Biomarker use in acute kidney injury: are we there yet?

Acute kidney injury (AKI) is an increasingly common disorder with significant heterogeneity. AKI is closely associated with short- and long-term patient outcomes, and its diagnosis and monitoring are critically important. In clinical practice and research studies, this is primarily achieved by serum creatinine concentrations, which have several well-defined limitations. We have witnessed the emergence of novel biomarkers aiming to advance the clinical phenotyping of AKI In the past 2 decades. Despite the abundance of candidate biomarker studies, the utility of these tests has been scrutinized, leading to limited penetration into the clinical settings. This rather disappointing advancement is discussed from 2 different perspectives in the current issue of Kidney International. In their claim for more persistent use of several AKI biomarkers, Parikh and Coca1Parikh C.R. Coca S.G. Are biomarkers in acute kidney injury ready for prime time? The time is right for a second look.Kidney Int. 2024; 105: 675-678Google Scholar argue that several kidney injury and repair biomarkers have systematically met the potential milestones for use in clinical trials and clinical care. They discuss studies where the diagnostic value of urine neutrophil gelatinase-associated lipocalin, urinary tumor necrosis factor-α, interleukin-9, and CXC chemokine ligand 9 have been proven by the compelling area under the curve values. They also note the US Food and Drug Administration's approval of the composite biomarker for monitoring kidney toxicity in animal studies for drug safety. Their examples of prognostic and predictive biomarker studies are mostly limited to their studies in select patient populations. In the end, they acknowledge that the utility of the biomarkers for their impact on clinical outcomes still needs rigorous assessment in future studies. In a more skeptical point of view, Waikar2Waikar S.S. Biomarker blues: balancing hope and hype in acute kidney injury.Kidney Int. 2024; 105: 679-682Google Scholar points out the obvious fact that despite extensive research efforts, few clinicians are ordering AKI biomarkers. He astutely notes that a useful AKI biomarker must provide information that materially changes the physician's behavior and translates into better care, with examples from other disciplines, like the use of procalcitonin for antibiotic therapy. He argues that current AKI biomarker studies are limited mostly to prognostic information and do not provide useful information for the actual management of the individual patient. He notes the value of preliminary studies targeted for diagnostic accuracy but recommends that multiple additional steps be taken, such as randomized controlled biomarker-strategy trials to advance these biomarkers to clinical settings. The arguments summarized above give us hope that if appropriate steps are taken to advance our future biomarker studies beyond ones with only prognostic information (Box 1), there is a high probability of significant advancements in the care of patients with AKI.Box 1Guidelines for biomarker studies(i)The biomarker study could include ≥1 of the following features.a.Diagnostic,b.Prognostic, orc.Mechanistic (relevant to disease pathogenesis).(ii)The biomarker(s) under study could be in 1 of the following phases.a.Early phase 1 studies include both discovery and proof-of-concept studies demonstrating differences in biomarker levels between patients with and without the outcome of interest (i.e., CKD, AKI, and CVD);b.Phase 2 studies include prospective studies designed to determine the association between levels, disease behavior, and future outcomes;c.Phase 3 studies should consider aspects of clinical incorporation, including determining the incremental predictive value of a candidate marker beyond established risk predictors;d.Later-phase studies (4–6) should examine whether biomarker use changes therapy for at-risk patients, improves outcomes, and is cost-effective.AKI, acute kidney injury; CKD, chronic kidney disease; CVD, cardiovascular disease. (i)The biomarker study could include ≥1 of the following features.a.Diagnostic,b.Prognostic, orc.Mechanistic (relevant to disease pathogenesis).(ii)The biomarker(s) under study could be in 1 of the following phases.a.Early phase 1 studies include both discovery and proof-of-concept studies demonstrating differences in biomarker levels between patients with and without the outcome of interest (i.e., CKD, AKI, and CVD);b.Phase 2 studies include prospective studies designed to determine the association between levels, disease behavior, and future outcomes;c.Phase 3 studies should consider aspects of clinical incorporation, including determining the incremental predictive value of a candidate marker beyond established risk predictors;d.Later-phase studies (4–6) should examine whether biomarker use changes therapy for at-risk patients, improves outcomes, and is cost-effective. AKI, acute kidney injury; CKD, chronic kidney disease; CVD, cardiovascular disease. Biomarker blues: balancing hope and hype in acute kidney injuryKidney InternationalVol. 105Issue 4PreviewI have the biomarker blues. Despite several million dollars of active research funding this year from the National Institutes of Health and thousands of published articles when searching PubMed for "acute kidney" and "biomarkers," they remain infrequently used by the vast majority of clinicians around the world. Our rallying cries of the early 2010s on biomarkers1 ("Anything but creatinine!") have failed to dethrone the humble metabolite, which retains its dominance for the diagnosis and monitoring of acute kidney injury (AKI). Full-Text PDF Are biomarkers in acute kidney injury ready for prime time? The time is right for a second lookKidney InternationalVol. 105Issue 4PreviewSince the early 2000s, the definition of acute kidney injury (AKI) has become sensitive and refined, but the current definition of AKI still has many flaws. Serum creatinine is affected by factors that have no relationship to changes in glomerular filtration rate, for example, changes in creatinine kinetics or muscle mass due to inflammation, medications affecting secretion of creatinine, and hydration. Because of analytic and biological variability, serum creatinine can fluctuate enough to meet the 0.3-mg/dl criterion for AKI without any actual injury. Full-Text PDF