Strategies for initiating RRT in AKI. Stéphane Gaudry Réanimation médico-chirurgicale Hôpital Louis Mourier, Colombes Sorbonne-Paris-Cité University

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1 Strategies for initiating RRT in AKI Stéphane Gaudry Réanimation médico-chirurgicale Hôpital Louis Mourier, Colombes Sorbonne-Paris-Cité University

2 Conflict of interest Educational grants from Xenios France No conflict of interest regarding RRT AKIKI study funded by a grant from French Ministry of Health

3 Invention of the artificial kidney The father of artificial organs Hemodialysis, first life saving (1945) Membrane oxygenators (1948) Artificial heart (with Jarvik) (1957) He immigrated to USA (1950) Albert Lasker award (2002) Willem Johan "Pim" Kolff February 14, 1911, Leiden February 11, 2009 He was recognized Righteous Among the Nations by Yad Vashem Jerusalem center (2012) for hiding jews during WW2

4 Kolff WJ First clinical experience with artificial kidney Ann Intern Med 62: ; 1965

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6 Reversible renal failure? Reversibility Rapid (hours) Slow (-- weeks)

7 Kidney International 1972 Control Prophylactic RRT

8 Early RRT initiation Pros: Better fluid balance control Improved acid-base status Better control of electrolytes abnormalities Removal of toxins or cytokines in sepsis?? Cons: Potential harm (catheter, hypotension, metabolic) Costs

9 Available data on the timing of RRT Observational studies Randomized controlled trials

10 Cohort studies RCTs N=270 N=2118 Early RRT Delayed RRT

11 Paul M. Palevsky Crit Care Med 2008 Patients with AKI Patients managed with RRT Early RRT initiation Late RRT initiation No RRT

12 Paul M. Palevsky Crit Care Med 2008 Patients with AKI Patients managed with RRT Early RRT initiation Late RRT initiation No RRT Observational studies

13 Paul M. Palevsky Crit Care Med 2008 study design to adequately answer clinical question of timing of RRT in AKI Patients with AKI Early RRT strategy Late RRT strategy Receive RRT Receive RRT No RRT

14 ICM March 2016 When to start?

15 When to start? Why start it? Criteria? ICM March 2016

16 ICM March 2016 To compare strategies we need RCTs

17 RCTs on the timing of RRT Bouman et al Jamale et al Zarbock et al (ELAIN) Wald et al (Pilot STARRT-AKI) Combes et al (HEROICS) Gaudry et al (AKIKI)

18 RCTs on the timing of RRT Patients n Center(s) Population Bouman 106 Single-center Surgical (cardiac surgery +++) Jamale 208 Single-center Medical ELAIN 231 Single-center Surgical (cardiac surgery +++) Pilot STARRT-AKI 100 Multicenter Mixed HEROICS 224 Multicenter Cardiac surgery AKIKI 620 Multicenter Mixed

19 Time to RRT initiation in the delayed strategy AKI Time to RRT initiation ELAIN BOUMAN JAMALE HEROICS STARRT (Pilot) Time difference (h) 20 35?? AKIKI

20 Time to RRT initiation in the delayed strategy AKI Time to RRT initiation ELAIN BOUMAN JAMALE HEROICS STARRT (Pilot) Time difference (h) 20 35?? Free of RRT (delayed group) AKIKI 9% 17% 17% 43% 37% 49%

21 RCTs on the timing of RRT Bouman et al Jamale et al Zarbock et al (ELAIN) Wald et al (Pilot STARRT-AKI) Combes et al (HEROICS) Gaudry et al (AKIKI)

22 28-Day Survival Bouman et al: Crit Care Med 2002 Vol. 30, No. 10 RRT within 12h RRT if: urea >40 mmol/l K>6.5 mmol/l severe pulmonary edema 100% 74.3% 68.8% 75.0% 80% 60% 40% n=35 n=35 n=36 20% 0% EarlyHV EarlyLV LateLV

23 RCTs on the timing of RRT Bouman et al Jamale et al Zarbock et al (ELAIN) Wald et al (Pilot STARRT-AKI) Combes et al (HEROICS) Gaudry et al (AKIKI)

24 Mortality JAMA 2016 Delayed RRT Early RRT

25 Mortality JAMA 2016 Delayed RRT Early RRT Early RRT Delayed RRT

26 Mortality JAMA 2016 P=0.03 Delayed RRT Early RRT P=0.07 Early RRT Delayed RRT

27 JAMA 2016 Early RRT: KDIGO 2 Delayed RRT: KDIGO 3

28 JAMA 2016 Early RRT: KDIGO 2 Delayed RRT: KDIGO 3 Observational data have suggested that in practice, very few patients with stage 2 AKI and only a minority of patients with stage 3 AKI receive RRT Hoste EA Intensive Care Med 2015 Hoste EA et al Crit Care 2006 Liu and Pavlesky CJASN 2016

29 JAMA 2016 Early RRT: KDIGO 2 Delayed RRT: KDIGO 3 Only 9% in the delayed RRT group did not receive RRT Early RRT Delayed RRT Time to RRT (h)

30 JAMA 2016 Early RRT: KDIGO 2 Delayed RRT: KDIGO 3 The high rate of progression from stage 2 to stage 3 AKI contrasts with observational data (less than 50% of critically ill patients with the equivalent of stage 2 AKI progress to stage 3 AKI) Hoste EA et al Crit Care 2006 Liu and Pavlesky CJASN 2016

31 JAMA 2016 ns ns p 0.03

32 ELAIN Fragility index 3 Fragility index Number of nonevents in the treatment group with the lowest event rate that must be changed to events in order for the p value calculated by the Fisher exact test to equal or exceed 0.05.

33 JAMA 2016 Early Delayed p Duration of RRT (d) Hospital stay (d) <.001

34 It is difficult to reconcile how such a relatively small difference in the timing of initiation of RRT (< 24 hours) resulted in not only 34 % reduction in the hazard for death but also reductions in median duration of RRT of > 2 weeks and median duration of hospital stay of > 4 weeks

35 The results from single-center trials must be viewed with caution Center-specific effects (particular systems of care and background therapies used) may preclude the generalizability of the findings Results from single-center studies should rarely serve as the basis for changing guidelines unless the results have been validated in subsequent multicenter trials.

36 Similarity between ELAIN and HEROICS Surgery (cardiac surgery) Early group : very early Baseline creatinine: 98 µmol/l (ELAIN) 150 µmol/l (HEROICS) But HEROICS is a multicenter trial

37 Delayed Strategy = Standard Care Severe hyperkalemia Urine output < 0.3 ml/kg/h 24h Urea > 36 mmol/l Creatinine > 352 µmol/l (or > X 3 baseline)

38 43% in the Standard Care group did not receive RRT

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40 RCTs on the timing of RRT Bouman et al Jamale et al Zarbock et al (ELAIN) Wald et al (Pilot STARRT-AKI) Combes et al (HEROICS) Gaudry et al (AKIKI)

41 Delayed strategy = Standard RRT initiation Hyperkalemia (>6 mmol/l) Severe metabolic acidosis Pulmonary edema (PaO2/FiO2 <200) Kidney international 2015

42 Kidney international % in the Standard RRT initiation group did not receive RRT

43 Kidney international 2015 Accelerated RRT Standard RRT Death by day (38) 19 (37) 0.92 p

44 We need Large RCTs!

45 Large RCTs RCT n patients Status AKIKI 620 Published IDEAL-ICU 864 Recruitment terminated STARRT-AKI 2800 Recruiting

46 July 2016

47 Wednesday November 2, 2016

48 5528 Had AKI and received vasoactive agent and/or invasive MV 3430 Had AKI stage 3 of KDIGO classification 620 Underwent randomization Early RRT Strategy n=312 Delayed RRT Strategy n=308 1 patient refused the use of data 619 Were included in the analysis

49 Delayed Strategy Group Pre-specified criteria Severe hyperkalemia Severe acidosis (ph <7.15) Acute pulmonary edema due to fluid overload Responsible for severe hypoxemia Oliguria/Anuria >72 hours Serum urea concentration > 40mmol/l

50 Proportion of patients free of RRT B Patients free of RRT Early RRT strategy Delayed RRT strategy p value: < Days

51 Proportion of survivors 1 A Survival Early RRT strategy Delayed RRT strategy p value: Days

52 Proportion of patients free of RRT Proportion of survivors A Survival Early RRT strategy Delayed RRT strategy p value: Days B To detect an effect size of 1.2 % (i.e., the difference in mortality that we found between the two groups) Early RRT strategy Delayed RRT strategy with a power of 90%: p value: <0.001 > 70,000 patients would be required Days

53 Secondary outcomes Outcomes Early RRT strategy (N=311) Delayed RRT strategy (N=308) P value RRT-free days median (IQR) day (2-26) 19 (5-29) <0.001 Catheter-related bloodstream infection no. (%) 31 (10) 16 (5) 0.03

54 Probability of adequate diuresis with no need for renal replacement therapy Secondary outcomes Outcomes Early RRT strategy (N=311) Delayed RRT strategy (N=308) P value RRT-free days median (IQR) day (2-26) 19 (5-29) <0.001 Catheter-related bloodstream infection no. (%) 31 (10) 16 (5) Adequate urine output with no need for RRT Delayed strategy more rapid renal function recovery 0.2 Early RRT strategy Delayed RRT strategy p value: < Days

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56 Take home message We need to compare strategies with large RCTs November 2016: A conservative strategy might be considered as the standard Benefits of the conservative strategy Obviated the need for RRT in almost 50% of cases Mortality did not differ significantly Renal function recovery was more rapid Perspective: IDEAL-ICU/ STARRT-AKI (accumulation of evidence base data from Large RCTs)

57 Thank you

58 Wait and see approach: safe but careful surveillance is mandatory Is it more dangerous to draw several blood samples for potassium and ABGs determination or to indwell a dialysis catheter and initiate an unnecessary RRT in unstable patients?

59 Patients n Early group Bouman 106 UO < 30ml/h + Cr cl < 20 ml/min Jamale 208 Urea > 25 mmol/l Creat > 616 µmol/l Delayed group Urea> 40 mmol/l K > 6.5 mmol/l Severe pulmonary edema Clinically indicated as judged by physician ELAIN 231 KDIGO 2 KDIGO 3 Pilot STARRT-AKI 100 ~ KDIGO 2 +/- NGAL 400 ng/ml HEROICS 224 Severe post-cardiac surgery shock K > 6 mmol/l Severe acidosis Severe pulmonary edema Severe hyperkalemia UO < 0.3 ml/kg/h 24h Urea > 36 mmol/l Creatinine > 352 µmol/l (or > X 3 baseline) AKIKI 620 KDIGO 3 Severe hyperkalemia Severe acidosis Severe pulmonary edema Oliguria/Anuria >72 hours

60 Judged by physician KDIGO 3 Criteria to start RRT in the delayed groups Bouman Jamale ELAIN Pilot STARRT HEROICS AKIKI Severe Hyperkalemia Severe acidosis Severe pulmonary edema Urea or Creatinine concentration Oligoanuria (duration)