acute kidney injury role of novel biomarkers r bhimma department of paediatrics and child health...
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ACUTE KIDNEY INJURY Role of Novel Biomarkers
R Bhimma
Department of Paediatrics and Child HealthNelson R Mandela School of Medicine
University of KwaZulu-Natal
Diagnosis Increase serum creatinine and/or blood urea nitrogen levels and/or decrease urine output
Sudden impairment of kidney function occurring over a period of hours to days.
Definition of AKI
Why is it important to detect AKI early?
A rise in serum creatinine of just 0.3mg/dl (26.5
mmol/l) has a four fold higher multivariable –
adjusted risk of death.
Children with AKI may be at risk for long-term
chronic kidney disease.
Acute Kidney Injury Network (AKIN) classification of AKI
Serum creatinine (SCr) criteria
Urine output (UO) criteria
Stage 1 ≥0.3 mg/dl (26.5 μmol/l) rise or rise to 1.5–1.99 X baseline
UO <0.5 ml/kg/h for 6 h
Stage 2 Rise to ≥2–2.99 X baseline UO <0.5 ml/kg/h for 12 h
Stage 3 Rise to ≥3 X baseline or ≥4 mg/dl (354 μmol/l) rise with an acute rise of at least 0.5 mg/dl (44 μmol/l)
UO<0.3 ml/kg/h for 24 h or anuria for 12 h
Ped Nephrol ,10 July 2010, Zubaida Al-Ismaili
Modified pediatric Risk, Injury, Failure, Loss, End-stage kidney disease (pRIFLE) criteria
Estimated creatinine clearances (eCCl)
Urine output (UO) criteria
Risk eCCl decreased by 25% UO<0.5 ml/kg/h for 8 h
Injury eCCl decreased by 50% UO<0.5 ml/kg/h for 16 h
Failure eCCl decreased by 75% or eCCl <35 ml/min/1.73 m2
UO<0.3 ml/kg/h for 24 h or anuria for 12 h
Lossᵃ Persistent failure >4 weeks
End-stage kidney diseaseᵃ Persistent failure >3 months
aThe pRIFLE stages “loss” and “end-stage kidney disease” are not AKI stages per se; they describe chronic outcomes of AKI
Limitations of serum creatinine and BUN
Limitations of Serum creatinine and BUN cont…
Elevated serum creatinine concentrations are not specific for AKI
and require differentiation from other pre-renal or extra-renal
causes.
Serum creatinine concentrations are not specific for renal tubular
lesions, pathogenetically related to AKI development.
Reflect the loss of glomerular filtration function, accompanying
the development of AKI.
Limitations of serum creatinine and BUN cont…
Increases in serum creatinine are detected later than the actual
GFR changes as creatinine accumulates over time.
Serum creatinine is a poor marker of kidney dysfunction as
changes in its concentrations are neither sensitive nor specific in
response to slight GFR alterations.
Changes in serum creatinine become apparent only when the
kidneys have lost ≥50% of their functional capacity.
What is a biomarker?
“ a characteristics that is objectively measured and evaluated as an
indicator of normal biological process, pathogenic process, or
pharmacologic response to a therapeutic intervention”.
Test Biomarker
Height Growth
Urinary dipsticks for nitrites UTI
Proteinuria Disease severity in IgA nephropathy.
Anti-GBM Ab Good pastures syndrome
Ideal Biomarker AKI
Non – invasive
Easily obtainable
Measurable using standardized assays
Fast results
Incur reasonable cost to perform
Possible roles for novel kidney injury biomarkers
Ismaili Z Al et al Ped Nephrol , 2010
Pathophysiological mechanics of AKI and repair
Proposed mechanisms for increased biomarker levels in plasma and urine
(3) Glomerular filtration
Increased biomarkerlevels in urine
(1) Increased synthesis in extrarenal tissues
(2) Release fromcirculating immune cells
Increased biomarkerlevels in plasma
(4) Impaired reabsorptionin the proximal tubule
(5) Increased synthesis intubular cells
(6) Release from infiltratingimmune cells
Martensson J et al BJA , 2012
Proposed phase of biomarker developmentGoals Phase Biomarker aims
Discoveryphase
Phase 1 • Identify leads for AKI biomarker.• Prioritize identified leads
Translationalphase
Phase 2 • Evaluate diagnostic accuracy• Assess the ability to distinguish AKI from non-AKI
Phase 3 • Evaluate the capacity of the biomarker to detect preclinical AKI or other AKI characteristic (e.g. severity, prognosis)
• Define criteria for a positive screening test (e.g. cut-off)
Validationphase
Phase 4 • Determine the operating characteristics of the biomarker-based screening test in a relevant population by determining the detection rate and the false referral rate (prospective study)
Phase 5 • To estimate the reduction in AKI morbidity and mortality afforded by the screening test (effects on population)
Coca SG, et al (2008) Urinary biomarkers for acute kidney injury: perspectives on translation. Clin J Am Soc Nephrol 3:481–490, Pepe MS, et al. (2001) Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 93:1054–1061
Summary of calculating diagnostic characteristics: sensitivity, specificity, positive predictive value, and negative predicative value.
Disease present Disease not present
Biomarker test positive True positive (TP) False positive (FP) TP+FP=total with positive test
Biomarker test negative False negative (FN) True negative (TN) FN+TN=total with negative test
TP+FN=total with disease FP+TN=total with no disease
How to calculate diagnostic characteristics
Sensitivity TP/(TP+FN): TP/total with disease
Specificity TN/(TN+FP): TN/total without disease
Positive predictive value (PPV)
TP/(TP+FP): TP/total with positive test Probability of actually having the disease when test is positive
Negative predictive value (NPV)
TN/(TN+FN): TN/total with negative test Probability of not having the disease when test is negative
Ismaili Z Al et al Ped Nephrol ,10 July 2010,
Hypothetical ROC: plot of the sensitivity of a test vs. 1-specificity for may different cut-off values of a biomarker
Kidney Biomarkers
> 20 protein biomarkers have been intensively studied.
Urinary biomarkers are regarded as more non invasive, easy to
measure, easily obtainable and provide earlier detection of AKI.
Depending on the time of appearance after AKI, urinary
biomarkers many be classified as those of structural injury or
functional injury.
Biomarkers of structural injury
Type of biomarkers Selective sites and associated types of injury
Kidney injury molecule-1 (KIM-1)* Proximal tubule injury (Ischemic AKI, nephrotoxins, RCC)
n-acetyl glucosaminadase (NAG) Proximal tubule injury
Neutrophil gelatinase-associated lipocalin (NGAL)*
Tubule and collecting duct injury (Ischemic AKI, nephrotoxins, delay allograft renal function)
Interleukin (IL)-18* Tubule injury (AKI, delayed allograft renal function)
Clusterin Tubule injury
Biomarkers of functional injuryCystatin C* Glomerular injury; in urine indicates proximal tubule injury
Total protein β2-microglobulin albumin Glomerular and tubular dysfunction
Brush border antigens
Adenosine deaminase binding protein
Carbonic anhydrase Proximal tubule injury
Other tubular antigens
Urinary enzymes
N-acetyl-β-D-glucosaminidase
Alanine aminopeptidase
Cathepsin B Proximal tubule injury
γ-glutamyltransferase
α-glutathione-S-transferase
β-glucosidase Proximal tubule > distal tubule injury
Alkaline phosphatase
Lactate dehydrogenase Distal tubule > proximal tubule injury
Others
Type IV Collagen Glomerular injury
Gamma-glutamyl transferase (γ-GT)
Liver type fatty acid binding protein (L-FABP)
Tubular epithelium injury
Retinol binding protein 4 (RBP4)
Sodium/hydrogen exchanger isoform
Alpha-glutathione S-transferase (α-GST)
Proximal tubule injury
Exosomal fetuin-A
Tamm-horsfall glycoprotein Distal tubule injury
pi-glutathione S-transferase (π-GST)
Neutrophil gelatinase – associated lipocalin (NGAL)
25–kDa polypeptide covalently bound to gelatinase
secreted from activated human neutrophils.
Most consistent biomarkers found during AKI.
Predominantly found in proliferating nuclear antigen–
positive proximal tubule cells.
Predicts the occurrence of AKI in paediatric and adult
patients after cardiac surgery.
Cont…
Neutrophil gelatinase – associated lipocalin (NGAL)
AUC- ROC for NGAL is 0,92 at 2 hours and 1,00 at 4 hours CBP.
Also predicts mobility and mortality in children who undergo
cardiac surgery.
Also predicts development of DGF.
Kidney Injury Molecule-1 (KIM-1)
Orphan trans-membrane receptor of unknown function.
Undetectable in normal kidney tissue or urine.
Markedly increased in ischaemic and nephrotoxic proximal tubular cell
injury, and in renal cell carcinoma.
Higher urinary KIM-1 associated with worse outcome in established AKI.
Cont…
W. K. Han et al Advances in Clinical Chemistry, Vol. 49, 2009, pp. 73-97.
Kidney Injury Molecule-1 (KIM-1)
AUC – ROC 0,57 at 2 hours, 0,83 at 12 hours, and 0,78 at 24 hours
after cardiac surgery.
Also predicts graft loss in renal transplant patients.
Useful in some studies to differentiate between AKI, CKD and
normal patients.
W. K. Han et al Advances in Clinical Chemistry, Vol. 49, 2009, pp. 73-97.
Interleukin (IL) -18
Pro-inflammatory cytokine
Mediates inflammatory process during ischaemic, sepsis and
nephrotic AKI.
Recruits neutrophils during ischaemic injury.
Can predict AKI 1 day ahead of serum creatinine.
Cont…
Interleukin (IL) -18
AUC – ROC 0.73 for development of AKI in patients with acute
respiratory distress syndrome.
Independent predictor of mortality in the above group of patients.
Also elevated after CPB --- ROC- AUC 0.61 at 4 hours, 0.75 at 12
hours and 0.73 at 24 hours.
Cystatin C
13 kDa cysteine protease inhibitor.
Secreted by all nucleated cells into plasma.
Freely filtered at the glomerulus and not secreted in the tubules.
Less influenced by factors other than GFR (e.g. age, sex, race, or
muscle mass).
Therefore change in serum and urinary cystatin C is more sensitive
than a change in serum Cr in predicting change in GFR.
Cont…
Cystatin C
Predicts the risk of AKI-associated CV morbidity.
Levels > 1.0mg/L also predict CV events and mortality in patients
with a GFR >60mls/min/1.73m².
Increase urinary cystatin C and alpha 1 - microglobulin are
predictors of an unfavourable outcome in ATN.
Has higher sensitivity and higher negative predictive value in
determining GFR in CKD.
Proposed Biomarker strategies for Renal Replacement Therapy (RRT)- initiation in AKI.
Some studies have shown better renal outcomes in patients who
start RRT while in RIFLE-risk or injury compared to failure.
However some patients may recover spontaneously.
Biomarkers like NGAL, cystatin C, NAG, KIM-1 and alpha 1 -
microglobulin can help distinguish patients in whom RRT will be
needed.
Proposed biomarkers – based strategy for RRT
Consider initiating RRT
BM indicatesRRT necessary
Severe AKI(AKIN stage 3)
MILD/ MODERATE AKI(Akin stage 1-2)
Conservative treatment
BM Intermediate
BM indicate RRT Unlikely
Measure BMAKI present
Conclusion
Need a ‘panel’ of biomarkers making it possible for early
detection, treatment, and hopefully, preventing AKI.
As cardiology moved form LDH to troponins for the
diagnosis of MI, intensive care nephrology will hopefully
evolve from serum Cr to tissue specific injury biomarkers.
