Download AKI

Biomarkers of Acute
Kidney Injury
Dr Sameena Ghayur
Shifa College of Medicine /Shifa International Hospital
[email protected]
AKI: A Common, Serious Problem

In 5% of all hospitalized patients, 50% patients in
ICUs

The incidence is increasing –globally

Mortality rate 50 - 80% in dialyzed ICU patients– 4
Million die each year of AKI

AKI requiring dialysis is one of the most important
independent predictors of death in ICU patients

25% of ICU dialysis survivors progress to ESRD
within 3 years
Pathogenesis
Pathophysiology
AKI – A Systemic Condition
Functional and
structural
extra-renal organ
injury occurs in
AKI
Potential
mediators
•uraemic toxins
•cytokines
•leukocytes
Definitions - KDIGO
 Serum creatinine rises by ≥ 26µmol/L within
48 hours or
 Serum creatinine rises ≥ 1.5X the reference
value which is known or presumed to have
occurred within one week or
 Urine output is < 0.5ml/kg/hr for >6
consecutive hours
RIFLE Criteria
Acute dialysis quality initiative(ADQI) group
Diagnosis of AKI is Often Delayed

Clinicians have used SCr to diagnose AKI for
decades.

Acknowledged as inadequate gold standard:
 Poor specificity in some settings that are not
associated with kidney injury
 Poor sensitivity in setting of adequate renal reserve
 Relatively slow kinetics after injury

Varies widely with age, gender, diet, muscle mass,
muscle metabolism, medications, hydration status

In AKI, serum creatinine can take several days to
reach a new steady state
Diagnosis of AKI is Often Delayed

Considerable interest in identifying better
biomarkers of tubular injury: potentially
more accurate and earlier diagnosis
How to evaluate new
biomarkers?
Ideal Biomarker






Highly organ specific
Allow recognition of etiology of AKI
Correlate with histological findings
Correlate with degree of tubular damage
Noninvasive
Test be simple, quick, accurate, reliable ,
inexpensive and commonly available
Serum Biomarkers
Neutophil Gelatinase Associated
Lipocalin (NGAL)


Growth and differentiation of Renal
tubular epithelial cells
Bacteriostatic effect in distal urogenital
tract by interfering with bacterial
siderophore mediated iron aquisition
J Am Soc Nephrol 2006: 17:1503-1520
Neutophil Gelatinase Associated Lipocalin
(NGAL)
Neutophil Gelatinase associated
Lipocalin (NGAL)
Biomark Med. 2010April : 4 (2):265-280
Urine NGAL Platform


Abbott Diagnostics
ARCHITECT: Standardized clinical
platform
Plasma NGAL Kit
* In development. Currently not for sale in US
Cystatin C

Serum cystatin C -a nonglycosylated, 13.3-kDa protein
belonging to cystatin protease
inhibitors.

After glomerular filtration, it is
fully catabolized in the proximal
renal tubule and is not returned
to blood.

When GFR decreases, cystatin
C level begins to rise
proportionately
Cystatin C

Endogenous, detected earlier than serum creatinine
to diagnose and identify progress

Independent of age, sex, race, body mass and
hydration

Nephlometry

Not diagnostically specific for AKI

Early marker of impaired glomerular function
rather than tubular lesion
Curr Med Chem 2007; 2007: 14 2314-2317
Blood Purif 2006; 24: 67-70
Uric Acid
Acute urate nephropathy
 Marker of Imminent onset of AKI
 Diagnostic marker
 Active indicator of intra-renal injury to
microvasculature
 Potent regulator of endothelial NO
levels
 Inhibitor of proliferation and migration
of epithelial cells

Nucleosides Nucleosides Nucleotides Nucleic acid 2008; 27 (8): 967-78
Uric Acid
Urine Biomarkers
Urine as Clinical material for
AKI
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Urinary enzymes of renal origin
Urinary low molecular weight proteins
Gene products - AKI markers specially
produced in the Kidney
Urinary Enzymes of Renal Origin

Site specific

Alkaline phosphatase, G glutamyl transpeptidase,
Alanine aminotranpeptidase:
Reflect damage of brush border membrane, loss of micro
villi
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

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Glutatione transferase: proximal and distal tubules
Critically ill patients
N acetyl β Dglucosaminidase (NAG): lysosomes of
proximal tubular cells
Shock 2006;26:245-53
Nephrol DialTransplant 2003;18:543-51
J Am Soc Nephrol 2007;18:904-12
Urinary Enzymes of Renal
origin
Very sensitive marker directly correlated with
serum creatinine and reduced GFR
 As early as first day of kidney injury
 Predictive value low
 Do not identify the cause or reversibility of
process
 May identify patients at Risk
 Prognosis
 Rapid inactivation of enzymes –collection and
storage

Urinay low molecular weight
proteins
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α1 microglobulin:Liver, bound to IgA, free form
excreted in urine
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β 2 microglobulin:Nephrotoxic agents , hypoxia
Instability of protein at pH <6 and alkalination of urine
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RBP:Stability at low pH
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Cystacin C:
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Tubular proteinuria better predictor of AKI than
enzymuria
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ELISA
AKI markers specially produced in in
Kidney
Protein products of genes specifically related to AKI
 Urinary cytokines and chemokines
 Structural and functional proteins of renal tubules
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Protein Products of Genes
Specifically related to AKI
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CYR61: Heparin binding protein, member of

KIM -1: Marker of ischemia and and toxic injury,
transmenbrane and extracellular ectodomains,
sensitive, specific , not affected by urine
characteristics
NGAL
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family of EGF, signaling molecule , protective role in
process of repair and neovascularization, earlier
marker
Am J physiol Renal Physiol 2006;291:456-64
J Am Soc Nephrol 2007;18:2704-2714
Urinary Cytokines and
Chemokines
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Immune response-Role in pathogenesis
Non specific parameters
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Gro α: 3 h after ischemia, after transplant
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IL-18: Chemotactic, ischemic tissue damage,
sensitivity and specificity of >90%

Am J physiol Renal Physiol 2006;29:1187-1193
J Clin Inves 2001;107:1145-1152
Structural and Functional
proteins of Renal tubules

F-Actin: Apical membrane of proximal tubular
cells , pH change causes depolymerization, actin
in the microvilli, 30 min after ischemia

NHE3: Most abundant sodium transporter in
renal tubules (60-70% reabsorption), observed
drop in sodium reabsoption , urinary excretion
of NHE3 may be regarded as a marker of AKI
Am J physiol Renal Physiol 1999;276:544-551
Am J Kidney Dis 2003; 42: 599-600
Summary Urinary Markers

Mainly used in experimental studies

Medical laboratories-sensitive , specific and
relatively costly immunological methods

Require active validation

Guidelines need to be developed for urine
collection, storage and centrifugation
Conclusion

AKI is a continuing problem in clinical practice associated
with high mortality and morbidity

Standard lab diagnosis of AKI is based on determination
of serum creatinine which is imperfect

Despite intense research no single ideal biomarker has
yet been found

Proteins in urine and plasma are a step forward in the
development of clinical practice with potential impact on
treatment outcomes

They require validation and trials in large patient
populations