Using Kidney Biomarkers for AKI: Risk Assessment, Diagnosis, and Staging. Rajit K. Basu Patrick Murray Jay L. Koyner

Transcription

1 Using Kidney Biomarkers for AKI: Risk Assessment, Diagnosis, and Staging Rajit K. Basu Patrick Murray Jay L. Koyner

2 Using Kidney Biomarkers for AKI: Risk Assessment, Diagnosis, and Staging Starting the Fast Break Rajit K. Basu, MD MMI FAAP FCCM Co-Director, Center for Acute Care Nephrology Assistant Professor, Division of Critical Care Medicine Cincinnati Children s Hospital Medical Center

3 Disclosures Research Funding from NIH/NIDDK Consulting Baxter-Gambro Renal Products La Jolla Pharmaceuticals

4 Proper Positioning à Scoring Probability How does this relate to AKI and biomarkers?

5 pensa what was. It is Gabriel Stallman is a 65 year old overweight smoker. After getting into a heated argument with his son 25 year-old son Bob about his career choices and not working in the factory like the rest of his family, he sits down to read the paper. He begins to feel tightness in his chest and abdomen and tells his wife. Concerned, his wife takes him to the hospital. After a few hours in the smoke filled ED of their local hospital, the doctors take a full history, draw some blood and determine this is not indigestion or abdominal pain. They perform an ECG and are concerned about heart injury but his pain progresses and he develops shortness of breath. He goes unconscious and amidst a flurry of sudden activity, including consultation with a cardiologist and treatment with aspirin, he dies in the ED 8 hours after arriving.

6 pensa what is. It is Robert Stallman is a 65 year old overweight smoker. After getting into a heated argument with his son 25 year-old son Jay about his career choices and having to move back into the house, he sits down to read the paper. He begins to feel tightness in his chest and abdomen and tells his wife. He remembers watching his father die 50 years earlier of a heart attack. Concerned, his wife takes him to the hospital. After a few minutes in the ED of their local hospital, the doctors perform an ECG, are concerned about coronary syndrome, and draw some blood for serum troponin. The clock is started and the interventional cardiologists are called as he is given oxygen and morphine. This is not indigestion or abdominal pain. Within 8 hours after arrival, a catheterization and stent placement is performed, he is recovered in post-anesthesia, and he wakes up in his cardiac ICU bed and resumes reading his paper.

7 agenda Troponin, The Cherry Picking Biomarker AKI Biomarkers, Finally Usable? Risk stratification and Renal Angina Risk Assessment and Moving the Needle

8 agenda Troponin, The Cherry Picking Biomarker AKI Biomarkers, Finally Usable? Risk stratification and Renal Angina Risk Assessment and Moving the Needle

9 Dawber and Framingham, MA Dawber, Am J Pub Health 1951

10 Framingham Follow-up D Agostino, Circulation 2008 Dawber, Am J Pub Health 1959

11 Courtesy of Kellum JA, 2012 Risk Factors Enough? Age-Adjusted Death Rates for Coronary Artery Disease in the US First CABG performed in US 1967 CCUs Widely adopted CK test Streptokinase FDA Approval 1977 CABG widely adopted First PTCA 1987 tpa Approved Vital Statistics US, NCHS 1 Rosalki SB. An improved procedure for serum creatine phosphokinase determination. J Lab Clin Med 1967;69: Killip T 3rd, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol 1967;20:457 64

12 The Gold Standard Troponin to predict MI is optimized because of context dependent use Classic Risk Factors Ancillary Tests + Early Dx Early Tx Early Recovery Troponin

13 Gold Standard?

14 Troponin Value Analysis San Diego County: 16 Major medical centers Average of 100 ER visits/day = 16 * 100 * 365 = ER visits/year Cost of Troponin-I (~ $15/sample) Cost of one Troponin per visit SD County EDs - $8,760,000 Context Dependent Troponin Testing If number of ED patients with chest pain, EKG changes is less.. % Pts with Acute Coronary Syndrome # pts Troponin cost per pt (millions) Cost savings (millions)

15 Pre- / Post- Test Probability Cherry Picking X Enhanced pre-test probability optimizes utility of a confirmatory test Context, or targeting, optimizes the utility of a biomarker

16 agenda Troponin, The Cherry Picking Biomarker AKI Biomarkers, Finally Usable? Risk stratification and Renal Angina Risk Assessment and Moving the Needle

17 Risk Stratification Continuum Biomarkers SCr/UOP

18 Honore et al. Annals of Intensive Care 2012, 2:24 Review Urinary Biomarkers in Acute Kidney Injury: Ready for Prime Time? REVIEW Related Article, p. 632 humans repeatedly fail to alter the course of clinical AKI (such as insulin-like growth factor cute kidney injury (AKI) is a serious and A 8 or atrial natriuretic peptide 9 ). There are several potentially devastating complication in potential reasons for this. First, the current paradigm is derived from animal models, and so may hospitalized patients. In the setting of cardiac surgery with cardiopulmonary bypass (CPB), not be completely applicable to human AKI. acute kidney failure requiring dialysis occurs in Second, even if the paradigm is broadly applicable, it is probably incomplete. The response of approximately 1%-2% of patients and is associated with a mortality in excess of 60%. 1,2 Less the kidney Elisabeth to andeischemic Waele 1, insult WillemisBoer complex 3, Vincent and Collin 4 and Herbert D Spapen 1 severe stages of AKI, not requiring dialysis, can multifaceted, involving induction of multiple P r a s a d Devarajan a occur in up to 17% of patients 3,4 and are independently associated with a 19-fold increase in short- others injurious Abstract(maladaptive), and many of them pathways, some of them protective (adaptive), term mortality. 3 Even mild kidney impairment, undiscovered. Finally, current, noninvasive serum markers of AKI (such as creatinine or cysta- College Dublin, Dublin, Ireland defined as a rise in serum creatinine of 25% over baseline, is associated with a doubling in longterm mortality up to 10 years after surgery. 4 The and become abnormal well after AKI has been tin C) are markers of filtration rather than injury negative effect is independent of other prognostic factors, and persists even if kidney function sible 10 and giving no insight into the degree or established, rendering early intervention impos- recovers to baseline. 4 In order for potential therapeutic interventions to be successful, it is critical human AKI. nature of kidney injury or the pathophysiology of to identify biomarkers that are capable of detecting AKI early in the course of the disease. In this cused on Recent research efforts, therefore, have fo- rate, identification may enhance of diagnostic urinary biomarkers and prognostic of accuracy in the future. issue of the American Journal of Kidney Diseases, Devarajan et al utilize unbiased proteomic several reasons. First, urine is easily accessible kidney injury. This is an attractive strategy for K e y W o r d s techniques to identify 1 -microglobulin, 1 -acid in human apoptosis, cohorts. Sepsis Second, modulation, in the Blood presence purification, of function Dialysis, CRRT, Review glycoprotein, and albumin as diagnostic and prognostic markers of AKI in children undergoing tionalreview proteins (biomarkers) that are either fil- tubular injury, the urine is likely to contain addi- CPB. 5 tered but Introduction not reclaimed by the injured tubule or A b s t r a c t Ischemic AKI represents a sequence of events released Accurate or secreted diagnosis into the of AKI urineinbyanthe ICU injured setting is challenging. cellindeed, or by infiltrating the characteristic inflammatory swingscells. renal function conceptually separated into initiation, extension, tubular maintenance, and repair phases. The initiation Third, over discovery time in of critically novel ill proteins patientsassociated largely reduce the validitymay of auncover sole creatinine-based novel pathways AKI ofassessment. kidney This has and extension phases are characterized by alteration of microvascular hemodynamics and activa- injurystimulated or repair. This researchers might provide to establish the basismultidimensional for with AKI tion of inflammatory pathways in response to both the classification early diagnosis systems andthat therapy use of specific AKI. criteria to grade still underway. ischemic insult. Tubular epithelial injury resulting from these insults can induce apoptosis and, and proteomics sents the most provide widely anaccepted alternative tooland score AKI Recent AKIadvances severity. At in present, genomics, themetabolomics, RIFLE classification repre- in severe injury, necrosis, luminal sloughing of complementary severity. approach to the process of biomarkerto discovery. better discriminate These technologies for AKI severity, allow aearly recogni- epithelial cells, tubular obstruction, and back leak. Sublethally injured tubular cells can lose systematic tion of interrogation renal dysfunction, of the genome, i.e., well metabolome, serum or proteome, creatinine respectively, do occur, aimed hasatgained identi- considerable before changes in their cytoskeletal integrity, brush border membranes, and cell polarity. Mislocalization of adhesion molecules leads to loss of viable epithelial (or absence increases of disease). in serumonce creatinine identified, are associated the role with a confying interest. genes orit proteins has been associated evidenced withthat disease small or relative cells into the tubular lumen. In the repair phase, comitant increase in patient mortality. However, and clinical evenoutcomes. surviving epithelial cells undergo dedifferentiation, serial evaluation of serum creatinine levels does not proliferation, and subsequently redifferentiation Address correspondence to Martina Reslerova, MD, PhD, leading to restitution of normal tubular epithelium Nephrology Section, University of Manitoba, St. Boniface (reviewed in detail in 6,7 * Correspondence: Patrick.Honore@uzbrussel.be ). General 1 Intensive Hospital, Care 409 Dept, Tache Universitair Ave, Winnipeg, Ziekenhuis MB Brussel, R2HVrije 2A6. Universiteit Brussel, nosis of AKI [2]. Brussels, mreslerova@sbgh.mb.ca Belgium Although this paradigm has provided a framework for possible therapeutic interventions in 5 Critical Care Nephrology Platform, Intensive Care Department, Universitair 2010 by the National Kidney Foundation, Inc /10/ $36.00/0 Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium animal models of AKI, similar interventions in doi: /j.ajkd Full list of author information is available at the end of the article N e p h r o n C l i n P r a c t ; : D O I : / Open Access Biomarkers for early diagnosis of AKI in the ICU: ready for prime time B i ouse m aat r k ethe r s ibedside? n A c u t e K i d n e y I n j u r y : Patrick M Honore 1,5*, Rita Jacobs 1, Olivier Joannes-Boyau Are We 2, LiesReady Verfaillie 1, Joukefor De RegtPrime 1, Viola Van Gorp Time? 1, P a t r i c k Murray b a N e p h r o l o g y a n d H y p e r t e n s i o n, C i n c i n n a t i C h i l d r e n s H o s p i t a l M e d i c a l C e n t e r, U n i v e r s i t y o f C i n c i n n a t i C o l l e g e of Medicine, Cincinnati, Ohio, USA; Because of its still rising incidence and high mortality rate in intensive care b S c h o o l o f M e d i c i n e a n d M e d i c a l S c i e n c e, H e a l t h S c i e n c e s C e n t r e, U n i v e r s i t y unit (ICU) patients, early recognition of acute kidney injury (AKI) remains a critical issue. Surprisingly, effective biomarkers for early detection and hence appropriate and timely therapy of AKI have not yet entered the clinical arena. We performed a systematic search of the literature published between 1999 and 2011 on potential early biomarkers for acute renal failure/kidney injury in an at-risk adult and pediatric population following the Quorum Guidelines. Based on this review, recommendations for the clinical use of these biomarkers were proposed. In general, kidney biomarkers may aid to direct early aggressive treatment strategies for AKI thereby decreasing the associated high mortality. To date, however, sensitivity and specificity of individual biomarker assays are low and do not sustain their routine clinical use. Kits containing a combination of established biomarkers, in conjunction with measured glomerular filtration Our long-standing reliance on serum creatinine measurements has clearly hindered progress in acute kidney Keywords: Hemofiltration, Biomarkers, EarlyB idiagnosis, o m a r k e r Sepsis, A c u t e Septic k i d n e y shock, i n j u r y SIRS, K i dacute n e y d akidney m a g e injury, K i d n eacute y tubular injury (AKI), the incidence of which is increasing globally [1]. This condition accounts for 3 5% of admissions allow to intercept adequately the rapidly in evolving general hospitals, with serious adverse outcomes that changes in renal function in severely ill subjects. have There- s a r e attention r e q u i r e d has t o i mfocused p r o v e on t h e the t i mdevelopment e l y d e t e c - of Serum early creatinine, the current standard for measurement not changed significantly in the past several decades. N o v e l b i o m a r k e rfore, tion of early acute biomarkers, kidney injury enabling (AKI) and diagnosis to improve of AKI the long differential diagnosis, atinine prognostic levels start assessment, to increase. and Logically, manage- a combination marker for many reasons. First, a single measurement of before of kidney cre- function and dysfunction, is a flawed AKI ment of AKI cases. of It biomarkers is anticipated could that enhance novel biomarkers diagnostic of accuracy, serum but creatinine cannot distinguish true structural (intrinsic) is AKI (with acute renal tubular damage) from early structural AKI validation ( acute of kidney current damage ) individual will provide candidate critical diagnostic and prognostic stratification and comple- chronic kidney disease or from functional, and potential- biomarkers ment functional markers such as serum creatinine. Further ly hemodynamically reversible, AKI ( prerenal azotemia ) studies are required Looking to conclusively for the kidney demonstrate troponin the association between The early intensive kidney damage care community biomarkers is faced and clini- with anagement import- of each is distinct and mismanagement is delete- [2]. It is critical to make these distinctions, since the mancal outcomes, both ant and with frustrating and independently dilemma. On of functional the one hand, rious. AKI is Second, creatinine levels are dramatically influenced critic- by several nonrenal factors such as age, gender, markers, and to increasingly discern whether complicating or not randomization the course of disease to a in treatment for AKI allybased ill patients on high causing structural/damage several million deaths biomarker levels results everyin year an improvement [1]. On the other in kidney hand, function despite being tion aware status, and nutrition status. Third, an increase in se- worldwide muscle mass, muscle metabolism, medication use, hydra- of the AKI burden on outcome, S. KICU a r g e r Aphysicians G, B a s e l rum remain creatinine is delayed in AKI due to a number of factors, including: of significant renal functional reserve (in deprived of effective biomarkers for early recognition AKI. As a consequence, the delay in initiating appropriate therapy contributes significantly to the dismal kidney prog-disease), the obligatory time required for the ac- many patients, but not necessarily in those with chronic Changing Paradigms cumulation of circulating creatinine before a new steadystate serum concentration is reached, and the masking Inin contrast Acute Kidney with Injury: the variety From of Mechanisms biologicalto markers (including troponins) for early diagnosis of cardiac damage Management Proceedings of the 5th Annual UAB-UCSD O Brien Center Symposium (San Diego, Calif., USA, March 4, 2014). and further delay of serum creatinine increments by a [3], standard assessment of renal function in ICU 2012 Honore et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp Attribution License 609 ( which permits unrestricted use, distribution, and reproduction 2014 S. Karger AG, Basel Patrick Murray in any medium, provided the original work is properly cited /14/ $39.50/0 School of Medicine and Medical Science Health Sciences Centre, University College Dublin karger@karger.com Belfield, Dublin 4 (Ireland) ucd.ie P u b l i s h e d o n l i n e : S e p t e m b e r 2 4, Downloaded by: /27/2016 7:22:31 PM

19 What about biomarkers to predict AKI? Vanmassenhove, NDT 2012

20 Table 3. Cardiac surgery Author PY Biomarker U/S/P Outcome AKI def/outcome def Patients/events AURoC PPV (%) Parikh [67] 2011 NGAL U AKI Doubling of Screa 1219/ NA NA P 0.7 NA NA Screa immediate P 0.72 NA NA postop Xin [68] 2008 NGAL U AKI AKIN both 33/ Wagener [69] 2007 NGAL U AD Screa*1.5 81/ Wagener [46] 2008 NGAL U AKI AKIN crea 426/ Haase-Fielitz [50] 2009 NGAL P AKI Screa*1.5 within 5 days 100/ /0.87 (ICU arr/24 h 52/53 93/97 postoperatively post) NGAL P AKI RIFLE egfr >60 ml/min: 73/ 0.80/ /57 94/95 15 NGAL P AKI RIFLE 100/5 0.73/ /69 69/61 NGAL P RRT + M NGAL P RRT + M egfr >60 ml/min: 73/ NA NA NA 2 Haase-Fielitz [19] 2009 NGAL P AKI Screa* 1.25 within 48 h 100/ Screa* 1.25 within 72 h 100/ Screa*1.25 within 120 h 100/ Screa* within studies 168 h 100/ Screa 0.3 mg/dl or * h 100/ Screa*1.25 or RRT within 72 h 100/ ROC Screa*1.5 Range: within 48 h / Screa*1.5 within 72 h 100/ Screa* h 100/ Majority Screa*1.5 within: h / RIFLE R RIFLE both 100/ RIFLE I 100/ RIFLE F 100/ AKIN I AKIN both 100/ AKIN II 100/ AKIN III 100/ RRT 100/ Tuladhar [70] 2009 NGAL U AKI Screa 0.5 mg/dl within 48 h 50/ P Perry [49] 2010 NGAL P AKI Screa*1.5 within 4 days 879/ Prabhu [71] 2010 NGAL P AKI RIFLE crea 30/ McIllroy [51] 2010 NGAL U AKI AKIN crea 426/85 egfr <30 21/ egfr / egfr / egfr / egfr >120 53/ Koyner [20] 2008 NGAL P AKI Screa*1.25 or RRT 72/ NA NA NGAL U need within 72 h Haase [72] 2009 NGAL P AKI AKIN both 100/ NGAL + CysC S Koyner [73] 2012 NGAL U AKI AKI progression 380/45 NA NA NA P NPV (%) 4 J. Vanmassenhove et al.

21 Ho AKJD 2015

22 Table 4. Emergency department Author PY Biomarker U/S/ P Outcome AKI def/outcome def Patients/events AURoC PPV (%) NPV (%) Nickolas et al. [21] Shapiro et al. [23] Nickolas et al. [22] Nickolas et al. [21] 2008 NGAL U AKI RIFLE crea 635/ NGAL P AKI 0.5 mg/dl or 661/ RRT need within 72 h RIFLE R Screa* /27 NA 7 98 RIFLE I Screa*2 661/15 NA NGAL U Intrinsic 1635/ AKI T0 creatinine > S studies T0 creatinine > S NA IL-18 ROC Range: KIM-1 U U Limited data / 3 groups 2008 NAG U AKI RIFLE crea 635/ α 1 MG U α 1 acidgp U FENA U Creatinine S Creatinine P RIFLE I Screa* /27 NA 4 99 Shapiro et al. [23] Soto et al. [24] 2010 Cystatin C S AKI AKIN crea 616 AKI: 130 Prerenal azotaemia: 159 Stable CKD: 15 AKI Screa*2 661/15 NA U Creatinine S AKI AKIN crea U 0.62 NA NA

23 Table 5. Critically ill patients at ICU Author PY Biomarker U/S/P Outcome AKI def/outcome def Patients/events AURoC PPV (%) Ahlström [83] 2004 Cystatin C S ARF RIFLE F both 202/ NA NA Herget-Rosenthal 2004 Cystatin C U RRT Patients with non-oliguric ATN 73/ [84] Herget-Rosenthal 2004 Cystatin C S ARF RIFLE crea 85/44 Rday-2/-1: 0.82/ /95 66/83 [85] Iday-2/-1: 0.92/ /100 63/81 Fday-2/-1:0.97/ /100 76/93 Cystatin C S RRT 85/17 Rday-2/-1:0.69/ /76 86/93 Mazul-Sunko 2004 Cystatin C P ARF Screa 267 µmol/l or diuresis <30 29/10 NA NA NA [86] ml/h in patients without CKD Hei [87] 2008 Cystatin S ARF Screa to 132 µmol/l or BUN to 60/10 NA S 18 mmol/l Perianayagam 2009 Cystatin C S RRT or M Inclusion of patients with ARF 200/ NA NA [58] Clinical model + cystatin C defined as BL 1.9 mg/dl: Screa 0.83 NA NA Clinical model + creatinine 0.5 mg/dl 0.83 NA NA Clinical model + urea 0.84 NA NA Clinical model + urine output 45 studies 0.84 NA NA Clinical model alone 0.82 NA NA Portal [88] 2010 Cystatin C S AKI AKIN crea 80/ NA NA Cystatin C S ROC Severe AKI Range: Severe AKI: stage / NA NA Nejat [89] 2010 Cystatin C P AKI AKIN crea 444/ NA NA Creatinine S Majority : NA NA Cystatin C P AKI 7d AKIN crea within 7 days 319/73 (no AKI on 0.65 NA NA Creatinine S entry) 0.61 NA NA Cystatin C P AKI sust Screa*1.5 within 7 days and 24 h 319/19 (no AKI on 0.80 NA NA Creatinine S entry) 0.57 NA NA Cystatin C P RRT 319/? (no AKI on 0.84 NA NA Creatinine S entry) 0.77 NA NA Nejat [59] 2010 Cystatin C U AKI 48 h AKIN crea 319/73 (no AKI on 0.54 NA NA entry) U AKI 48 h 51/? (sepsis, no AKI 0.71 NA NA on entry) 51/? (sepsis, no AKI on entry) P AKI 48 h 268/? (no sepsis, no Not predictive NA NA AKI on entry) U AKI 48 h 268/? (no sepsis, no 0.45 NA NA AKI on entry) P AKI 48 h NA NA NA Metzger [63] 2010 Cystatin C S AKI AKIN both 2/16 20/ NA NA NPV (%) Continued nd serum biomarkers for diagnosis of AKI

24 Table 2. Paediatric setting Author PY Biomarker U/ S/P Outcome AKI def/outcome def Patients/ events AURoC PPV (%) NPV (%) Mishra et al. [12] Hirsch et al. [17] 2005 NGAL U AKI Screa*1.5 71/ S NGAL U CIN Screa*1.5 91/ P Zappitelli [43] 2007 NGAL U AKI prifle crea 140/ NA NA Persistent AKI lasting >48 h 140/? 0.79 NA NA AKI Dent et al. [8] 2007 NGAL P AKI Screa* / Bennett et al. [6] 2008 NGAL U AKI Screa* / RRT 196/ NA NA Wheeler et al. [42] 2008 NGAL S AKI BUN > 100 mg/dl, Screa >2 mg/dl in absence of CKD or RRT 143/ Krawczeski 2011 NGAL U AKI Neonates: Screa > / (neonates) et al. [10] mg/dl 20 Children: studies Screa*1.5 within 0.92 (others) h after CPB P 0.95 (neonates) ROC Range: (others) Portilla et al NGAL U AKI Screa*1.5 40/ [14] Du et al. [18] 2011 NGAL U AKI prifle crea 252/ NA NA Majority : Parikh et al. [13] 2011 NGAL U AKI Progression of established 311/ AKI P Parikh et al. [13] 2011 IL-18 UMajority AKI are Progression CPB of established patients! 311/ AKI Parikh et al. [16] 2006 IL-18 U AKI Screa*1.5 55/ Du et al. [18] 2011 IL-18 U AKI prifle crea 252/ NA NA IL-18 U RIFLE-I NA NA Washburn [41] 2008 IL-18 U AKI prifle crea 137/ Portilla et al LFABP U AKI Screa*1.5 40/ [14] Dennen et al IL-6 U AKI Screa*1.5 23/10 NA [7] Liu et al. [11] 2009 IL-6 S AKI Screa*1.5 within 3 days 39/ IL-8 S Zappitelli et al. [15] 2011 Clinical model (CM) S AKI Screa* / NA NA 0.81 NA NA Cystatin C NA NA CM Screa + CM 2010 Cystatin C S AKI Screa*1.5 within 48 h 374/ Krawczeski et al. [9] Du et al. [18] 2011 KIM-1 U AKI prifle crea 252/ NA NA β2-mg U RIFLE-I 252/ NA NA KIM-1 U 0.73 NA NA β2-mg U 0.80 NA NA

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27 agenda Troponin, The Cherry Picking Biomarker AKI Biomarkers, Finally Usable? Risk stratification and Renal Angina Risk Assessment and Moving the Needle

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30 Can it be simpler? More AKI focused? Basu, Peds Neph 2012

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32 The Importance of Context Heart attack PAIN Kidney attack NO PAIN

33 Renal Angina?

34 Renal Angina Index RISK X INJURY INDEX > 8 = ANGINA + (ANG) RANGE (1-40)

35 RAI Directing Biomarker Testing

36

37 Models (Clinical Only): AUC = Models + ecr Elev: AUC =

38 Risk Stratification of Global AKI RAI Performance in AWARE Day 0 Renal angina (RA) 9.6% of 5231 pts RAI AUC-ROC for Day 3 AKI = ( ) Outcome RA (-) RA (+) p value Day 3 AKI (%) < 0.001, χ 2 = MV duration (days) Length of Stay (days)* <0.001 RRT use (%) < 0.001, χ 2 = ECMO use (%) , χ 2 = 9.3 Mortality (%) < 0.001, χ 2 = 33.3

39 Renal Angina Value Analysis San Diego County: 16 Major medical centers Average of 8-10 ICU admissions/day = 16 * 10 * 365 = ICU admissions/year Cost of ungal (~ $225/sample) Cost of one AKI biomarker per ICU admission in SD - $13,140,000 Context Dependent Biomarker Testing If renal angina used to direct confirmatory biomarker testing for AKI % Pts with Renal Angina # pts Biomarker cost (in millions) Cost savings (in millions)

40 The Renal Angina Index Pragmatic (non-logarithmic, non-exponential model) Usable at the bedside (i.e., for the intensivist ) Early Risk stratification (pre-test probability) Carries high negative predictive value To rule out AKI Identifies which patients might be optimal candidates to use an AKI biomarker To rule in AKI Targets biomarkers Saves $$$$

41 Risk Assessment The Real Window BEFORE ACUTE INSULT Framingham main difference has been to lead the public in modification of risk factors Shown to movements for reduction in risk factors How do we mirror the truth of the ark? Are there predisposing factors to AKI and can we assess for these? (actionable BEFORE injury)

42 GWAS and Predisposition Studies

43 NephroNINJA Reducing Exposure

44 Sub-clinical AKI? Biomarker+/Creatinine-

45 Kashani et al. Critical Care 2013, 17:R25 RESEARCH Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury Open Access Kianoush Kashani 1, Ali Al-Khafaji 2, Thomas Ardiles 3, Antonio Artigas 4, Sean M Bagshaw 5,MaxBell 6,AzraBihorac 7, Robert Birkhahn 8,CynthiaMCely 9, Lakhmir S Chawla 10, Danielle L Davison 10,ThorstenFeldkamp 11,LuiGForni 12, Michelle Ng Gong 13, Kyle J Gunnerson 14, Michael Haase 15, James Hackett 16,PatrickMHonore 17, Eric AJ Hoste 18, Olivier Joannes-Boyau 19, Michael Joannidis 20, Patrick Kim 21,JayLKoyner 22,DanielTLaskowitz 23, Matthew E Lissauer 24, Gernot Marx 25, Peter A McCullough 26,ScottMullaney 27, Marlies Ostermann 28,ThomasRimmelé 29, Nathan I Shapiro 30, Andrew D Shaw 31,JingShi 32, Amy M Sprague 33, Jean-Louis Vincent 34, Christophe Vinsonneau 35, Ludwig Wagner 36, Michael G Walker 32, R Gentry Wilkerson 37, Kai Zacharowski 38 and John A Kellum 39* See related commentary by Ronco et al.,

46 Cut-offs ~ Risk? Kellum and Chawla, NDT 2015

47 CLINICAL RESEARCH Table 5. Prediction of the composite of AKIN stage 3 and death Furosemide Stress Test P Value for and Biomarkers P Value Compared for the Biomarker AUC6SEM Biomarker Alone With FST alone Prediction of AKI Severity AUC of Biomarker and FST6SEM P Value for Biomarker and FST Compared With FST Alone FST (2-hr UOP) , NA NA NA Urine JayNGAL L. Koyner,* Danielle L. Davison, Ermira Brasha-Mitchell, 0.07 Divya M Chalikonda, Urine John IL-18M. Arthur, Andrew D. Shaw, James 0.07 A. Tumlin, Sharon A. Trevino,* Urine Michael KIM-1 R. Bennett, Paul L. Kimmel,** 0.04Michael G. Seneff, 0.04 and Lakhmir S. Chawla Uromodulin *Section of Nephrology, Department of Medicine, 0.58 University of Chicago, 0.004Chicago, Illinois; Department of Urine Anesthesiology IGFBP-7 and Critical Care Medicine and 0.07 **Department of Medicine, 0.19 George Washington University Medical Urine Center, TIMP-2 Washington DC; Division of Nephrology, 0.06Department of Medicine, 0.18 Medical University of South Carolina, Charleston, South Carolina; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Urine IGFBP-73TIMP Tennessee; Renal Division, University of Tennessee College of Medicine at Chattanooga, Chattanooga, Tennessee; Urine Division Creatinine of Nephrology and Hypertension, Cincinnati 0.56 Children s Hospital, Cincinnati, Ohio; and Department of 0.23 Urine Medicine, ACR Division of Intensive Care Medicine and 0.96Division of Nephrology, Washington DC Veterans Affairs Medical 0.32 FeNa Center, Washington, DC Plasma NGAL NA, not applicable; ACR, albumin-to-creatinine ratio. Koyner, JASN Sept 2015

48 agenda Troponin, The Cherry Picking Biomarker AKI Biomarkers, Finally Usable? Risk stratification and Renal Angina Risk Assessment and Moving the Needle

49 Patient admitted/transferr ed to PICU Epic / Web Service Epic ADT message Epic flow sheet records (fluid ins/outs, medications) passed real-time Labs object Other flow sheet records (weight, transplant status, etc.) Score presented Real-time Business Events Engine Clock started Flow sheet records aggregated for later use At 12 hours post PICU admission, requests sent for aggregated real-time flow sheet records, labs, and other flow sheet records Score calculated

50

51 Risk Stratification Continuum Renal Angina + Biomarkers Biomarkers SCr/UOP

52 Risk Stratification Continuum Renal Angina + Biomarkers SCr/UOP Early Recognition Early Treatment Early Recovery

53 REGISTER NOW 2nd International Symposium on AKI in Children June 24-26, 2016 Hilton Cincinnati Netherlands Hotel Cincinnati, Ohio, USA Keynote Speaker: Professor Claudio Ronco, MD Director, Department of Nephrology, Dialysis and Transplantation International Renal Research Institute St. Bortolo Hospital, Vicenza, Italy Themes State of the Art Symposium in Critical Care Nephrology CRRT University* Simulation Course Continuing Education Credit For CEC details, visit Sponsors Cincinnati Children s HeartInstitute Cincinnati Children s Center for Acute Care Nephrology *CRRT University is funded through a separate educational grant from Baxter Healthcare, Inc.

54 acknowledgements and thanks.