biomarkers of acute kidney injury dr sameena ghayur shifa college of medicine /shifa international...
TRANSCRIPT
![Page 1: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/1.jpg)
![Page 2: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/2.jpg)
Biomarkers of Acute Kidney
Injury
Dr Sameena GhayurShifa College of Medicine /Shifa International
![Page 3: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/3.jpg)
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
![Page 4: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/4.jpg)
Pathogenesis
![Page 5: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/5.jpg)
Pathophysiology
![Page 6: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/6.jpg)
AKI – A Systemic Condition
Functional and structural extra-renal organ injury occurs in AKI
Potential mediators •uraemic toxins •cytokines•leukocytes
![Page 7: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/7.jpg)
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
![Page 8: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/8.jpg)
RIFLE Criteria
Acute dialysis quality initiative(ADQI) group
![Page 9: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/9.jpg)
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
![Page 10: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/10.jpg)
Diagnosis of AKI is Often Delayed
Considerable interest in identifying better biomarkers of tubular injury: potentially more accurate and earlier diagnosis
![Page 11: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/11.jpg)
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
![Page 12: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/12.jpg)
Serum Biomarkers
![Page 13: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/13.jpg)
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
![Page 14: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/14.jpg)
Neutophil Gelatinase Associated Lipocalin (NGAL)
![Page 15: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/15.jpg)
Neutophil Gelatinase associated Lipocalin (NGAL)
Biomark Med. 2010April : 4 (2):265-280
![Page 16: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/16.jpg)
Urine NGAL Platform
Abbott Diagnostics ARCHITECT: Standardized clinical
platform
![Page 17: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/17.jpg)
Plasma NGAL Kit
* In development. Currently not for sale in US
![Page 18: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/18.jpg)
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
![Page 19: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/19.jpg)
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
![Page 20: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/20.jpg)
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
![Page 21: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/21.jpg)
Uric Acid
![Page 22: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/22.jpg)
Urine Biomarkers
![Page 23: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/23.jpg)
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
![Page 24: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/24.jpg)
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
![Page 25: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/25.jpg)
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
![Page 26: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/26.jpg)
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
![Page 27: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/27.jpg)
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
![Page 28: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/28.jpg)
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
![Page 29: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/29.jpg)
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
![Page 30: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/30.jpg)
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
![Page 31: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/31.jpg)
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
![Page 32: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/32.jpg)
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
![Page 33: Biomarkers of Acute Kidney Injury Dr Sameena Ghayur Shifa College of Medicine /Shifa International Hospital Sameena.ghayur@yahoo.com](https://reader035.vdocument.in/reader035/viewer/2022062217/56649ee15503460f94bf12bf/html5/thumbnails/33.jpg)