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Biomarkers of Acute Kidney
Injury
Dr Sameena GhayurShifa College of Medicine /Shifa International
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 non-
glycosylated, 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
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
Glutatione transferase: proximal and distal tubules
Critically ill patients
N acetyl β Dglucosaminidase (NAG): lysosomes of proximal tubular cells
Shock 2006;26:245-53Nephrol 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
α1 microglobulin:Liver, bound to IgA, free form excreted in urine
β 2 microglobulin:Nephrotoxic agents , hypoxia Instability of protein at pH <6 and alkalination of
urine RBP:Stability at low pH
Cystacin C:
Tubular proteinuria better predictor of AKI than enzymuria
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
Protein Products of Genes Specifically related to AKI
CYR61: Heparin binding protein, member of family of EGF, signaling molecule , protective role in process of repair and neovascularization, earlier marker
KIM -1: Marker of ischemia and and toxic injury, transmenbrane and extracellular ectodomains, sensitive, specific , not affected by urine characteristics
NGALAm J physiol Renal Physiol 2006;291:456-64
J Am Soc Nephrol 2007;18:2704-2714
Urinary Cytokines and Chemokines
Immune response-Role in pathogenesis Non specific parameters
Gro α: 3 h after ischemia, after transplant
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