The Path to Precision in Acute Kidney Injury
The clinical syndrome of acute kidney injury (AKI) is a common complication within the hospital and intensive care unit (ICU) settings. It is associated with negative economic and health outcomes, such as new or worsening chronic kidney disease, dialysis, or death. Despite the insight into AKI outcomes, current diagnostic tools such as serum creatinine and urine output, which are categorized as functional biomarkers, are limited in the syndrome of AKI (1). In clinical practice, the limitations of functional biomarkers become evident when clinicians must differentiate “prerenal” or functional AKI—characterized by reduced kidney perfusion without tubular injury—from intrinsic injury, such as acute tubular necrosis (ATN), as this distinction impacts management.
To overcome the limitations of functional biomarkers, the 10th Acute Disease Qualitative Initiative (ADQI) meeting proposed the use of novel biomarkers in AKI, and the 23rd ADQI meeting proposed augmenting the Kidney Disease: Improving Global Outcomes (KDIGO) AKI criteria with novel damage biomarkers for the diagnosis and staging of AKI (Figure 1) (2, 3). This has set the groundwork for redefining AKI and identifying subphenotypes (e.g., hepatorenal syndrome, sepsis-associated AKI, acute interstitial nephritis, and ATN).
As clinical medicine evolves, the goal of precision medicine through phenotyping becomes achievable. In AKI, some novel urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 (TIMP-2 × IGFBP-7), and C-C motif chemokine ligand-14 (CCL14), have been developed for clinical use. In some cases, these biomarkers have been implemented into clinical practice due to their superiority in identifying subphenotypes (Figure 2).
A common clinical scenario is trying to differentiate “prerenal” (functional) from “intrarenal,” such as ATN AKI. Urinary NGAL (uNGAL) is upregulated in the presence of tubular injury, making it a valuable tool for distinguishing functional AKI—such as hypovolemia, cardiorenal syndrome, and hepatorenal syndrome—from ATN (4–6). It has demonstrated clinical utility in the heterogeneous adult population with AKI, particularly in patients with liver cirrhosis, in whom a negative NGAL test suggests the diagnosis of hepatorenal syndrome—especially if they have not responded to fluid resuscitation—and may guide the use of vasoactive agents (e.g., terlipressin) (5, 7, 8).
Another common clinical scenario is identifying patients at high risk for persistent severe AKI (PS-AKI), with the goal of modifying treatment to prevent progression. This is where uNGAL has shown utility, particularly in the pediatric ICU population. The uNGAL (ProNephro AKI) test was recently approved by the US Food and Drug Administration (FDA) for clinical use. It helps identify pediatric patients at risk of developing PS-AKI (stage 2/3 AKI) within 48–72 hours of ICU admission and thus allows clinicians to adjust management—such as avoiding nephrotoxic agents—to reduce AKI incidence or severity (9, 10).
As uNGAL becomes more integrated into clinical practice, its limitations must be acknowledged. In the presence of a urinary tract infection, uNGAL levels may be elevated, complicating interpretation—particularly when distinguishing between functional and intrinsic AKI in adults or predicting AKI severity in pediatric populations. Therefore, clinical context remains essential, and uNGAL should be interpreted alongside standard tools such as clinical history, examination findings, imaging, and fractional excretion of sodium (6, 9, 10).
AKI is common in the ICU, and early identification of patients at risk is clinically important. TIMP-2 × IGFBP-7 (NephroCheck), a cellular stress biomarker, has demonstrated utility in the adult ICU population and received FDA approval for early detection of patients at risk of developing moderate-to-severe AKI (stage 2/3) within 12 hours of ICU admission. Its role in guiding clinical management was clearly demonstrated in the Biomarker-Guided Implementation of the AKI Bundle (PrevAKI-mc) study, in which the implementation of the KDIGO care bundle was used in patients above the threshold for high risk and led to reduction in AKI severity (11).
More recently, CCL14, a renal inflammation cytokine involved in the chemotaxis of monocytes and macrophages, shows promise in identifying the cohort of patients at greatest risk of PS-AKI. Knowing which people living with severe AKI are likely to stay at stage 2/3 AKI can aid clinical decision-making regarding the need for frequent monitoring and potentially guide dialysis initation (1, 12).
As novel biomarkers begin their translation into clinical practice, it can be seen how each tool may be implemented to identify subphenotypes and guide clinical practice. Interestingly, all of these tools show their power when used with standard clinical tools, such as clinical examination and functional biomarkers. Therefore, despite these biomarkers showing promise in their respective clinical situations, the basics of clinical history, examination, and standard tools play an integral role in identifying and managing these subphenotypes.
The goal to precision is looking bright, and the potential of a panel of biomarkers for different clinical scenarios may pave the way forward in AKI diagnosis and management.
12.↑
Hoste E, et al.; RUBY Investigators. Identification and validation of biomarkers of persistent acute kidney injury: The RUBY study. Intensive Care Med 2020; 46:943–953.
