1228446
review-article2024
SMO0010.1177/20503121241228446SAGE Open MedicineBufkin et al.
SAGE Open Medicine
Review
SAGE Open Medicine
Review of the limitations of current Volume 12: 1–10
© The Author(s) 2024
Article reuse guidelines:
biomarkers in acute kidney injury sagepub.com/journals-permissions
DOI: 10.1177/20503121241228446
https://doi.org/10.1177/20503121241228446
clinical practices journals.sagepub.com/home/smo
Kendra B Bufkin1 , Zubair A Karim1
and Jeane Silva2
Abstract
Acute kidney injury is a prevalent disease in hospitalized patients and is continuously increasing worldwide. Various efforts
have been made to define and classify acute kidney injury to understand the progression of this disease. Furthermore,
deviations from structure and kidney function and the current diagnostic guidelines are not adequately placed due to
baseline serum creatinine values, which are rarely known and estimated based on glomerular function rate, resulting in
misclassification of acute kidney injury staging. Hence, the current guidelines are still developing to improve and understand
the clinical implications of risk factors and earlier predictive biomarkers of acute kidney injury. Yet, studies have indicated
disadvantages and limitations with the current acute kidney injury biomarkers, including lack of sensitivity and specificity.
Therefore, the present narrative review brings together the most current evidenced-based practice and literature associated
with the limitations of the gold standard for acute kidney injury diagnoses, the need for novel acute kidney injury biomarkers,
and the process for biomarkers to be qualified for diagnostic use under the following sections and themes. The introduction
section situates the anatomy and normal and abnormal kidney functions related to acute kidney injury disorders. Guidelines in
providing acute kidney injury definitions and classification are then considered, followed by a discussion of the disadvantages
of standard markers used to diagnose acute kidney injury. Characteristics of an ideal acute kidney injury biomarker are
discussed concerning sensitivity, specificity, and anatomic location of injury. A particular focus on the role and function of
emerging biomarkers is discussed in relation to their applications and significance to the prognosis and severity of acute
kidney injury. Findings show emerging markers are early indicators of acute kidney injury prediction in different clinical
settings. Finally, the process required for a biomarker to be applied for diagnostic use is explained.
Keywords
Kidney, biomarker, limitations, acute, renal, ideal, biomarker discovery and development
Date received: 26 September 2023; accepted: 4 January 2024
Introduction continues to be a clinical and therapeutic challenge for phy-
sicians due to limitations within the current implemented
Acute kidney injury (AKI) is a clinical syndrome that is a diagnostic biomarkers.5
common problem in hospitalized patients and is classified Traditionally, the diagnosis of AKI is measured by the
by a rapid decline in kidney excretory function and accu- level of indirect biomarkers, that is, blood urea and nitrogen
mulation of waste and nitrogen metabolism products.1 The and SCr, but these methods lack sensitivity and specificity.
clinical practice guidelines of AKI is based upon the infor-
mation provided by the Kidney Disease Improving Global
1
Outcomes (KDIGO),2,3 the most accepted and consent epartment of Interdisciplinary Health Science, College of Allied Health
D
Science, Augusta University, Augusta, GA, USA
approach to the diagnostic criteria of AKI with serum cre- 2
Department of Health Management, Economics and Policy, Augusta
atinine (SCr) and estimated glomerular filtration rate University, Augusta, GA, USA
(eGFR), alongside urine output leading to current classifi-
Corresponding author:
cation and severity of the disease.4 Although KDIGO clini- Jeane Silva, Department of Health Management, Economics and Policy,
cal recommendations for AKI stress the significance of Augusta University, 1120 15th Street, Augusta, GA 30912, USA.
earlier detection of AKI to improve patient outcomes, AKI Email:
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open
Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
, 2 SAGE Open Medicine
Nevertheless, there are disagreements and controversies Normal kidney function
among clinicians for the clinical assessment and the role
and effectiveness of biomarkers, such as SCr and eGFR.6–9 The kidneys play a vital role in several physiological pro-
In this context, assessment of structural kidney injury has cesses such as acid-base balance, fluid and electrolytes regu-
notably been absent due to the current focus on glomerular lation, excretion of uremic toxin, and production of various
filtration rate and functional kidney injury markers.10 hormones, that is, activation of cholecalciferol, erythropoie-
Nonetheless, many improvements are needed to discover tin, and renin. Moreover, Dhondup and Qian et al.11 describe
novel biomarkers for kidney injury and increase the sensi- the mechanisms and pathways of glomerular filtration and
tivity and specificity of biomarkers of AKI. Thus, there is tubular reabsorption and secretion, which play a vital role in
an urgency to discover early diagnostic markers that are maintaining the volume and composition of extracellular
reliable biomarkers of kidney injury in clinical practice, fluid in the body.11 Normally, the glomerular filtration rate
whereas these biomarkers can be used to predict structural (GFR) is approximately 125 mL/min or 180 L/day 1–2 L of
injury to the kidney. urine is excreted, and the rest of the 99% of filtrates are reab-
This narrative review aims to provide a better and com- sorbed into the peritubular capillaries and return to the
blood.12 GFR primarily depends on three major factors, that
prehensive understanding of normal kidney function and
is, blood pressure, filtration pressure, and permeability of
AKI. Firstly, this article begins by describing current AKI
the glomerular capillary walls. Hence, the GFR describes
definitions and classification guidelines and discussing the
renal function, whereas creatinine clearance is the standard
disadvantages of standard markers used in diagnosing AKI.
method to measure glomerular filtration. Furthermore, the
Secondly, the characteristics of an ideal AKI biomarker are
amount of dissolved substance removed by the kidney is
discussed in relation to its sensitivity, specificity, and ana-
determined by comparing the creatinine levels in serum and
tomic location of the injury. Thirdly, the role and function
urine.13
of early and reliable biomarkers of AKI, with application
Nonetheless, the kidney filters unwanted substances
and characterization as critical features of describing the
from the blood and excretes them in the form of urine
etiology and anatomic location of the injury are dealt with.
through the following processes: glomerular filtration,
Finally, the process required for validating a biomarker for reabsorption, and secretion, certain molecules move across
clinical diagnostic purposes is explained. Overall, this narra- membranes by specific mechanisms, including active trans-
tive review highlights the importance of developing novel port, diffusion, facilitated diffusion, and osmosis. The
biomarkers that are highly specific and sensitive in predict- proximal tubule is the leading site of reabsorption while the
ing and providing information to guide early therapeutic other substances move through the loop of Henle, the distal
intervention for AKI. tubule, and the collecting ducts. Using active transport and
passive diffusion, a substance passes through the peritubu-
Search strategy lar blood into the tubular lumen by tubular secretion (Figure
1). The homeostatic balance is maintained by hormones,
The overall theme of this review article was the current ther- such as antidiuretic (vasopressin) and aldosterone, which is
apeutic implications of AKI in practice. The following key synthesized by the renin–angiotensin system, playing a sig-
points have been considered: kidney function, current AKI nificant role in the regulation of tubular reabsorption and
guidelines limitations, emerging biomarkers, and biomarker secretion of solutes and water.14 Thus, an accumulation of
discovery and development. metabolic products or electrolytes in the blood makes it dif-
The search was conducted via a broad range of health- ficult for the kidneys to regulate fluid balance and electrolyte
care-related databases. Multi-field database searches were instabilities, leading to AKI.
conducted using Medline, PubMed, and Google Scholar
from September 15, 2021, to November 20, 2023.
The researchers identified 63 papers using the following Acute kidney injury
criteria: papers reporting on AKI classifications and defini- AKI is characterized by an unexpected loss of kidney func-
tions and papers focusing on current limitations in AKI diag- tion that is defined based on SCr, a kidney excretory func-
nosis and therapeutic interventions. The topics included in tion marker, and urinary output, a quantitative marker of
these manuscripts are based on ideal characteristics of a kid- urine production.16 Hence, AKI is one of the clinical cases
ney biomarker, emerging AKI biomarkers, and discovery that does not cover a single disease entity but covers a
and development of markers of AKI. Furthermore, editorials, broad spectrum of disorders with different etiologies classi-
letters, and case reports were excluded from this article. In fied according to the cause and stage of the disease.17 In
addition, the search was focused on those articles published this context, several diseases come under the AKI class:
in English. The search terms included an abbreviated form of acute tubular necrosis, acute interstitial nephritis, acute
biomarker combined with the following terms: renal, kidney, glomerular and vasculitis, pre-renal azotemia, and acute
acute, function, and validation. postrenal obstructive nephropathy. Once there is impaired
review-article2024
SMO0010.1177/20503121241228446SAGE Open MedicineBufkin et al.
SAGE Open Medicine
Review
SAGE Open Medicine
Review of the limitations of current Volume 12: 1–10
© The Author(s) 2024
Article reuse guidelines:
biomarkers in acute kidney injury sagepub.com/journals-permissions
DOI: 10.1177/20503121241228446
https://doi.org/10.1177/20503121241228446
clinical practices journals.sagepub.com/home/smo
Kendra B Bufkin1 , Zubair A Karim1
and Jeane Silva2
Abstract
Acute kidney injury is a prevalent disease in hospitalized patients and is continuously increasing worldwide. Various efforts
have been made to define and classify acute kidney injury to understand the progression of this disease. Furthermore,
deviations from structure and kidney function and the current diagnostic guidelines are not adequately placed due to
baseline serum creatinine values, which are rarely known and estimated based on glomerular function rate, resulting in
misclassification of acute kidney injury staging. Hence, the current guidelines are still developing to improve and understand
the clinical implications of risk factors and earlier predictive biomarkers of acute kidney injury. Yet, studies have indicated
disadvantages and limitations with the current acute kidney injury biomarkers, including lack of sensitivity and specificity.
Therefore, the present narrative review brings together the most current evidenced-based practice and literature associated
with the limitations of the gold standard for acute kidney injury diagnoses, the need for novel acute kidney injury biomarkers,
and the process for biomarkers to be qualified for diagnostic use under the following sections and themes. The introduction
section situates the anatomy and normal and abnormal kidney functions related to acute kidney injury disorders. Guidelines in
providing acute kidney injury definitions and classification are then considered, followed by a discussion of the disadvantages
of standard markers used to diagnose acute kidney injury. Characteristics of an ideal acute kidney injury biomarker are
discussed concerning sensitivity, specificity, and anatomic location of injury. A particular focus on the role and function of
emerging biomarkers is discussed in relation to their applications and significance to the prognosis and severity of acute
kidney injury. Findings show emerging markers are early indicators of acute kidney injury prediction in different clinical
settings. Finally, the process required for a biomarker to be applied for diagnostic use is explained.
Keywords
Kidney, biomarker, limitations, acute, renal, ideal, biomarker discovery and development
Date received: 26 September 2023; accepted: 4 January 2024
Introduction continues to be a clinical and therapeutic challenge for phy-
sicians due to limitations within the current implemented
Acute kidney injury (AKI) is a clinical syndrome that is a diagnostic biomarkers.5
common problem in hospitalized patients and is classified Traditionally, the diagnosis of AKI is measured by the
by a rapid decline in kidney excretory function and accu- level of indirect biomarkers, that is, blood urea and nitrogen
mulation of waste and nitrogen metabolism products.1 The and SCr, but these methods lack sensitivity and specificity.
clinical practice guidelines of AKI is based upon the infor-
mation provided by the Kidney Disease Improving Global
1
Outcomes (KDIGO),2,3 the most accepted and consent epartment of Interdisciplinary Health Science, College of Allied Health
D
Science, Augusta University, Augusta, GA, USA
approach to the diagnostic criteria of AKI with serum cre- 2
Department of Health Management, Economics and Policy, Augusta
atinine (SCr) and estimated glomerular filtration rate University, Augusta, GA, USA
(eGFR), alongside urine output leading to current classifi-
Corresponding author:
cation and severity of the disease.4 Although KDIGO clini- Jeane Silva, Department of Health Management, Economics and Policy,
cal recommendations for AKI stress the significance of Augusta University, 1120 15th Street, Augusta, GA 30912, USA.
earlier detection of AKI to improve patient outcomes, AKI Email:
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open
Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
, 2 SAGE Open Medicine
Nevertheless, there are disagreements and controversies Normal kidney function
among clinicians for the clinical assessment and the role
and effectiveness of biomarkers, such as SCr and eGFR.6–9 The kidneys play a vital role in several physiological pro-
In this context, assessment of structural kidney injury has cesses such as acid-base balance, fluid and electrolytes regu-
notably been absent due to the current focus on glomerular lation, excretion of uremic toxin, and production of various
filtration rate and functional kidney injury markers.10 hormones, that is, activation of cholecalciferol, erythropoie-
Nonetheless, many improvements are needed to discover tin, and renin. Moreover, Dhondup and Qian et al.11 describe
novel biomarkers for kidney injury and increase the sensi- the mechanisms and pathways of glomerular filtration and
tivity and specificity of biomarkers of AKI. Thus, there is tubular reabsorption and secretion, which play a vital role in
an urgency to discover early diagnostic markers that are maintaining the volume and composition of extracellular
reliable biomarkers of kidney injury in clinical practice, fluid in the body.11 Normally, the glomerular filtration rate
whereas these biomarkers can be used to predict structural (GFR) is approximately 125 mL/min or 180 L/day 1–2 L of
injury to the kidney. urine is excreted, and the rest of the 99% of filtrates are reab-
This narrative review aims to provide a better and com- sorbed into the peritubular capillaries and return to the
blood.12 GFR primarily depends on three major factors, that
prehensive understanding of normal kidney function and
is, blood pressure, filtration pressure, and permeability of
AKI. Firstly, this article begins by describing current AKI
the glomerular capillary walls. Hence, the GFR describes
definitions and classification guidelines and discussing the
renal function, whereas creatinine clearance is the standard
disadvantages of standard markers used in diagnosing AKI.
method to measure glomerular filtration. Furthermore, the
Secondly, the characteristics of an ideal AKI biomarker are
amount of dissolved substance removed by the kidney is
discussed in relation to its sensitivity, specificity, and ana-
determined by comparing the creatinine levels in serum and
tomic location of the injury. Thirdly, the role and function
urine.13
of early and reliable biomarkers of AKI, with application
Nonetheless, the kidney filters unwanted substances
and characterization as critical features of describing the
from the blood and excretes them in the form of urine
etiology and anatomic location of the injury are dealt with.
through the following processes: glomerular filtration,
Finally, the process required for validating a biomarker for reabsorption, and secretion, certain molecules move across
clinical diagnostic purposes is explained. Overall, this narra- membranes by specific mechanisms, including active trans-
tive review highlights the importance of developing novel port, diffusion, facilitated diffusion, and osmosis. The
biomarkers that are highly specific and sensitive in predict- proximal tubule is the leading site of reabsorption while the
ing and providing information to guide early therapeutic other substances move through the loop of Henle, the distal
intervention for AKI. tubule, and the collecting ducts. Using active transport and
passive diffusion, a substance passes through the peritubu-
Search strategy lar blood into the tubular lumen by tubular secretion (Figure
1). The homeostatic balance is maintained by hormones,
The overall theme of this review article was the current ther- such as antidiuretic (vasopressin) and aldosterone, which is
apeutic implications of AKI in practice. The following key synthesized by the renin–angiotensin system, playing a sig-
points have been considered: kidney function, current AKI nificant role in the regulation of tubular reabsorption and
guidelines limitations, emerging biomarkers, and biomarker secretion of solutes and water.14 Thus, an accumulation of
discovery and development. metabolic products or electrolytes in the blood makes it dif-
The search was conducted via a broad range of health- ficult for the kidneys to regulate fluid balance and electrolyte
care-related databases. Multi-field database searches were instabilities, leading to AKI.
conducted using Medline, PubMed, and Google Scholar
from September 15, 2021, to November 20, 2023.
The researchers identified 63 papers using the following Acute kidney injury
criteria: papers reporting on AKI classifications and defini- AKI is characterized by an unexpected loss of kidney func-
tions and papers focusing on current limitations in AKI diag- tion that is defined based on SCr, a kidney excretory func-
nosis and therapeutic interventions. The topics included in tion marker, and urinary output, a quantitative marker of
these manuscripts are based on ideal characteristics of a kid- urine production.16 Hence, AKI is one of the clinical cases
ney biomarker, emerging AKI biomarkers, and discovery that does not cover a single disease entity but covers a
and development of markers of AKI. Furthermore, editorials, broad spectrum of disorders with different etiologies classi-
letters, and case reports were excluded from this article. In fied according to the cause and stage of the disease.17 In
addition, the search was focused on those articles published this context, several diseases come under the AKI class:
in English. The search terms included an abbreviated form of acute tubular necrosis, acute interstitial nephritis, acute
biomarker combined with the following terms: renal, kidney, glomerular and vasculitis, pre-renal azotemia, and acute
acute, function, and validation. postrenal obstructive nephropathy. Once there is impaired
