Journal Club: Initiation Strategies for Renal Replacement Therapy (RRT) in the ICU Toby Chanin

Background Acute Kidney Injury/failure is a common condition in Critical care RRT has different modes and methods Standard indications for RRT: Symptomatic uraemia Resistant fluid overload Electrolyte abnormalities Acid/base disturbance unresponsive to medical Mx Drug filtering

Complications of RRT As with any intervention downsides: Hypotension/haemodynamic instability Clotting - increases blood loss Bleeding risk Hypothermia Access issues Therefore having clear indications for initiation is key to avoid harms.

Paper NEJM 07/2016 - impact factor - 59.558 (2015) Aim to examine outcomes for patients with AKI #3 who receive early vs delayed RRT Definition used of AKI #3 is that of Kidney Disease: Improving Global Outcomes classification (KDIGO) [Cr]p x3 of baseline or>354µmol/L Or UO <0.3ml/kg over 24 hr Or anuria for 12 hours

Hypothesis Delayed RRT in patients with AKI#3 will have a 15% lower mortality when compared with early RRT This was based on their evaluation of current data Expected mortality to be approximately 55%

Study design AKIKI - artificial kidney initiation in kidney injury trial Unblinded, prospective, multi-centre, open- label, two-group, randomised trial Across 31 ICUs in France from 09/13-01/16 Written consent not required

Inclusion criteria Age>18 yrs Had Dx of AKI 2o to ATN of ischaemic or toxic injury Received Mechanical ventilation and/or Catecholamine infusion Meet KDIGO criteria for AKI #3 Once identified they were randomised within 5 hours.

Exclusion Criteria Excluded if any of the following were present at enrollment: BUN> 40mmol/L K+ >6 or >5.5 after medical mx pH <7.15 Acute pulmonary oedema requiring O2 >5L/min to keep SpO2>95% or FiO2>50%

Intervention Early initiation of RRT Had to be started ASAP after randomisation Needed to be within 6 hours of identification of AKI #3 Decision regarding mode, timing and method of RRT not controlled between sites.

Comparator Delayed initiation group were patients with AKI#3 who went on to develop: Any of the previous exclusion criteria BUN> 40mmol/L K+ >6 or >5.5 after medical mx pH <7.15 Acute pulmonary oedema requiring O2 >5L/min to keep SpO2>95% or FiO2>50% Or remained oligouric/anuric for 72 hours.

Outcome Patients followed up for 60 days after randomisation Primary outcome was survival at 60 days. Secondary measures Need for RRT in the delayed group Number of RRT-free days Number of dialysis cath free days Number of MV-free days Number of Vasopressor-free days SOFA score at day 3 and 7 LOS in ITU and Hospital Rate of nosocomial infection

Statistical Power Study was powered to detect a 15% difference in mortality between the groups Required 560 patients

Results 5528 eligible patients - 620 were randomised 80% of patients were septic 63% had been exposed to nephrotoxic agents

Primary Outcome 614 patients’ had data available at 60 days 303 had died - Overall mortality was 49.1% No significant difference between groups 150 in early group 153 in delayed

Post-hoc analysis Further analysis of primary outcome Broke down delayed group into those who needed RRT and those who did not Revealed: Never receiving RRT mortality of 37.1% Early RRT mortality of 48.5% Delayed with RRT mortality of 61.8% (p<0.001)

Secondary Outcomes No of delayed group needing RRT - 157 (51%) Vs. 98% of early group (p<0.001) Number of RRT free days Delayed 19 vs early 17 (p<0.001) No significant difference in requirement for respiratory or cardiovascular support No significant difference in LOS Significant difference in vasc. catheter related infections 30 (10%) in early vs 16 (5%) in delayed (p<0.03)

Discussion Main aim of the study was really to try to use AKI #3 as early predictor as an advancement on traditional indications No significant difference between the intervention groups in mortality Perhaps instead using earlier targets on the traditional indicators may yield different results?

Discussion Delayed group had significantly fewer RRT sessions. Has benefits of cost and time saving as well as obviating the complications risks. Study not powered to breakdown delayed group - significant subgroup Also how can you Identify which members of the 2nd group need earlier RRT? Perhaps there is a way to identify trends of creatinine rise and identify earlier people who will need RRT

Limitations Investigators identify several: Underpowered to identify a small mortality difference Not using Kt/V to control RRT dosing Only applicable to critically ill patients with AKI #3

Limitations Quite narrow inclusions and exclusion criteria Unable to control for method of RRT used Investigators recognised this and went on to state that 50% of pts received intermittent HD and only 30% had continuous HF alone This may account for a higher mortality as HD is more haemodynamically destabilising vs HF

Interpretation Investigators are cautious to ensure that the readers do not conclude, from this paper, that a ‘wait and see’ approach is safe. My own interpretation would be that perhaps there is a potential to identify patients who may recover alone and those who we might be able to predict if they were worsening.

Conclusions KDIGO AKI #3 is not a reliable single- predictor for the need to start RRT. RRT therapy is not an intervention that should be started lightly given the high mortality attached to it.

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