urinary biomarkers in acute kidney injury · urinary biomarkers in acute kidney injury max bell md,...

Urinary biomarkers in acute kidney injury

Max BellMD, PhDKarolinska University Hospital Solna/Karolinska Institutet

Development of AKI-biomarkers

Early markers of AKI, do we need them?

Identify risk Identify injury Monitor injury & repair Monitor outc.

GFRdrop

Creatinine rise

Primaryprevention

Secondary prevention(post biomarker change)

Renal replacement therapy

Injury evolutiontime

Nor

mal

Rena

lrec

over

y?

Patients with septic AKI randomized to receivealkaline phosphatase (AP) och placebo

•AP, n = 16•Placebo, n = 19

Kidney status at study entry:

AP Placebo

Too late?

Pickers et al. Critical Care 2012

Patients with septic AKI randomized to receiveAlkaline phosphatase (AP) or placebo

Pathophysiology

Markers of kidney injury


uCystatin C

• Reabsorbed via megalin receptor in proxtubule.

• Poor AKI prediktor (AuROC 0.64)according to recent meta analysis1.

• Sepsis per se increases uCys C2.Competitive inibition of megalin rec due to increased

urinary albumin in sepsis?

1Zhang et al. Am J Kidney Dis 20112Nejat et al. Crit Care 2010


Kidney Injury Molecule (KIM) 1

• Transmembrane glycoprotein expressed on epithelial cells after injury

• Involved in the cellular repair process

• Moderate ability to predict AKI (AuROC 0.68 0.78)


Interleukin (IL) 18

• Proinflammatory cytokine

• Secreted by proximal tubular cells and leukocytes

• Varying ability to predict AKI (AuROC 0.53 0.89)


N acetyl d glucosaminidase (NAG)

• Lyzosomal enzyme

• Found in several human cells including tubular

• > 130 kDa. Not filtered

• Elevated urin levels in several active renal diseases

• Moderate ability to predict AKI (AuROC 0.61 0.72)


Urinary liver-type fatty acid-binding protein (L-FABP)

• Fatty acid-binding protein

• Molecular weight of approximately 14 kDa

• Distribution confined to the proximal tubular cells

• In healthy human kidneys, L-FABP is reportedly found inthe cytoplasm of the proximal tubular cells and is rapidlyreleased into the tubular lumen in response to ischaemiaor oxidative stress


Neutrophil gelatinase associated lipocalin (NGAL)

NGAL

• 25 000 Da (monomeric); 45 000 Da (dimeric)

• Involved in iron transport

• Released by neutrophils upon activation

• Increased expression in several tissues inresponse to inflammation

• Among the most up regulated genes intubular cells after ischaemic AKI in animalmodels

Markers of kidney injuryuNGAL

Time after cardiopulmonary bypass (h)

uNG

AL

(ng/

gcr

eati

nin)

RIFLEExcellent predictor of CS inchildren (AuROC 0.998).

AKI

•20 children developed AKI•51 children without AKI

Mishra et al. Lancet 2005;365:1231 1238

Plasma NGAL is not an AKI-predictor

5

10

100

1000Pl

asm

a N

GAL

(ng/

mL)

30 100 500eGFR (mL/min/1.73m2)a

5

10

100

1000

Plas

ma

NG

AL (n

g/m

L)

30 100 500eGFR (mL/min/1.73m2)b

Fig. 2 Scatter plots showing the relationship between HNL/NGAL and GFR, estimated by the MDRD formula (eGFR), on sepsis-free (a) and onseptic (b) days, respectively. Superimposed on the plots are the fitted 25th, 50th and 75th percentile regression lines. The horizontal, dashed linesindicate the upper reference limit for plasma HNL/NGAL. MDRD modification of diet in renal disease.

Mårtensson, Bell et al, in press

But urine NGAL seems decent…

Peak levels of pNGAL (a)and uNGAL (b) in non-AKIpatients with SIRS, severesepsis, and septic shockand in AKI patients withseptic shock.

The horizontal lines indicatethe upper reference limitsfor pNGAL and uNGAL,respectively. SIRS systemicinflammatory responsesyndrome, AKI acute kidneyinjury

Mårtensson, Bell et al, ICM 2010 Aug;36(8):1333-40

Plasma

Urine

And urine NGAL is less confounded by sepsis

Mårtensson, Bell et al, ICM 2010 Aug;36(8):1333-40

VariablesCutoffvalue

AUC-ROC Sensitivity Specificity

Compared to all non-AKI patients

pNGAL>120 ng/mL

0.85(0.67–1.0)

0.83(0.34–1.0)

0.86(0.64–0.97)

uNGAL>68 ng/mgcreatinine

0.86(0.68–1.0)

0.71(0.29–0.96)

1.0 (0.85–1.0)

Compared to non-AKI patients with septic shock

pNGAL>120 ng/mL

0.67(0.39–0.94)

0.83(0.36–1.0)

0.50(0.12–0.88)

uNGAL>68 ng/mgcreatinine

0.86(0.68–1.0)

0.71(0.29–0.96)

1.0 (0.54–1.0)

Plasma NGAL may actually be a sepsis-predictor

Sepsis/nosepsis

n

Crude OR(95% CI)

Adjusted ORa

(95% CI)Adjusted ORb

(95% CI)Adjusted ORc

(95% CI)Adjusted ORd

(95% CI)

Plasma HNL/NGAL(ng/ml)

< 77 128/198 1.0 1.0 1.0 1.0 1.0

77 – 110 151/175 1.33 (0.8 – 2.3) 1.37 (0.8– 2.3) 1.34 (0.8 – 2.3) 1.32 (0.8 – 2.2) 1.33 (0.8 – 2.3)111 – 168 227/100 4.75 (2.5 – 8.9) 4.92 (2.6 – 9.2) 4.74 (2.5 -8.9) 4.56 (2.4 – 8.5) 4.68 (2.5– 8.7)

> 168 268/58 14.51(6.6-32.2) 15.00(6.7-33.4) 12.90(5.7–29.2) 12.71(5.6–28.7) 13.01 (5.8 – 29.2)aAdjusted for agebAdjusted for age and delta creatininecAdjusted for age, delta creatinine and APACHE II scoredAdjusted for age, delta creatinine APACHE II score and cardiovascular disease

Table 2. Multivariate logistic regression analysis showing the odds ratios (ORs) for sepsis in relation to HNL/NGAL levels in plasma.

Mårtensson, Bell et al, in press

What about monomeric NGAL in plasma (ELISA)?

Fig. 3. Kinetics of monomeric and dimeric HNL/NGAL during AKI development.(A) Median HNL/NGAL levels quantified by the ELISA-1 (closed circles) andELISA-2 (open circles) during the time frame from 24 h before AKI (AKI day 1)and up to 48 h after the AKI diagnosis (AKI day 2). (B) The ELISA-1/ELISA-2ratios (hollow diamonds) during the development of AKI are shown. Levels aredisplayed as medians and error bars are interquartile range. Mårtensson, Xu, Bell et al Clin Chim Acta. 2012 May 17.

Other urinary markers, detection of AKI

Evaluation of new acute kidney injury biomarkers in amixed intensive care unit *.Doi et al. Critical Care Medicine. 39(11):2464-2469,November 2011.

Table 2. Five urinary biomarkers for AKI detection andprediction

Other urinary markers, grading of AKI


Figure 2. Five urinary biomarker values grouped by acutekidney injury (AKI) severity

Other urinary markers, mortality prediction


Figure 3. Receiver operating characteristic analysis for14-day mortality

Table 3. Acute kidney injury biomarkers and 14-dmortality

Urinary markers post CABG

Urinary biomarkers in the clinical prognosis and earlydetection of acute kidney injuryKoyner J L et al. CJASN 2010;5:2154-2165

Urinary markers post CABG, areas of injury?

Urinary biomarkers in the clinical prognosis and earlydetection of acute kidney injuryKoyner J L et al. CJASN 2010;5:2154-2165

Koyner et al showed in patients undergoing cardiacsurgery that:

Kidney injury molecule-1 was best predictive fordetection of AKI before the procedure

Urinary cystatin C immediately afterward, andNeutrophil gelatinase-associated lipocalin within

the first 6 hrs after surgery

Do different biomarkers point to the differentareas of damage during AKI in the kidney?

Other promising urinary markers of AKI

Haptoglobin Am J Physiol Renal Physiol. 2012 May 9. Proximal Tubule Haptoglobin Gene Activation Is An IntegralComponent Of The Acute Kidney Injury "Stress Response” Zager RA et al

Heme oxygenase 1 (HO-1) J Am Soc Nephrol. 2012 Mar 22. Plasma and Urinary HemeOxygenase-1 in Acute Kidney Injury. Zager RA et al

Fibulin-1Vanin-1 J Pharmacol Exp Ther. 2012 Mar 7. Urinary vanin-1 as a novel biomarker for early detection of drug-inducedacute kidney injury. Hosohata K et al

Back to urine NGAL, non-specific elevation?

Astute Medical Confidential Data

The Astute Panel has a compelling specificity profile


Conclusions


Markers of renal function still has a place in the ICU…but

We need injury markers

Urinary markers of renal injury may beuseful…acknowledging

That we are comparing novel biomarkers against an agingand suboptimal golden standard

urinary biomarkers in acute kidney injury · urinary biomarkers in acute kidney injury max bell md,...

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