Evaluating Novel Biomarkers in Acute Kidney Injury
Condition: Acute Kidney Injury
MeSH terms: Acute Kidney Injury; Wounds and Injuries
Study type: Interventional

Summary: 
      The investigators have a new technique of looking at urine to see whether it contains protein
      fragments that are released by damaged kidneys. These fragments seem to be more accurate than
      the current blood tests that the investigators use to diagnose renal failure. This technique
      needs to be validated with a group of patients that have a relatively high incidence of renal
      failure, cardiopulmonary bypass.

      The investigators hypothesise that using novel markers of renal dysfunction will identify
      patients who go on to develop renal failure earlier, and in a higher number than the standard
      blood tests.

      The investigators aim to collect urine from patients before going onto bypass, and then at
      Day 1 and Day 2 after bypass. This urine will be analysed for protein fragments, as well as
      other new markers of renal dysfunction. The investigators will also take blood at baseline
      and for the first two days in Cardiac Intensive Care, and compare the accuracy of the new
      tests with the 'gold standard' that is creatinine.
    

Detailed description: 
      The diagnosis of acute renal failure has been problematic, with a review showing 35 working
      definitions being used in the literature. This lack of clarity gave rise to the ADQI group
      creating the terminology of acute kidney injury (AKI). AKI has been used to give foundation
      to both the RIFLE and AKIN criteria, which have been shown to perform well in predicting
      critical care and hospital mortality. Their criteria are based on measuring increases of
      serum creatinine from baseline levels, and tallying this with weight-based urinary volumes.
      Problems with these techniques lie in having accurate baseline creatinine values, with the
      MDRD formula often proving inaccurate. Criticisms have also been levelled at using serum
      creatinine at all, given its variance with different body-mass compositions and fluid-balance
      status, as well as its relatively late rise in AKI compared to its utility in chronic renal
      failure.

      Many novel biomarkers have been investigated in AKI, either serum or urine (cystatin-C,
      Il-18, KIM-1, NGAL). Results have been varied, with potential problems being lack of
      specificity to AKI, cost and the heterogeneous nature of patient populations in the various
      studies. NGAL has emerged as potentially the most specific to early AKI and additionally a
      number of commercially available assays are now available. Interest has been shown in the use
      of biomarker panels, allowing for improved sensitivity, albeit at a higher cost. Urinary
      proteomic analysis has been used as an investigative technique for AKI for the last ten
      years, but diverse populations and lack of blinding hampered early studies. A recent paper
      used techniques developed by collaborators on this proposal to improve the performance of
      proteomic assays, with impressive performance of these assays when looking at critically ill
      patients with AKI.

      A problem with assessing the utility of diagnostic or screening tools for AKI in the
      critically ill is the heterogeneity of pathological insults, and the unpredictable early
      clinical course. This leads to difficulties in identifying control groups, and in capturing
      the evolution of AKI. We propose investigating the use of these novel biomarkers and
      proteomic techniques in the more homogenous group of patients undergoing cardiopulmonary
      bypass. This carries with it the benefits of thorough pre-operative testing with stable
      baseline measurements and a clearly definable renal insult in the form of bypass time.
      Post-bypass renal failure requiring RRT is estimated to occur in 1.5-2% of coronary artery
      grafting cases, and around 5% of combined graft/valve replacement cases; however, there is a
      far higher incidence of AKI as measured by creatinine rise and/or oliguria.

      As part of standard operative technique patient's bladders are catheterised prior to the
      start of surgery and the first 100mls urine voided will be collected as the baseline sample.
      Venous blood will be taken at cannulation with serum spun and frozen for later analysis of
      NGAL (and any emergent biomarkers of AKI of interest). Finger prick blood sampling will be
      performed for baseline point of care analysis of NGAL/brain natriuretic peptide using the
      Alere platform.

      Details of intra-operative conduct will be gathered from the computerised anaesthetic record
      and the cardiac perfusionist records including anaesthetic technique (volatile/TIVA),
      duration of bypass and perfusion pressures on bypass.

      When in the Cardiac Intensive Care Unit (CICU) further 100mls urine will be collected at
      24hrs after induction of anaesthesia, and at 48 hours. This will be a 'clean' sample (ie not
      from urine lying overnight). Accompanying laboratory values of serum creatinine will be
      collected for diagnosis of AKI and comparison to proteomic values. At the same point blood
      will be taken and stored for NGAL as well as finger prick measures using point of care
      NGAL/BNP.

      Copies of the corresponding electronic ICU physiological records will be collated for data
      relating to cardiovascular parameters, diagnosis of AKI and use of vasopressors. APACHE-II
      scores will be calculated at 24 hours post admission in addition to daily SOFA scores. AKI
      will be defined as AKIN stage I (increase of serum creatinine >50% of baseline measurement,
      and/or urinary output <0.5ml/kg/hour for six hours) or RRT up to 48 hours post-surgery.
      Patient outcomes will be recorded in respect to CICU mortality, 90-day mortality, need for
      ongoing RRT, development of chronic kidney disease (moving from eGFR >60ml/min/1.73m2
      pre-admission to eGFR <60ml/min/1.73m2 at hospital discharge).
    

Intervention name(s): Proteomic assay; Blood sampling; Biomarker sampling
Intervention type(s): Other; Other; Other
Intervention description(s): Urine will be taken for proteomic assay at baseline, day 1 and day 2; Point of care testing of blood for NGAL/BNP at baseline, day 1 and day 2; Urine will be taken at baseline and day 1, day 2 for evaluation of renal biomarkers at later date
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: Diagnosis; Acute Kidney Injury