Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference

Abstract

Over the last decade there has been considerable progress in the discovery and development of biomarkers of kidney disease, and several have now been evaluated in different clinical settings. Although there is a growing literature on the performance of various biomarkers in clinical studies, there is limited information on how these biomarkers would be utilized by clinicians to manage patients with acute kidney injury (AKI). Recognizing this gap in knowledge, we convened the 10th Acute Dialysis Quality Initiative meeting to review the literature on biomarkers in AKI and their application in clinical practice. We asked an international group of experts to assess four broad areas for biomarker utilization for AKI: risk assessment, diagnosis, and staging; differential diagnosis; prognosis and management; and novel physiological techniques including imaging. This article provides a summary of the key findings and recommendations of the group, to equip clinicians to effectively use biomarkers in AKI.

Fig 1. Clinical need for biomarkers to improve management of acute kidney injury

Several components typically need to be considered for each decision that guides biomarker utilization. These key issues are pertinent for the efficient adoption of biomarkers in clinical practice.

Fig 2. Potential mechanisms and specificity of urinary biomarkers of kidney damage

Panel A: Biomarkers may appear in the urine through several mechanisms including filtration across the glomerular basement membrane (e.g. proteinuria, micro albuminuria); increased (or decreased) passive release (e.g. alpha and pi GST); active induction (or repression) followed by release and/or secretion (e.g. NGAL, KIM-1) and decreased (or increased) resorption/catabolism (e.g. cystatin C, Beta 2 macroglobulin). (modified from ref ) Panel B: Damage biomarkers are also site specific and the magnitude and duration of biomarker change can potentially identify the extent of damage (modified from Ref ).

Fig 3. Potential utilization of Biomarkers for AKI

I (reprinted with permission from ref ) Several biomarkers are now available for assessing changes in kidney function and detecting kidney damage. They can be utilized for initial diagnosis and staging, differential diagnosis and prognosis.

Figure 4. Proposed framework for evaluating AKI based on Biomarkers

A combination of kidney functional and damage markers simultaneously provides a simple method to stratify patients with AKI. At initial presentation, patients would be evaluated in terms of these two domains, and then could be assessed over time to monitor their transitions across the domains.

Figure 5. Modified conceptual model of acute kidney injury

The availability of specific biomarkers permits recognition of kidney damage separately from changes in kidney function. Kidney damage and changes in function may precede each other or occur concurrently. The time sequence of events depends on the nature and duration of the insult and the underlying state of health of the kidney. Consequently, we propose a modified conceptual framework to include evidence of isolated kidney damage as a potential criterion for diagnosis of AKI. The timing of diagnosis will depend on the frequency with which specific biomarkers of kidney damage and function are assessed.

Figure 6. Proposed new criteria for AKI Diagnosis and Staging using Biomarkers

New criteria for AKI diagnosis are displayed. In order to diagnose AKI selecting the worst criterion (function [RIFLE/AKIN] or damage) is recommended. In the appropriate clinical setting, this new damage biomarker criterion will enhance the ability of RIFLE/AKIN to define AKI. There are currently insufficient injury biomarker data to support staging of AKI, however, AKI stages basing on renal function changes are suggested to remain. The semi-quantitative trend for increasing biomarker severity associated with increasing kidney damage is suggested by the literature and is displayed by darkening background color as well as the symbols: +/++/+++. *Adapted from RIFLE/AKIN criteria. AKIN= acute kidney injury Network; sCrea=serum creatinine; UO=urine output; RRT=renal replacement therapy.

Figure 7. Utilization of functional and damage markers concurrently to manage patients with AKI and CKD (modified from reference)

The utilization of biomarkers to evaluate changes in kidney function in the presence of pre-existing CKD offers unique challenges. A combination of function and damage markers can be used to evaluate patients as shown in Fig 4. However, the thresholds for biomarkers will likely be different based on the underlying pre-existing level of renal function. This distinction will be important mechanistically to define outcomes and understand the pathophysiology.