Evaluating Novel Biomarkers in Acute Kidney Injury

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).