Do Novel Biomarkers Have Utility in the Diagnosis and Prognosis of AKI? PRO

This article will present the pro-side of debate concerning the utility of novel biomarkers in the diagnosis and prognosis of AKI.


Damage versus Dysfunction
With kidney damage difficult to measure, and with dysfunction an unreliable surrogate for damage, it is no surprise that clinicians have difficulty diagnosing AKI.Decreased kidney function measured by increased SCr or decreased UOP may also occur without kidney damage, for example, in the setting of hypovolemia.In this setting, AKI may be purely "functional."Unfortunately, ancillary tests (e.g., imaging) are insensitive to kidney damage and may seem normal despite injury.Sometimes kidney damage can be inferred from persistent functional impairment, but the absence of persistent dysfunction does not exclude irreversible loss of nephrons because of substantial reserve capacity.Detecting kidney damage in settings where function is normal or only mildly or transiently impaired is critical because kidneys have limited capacity to regenerate.Once fibrosis has occurred, those nephrons are lost.Conversely, determining that dysfunction is not related to damage can guide management.Some AKI biomarkers were discovered by inducing kidney injury in animals, and they have subsequently been established to detect damage in different parts of the human kidney. 5

Time
Another critical limitation of SCr is that it may take up to 24 hours to indicate a significant change in function.UOP may change faster, but it may not change at all, and when it does, it still takes some time to assess-i.e., it must be measured over at least 6 hours to determine whether it is reduced.Novel biomarkers are considerably faster.Tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are preformed molecules that are released into the urine within minutes of injury. 6Similarly, neutrophil gelatinase-associated lipocalin (NGAL) is upregulated and observed in the urine at 2 hours, 36 hours before changes in SCr for patients with AKI. 7 Failure to detect kidney damage promptly may reduce the ability to reverse it.Existing management strategies for AKI include discontinuing offending drugs, relieving obstruction, and optimization of hemodynamics. 1 Biomarkerguided implementation of a care bundle on the basis of the KDIGO guideline demonstrated a significant reduction in AKI events 8,9 after cardiac surgery, and these studies have also shown that these interventions are not applied routinely in patients without AKI, so the biomarker has a material effect on patient care.

Prognosis
AKI negatively affects short-term and long-term survival.In adults, mortality in the year after AKI exceeds 25%, and the rate of progression of or to CKD exceeds 20%. 10 Furthermore, AKI recures in nearly a third of patients in the year after an episode.Although not developed for this purpose, novel AKI biomarkers provide additional prognostic information over and above KDIGO-based AKI staging.Importantly, death or dialysis rates by nine months 11,12 or by hospital discharge 13 are higher in patients with increased TIMP-2cIGFBP7 only when functional changes have also occurred.As such, the prognostic signal would seem to be specific to AKI and not a "general" mortality indicator.The results are also consistent with the nature of TIMP-2 and IGFBP7 as stress rather than damage biomarkers.Stress in isolation may be benign, but when it coexists with dysfunction, it may signal actual damage.However, this interpretation is challenged by the work of Husain-Syed and colleagues who have demonstrated that increased urinary TIMP-2 c IGFBP7 after cardiac surgery is associated with loss of renal functional reserve at three months even in the absence of AKI. 14 It may be that crude measures, such as death or dialysis, do not change when kidney stress occurs without dysfunction, but measuring renal functional reserve may reveal that this stress resulted in kidney damage.
Given the potential for novel biomarkers to provide information beyond KDIGO staging, the 23rd Acute Disease Quality Initiative workgroup proposed an expanded classification for AKI adding biomarkers for each stage (Table 1). 15he first validation of this classification has been recently published using TIMP-2 c IGFBP7 in adults with sepsis.In patients who developed AKI using standard functional criteria (SCr and UOP) according to KDIGO staging, the addition of urinary TIMP-2 c IGFBP7 .2.0 (ng/ml) 2 /1000 identified patients with lower 30-day survival within the functional stages.Furthermore, TIMP-2cIGFBP7 .1.0(ng/ml) 2 /1000 may be helpful in stratifying patients in the absence of functional criteria for AKI.
Systematic reviews of NGAL in adults and children similarly demonstrate worse outcomes (mortality and hospital length of stay) in patients with both functional and structural AKI. 16,17Although mortality rates for critically ill children are lower than those for adults, NGAL has been studied extensively to delineate functional vs structural vs. combined in children after cardiac surgery and sepsis, 18,19 also showing worse outcomes for patients with structural or combined structural and functional AKI.

Clinical Experience
It is not known what proportion of physicians use novel AKI biomarkers in their clinical practice, but estimates are quite low-even among those with a critical care nephrology focus. 20TIMP-2 and IGFBP7 were incorporated into a clinical laboratory test, the NephroCheck test, which received US Food and Drug Administration approval in 2014. 21NGAL use was first reported clinically in 2017. 22e use these tests daily in our clinical practice and find utility in them.Most arguments against their use do not reflect experience and instead challenge whether they are accurate enough despite multiple meta-analyses concluding acceptable operating characteristics or are concerned about limitations when CKD or diverse etiologies of AKI are present. 23However, biomarkers, such as TIMP-2cIGFBP7 and NGAL, have been shown to perform quite well in patients with CKD 24,25 or when the etiology of AKI is  5) on www.ADQI.organd published by Ostermann and colleagues. 15epsis, 19,26 surgery, 27,28 or nephrotoxins. 29,30Some clinicians have wondered whether interventions can be effective or even whether all available are already being applied.However, the intent of diagnostic and prognostic testing is to bring personalized medicine to the bedside.One size does not fit all for AKI any more than for other illnesses.Consensus across subspecialties exists for personalized care in response to biomarkers, 31 and various experts have already included biomarkers in standardized AKI management guidelines for cardiac surgery. 32Others are likely to follow.Finally, many authors seem confused by how the costs of diagnostic tests fit into the health care landscape and who pays for them. 23Novel AKI biomarkers are quite inexpensive in comparison with many other routine tests, including imaging and electrophysiologic testing.Of course, they are currently more expensive than creatinine, but any new test will cost more relative to established clinical laboratory assays.In all cases, the cost of AKI itself, estimated to be in thousands to tens of thousands, 33 should be considered when evaluating the costs of tools used to prevent it.
It is thus our opinion, as clinicians, scientists, and AKI experts, that novel biomarkers, such as NGAL and TIMP-2cIGFBP7, have considerable utility in the diagnosis and prognosis of AKI.This judgment is based on an extensive literature base including our own studies but also our own extensive clinical experience.

Funding
None.