urinary biomarkers in acute kidney injury · urinary biomarkers in acute kidney injury max bell md,...
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Urinary biomarkers in acute kidney injury
Max BellMD, PhDKarolinska University Hospital Solna/Karolinska Institutet
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
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
Markers of kidney injury
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)
Markers of kidney injury
Interleukin (IL) 18
• Proinflammatory cytokine
• Secreted by proximal tubular cells and leukocytes
• Varying ability to predict AKI (AuROC 0.53 0.89)
Markers of kidney injury
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)
Markers of kidney injury
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
Markers of kidney injury
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
Evaluation of new acute kidney injury biomarkers in amixed intensive care unit *.Doi et al. Critical Care Medicine. 39(11):2464-2469,November 2011.
Figure 2. Five urinary biomarker values grouped by acutekidney injury (AKI) severity
Other urinary markers, mortality prediction
Evaluation of new acute kidney injury biomarkers in amixed intensive care unit *.Doi et al. Critical Care Medicine. 39(11):2464-2469,November 2011.
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
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