Fig. 2. Subclinical acute kidney injury (AKI). Three scenarios are depicted, which may highlight the clinical use of AKI biomarkers over and above the prediction of AKI stage. Subject A has normal renal function with a significant renal reserve. Despite a fall in glomerular filtration rate (GFR) by about 40%, the rise in serum creatinine (SCr) does not reach the diagnostic threshold for AKI, but the subject has a positive biomarker in keeping with significant tubular damage and subclinical AKI. In case B, there is a much smaller fall in GFR (and significantly reduced renal reserve) and following insult a small fall in GFR translates to AKI stage 1. Under certain circumstances, the biomarker may be negative such as following administration of drugs that interfere with creatinine tubular secretion. Case C highlights a scenario where the urine output criteria for AKI are satisfied, but the biomarker is not elevated. This may represent physiological oliguria following major surgery, for example.
Can Biomarkers Be Used to Guide Therapy?
Ultimately the desired aim of integrating AKI biomarkers into clinical practice is to improve clinical outcomes with one of the driving forces being early recognition and hence, timely intervention. However, a potential application of AKI biomarkers may be the enrichment of patient selection in clinical trials. Such integration may reduce misclassification of AKI and allow more accurate diagnosis improving statistical power in tandem with reducing sample size. Application of prognostic biomarkers may enhance the enrollment of patients likely to successfully meet trial end points enabling the use of specific therapies particularly as they may help identify a cohort at higher risk of developing AKI, for example. This is of particular value. Of late, such trial enrichment has indeed been employed with success. The PrevAKI trial examined the implementation of a care bundle in cardiac surgery patients deemed at high risk for AKI. Of 1,046 patients identified, 882 were screened of which 111 were unsuitable. This left a cohort of 771 patients, 276 of whom were randomized following risk stratification with a biomarker (TIMP-2/IGFBP-7) [51]. The high-risk group were defined by TIMP-2.IGFBP-7 >0.3 with a primary endpoint defined as the rate of AKI as defined by KDIGO criteria within 72 h of surgery. AKI was significantly reduced with the intervention compared to controls (55.1 vs. 71.7%; [95% CI 5.5–27.9]; p = 0.004). The implementation of the bundle resulted in significantly improved hemodynamic parameters at different time points (p < 0.05), less hyperglycemia (p < 0.001) and use of ACEi/ARBs (p < 0.001) compared to similar parameters in controls. Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls, although in over 80% of cases AKI was defined by changes in urine output alone rather than SCr criteria or both, which accounted for about 5%. However, no effects were seen on 30-day outcomes including mortality. Certainly if this biomarker approach were not employed in this study, then a far greater sample size would have been needed to achieve the desired statistical power and this may have made the approach untenable.
Even more recently, a similar study in major non-cardiac surgery again demonstrated that biomarker-triggered KDIGO care bundle implementation translated into improved outcomes. Subgroup analysis demonstrated a significantly reduced incidence of AKI after major abdominal surgery together with reduced length of stay [52]. Although these are small single-centre studies, they may hold great promise in terms of risk stratification and directing therapy to those individuals at risk of AKI but, importantly those who exhibit a degree of renal stress. It may be that the benefits are not seen immediately but may be reflected in the long-term reduction in CKD and the inherent risks associated with the development of chronic kidney disease.
Conclusions
There has been a considerable increase in the literature examining AKI biomarkers in many situations. Understandably this has led to confusion and perhaps unrealistic expectations as to what can be achieved. What is becoming clear is that the presence of a positive biomarker cannot be regarded as an innocent bystander in that increased risk is associated with this phenomenon, although this will not be applicable to all candidates. The adoption of appropriate AKI biomarkers may well herald an improvement in the outcomes of patients with, or indeed at risk of, AKI, which hopefully will translate into both short- and long-term benefits.
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