Biomarkers of Acute Kidney

Injury

Dr Sameena GhayurShifa College of Medicine /Shifa International

HospitalSameena.ghayur@yahoo.com

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