Acute kidney injury | SpringerLink

Biomarker-based characterisation

The discovery of kidney damage biomarkers (e.g. NGAL, KIM-1, IL-18, TIMP-2, IGFBP7 and CCL14) and alternative functional markers (e.g. Cystatin C and Proenkephalin) has provided insight into the potential aetiology, pathophysiology and prognosis of AKI [8]. For instance, evidence from about 4,000 patients revealed that 15–20% had elevated NGAL levels without a SCr rise. This was associated with a two-to-threefold increased risk of death or need for renal replacement therapy (RRT) compared to patients without a SCr or NGAL rise [9].

AKI subphenotypes

Subphenotyping identifies subgroups of patients with different biological mechanisms, treatment responses or prognosis [10]. Using latent class analysis of clinical and biomarker data from the first 48 h in intensive care unit (ICU), Bhatraju et al. analysed 1800 patients of whom 794 had AKI [11]. They identified two independent populations: Subphenotype 1 was characterised by a low ratio of angiopoietin (Ang) 2/Ang1 and soluble tumour necrosis factor receptor (sTNFR) 1 and signified a hypo-inflammatory state. Mortality was lower compared to subphenotype 2 which had high Ang2/Ang1 ratios and higher sTNFR-1 and represented a hyper-inflammatory state with increased vascular permeability. These findings were replicated in 800 patients enrolled in a different sepsis trial showing that mortality and dialysis need were higher in patients with subphenotype 2. Similarly, a post hoc analysis of the Finnish Acute Kidney Injury (FiNNAKI) study of patients with sepsis-associated AKI identified two subphenotypes with subphenotype 2 having elevated levels of inflammatory and endothelial markers, lower short-term recovery and a higher 90-day mortality [12]. The identification of these different subphenotypes underpins the change in our perception of AKI as a ‘single disease’ to AKI being a complex syndrome (Supplementary Fig. 1).

AKI across the lifespan

Neonatal and paediatric AKI have emerged as important paradigms of critical care nephrology. Multi-centre studies including the AWARE and AWAKEN study have revealed unique, discernible AKI phenotypes in children different from adults [13,14,15] (Fig. 1). Even though AKI demonstrates a synergism with adult comorbidities on patient outcome, AKI in children with both unique co-morbid conditions (e.g. inborn errors of metabolism) and in those without any medical history demonstrates the independent contribution of AKI with host outcome. Further, the effects of premature birth on kidney maturation and the impact of a single AKI episode during kidney development on short- and long-term outcomes remain incompletely understood. Finally, the influence of sex, nutrition and biological development (growth) throughout childhood and puberty on the risk and prognosis of AKI has yet to be fully characterised [14]. The kindle of injury which may start in the neonatal period of life can build on itself and manifest in a patient throughout life, being full ablaze in adulthood with higher risks of AKI related morbidities (e.g. CKD and cardiovascular events).

Prognosis

It is now widely accepted that AKI survivors remain at risk of serious long-term renal and non-renal complications and warrant follow-up. As the data in children underscore, even following a single episode, AKI is a longitudinal, life continuum disease process. “Return of SCr to baseline” after an episode of AKI can no longer be viewed as “full renal recovery”. “Acute kidney disease” has evolved as a construct, emphasising the need for follow-up [4].