Following detailed review of the existing literature and in-depth discussions, the working groups identified and developed the following proposals:
A. Group 1: Diagnosis and evaluation of AKI
The reported incidence of AKI is highly variable . This heterogeneity might be explained by the definitions used (RIFLE, AKIN or KDIGO criteria), differences in patient populations, case-mix, and clinical setting as well as differences in managing missing data. Furthermore, the current consensus definition of AKI includes the notion of a continuum of disease but there is clear evidence of different sub-categories of AKI, for instance, rapid reversal AKI (duration < 48 h), persistent AKI (duration between 2 and 7 days) and acute kidney disease (up to 90 days). To the best of our knowledge, there are only limited data evaluating the epidemiology and outcomes of patients with AKI of different durations (using current criteria, including AKI stages) .
Proposal for systematic review
Aim: to summarize the existing data related to the epidemiology of AKI with stratification by different patient populations and diagnostic criteria in order to increase granularity
Endpoints: Primary endpoint: overall AKI prevalence; Secondary endpoints: AKI prevalence stratified by diagnostic criteria, population type and management of missing data.
Statistical Analysis: meta-regression and multivariable meta-regression
Criteria for study selection: (a) Publication date after 2012; (b) Publication language: English; (c) Study design: multicentre or > 100 patients recruited from the same center; and (d) Published as a full paper (no abstract)
Search Strategy: Search in Pubmed and Embase using the following MESH criteria: “Acute kidney injury” or “AKI”
Proposal for Prevalence Study
Aim: to explore the epidemiology and outcome of critically ill patients according to AKI duration.
Methods: Observational retrospective multicentre prevalence study including 10 to 20 centres.
Eligibility criteria: Inclusion criteria: all patients admitted to a participating ICU during the study period (1 month); Exclusion criteria: end-stage renal disease treated with chronic dialysis or renal transplant
Definitions: AKI will be defined by the KDIGO criteria (> 26.5 μmol/l or 1.5× baseline rise in serum creatinine and/or urine output < 0.5 ml/kg/hr for 6 h) ; AKI will be stratified according to the duration of the alteration [persistence of AKI criteria or need for renal replacement therapy (RRT)].
Endpoints: Primary endpoint: prevalence of AKI according to duration category; Secondary endpoints: specific mortality for each AKI duration category and renal recovery at 90 days (absence of AKI criteria and need for RRT)
B. Group 2: Medical management of AKI
To date, the management of AKI patients focuses on correction of the underlying cause, avoidance of further renal insults, strategies to prevent progression to a more severe stage of AKI and if possible, facilitation of renal recovery. A key component of this approach is haemodynamic optimization . However, there is uncertainty about the exact haemodynamic targets.
The current Kidney Disease Improving Global Outcomes (KDIGO) guideline and the ESICM recommendations for “Prevention of acute kidney injury and protection of renal function in the intensive care unit” advise to consider haemodynamic monitoring early and to aim for a mean arterial pressure (MAP) greater than 65 mmHg to prevent AKI [8, 10]. Concern has been raised that this target may be too low for individual patient groups. In patients with septic shock, for instance, a retrospective study concluded that a higher target MAP was associated with better kidney function . Similarly, a sub-group analysis of a randomized controlled trial (RCT) comparing different MAP targets suggested that the rate of RRT in patients with pre-existing hypertension was significantly lower if randomized to the higher blood pressure group . Among patients with vasopressor-dependent shock post-cardiac surgery, those with progression of AKI had a greater difference (deficit) in hemodynamic pressure-related parameters between baseline and within-ICU stay compared to those without AKI progression . Finally, there are also data suggesting that a higher MAP in critically ill patients with early AKI is associated with a reduced risk of progression to more severe AKI . It is our hypothesis that a higher target MAP in critically ill patients with pre-existing hypertension is associated with better renal outcomes.
Proposal for systematic review and meta-analysis
Objective: To explore whether a higher target MAP in patients at risk of AKI admitted to ICU with known hypertension is associated with improved outcomes
Search criteria: a) RCTs only, including indirect data from RCTs; b) published after 2004; c) published in all languages
Search engines: bibliographic databases (MEDLINE, Embase, Cochrane Library, CINAHL and Web of Science) from January 2004 to January 2018
Patient population: adult patients (≥18 years) in Critical Care or ICU
Definitions: a) AKI as defined by RIFLE, AKIN or KDIGO criteria; b) Hypertension as defined by criteria used in the individual studies.
Proposal for randomized controlled trial
Objective: To investigate whether a higher MAP in critically ill patients with known hypertension is renoprotective.
Patient population: subgroup of critically ill adult patients (i.e. septic shock, post cardiac surgery or trauma; to be determined at later stage)
Eligibility criteria: Inclusion criteria: (a) admitted to a critical care unit; (b) known hypertension (i.e. hypertension treated with at least 1 antihypertensive), and c) expected to stay in ICU for at least 48 h; Exclusion criteria: a) in ICU for > 36 h; b) MAP > 70 mmHg at screening and enrolment without vasopressor support; (c) chronic kidney disease stage 4 or 5; (d) chronically dialysis dependent ESRD; (e) treatment with RRT at time of enrolment; (f) need for ECMO at time of enrolment; (g) any contraindication to higher or lower MAP target
Group allocation and interventions: Standard care: target MAP 65–75 mmHg for at least 48 h after randomization. Intervention group: target MAP 80–90 mmHg for at least 48 h after randomization.
Interventions to achieve MAP target: Traditional strategies, including fluids, vasopressors and/or inotropes as per judgement of clinical team. However, starches should not be used for fluid therapy.
Concomitant treatments: All other aspects of care will be according to local practice and discretion of the treating clinical team. The decision to initiate RRT will be made by the clinical team based on traditional clinical parameters.
Outcomes: Depending on whether patients already have AKI or no AKI at time of randomization:
In patients without AKI at randomization:
Primary outcome: prevention of AKI in 7 days; Secondary outcomes: (a) mortality; (b) creatinine at 28 days; (c) Major adverse kidney event (MAKE) at 28 days; (d) hospital length of stay; (e) if AKI develops: duration and severity of AKI, including treatment with RRT; f) adverse events; (g) max dose and duration of catecholamine treatment
In patients with AKI at enrolment and no immediate need for RRT at randomization
Primary outcome: MAKE at 28 days; Secondary outcomes: (a) mortality; (b) creatinine at 28 days; (c) hospital length of stay; (d) duration and severity of AKI; (e) treatment with RRT; (f) adverse events; (g) max dose and duration of catecholamine treatment
Potential challenges: The main limitation is the fact that the intervention strategies to raise MAP and all other concomitant therapies are not standardized. As such, the outcomes may be influenced by factors other than target MAP, for instance choice and volume of fluids, use of nephrotoxic drugs and decision to initiate RRT.
C. Group 3: Renal replacement therapy for AKI
The optimal modality of continuous renal replacement therapy (CRRT) for AKI is unknown and clinical practice is highly variable [15, 16]. To date, precise and exhaustive information about how CRRT is administered worldwide in 2020 is lacking. There is no clear evidence that specific modalities of CRRT are superior to others, and detailed analyses of the effects of CRRT modality on solute clearance are limited [17,18,19,20]. It is assumed that continuous venovenous haemofiltration (CVVH) leads to better clearance of larger molecules compared to continuous venovenous haemodialysis (CVVHD) due to solutes being dragged by the solvent. However, this has not been confirmed [21, 22]. In addition, clearance of larger molecules in CVVH may be impacted with time by clogging related to hemoconcentration inside the filter (depending on the filtration fraction). Lastly, there are no recent data about the clinical effects of convection versus diffusion in CRRT.
Proposal for systematic review and meta-analysis
Aim: To systematically search and compile the available data focusing on the comparison of CVVH versus CVVHD
Endpoints: Primary endpoint: Solute clearance of various molecules, cytokines and antibiotics; Secondary endpoints: clinical endpoints
Study Selection: (a) studies comparing CRRT with diffusion (CVVHD) versus CRRT with convection (CVVH); (b) published as full papers; (c) published in English
Proposal for observational study
Aim: to capture data related to the current clinical practice of CRRT
Design: International survey sent to institutions worldwide (using ESICM research network). Methodology: Questions will be primarily focused on CRRT modality to explore the use of CVVH, CVVHD and CVVHDF. Additional questions will intend to describe how these 3 modalities are administered in daily clinical practice (dose, anticoagulation, timing, type of hemofilter, average filter duration, compulsory change of set every 24 h (yes/no), number of treatment days per year or number of treated patients/year).
Proposal for interventional study
Hypothesis: Solute clearance is similar between CVVH and CVVHD, including for middle molecular weight solutes
Aim: To compare clearances of different solutes with various molecular weights between CVVH and CVVHD over 72 h
Inclusion criteria: Critically ill patients undergoing CRRT
Design: Patients will be randomized in two groups, CVVH or CVVHD. CRRT dose and anticoagulation (citrate) will be the same in both groups, based on current KDIGO recommendations . Membranes will be polysulfone-based (e.g. HF1400, AV1000S) with a standard cut-off of 30,000 Da. Solute clearances will be calculated at the following time-points: 1 h, 6 h, 12 h, 24 h, 48 h, 72 h. Cross-over will not be allowed.
Outcomes: Primary outcome: clearance of one large molecular solute (e.g. beta 2 microglobulin); Secondary outcomes: a) time weighted average solute clearances including urea, creatinine, Interleukin-6, tumor necrosis factor (TNF), kappa Free Light Chain (25,000 Da), lambda Free Light Chain (50,000 Da), albumin; b) Metabolic endpoints: acid-base status and electrolyte disturbances; c) Hemodynamic impact endpoint: vasopressor treatment; d) filter life; e) survival at 30 day and hospital discharge; f) CRRT free days; g) Renal recovery: dialysis dependence at hospital discharge; h) filter survival time
Number of patients per group: 60 patients
Additional remarks: the study will only be conducted in centres where both modalities (CVVH and CVVHD) can be delivered in order to minimize potential confounders.