controversies in nephrology
into helping and not harming the patient in front allograft monitoring by urine CXCL10 chemokine. J Am
of us. This will require innovative trial designs
that ask questions that we are not afraid to
answer, even if they point to conventional care
instead of the shiniest and newest biomarker. For
AKI biomarkers to help our patients, future
biomarker studies need to move beyond estab-
lishing prognostic significance (about which, as
B. B. King lamented, “The thrill is gone.”) and
toward actionable clinical insights.
DISCLOSURE
The author declared no competing interests.
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management. Accessed November 15, 2023. https://
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From the Editor
biomarker use for acute kidney
injury
Biomarker
use in acute kidney
injury: are we there yet?
Kidney International (2024) 105, 682–683; https://doi.org/
10.1016/j.kint.2024.02.005
Copyright ª 2024, International Society of Nephrology.
Published by Elsevier Inc. All rights reserved.
A
cute kidney injury (AKI) is an increas-
ingly 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 Coca1 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-a, 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
Kidney International (2024) 105, 675–683
 controversies in nephrology

Box 1 | Guidelines for biomarker studies

(i) The biomarker study could include $1 of the following features.

a. Diagnostic,
b. Prognostic, or
c. 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, im-
proves outcomes, and is cost-effective.

AKI, acute kidney injury; CKD, chronic kidney disease; CVD, cardiovascular disease.

of prognostic and predictive biomarker studies controlled biomarker-strategy trials to

are mostly limited to their studies in select pa-
tient 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, Waikar2
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 phy-
sician’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
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 signifi-
cant advancements in the care of patients with
AKI.
T. Alp Ikizler1
1
Division of Nephrology and Hypertension, Vanderbilt
University Medical Center, Nashville, Tennessee, USA
Correspondence: T. Alp Ikizler, Division of Nephrology and
Hypertension, Vanderbilt University Medical Center, 1161
21st Ave. S and Garland, Nashville, Tennessee 37232-2372,
USA. E-mail: alp.ikizler@vanderbilt.edu
REFERENCES
1. Parikh CR, Coca SG. Are biomarkers in acute kidney
injury ready for prime time? The time is right for a
second look. Kidney Int. 2024;105:675–678.
2. Waikar SS. Biomarker blues: balancing hope and
hype in acute kidney injury. Kidney Int. 2024;105:
679–682.

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