Perioperative acute kidney injury (AKI): diagnostic criteria, risk factors and the challenge of early recognition

Acute kidney injury (AKI) is a frequent and serious perioperative complication. No interventions to prevent or reverse AKI have yet proven effective. Suggested factors contributing to this lack of success include an uncertain and variable definition of AKI as well as a typically delayed recognition of renal injury. Recent focus has shifted to identifying potentially modifiable risk factors for AKI that may allow a reduction in AKI burden through targeted implementation of pre-emptive strategies. This thesis presents 9 manuscripts (8 published and 1 that has been submitted for peer-review) addressing these aspects of perioperative AKI.

Published diagnostic consensus criteria for AKI include both creatinine-based and oliguria-based criteria. While prognostic utility of creatinine-based criteria for clinically important adverse outcomes are well established the impact of oliguric-criteria are less well studied. In a cohort of 311 patients undergoing cardiac surgery (Chapter 2) the incorporation of oliguric AKI criteria together with creatinine-based criteria resulted in a 3-fold increase in observed incidence of AKI compared to creatinine alone. Importantly, AKI defined by oliguric criteria was not associated with adverse clinical outcomes, thus questioning its validity in this context.

Modifiable risk factors for AKI may provide an opportunity for targeted interventions prior to the development of AKI. The following 3 studies (Chapters 3-5) explore the association between the time interval from contrast angiography to cardiac surgery and postoperative AKI, the decline in serum haemoglobin after cardiac catheterisation and any association between this acute decline and postoperative AKI; and finally, the association between endothelial dysfunction and AKI after non-cardiac surgery. In each case no association was identified between the potentially modifiable risk factor and the outcome of postoperative AKI. An invited editorial (Chapter 6) then articulates the challenges of reducing the burden of AKI through risk factor modification.

The following four manuscripts (Chapters 7-10) first identify the need for novel diagnostic tools for AKI and then systematically evaluate several candidate biomarkers for this role. Post-hoc analyses initially suggested that urinary neutrophil gelatinase-associated lipocalin (NGAL) may be best suited to identification of AKI in patients with preserved renal function, potentially explaining previously identified variability in diagnostic performance. However, a follow-up prospective study in 603 patients failed to confirm this hypothesis. Importantly, urinary NGAL did provide prognostic utility for clinically important adverse outcomes that may reflect renal injury after cardiac surgery (death or dialysis) and this prognostic utility was greatly enhanced when NGAL combined with an early assessment of delta serum creatinine (ΔSCr). Multiple biological pathways that may all lead to AKI have led to a belief that a panel of biomarkers will likely be required for optimal early detection of evolving injury. In the final study presented we evaluate 4 additional candidate novel biomarker of AKI, both alone and in combination. Evaluated in isolation, none of the novel biomarkers provided better prognostic utility than seen with ΔSCr at the conclusion of surgery. However, combining the four novel biomarkers together with urinary NGAL and ΔSCr into a simple 6-point additive score from around the time of ICU admission provided good discrimination for the primary outcome while also improving risk classification when added to established measures of risk.

The body of work represented by this thesis addresses several identified knowledge gaps in the field of perioperative AKI. While our concluding remarks (Chapter 11) highlight the specific contribution of this work to further our understanding of perioperative AKI it also articulates a broad research agenda and strategy that we hope to pursue, in collaboration with others, over the next decade to meaningfully reduce the burden of this common perioperative complication.