-0.60)

OR 0.27 (95% CI 0.07-1.09)


90-day mortality OR 0.80 (95% CI 0.31-2.10)

Barbieri L et al.

2014 [97]

Meta-analysis

A

Patients undergoing

contrast angiography /

angioplasty

Statin

Placebo

8 RCTs including

4734 patients

AKI OR 0.50 (95% CI 0.38–0.66)

RCT = randomised controlled trial, RRT = renal replacement therapy, AKI = acute kidney injury; OR = odds ratio, RR = relative risk, CI = confidence interval


Table S15: Recent meta-analyses and randomised controlled studies not included in the meta-analyses evaluating the renoprotective

effect of statins in cardiac surgeryAuthoryear




Park JH 2016 [98] RCT

B

Patients undergoing

valvular surgery

Statin

Placebo

200 patients AKI 21% versus 24%; p=0.40

Xiong B 2017 [99] Meta-analysis

A

Patients requiring

cardiac bypass

surgery

Statin

Placebo

9 RCTs including

3201 patients

AKI

RRT

RR 1.12 (95% CI 0.97 – 1.29)

RR 1.13 (95% CI 0.45 – 2.85)

Yuan X 2017

[100]

Meta-analysis

A

Patients requiring

cardiac bypass

surgery

Statin

Placebo / control

8 RCTs including

3204 patients

AKI OR 1.01 (95% CI 0.75 – 1.36)

Putzu A 2016

[101]

Meta-analysis

A

Patients requiring

cardiac bypass

surgery

Statin

Placebo or no

treatment

23 RCTs including

5102 patients

AKI OR 1.26 (95% CI 1.05 – 1.52)

Li M

2016 [102]

Meta-analysis

C

Patients requiring

cardiac bypass

surgery

Statin

Control

17 studies

41717 patients

AKI

mortality

OR 0.72 (95% CI 0.55 – 0.94)

OR 0.40 (95% CI 0.22 – 0.72)

Lewicki M 2015

[103]

Meta-analysis

A

Patients requiring

cardiac bypass

surgery

Statin

Placebo

7 RCTs including

662 patients

AKI

RRT

mortality

RR 0.76 (95% CI 0.46-1.28)

RR 0.80 (95% CI 0.23-2.81)

RR 3.86 (95% CI 0.43-34.4)

RCT= randomised controlled trial, RRT = renal replacement therapy, AKI = acute kidney injury


Table S16: Randomised controlled studies and meta-analyses evaluating the renal protective effect of remote ischaemic preconditioning Author/year Study design

Evidence (A-C)

Clinical setting Intervention

Number of patients included


Li 2013 [104] Meta-analysisB

Cardiac and vascular interventions

RIPC 924 AKI RR 0.73 (0.50, 1.06), p = 0.10

Yang 2014 [105]

Meta-analysisB


RIPC 13 studies, 1334 patients

AKI, RRT, kidney biomarkers, in-hospital mortality, length of stay in the ICU and in-hospital

AKI: RR 0.70 (0.48, 1.02), p = 0.06. All other endpoints also similar

Pei 2014 [106]

Meta-analysis B

Coronary intervention


CA-AKI OR 0.61 (0.38, 0.98), p = 0.04 Reduction of myocardial infarction OR0.68 (0.51, 0.91), p = 0.01

Li 2017 [107] Meta-analysis B



AKI, RRT AKI: RR 0.79 (0.66, 0.95), p = 0.01RRT: RR 1.02 (0.45, 2.30), p = 0.96

Reduced length of ICU stay, similar length of hospital stay

Hu 2016 [108]

Meta-analysisB

Cardiac or aortic surgery (IR) and contrast administration (CA)


AKI AKI: RR 0.834 (0.728, 0.955)IR-AKI: RR 0.905 (0.783, 1.045)CA-AKI: RR 0.430 (0.286, 0.648)

No effect on RRT, change in serum creatinine and eGFR, mortality (hospital and d30), or length of hospital stay

Zhang 2016 [109]

Meta-analysis B

On-pump cardiac surgery


AKI, RRT, postop creatinine

AKI: OR 0.84 (0.73, 0.98)RRT: OR 0.76 (0.46, 1.24)

Similar postop. creatinine on day 1 and 2Similar hospital mortality

Zhou 2016 [110]

Meta-analysis B

Elective coronary revascularization; PCI and CABG


AKI PCI AKI: OR 0.51 (0.31, 0.82)CABGAKI: OR 0.94 (0.73, 1.19)RRT: OR 1.04 (0.62, 1.76)

CABG: Similar hospital mortalityNo effct on AKI.


Zhang 2016 [111]

Meta-analysis B

PCI and CABG RIPC 37 studies, 81668 patients

AKI Investigator defined AKIRR 0.84 (0.73, 0.96)PCIRR 0.64 (0.46, 0.87)CABGRR 0.93 (0.82, 1.06)KDIGO variant AKIRR 0.87 (0.74, 1.02)

Uncertainty of effect due to use of non-standardized AKI definition

Yi 2016 [112] Meta-analysis B

PCI and cardiac surgery with CPB

RIPC 13 studies4370 patients

AKI RRT

AKI: RR 0.81 (0.66, 0.99)RRT: RR 0.82 (0.20, 3.39)

Sukkar 2016 [113]

Meta-analysis B

Invasive procedures


AKI AKI: RR 0.83 (0.71, 0.97) Beneficial effect on AKI was predominantly in AKIN 1, and attenuated in AKIN stage 2 and 3.Low event rate!No effect on mortality, myocardial infarction, stroke, major adverse cardiovascular events

Zhou 2017 [114]

Meta-analysis B

Cardiac surgery RIPC 21 studies6302 patients

AKI AKI: OR 0.79 (0.65, 0.96)AKI stage 1: OR 0.65 (0.47, 0.89)

Shorter duration of mechanical ventilation and ICU stayMeta-regression showed benefit in younger patients undergoing non-complex surgery

Pierce 2017 [115]

Meta-analysis B

Cardiac surgery RIPC 21 studies, 5262 patients

AKI

mortality

AKI: 24.7% vs. 27.2%, RR 0.839 (0.703, 1.001)Only studies with propofol free anaesthesiaAKI: 32.7% vs. 47.5%, RR 0.700 (0.527, 0.930)

Effect on AKI only if analysis was restricted to studies with propofol free anesthesia

No difference in mortality and myocardial infarction


Menting 2017 [116]

Meta-analysis B

Surgery (kidney transplantation excluded)


serum-creatinine d1, d2, d3

AKI (RIFLE)

AKI (AKIN)

RRT

Creatinine d1: mean diff 0. 02 mg/dL (-0.05, 0.02)Creatinine d2: mean diff -0.04 (-0.09, 0.02)Creatinine d3: mean diff –0.05 (-0.19, 0.10)AKI (RIFLE): RR 0.91 (0.75, 1.12)AKI (AKIN): RR 0.76 (0.57, 1.00)RRT: RR 0.85 (0.37, 1.9)

No difference in adverse effects, length of hospital stay

Effect on AKI depending on AKI definition used (AKIN or RIFLE)

Randomised controlled trialsWalsh 2016 [117]

RCT A

High risk cardiac surgery

RIPC 258 serum-creatinine

AKIRRT

Creatinine: mean diff 0.06 (-0.10, 0.23)AKI: RR 1.10 (0.68, 1.78)RRT: 4.8% vs. 0.8%

CK-MB myocardial infarction, stroke, and death were similar in both groups

Kim 2017 [118]

RCT B

Cardiac surgery on CPB

RIPC delayed (24-48h prior surgery)Sham

160 serum-creatinineAKI

Creatinine: p=0.615AKI: 30.0% vs. 47.5%, RR 0.768 (0.599, 0.985)

Lower rate of complications Troponin I (72h AUC) 743.5 vs. 530.8, p=0.662

Zarbock 2017 [119]

RCT A

High risk cardiac surgery

RIPC 240 90-day outcomes:MAKE90, RRT,

Non-recovery of AKI

MAKE90:14.2% vs. 25.0%, ARR 10.8% (0.9%, 20.8%)RRT d90: 14.3% vs. 2.6%, ARR 11.7% (1.2%, 22.1%)Non-recovery d90: 5.3% vs. 23.2%, ARR 17.9% (4.8%, 31.1%)

RIPC= remote ischaemic preconditioning, RCT= randomised controlled trial, RRT = renal replacement therapy, AKI = acute kidney injury, CA-AKI = conrast media associated AKI, MAKE= major adverse kidney events


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