BIOMARKERS IN ACUTE

KIDNEY INJURY IN ICU

HABIBI
 OBJECTIVES

DEFINITION
REVIEW CRITERIA
REVIEW POTENTIAL USE
REVIEW BIOMARKERS OF AKI IN ICU
CONCLUSIONS
 BIOMARKERS DEFINITION

 “Any substance, structure, or process that can be measured in the

body or its products and influence or predict the incidence of
outcome or disease”
 The measured response may be functional and physiological,
biochemical at the cellular level, or a molecular interaction. edict
the incidence of outcome or disease”

WHO International Programme on Chemical Safety. Biomarkers in Risk Assessment:

Validity and Validation. 2001.
 BIOMARKERS DEFINITION
 Diagnostic biomarkers : detects or confirms the presence of a disease or condition of
interest, or identifies an individual with a subtype of the disease
 Monitoring biomarkers: biomarker that can be measured serially to assess the status of a
disease or medical condition for evidence of exposure to a medical product or
environmental agent, or to detect an effect of a medical product or biological agent
 Pharmacodynamic/response biomarkers: biomarker that changes in response to
exposure to a medical product or an environmental agent
 Predictive biomarkers: biomarker that predicts an individual or group of individuals more
likely to experience a favorable or unfavorable effect from the exposure to a medical
product or environmental agent.
 Prognostic biomarkers: biomarker that is used to identify the likelihood of a clinical event,
disease recurrence, or disease progression in patients with a disease or medical condition
of interest

M.C Robert. Biomarker definitions and their applications. Experimental Biology and Medicine 2018; 243: 213–221
 BIOMARKER CATEGORY FOR AKI

Rizvi MS et al. Biomarkers for Early Detection of Acute Kidney Injury. JALM, 386 –399, 2017
 AKI DEFINITION

Acute kidney injury (AKI) is a syndrome characterized by the

rapid loss of the kidney’s excretory function and is typically
diagnosed by the decreased urine output or accumulation of
end products of nitrogen metabolism (urea and creatinine), or
both

Bellomo, R.K. Ronco, C. Acute kidney injury. Lancet 2012. 380, 756–766
AKI DEFINITION KRITERIA

Rizvi MS et al. Biomarkers for Early Detection of Acute Kidney Injury. JALM, 386 –399, 2017
THE AGREEMENT

COST

AKI MORBIDITY

MORTALITY
EARLY STRATEGIC
RECOGNITION MEASUREMENTS
AKI Etiologies

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev 37 (2) 2016
THE INSULTS → RISK FACTORS

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev 37 (2) 2016
 Current functional biomarkers
limitations
 Creatinine
 poor correlation with glomerular filtration rate during a dynamic state and variations in its
production, secretion, and extrarenal excretion.
 not a real-time biomarker, and its levels may not rise until after renal function is
compromised → a missed therapeutic window.
 Drugs may impaired secretions (trimetopim, cimetidine)
 Urinary output,
 Difficulties in collection of urine output data,
 Frequent use of diuretics, and
 Issues related to urinary catheters (e.g., early removal of urinary catheter to avoid catheter-
related urinary tract infection, catheter obstruction, lack of ability for automated collection
of urinary output data with currently used devices).

Edelstein C.L. Biomarkers in Acute Kidney Injury. Elsevier 2017

 An Ideal biomarker for AKI
(a) is measurable by a rapid test of readily available
samples (urine or blood);
(b) is measurable by a cost-effective, biologically and
physiologically plausible assay with high sensitivity and
specificity;
(c) has dynamic and rapidly changing levels that
correlate with disease progression or improvement;
and
(d) has prognostic value.

Rizvi MS et al. Biomarkers for Early Detection of Acute Kidney Injury. JALM, 386 –399, 2017
QUESTIONS FOR BIOMARKERS IN AKI

Murray P. et al. Potential use of biomarkers in acute kidney injury: 10th ADQI
consensus conference. Kidney International: 2014, 513–521
BIOMARKERS IN RENAL FUNCTION MITIGATION

RISKS INTERVENTION
• Volume uncontrolled • Volume optimization
• Hemodynamic • Hemodynamic
NO AKI DAMAGE instability
•
stabilization
Anemia correction
BIOMARKERS + • Anemia
NO SIGNS OR • Sepsis and • Control of
SYMPTOMS SCr N Inflamation inflammation
• Limitation of imaging
NO EVIDENCE GFR ↓ • Contrast media
procedures
• Nephrotoxic drugs • Control of toxic drugs
• Impaired cardiac • Improved cardiac
function function

DYSFUNCTION AKI
BIOMARKERS ++ BIOMARKERS
SCr ↑ +++
GFR ↓↓ CKD MORTALITY
SCr ↑↑
GFR ↓↓↓
Novel biomarkers of AKI in ICU
 NGAL
 KIM-1
 TIMP2 and IGFBP7
 IL-18
 Cystatin C
 Brush-Border Enzymes
 L-FABP
 CD163
 TREM-1
 ANG-2
 HSP-72
 Urinary GAGs
Edelstein C.L. Biomarkers in Acute Kidney Injury. Elsevier 2017
NGAL
Comparison

Srisawat M. Kellum J.A. The Role of Biomarkers in Acute Kidney Injury. Crit Care Clin 36 (2020) 125–140
 Neutrophil Gelatinase-associated
Lipocalin (NGAL)
 The most studied AKI biomarker
 NGAL is a 25-kD protein of the lipocalin family that is widely
expressed and functions as a growth and differentiation factor in
multiple cell types and also has a role in iron trafficking in renal
epithelium.
 Up-regulation of NGAL transcription and protein expression
occurs as a result of ischemic or nephrotoxic kidney injury,
which can be detected by elevations in both urine and plasma
NGAL.
 The thick ascending limb of the loop of Henle and the
intercalated cells of the collecting duct are the primary sites of
NGAL production in the kidney.
NGAL PRODUCTION SITE

Srisawat M. Kellum J.A. The Role of Biomarkers in Acute Kidney Injury. Crit Care Clin 36 (2020) 125–140
 NGAL as AKI biomarker in ICU

To predict/diagnosis AKI

To prediction transient AKI or persistent AKI
To predict short-term outcome and renal
recovery
To predict long-term outcomes
Decision making on treatment such as RRT
KIM-1
Comparison

Srisawat M. Kellum J.A. The Role of Biomarkers in Acute Kidney Injury. Crit Care Clin 36 (2020) 125–140
 Kidney Injury Molecule - 1
 Immunoglobuline like molecule
 Acute overexpression of KIM-1 in proximal renal tubular epithelial cells after
ischemia, hypoxia, and toxicity promotes transformation of the cells into
phagocytic cells.
 KIM-1 on the surface of the liposome that can identify the apoptosis body
and phosphatidylserine, which mediates further phagocytosis. Thus, KIM-1
plays a role in the removal of apoptotic cells and necrotic tissue fragments.
 KIM-1 is also involved in the repair process after injury to renal tubular
epithelial cells.
 Acute renal damage initiates increased levels of KIM-1 in blood and urine,
which can be used to diagnose acute renal tubular dysfunction.
 The KIM-1 level is also significantly correlated with the decline of the
estimated glomerular filtration rate (eGFR) and kidney damage.
KIM-1 PRODUCTION SITE

Srisawat M. Kellum J.A. The Role of Biomarkers in Acute Kidney Injury. Crit Care Clin 36 (2020) 125–140
Expression of KIM – 1 in Tubular cells

Charlton J R. A basic science view of acute kidney injury biomarkers. Nephrol Dial Transplant 2014. 29: 1301–1311
 KIM -1 as AKI biomarker in ICU
 To predict AKI
 To predict persistent AKI
TIMP2 and
IGFBP7
Comparison

Srisawat M. Kellum J.A. The Role of Biomarkers in Acute Kidney Injury. Crit Care Clin 36 (2020) 125–140
Tissue inhibitor of metalloproteinases-2 (TIMP-2)
Insulin-like growth factor-binding protein 7 (IGFBP7)
 TIMP2 and IGFBP7
 IGFBP7 and TIMP2 were subsequently shown to be biomarkers of risk stratification in AKI
in three studies: Sapphire, Topaz, and Opal studies. 340 candidate biomarkers were
measured in critically ill ICU patients with sepsis or one or more risk factors for AKI, for
example, hypotension, sepsis, and major trauma.
 In a discovery study, the biomarkers were ranked by the ability to predict RIFLE—Injury
and Failure within 12–36 h. The two best biomarkers that were discovered were the
cell-cycle arrest proteins, urinary IGFBP-7 and TIMP-2, both inducers of G1 cellcycle
arrest, a key mechanism implicated in AKI.
 In the Sapphire validation study, in 728 critically ill patients, the primary endpoint was
moderate to severe AKI (KDIGO Stage 2–3) within 12 h of sample collection [216].
IGFBP7 and TIMP-2 demonstrated an AUC of 0.80 (0.76 and 0.79 alone) for the primary
endpoint.
 Urine concentrations of IGFBP7 and TIMP-2 were significantly superior to all previously
described markers of AKI, for example, IL-18, NGAL and KIM-1, none of which
achieved an AUC >0.72.

Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25
THE DISCOVERY STUDY

Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25
 The Sapphire validation study

Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25
 Proposed mechanism of TIMP-2 IGFBP-7

Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25
 In the Topaz study, in 420 ICU patients, a predefined cutoff value of IGFBP7 and TIMP-2, was
prospectively validated for risk assessment in AKI diagnosed by a clinical adjudication
committee.
 Critically ill patients with urinary [TIMP-2] × [IGFBP7] greater than 0.3 had 7 times the risk for AKI
compared with critically ill patients with a test result below 0.3. Urinary [TIMP-2] × [IGFBP7]
greater than 0.3 identified patients at risk for imminent AKI.
 Cut of point value
TIMP-2, IGFBP-7

0.3 2
Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25
 Biomarkers re-check

Kellum AJ. Cell-cycle arrest and acute kidney injury: the light and the dark sides. Nephrol Dial Transplant (2016) 31: 16–22
ARE THE QUESTIONS ANSWERED?

Murray P. et al. Potential use of biomarkers in acute kidney injury: 10th ADQI
consensus conference. Kidney International: 2014, 513–521
 COST- EFFECTIVENESS

 Current evidence is inadequate to support the cost-effectiveness of general use of biomarker tests.
 £105,965 (NephroCheck),
 £539,041 (NGAL urine BioPorto)
 CONCLUSIONS
 Acute kidney injury (AKI) is a complex disorder that leads to high
morbidity and mortality
 Current functional AKI biomarkers have numerous limitations in AKI
management
 Novel biomarkers of AKI is proven to be helpful in AKI management
stages
 Cost effectiveness of novel biomarkers of AKI still need further
evaluation
Thank you for
your attention
POSSIBLE RISK FACTOR FOR AKI

Finlay S. Identification of risk factors associated with acute kidney injury in patients
admitted to acute medical units. Clin Med (Lond). 2013 Jun; 13(3): 233–238
Expanded diagnosis criteria