Urinary biomarkers in acute kidney injury. Max Bell MD, PhD Karolinska University Hospital Solna/Karolinska Institutet

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1 Urinary biomarkers in acute kidney injury Max Bell MD, PhD Karolinska University Hospital Solna/Karolinska Institutet

2 Development of AKI-biomarkers

3 Early markers of AKI, do we need them? GFR drop Normal Injury evolution time Creatinine rise Renal recovery? Identify risk Identify injury Monitor injury & repair Monitor outc. Primary prevention Secondary prevention (post biomarker change) Renal replacement therapy

4 Pickers et al. Critical Care 2012 Patients with septic AKI randomized to to receive alkaline Alkaline phosphatase (AP) (AP) och or placebo AP,n=16 Placebo,n=19 Kidney status at study entry: AP Placebo Too late?

5 Pathophysiology

6 Markers of kidney injury

7 Markers of kidney injury ucystatin C Reabsorbed via megalin receptor in prox tubule. Poor AKI prediktor (AuROC 0.64) according to recent meta analysis 1. Sepsis per se increases ucys C 2. Competitive inibition of megalin rec due to increased urinary albumin in sepsis? 1 Zhang et al. Am J Kidney Dis Nejat et al. Crit Care 2010

8 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 )

9 Markers of kidney injury Interleukin (IL) 18 Proinflammatory cytokine Secreted by proximal tubular cells and leukocytes Varying ability to predict AKI (AuROC )

10 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 )

11 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 in the cytoplasm of the proximal tubular cells and is rapidly released into the tubular lumen in response to ischaemia or oxidative stress

12 Markers of kidney injury Neutrophil gelatinase associated lipocalin (NGAL) Da (monomeric); Da (dimeric) Involved in iron transport NGAL Released by neutrophils upon activation Increased expression in several tissues in response to inflammation Among the most up regulated genes in tubular cells after ischaemic AKI in animal models

13 Markers of kidney injury ungal Excellent predictor of CS children (AuROC 0.998). 20 children developed AKI 51 children without AKI AKI in ungal (ng/g creatinin) RIFLE Mishra et al. Lancet 2005;365: Time after cardiopulmonary bypass (h)

14 Plasma NGAL is not an AKI-predictor Plasma NGAL (ng/ml) 100 Plasma NGAL (ng/ml) a egfr (ml/min/1.73m2) b egfr (ml/min/1.73m2) Fig. 2 Scatter plots showing the relationship between HNL/NGAL and GFR, estimated by the MDRD formula (egfr), on sepsis-free (a) and on septic (b) days, respectively. Superimposed on the plots are the fitted 25 th, 50 th and 75 th percentile regression lines. The horizontal, dashed lines indicate the upper reference limit for plasma HNL/NGAL. MDRD modification of diet in renal disease. Mårtensson, Bell et al, in press

15 But urine NGAL seems decent Plasma Urine Peak levels of pngal (a) and ungal (b) in non-aki patients with SIRS, severe sepsis, and septic shock and in AKI patients with septic shock. The horizontal lines indicate the upper reference limits for pngal and ungal, respectively. SIRS systemic inflammatory response syndrome, AKI acute kidney injury Mårtensson, Bell et al, ICM 2010 Aug;36(8):

16 And urine NGAL is less confounded by sepsis Variables Cutoff value Compared to all non-aki patients pngal ungal >120 ng/ ml >68 ng/mg creatinine AUC-ROC Sensitivity Specificity 0.85 ( ) 0.86 ( ) 0.83 ( ) 0.71 ( ) Compared to non-aki patients with septic shock pngal ungal >120 ng/ ml >68 ng/mg creatinine 0.67 ( ) 0.86 ( ) 0.83 ( ) 0.71 ( ) 0.86 ( ) 1.0 ( ) 0.50 ( ) 1.0 ( ) Mårtensson, Bell et al, ICM 2010 Aug;36(8):

17 Plasma NGAL may actually be a sepsis-predictor Table 2. Multivariate logistic regression analysis showing the odds ratios (ORs) for sepsis in relation to HNL/NGAL levels in plasma. Sepsis/no sepsis n Crude OR (95% CI) Adjusted OR a (95% CI) Adjusted OR b (95% CI) Adjusted OR c (95% CI) Adjusted OR d (95% CI) Plasma HNL/NGAL (ng/ml) < / / ( ) 1.37 ( ) 1.34 ( ) 1.32 ( ) 1.33 ( ) / ( ) 4.92 ( ) 4.74 ( ) 4.56 ( ) 4.68 ( ) > / ( ) 15.00( ) 12.90( ) 12.71( ) ( ) a Adjusted for age b Adjusted for age and delta creatinine c Adjusted for age, delta creatinine and APACHE II score d Adjusted for age, delta creatinine APACHE II score and cardiovascular disease Mårtensson, Bell et al, in press

18 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) and ELISA-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-2 ratios (hollow diamonds) during the development of AKI are shown. Levels are displayed as medians and error bars are interquartile range. Mårtensson, Xu, Bell et al Clin Chim Acta May 17.

19 Other urinary markers, detection of AKI Table 2. Five urinary biomarkers for AKI detection and prediction Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit *. Doi et al. Critical Care Medicine. 39(11): , November 2011.

20 Other urinary markers, grading of AKI Figure 2. Five urinary biomarker values grouped by acute kidney injury (AKI) severity Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit *. Doi et al. Critical Care Medicine. 39(11): , November 2011.

21 Other urinary markers, mortality prediction Table 3. Acute kidney injury biomarkers and 14-d mortality Figure 3. Receiver operating characteristic analysis for 14-day mortality Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit *. Doi et al. Critical Care Medicine. 39(11): , November 2011.

22 Urinary markers post CABG Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury Koyner J L et al. CJASN 2010;5:

23 Urinary markers post CABG, areas of injury? Koyner et al showed in patients undergoing cardiac surgery that: Kidney injury molecule-1 was best predictive for detection of AKI before the procedure Urinary cystatin C immediately afterward, and Neutrophil gelatinase-associated lipocalin within the first 6 hrs after surgery Do different biomarkers point to the different areas of damage during AKI in the kidney? Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury Koyner J L et al. CJASN 2010;5:

24 Other promising urinary markers of AKI Haptoglobin Am J Physiol Renal Physiol May 9. Proximal Tubule Haptoglobin Gene Activation Is An Integral Component Of The Acute Kidney Injury "Stress Response Zager RA et al Heme oxygenase 1 (HO-1) J Am Soc Nephrol Mar 22. Plasma and Urinary Heme Oxygenase-1 in Acute Kidney Injury. Zager RA et al Fibulin-1 Vanin-1 J Pharmacol Exp Ther Mar 7. Urinary vanin-1 as a novel biomarker for early detection of drug-induced acute kidney injury. Hosohata K et al

25 Back to urine NGAL, non-specific elevation? Astute Medical Confidential Data

26 The Astute Panel has a compelling specificity profile Astute Medical Confidential Data

27 Conclusions Markers of renal function still has a place in the ICU but We need injury markers Urinary markers of renal injury may be useful acknowledging That we are comparing novel biomarkers against an aging and suboptimal golden standard Astute Medical Confidential Data