4/24/2017

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Mark D. Williams MD, FCCM, FCCP

Associate Professor of Clinical Medicine

Indiana University School of Medicine

February 27th, 2017

Acute Kidney Injury:Thoughts from the trenches

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Case Study

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Patient Info• 68-year-old African American

female• Pre-Op Body Weight 60 kg• Hypertension• COPD• No Chronic Kidney Disease

(CKD)• Baseline SCr = 0.4 mg/dL

What are your concerns for this

patient??

ICU Course•Post-op surgery – uncomplicated bowel resection•Abdominal Peritoneal Resection•Sepsis Dx Post-Op Day #2•Mechanical Ventilation•Current SCr = 0.5 mg/dL

Incidence7-18% of hospitalized patients.1

Up to 50% of critically ill patients develop some stage of AKI.2

Morbidity & Mortality9-times higher risk of development of Chronic Kidney Disease3

2-times higher risk of premature death3

CostEstimated annual costs to US healthcare system attributable to hospital-acquired AKI is > $10 billion.4

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Acute Kidney Injury (AKI) Is Prevalent, Costly and Deadly

[1] Lewington AJP, Certa J, Mehta RL Raising Awareness of Acute Kidney Injury: A Global Perspective of a Silent Killer. Kidney Int. 2013;84(3):457-467.[2] Mandelbaum T, Scott D. et al. Outcome of Critically ill Patients with Acute Kidney Injury using the AKIN Criteria. Crit Care Med. 2011;39(12):2659–2664.[3] Mehta R, Certa J, Burdmann EA, et al. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet. 2015.[4] Chertow GM, Burdick E, Honour M, Bonventre JV, and Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol.2005;16:3365-3370.* Calculated from [5] American Hospital Association Database, accessed Jan 2014 on 6,416 hospitals , [6] Wunsch H, et. al. Comparison of Medical Admissions to Intensive Care Units in the US & UK. Am J Respir Crit Care Med. 2011;183:1666-1673, and [7] Hobson CE, Ozrazgat-Baslanti T, Kuxhausen A, et. al. Cost and Mortality Associated With Postoperative Acute Kidney Injury. Annals of Surgery. 2014;00:1–8

For a typical 400 bed community hospital, the incremental resources consumed by AKI in the ICU often exceeds $20M and 8,500 bed days annually*

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AKI Is Twice As Deadly As an MI

*Mortality calculated from: 1 – Kaplan-Meier Survival Estimates[7] Chawla LS, Amdur RL, Shaw AD, et al. Association between AKI and long-term renal and cardiovascular outcomes in United States veterans. Clin J Am Soc Nephrol. 2014;9(3):448-56.

A recent study of over 36,000 hospitalized veterans demonstrated that patients who developed AKI without myocardial infarction (MI) had a

higher mortality than those who suffered an MI without developing AKI.7

AKI is potentially worse for an individual than a ST elevation myocardial infarction (STEMI)

[9] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter, Suppl. 2012; 2:1-138[10]Tolwani A. Continuous Renal-Replacement Therapy for Acute Kidney Injury. N Engl J Med. 2012;367:2505-2514.

Acute Kidney Injury (AKI) is a rapid (typically within about 48 hours) loss of kidney

function9

• 96% of AKI does NOT require RRT10

RIFLE/AKIN/KDIGO criteria were validated over the past decade and provide a

standardized definition of AKI

The criteria are based on increases and serum creatinine and decreases in urine output

and stratify AKI into three severity levels:9

1. Mild AKI (RIFLE-R or Stage 1)

2. Moderate AKI (RIFLE-I or Stage 2)

3. Severe AKI (RIFLE-F or Stage 3)

The criteria are good for epidemiological studies but difficult to apply at the bedside; AKI

thus remains largely a clinical diagnosis9

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Recent Acute Kidney Injury (AKI) Definitions Have Helped Illuminate The Burden Of AKI

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AKI And Sepsis Is A Deadly Combination

[9] Murugan R et al. Acute Kidney Injury in Non-Severe Pneumonia is Associated with an Increased Immune Response and Lower Survival. Kidney Int. 2010;77:527-535.[12] Hoste EAJ et al. Acute Renal Failure in Patients with Sepsis in a Surgical ICU: Predictive Factors, Incidence, Comorbidity, and Outcome. J Am Soc Nephrol. 2003;14:1022-1030.

Mortality in hospitalized pneumonia patients9

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Surgery And AKI Leads To Poor Outcomes

[14] Bihorac A et al. National Surgical Quality Improvement Program Underestimates the Risk Associated with Mild and Moderate Postoperative Acute Kidney Injury. Crit Care Med. 2013;41(11):2570-2583.

Hospital Mortality 90-Day Mortality

In a single-center cohort of 27,841 adult surgical patients undergoing major surgery, it was identified that hospital and 90-day mortality were significantly higher among patients with AKI compared to patients with no AKI.14

8

Patients With AKI Have High Readmission Rates

[15] Brown JR et al. Impact of perioperative acute kidney injury as a severity index for thirty-day readmission after cardiac surgery. Ann Thorac Surg. 2014;97(1):111-7.

p < 0.001

2,209 consecutive patients who underwent either coronary artery bypass or valve surgery at 7 member hospitals of theNorthern New England Cardiovascular Disease Study Group Cardiac Surgery Registry between July 2008 and December 2010.15

Everything is at Least 2-3 Times Worse with Moderate to Severe AKI

[17] Dasta JF et al. Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant. 2008;23(6):1970-4.[18] Brown JR et al. Impact of perioperative acute kidney injury as a severity index for thirty-day readmission after cardiac surgery. Ann Thorac Surg. 2014;97(1):111-7

LOS17

Cost17

30-Day Readmissions1

8

HospitalMortality17

No AKI Moderate Severe

Short-term & long-term consequences associated

with increasing AKI severity

LOS: Total postoperative length of stay (days/patient); Cost: Total postoperative cost

(US$/patient); 30-Day Readmissions: % of postoperative patients; Hospital Mortality: % of

postoperative patients.

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Risk Assessment For AKI: An Unmet Clinical Need

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AKI is a Spectrum of Kidney Decline and Early Identification is Key to Potentially Stop the Progression

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Figure adapted from: [1] Lewington AJP, Certa J, Mehta RL Raising Awareness of Acute Kidney Injury: A Global Perspective of a Silent Killer. Kidney Int.2013;84(3):457-467.[19] Kellum JA, Chawla LS. Cell-Cycle Arrest and acute kidney injury: the light and dark sides. Nephrol Dial Transplant. 2016;1:16-22

Kidney Stress Decreased Function

Asymptomatic Symptomatic (Diagnosis)

Kidney stress is a precursor for AKI19

Suboptimal Diagnostic Tools Make AKI Improvement Difficult

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Figure adapted from: [1] Lewington AJP, Certa J, Mehta RL Raising Awareness of Acute Kidney Injury: A Global Perspective of a Silent Killer. Kidney Int.2013;84(3):457-467.[20] Martensson J et al. Novel Biomarkers of Acute Kidney Injury and Failure: Clinical Applicability. Brit J Anesth. 2012;109(6):843-50.[21] Wlodzimirow KA, et al. A comparison of RIFLE with and without urine output criteria for acute kidney injury in critically ill patients. Critical Care. 2012;16:R200.[22] Gould CV, et al. Guideline for Prevention of Catheter-Associated Urinary Tract Infections. HICPAC. 2009.

Kidney Stress Decreased Function

Asymptomatic Symptomatic (Diagnosis)

Serum Creatinine•Lagging indicator20

•Only elevates after 50% of kidney function lost20

•Non-diagnostic for up to 52% of moderate and severe AKI21

Urine Output•Lagging indicator21

•Tedious to measure21

•Affected by HAI initiatives22

Best Current Indicators for One Of Healthcare’s Biggest Problems:Lagging. Error Prone. Compromised by “well intended” QI.

Best Current Indicators for One Of Healthcare’s Biggest Problems:Lagging. Error Prone. Compromised by “well intended” QI.

Wouldn’t it be nice to identify Kidney Stress BEFORE the

dysfunction occurs?

Functional BiomarkersSerum Creatinine, Urine Output

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Clinical Risk Factors For AKI Are Common But Not Reliable For Establishing The Risk Profile For An Individual Patient

[9] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2012; 2: 1-138.[11] Murugan R et al. Acute Kidney Injury in Non-Severe Pneumonia is Associated with an Increased Immune Response and Lower Survival. Kidney Int. 2010;77:527-535.[13] Uchino S et al. Acute Renal Failure in Critically Ill Patients: a Multinational, Multicenter Study. JAMA. 2005;294:813-818.[23] Ronco C, Ricci Z. The concept of risk and the value of novel markers of acute kidney injury. Crit Care. 2013;17:117-118.

Patient Risk Factors9

• Dehydration or volume depletion• Advanced Age• Female gender• Black race• CKD• Chronic Disease (heart, lung, liver)

• Diabetes Mellitus• Cancer• Anemia

Acute Risk Factors9,11,13

• Sepsis• Pneumonia• Cardiogenic Shock• Major Surgery• Cardiac Surgery• Nephrotoxic Drugs• Radiocontrast Agents• Hypovolemia

A number of susceptibilities and exposures for AKI have been identified, but there is no reliable way for a clinician to use this information to establish a clear risk profile.23

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A 2009 NCEPOD study24 (Adding Insult to Injury) reported that of admitted patients who died from hospital-acquired AKI had:

[24]National Confidential Enquiry into Patient Outcome and Death. Adding Insult to Injury. 2009;1-98.

Avoidable AKI Unacceptable Delays in Recognition of AKI

Inadequate Risk Assessment for AKI

A recent study stated: “AKI is potentially fatal, but in many cases reversible when appropriately managed” and “…it is reasonable to surmise that, at least in some cases, the [patient] outcome…may have been different if the condition [AKI] had been recognized and managed better.”24

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AKI Identification in the ICU Can Be Inconsistent

15[25] Massicottee-Azarniouch, Magder S, Goldberg P, Alam A. Acute Kidney Injury in the Intensive Care Unit: Risk Factors and Outcomes of Physician Recognition Compared with KDIGO Classification. Poster presented at: Society of Critical Care Medicine; February 2016; Orlando, FL.

AKI Reported by ICU Staff

No AKI Reported by ICU Staff

2,393 patients admitted to academic hospital ICU in Montreal, Canada from January 2006 through December 2011.

KDIGO AKI calculated from SCr values. Physician definition of AKI was determined by asking ICU staff if a patient had “acute renal failure”.25

“ICU physicians only identified a small proportion of the patients with AKI. Many of the severe forms of AKI, which were most associated with adverse outcomes, were missed by the physician reporting.”

79% of the cases of

Moderate and Severe AKI Were Not

Identified by Reporting Physician

87.1%

73.5%

Early recognition and management of patients at risk for AKI is paramount since there are no specific therapies to reverse established AKI.9

As compared to myocardial infarction, AKI may not provide early signs and symptoms sufficient to guide risk assessment.23

Current methods for risk assessment are insufficient, placing substantial numbers of patients at serious risk of death and morbidity.9,26

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A Better Way To Identify Patients At Risk for AKI Is Paramount

[9] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2012; 2: 1-138.[23] Ronco C, Ricci Z. The Concept of Risk and the Value of Novel Markers of Acute Kidney Injury. Crit Care. 2013;17:117-118.[26] McCullough PA et al. Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib Nephrol. 2013;182:13-29.

Case Study

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Patient Info• 68-year-old African American female• Pre-Op Body Weight 60 kg• Hypertension• COPD• No Chronic Kidney Disease (CKD)• Baseline SCr = 0.4 mg/dL

What are your concerns for this patient now??

ICU Course•Post-op surgery –uncomplicated bowel resection•Abdominal Peritoneal Resection•Sepsis Dx Post-Op Day #2•Mechanical Ventilation•Current SCr = 0.5 mg/dL

Patient Status at ICU Day 4• Aztreonam and other antibiotics• Pressors to maintain SBP > 100 mm

Hg• SCr = 0.9 mg/dL• UO = 30 cc/hr (average)

Discovery Of Novel Biomarkers For Risk Assessment For AKI

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New Technology, Advance Warning Enables Better Outcomes

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What if we could get ahead of AKI? Instead of saying, “wait and see…”

•Early Warning•Stratify Patient Risk•Attention on “At Risk” patients

•Reduce Process Variation

•Improved Communication

Rigorous Discovery & Validation Studies Performed to Identify Biomarkers of Early AKI Risk Assessment

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[27] Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.[28] Bihorac A, et al. Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication. Am J Respir Crit Care Med. 2014;189(8):932-939.

340 Biomarkers Evaluated including NGAL & KIM-1

Discovered in 1,200+ Patientsincluding sepsis, shock, major surgery and trauma patients

Urinary [TIMP-2]*[IGFBP-7] stood out as the best-performing biomarkers to predict development of moderate or severe AKI within 12 hours27

Candidates identified through hypothesis based on AKI pathophysiology and evaluated individually and in combinations of 2-4 biomarkers27

Validated in 500+ Critically Ill Patients from Intended

Use Population

Patients had diverse ICU admissions (surgery, sepsis, trauma) and common comorbidities (including CKD, diabetes, heart disease) 28

Tissue Inhibitor of Metalloproteinase-2 (TIMP-2)

Insulin-like Growth Factor Binding Protein-7 (IGFBP-7)

TIMP-2 and IGFBP-7 are:31

•Biomarkers of cellular stress in the early phase of tubular cell injury caused by a wide variety of insults (inflammation, ischemia, oxidative stress, drugs, and toxins)

•Involved in G1 cell-cycle arrest that prevent cells from dividing until damage can be repaired

•Both biomarkers appear as “alarm” proteins from other nearby cells

This may help explain why urinary TIMP-2 and IGFBP-7 correspond to risk of AKI.

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Two Novel Urinary Protein Biomarkers Stood Out as a “Renal Alarm” System

[29] TIMP-2 figure adapted from: Tuuttila A et al. Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1 A resolution. J Mol Biol.1998;284:1133-1140.[30] IGFBP-7 figure adapted from: ModBase: Database of Comparative Protein Structure Models [accessed 2014 December 10]. Available from: http://modbase.compbio.ucsf.edu/modbase-cgi/model_details.cgi?queryfile=1418152585_2850&searchmode=default&displaymode=moddetail&referer=yes&snpflag=&. [31] Gocze I, et al. Urinary Biomarkers TIMP-2 and IGFBP7 Early Predict Acute Kidney Injury After Major Surgery. PLoS ONE. 2015;10(3).

The NephroCheck® Test For Risk Assessment For AKI

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The Astute Medical NephroCheck® Test System is intended to be used in conjunction

with clinical evaluation in patients who currently have or have had within the past 24

hours acute cardiovascular and or respiratory compromise and are ICU patients as

an aid in the risk assessment for moderate or severe acute kidney injury (AKI) within

12 hours of patient assessment. The NephroCheck® Test System is intended to be

used in patients 21 years of age or older.

The NephroCheck® Test Intended Use and Indications

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Identify Kidney Stress, Before Dysfunction Occurs

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Figure adapted from: [1] Lewington AJP, Certa J, Mehta RL Raising Awareness of Acute Kidney Injury: A Global Perspective of a Silent Killer. Kidney Int. 2013;84(3):457-467.[31] Gocze I, et al. Urinary Biomarkers TIMP-2 and IGFBP7 Early Predict Acute Kidney Injury After Major Surgery. PLoS ONE. 2015;10(3).[32] NephroCheck® Test Kit Package Insert. PN 300152 Rev E

Kidney Stress Decreased Function

Asymptomatic

Symptomatic (Diagnosis)

Functional BiomarkersSerum Creatinine, Urine Output

Stress BiomarkersTIMP-2 * IGFBP-7

AKIRisk® Score = [TIMP-2]*[IGFBP-7]AKIRisk® Score = [TIMP-2]*[IGFBP-7]

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The Clinical Cutoff Was Selected To Identify the Majority Of Patients At Risk For Moderate-Severe AKI

The NephroCheck® Test cutoff (AKIRisk® Score > 0.3) was prospectively selected prior to validation studies to achieve*:

High sensitivity and negative predictive value are important in risk assessment to ensure that:

• The majority of patients who will develop AKI test positive

• Few patients with a negative test result will be at risk of developing AKI

Study A (408 patients) Study B (126 patients)

High sensitivity 92% 76%

Acceptable specificity 46% 51%

High negative predictive value 96% 88%

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A Quantitative NephroCheck® Test Provides Confidence to Identify the Majority of Patients at Risk for AKI

High sensitivity and negative predictive value for confidence in identifying the majority of patients at risk for AKI.

Confidence the AKIRisk® Score is not elevated due to common comorbidities such as

CKD, diabetes, surgery, sepsis and trauma.

Confidence the AKIRisk® Score is not elevated due to common comorbidities such as

CKD, diabetes, surgery, sepsis and trauma.

Results from Study A and B are not statistically different (p>0.05) 26

AK

IRis

k®

Sco

re

Enhancing Patient CareIncorporating Clinical Expertise with AKI Risk Biomarkers

27

We’ve done this before…

Ventilator Bundles33

(Institute for Healthcare Improvement)• Elevation of the head

• “Sedation vacation”

• Stress ulcer prophylaxis

• DVT prophylaxis

• Daily oral decontamination

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Sepsis/Resuscitation bundle34

(St. Mary’s Hospital, Rochester New York)

• Measurement of lactate

• Blood cultures before antibiotics

• Timely administration of antibiotics

• Fluid administration based upon CVP, MAP, and lactate

• Vasopressor therapy

• RBC transfusion

• Inotropic support

Locally Developed Clinical Plans Lead to More Consistent And Timely Management of Common Critical Illnesses

…Why Not AKI?

[33] Resar R, Griffin FA, Haraden C, Nolan TW. Using Care Bundles to Improve Health Care Quality. IHI Innovation Series white paper. Cambridge, Massachusetts: Institute for Healthcare Improvement; 2012.[34] Sionitis B, et al. Multifaceted interventions to decrease mortality in patients with severe sepsis/septic shock – a quality improvement project. Peer J. 2015;3:e1290

Early Coordination of Care Among All Experts is Vital

Clinical success stories for multidisciplinary care in acute illness

• Sepsis

• Chest pain

• Rapid response teams

Evidence shows that this is important for AKI: earlier renal consultation improves outcomes35

29**Time of Consultation was calculated from rise in Serum Creatinine based on KDIGO Criteria[35] Ponce d, et al. Early nephrology consultation can have an impact on outcome of acute kidney injury patients. Nephrol Dial Transplant. 2011;26:3202-3206

23% Increased Mortality Rate with

Delayed consultation

Mortality Rate of AKI Patients by

Time of Nephrology

Consultation35

(<48 hours) (>48 hours)

Acute Coronary Syndromes:36

• CK activity (1960) CKMB (1980’s) Troponin I (1990)

Congestive Heart Failure:37

• BNP

Sepsis and Infectious Diseases:38

• Lactate • Procalcitonin

30

Diagnostic Tests and Biomarkers Play an Increasingly Important Role in Patient Care

[36] Ladenson J. Reflections on the Evolution of Cardiac Biomarkers. Clin Chem. 2012;58(1):21-24.[37] Brain Natriuretic Peptide (BNP) Test. WebMD. Accessed July 27, 2016. http://www.webmd.com/heart-disease/brain-natriuretic-peptide-bnp-test[38] Faix. Biomarkers of Sepsis. Crit Rev Clin Lab Sci. 2013;50(1):23-36.

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Age-Adjusted Death Rates for Coronary Artery Disease in the USA

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Figure adapted from: [39] NIH. Accessed on July 28, 2016. http://www.nhlbi.nih.gov/about/documents/factbook/2012/chapter4[40] Coronary Artery Bypass Surgery. Wikipedia. Accessed on August 4, 2016. https://en.wikipedia.org/wiki/Coronary_artery_bypass_surgery[41] Rosalki SB. An improved procedure for serum creatine phosphokinase determination. J Lab Clin Med 1967;69:696-705[42] 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.[43] Percutaneous Coronary Intervention. Wikipedia. Accessed on August 4, 2016. https://en.wikipedia.org/wiki/Percutaneous_coronary_intervention[44] Streptokinase I.V. Approved FDA Labeling Notes 47% Mortality Reduction. The Pink Sheet. Accessed August 4, 2016. https://pink.pharmamedtechbi.com/PS012747/STREPTOKINASE-IV-APPROVED-FDA-LABELING-NOTES-47-MORTALITY-REDUCTION[45] Heart Disease Health Center. WebMD. Accessed August 4, 2016. http://www.webmd.com/heart-disease/features/hope-for-heart-advances-in-treatment?page=2

1982Streptokinase

FDA Approval44

1987tPA Approved45

1977CABG widely adoptedFirst PTCA43

1960 First CABG performed in US40

1967 CK test41

1967 CCUsWidely adopted4

2

Testing, stratification &

better communication helped kick off the decline in

mortality

Deaths per 100,000 Population

Year

Unlike AMI, AKI Hasn’t Had New Biomarkers Available For Over 50 Years... Until Now

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[36] Ladenson J. Reflections on the Evolution of Cardiac Biomarkers. Clin Chem. 2012;58(1):21-24.

[46] Ahmad MI, Sharma N. Biomarkers in Acute Myocardial Infarction. J Clin Exp Cardiolog. 2012;3(11):222.[47] Edelstein C. Biomarkers of Kidney Disease. Waltham, Massachusetts:Academic Press;2011.

[48] FDA allows marketing of the first test to assess risk of developing acute kidney injury. FDA Press Release. Accessed August 4, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412910.htm

Period Acute Myocardial Infarction Acute Kidney Injury

1960’s LDH46 Serum Creatinine47

1970’s CPK46 Serum Creatinine

1980’s CK-MB46 Serum Creatinine

1990’s Troponin T35 Serum Creatinine

2000’s Troponin I35 Serum Creatinine

2010’s Troponin I35 The NephroCheck® Test48

Recent published literature has discussed the role of the NephroCheck® Test used in conjunction with clinical judgement and includes recommendations on preferred kidney sparing strategies to help prevent kidney damage.19

Published Recommendations to Help Prevent Kidney Damage

[19] Kellum JA, Chawla LS. Cell-Cycle Arrest and acute kidney injury: the light and dark sides. Nephrol Dial Transplant. 2016;1:16-22.

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With dynamic measurement of the risk for AKI, there will be the opportunity to initiate timely and appropriate preventative therapies and monitoring in the ICU, for those patients who are judged to be at high risk of AKI.49

As well, less costly interventions are easy and reasonable to implement if risk is identified, such as considering:9,19,49

•Discontinuing nephrotoxins or changing dosage•Volume status & perfusion pressure•Hemodynamic monitoring•Monitoring frequency of serum creatinine and urine output•Earlier nephrology consult.

Acute Kidney Injury (AKI) is a Significant Opportunity to Improve Quality of Patient Care

[9] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter, Suppl. 2012; 2:1-138[19] Kellum JA, Chawla LS. Cell-Cycle Arrest and acute kidney injury: the light and dark sides. Nephrol Dial Transplant. 2016;1:16-22[49] Bihorac A. Acute Kidney Injury in the Surgical Patient: Recognition and Attribution. Nephron. 2015;131(2):118-22.

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Case Study

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Patient Info• 68-year-old African American

female• Pre-Op Body Weight 60 kg• Hypertension• COPD• No Chronic Kidney Disease (CKD)• Baseline SCr = 0.4 mg/dL

What might you do differently with this

patient?

ICU Course•Post-op surgery – uncomplicated bowel resection•Abdominal Peritoneal Resection•Sepsis Dx Post-Op Day #2•Mechanical Ventilation•Current SCr = 0.5 mg/dL

Patient Status at ICU Day 4• Azreonam and other antibiotics• Pressors to maintain SBP > 100 mm Hg• SCr = 0.9 mg/dL• UO = 30 cc/hr (average)

AKIRisk® Score = 3.4

The NephroCheck® Test is• Validated in robust clinical trials• First urinary biomarkers for risk assessment of AKI• Highly sensitive and has acceptable specificity for risk assessment of

moderate to severe AKI within the next 12 hours• Not elevated with chronic comorbidities and non-AKI acute conditions

With the early identification of patients at risk, there is an opportunity for management strategies that may attenuate AKI severity,9 thereby impacting morbidity, mortality, length of stay, and cost associated with moderate to severe AKI.7,19

The “Renal Alarm” System: Don’t Act Now, Act Earlier!

[7] Hobson CE, et. al. Cost and Mortality Associated with Postoperative Acute Kidney Injury. Annals of Surgery. 2014;00:1–8[9] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter, Suppl. 2012; 2:1-138[19] Kellum JA, Chawla LS. Cell-Cycle Arrest and acute kidney injury: the light and dark sides. Nephrol Dial Transplant. 2016;1:16-22. 36

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The NephroCheck® Test aids in identifying patients at risk for moderate to severe AKI in the next 12 hours so physicians can proactively assess the need for AKI preventative

measures.

IdentifyThe NephroCheck® Test provides a quantitative AKIRisk™ Score allowing the clinician to discriminate patients at risk of AKI.

StratifyThe AKIRisk™ Score allows clinicians to triage patients into lower risk and greater risk groups for developing moderate to severe AKI in the next 12 hours.

MitigateThe assessment of risk 12 hours before moderate to severe AKI may clinically manifest allows the clinician to implement their preferred kidney sparing strategies to potentially mitigate the severe consequences associated with Acute Kidney Injury.

The NephroCheck® Test

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Case #1

• 78 yr old WF with a history of tobacco abuse, coronary artery disease, hyperlipidemia, chronic kidney disease and hypertension who presented with sudden severe upper back pain and a stat Chest CT with contrast detected a Acute type A aortic dissection.

• She was transferred to a level 1 Trauma hospital center where she underwent surgical repair including an aortic valve replacement.

• The aortic dissection had progressed to a location past her renal arteries placing her at risk for acute kidney injury.

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Case #1

• Initial postoperative urine output was >0.5 cc/kg/hr and serum creatinine was unchanged.

• On postoperative Day #1 the patient developed oliguria and received several boluses of Normal Saline and Plasmanate (serum albumin) with no increase in urine output which was approximately 25 cc/hr.

• Positive fluid balance of 6.5 liters placing patient at risk for organ edema.

• On postoperative Day #2 her serum creatinine increased from 2.0 to 2.5.

Case #1

Dialysis starts

Creatinine bumps

Last Dialysis

40

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Case #1

• On Hospital Day #20 patient urine output increased and no further hemodialysis was required.

• Discharged to a rehabilitation facility after 27 days in hospital including 10 days in ICU.

• Renal recovery occurred and patient survived this catastrophic vascular event.

Case #1

Dialysis starts

Creatinine bumps

Last Dialysis

Nephrocheck Testing in the Golden Hours for Kidney Protection

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Joe Skeptic MD

Not sure what we would different with the information Nephrocheck provides since we are constantly focused on protecting the kidney!

Williams reply –• “You’re not as good as you think you are”• “You could have done more to avoid RRT and the patient is

very fortunate to have survived with renal recovery”

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Do We Have a Problem With AKI?

For the year 2015 using data from our system:

• Approximately 916 cases of moderate or severe AKI

• Length of stay impact was additional 9521 days

• Cost impact estimated at 27 million dollars

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Case #2 – A High Risk Nephrocheck that led to action!

• 48 yr old woman with chronic HTN, chronic abdominal pain from ulcerative colitis with multiple surgeries and intra-abdominal abscesses is admitted with abdominal pain and fever.

• Abdominal CT shows an intra-abdominal abscess that requires surgical drainage.

• Postoperatively she is in septic shock and on Norepinephrine drip.

• Nephrocheck is ordered early in postoperative course.

Nephrocheck result: 2.9

46

IU Health Protocol for Nephrocheck

47

48

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Case #2 – A High Risk Nephrocheck that led to action!

• We pushed the patients Mean Arterial Pressure up to 85

• We used the NICOM device (Noninvasive Cardiac Output Monitor) to closely regulate the patient’s volume status.

• This target has been shown in a large Clinical Trial to reduce the development of AKI and the need for RRT

50/50

So Where Are The Outcome Studies On This Test?

Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial

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•INVESTIGATORS:• Meersch M, Schmidt C, Hoffmeier A, Van Aken H, Wempe C, Gerss J,

ZARBOCK A

•SITE:• Single center study• University Hospital Münster (Münster, Germany)

•PATIENTS:• 276 patients who underwent cardiac surgery (on-pump) at the University of

Münster who were deemed to be at high risk for AKI • High risk defined as Nephrocheck® > 0.3 from discarded urine sent 4

hours after discontinuation of cardiopulmonary bypass (CPB)

•TIME FRAME:• August 2014 through December 2015.

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• METHODS:• Patients at high risk (NephroCheck > 0.3) were randomized to the

following arms:• CONTROL GROUP: Standard therapy • INTERVENTION GROUP: “KDIGO CT Surgical Bundle” • 138 patients in each group (1:1 randomization) • August 2014 through December 2015. • Powered at 80%

• PRIMARY OUTCOME:• Development of AKI 72 hours after surgery, defined by KDIGO criteria

• SECONDARY OUTCOMES:• AKI severity• Need for dialysis• Length of stay (LOS)• Major Adverse Kidney Events (MAKE) at 30, 60, and 90 days

Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by

biomarkers: the PrevAKI randomized controlled trial

• Restart angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) once hemodynamics stabilized*

• Mean arterial pressure (MAP) > 65 mmHg

• Central venous pressure (CVP) between 8 and 10

• Discontinue ACEi and ARBs for the first 48 hours after surgery

• Avoid Nephrotoxic agents

• Close monitoring of sCr and UO

• Avoid hyperglycemia for 72h after surgery

• Consider alternatives to radiocontrast

• Close hemodynamic monitoring (PICCO catheter) and optimization by pre-specified algorithm (next slide)

*As per ACC guidelines

Standard Care KDIGO BundleVs.

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Hemodynamic Monitoring And Optimization Was Performed According To Strict Protocol In The KDIGO Intervention Arm

Standard of care in the control arm did not involve measurement/optimization of SVV or CI which require more sophisticated and rigorous monitoring

>11

SVV = stroke volume variability (high values mean volume depletion)CI = cardiac index (low values mean low cardiac output)MAP = mean arterial pressure (low values mean hypotension)

Optimize Preload

Optimize Contractilit

y

Optimize Afterload

Continue for 12h

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Control (n=138) Intervention (n=138) p-value

Patients with catecholamines during intervention period,

No. (%)

Dobutamine 13 (9.4) 43 (31.2) < 0.001

Epinephrine 21 (15.2) 29 (21.2) 0.201

Norepinephrine 91 (65.9) 94 (68.1) 0.701

Volume therapy during intervention period, median (Q1,

Q3), ml

Total volume 2745 (1968, 3625) 2575 (1965, 3518) 0.699

Atrial fibrillation within 12 hours, No. (%) 15 (10.9) 13 (9.4) 0.690

Hyperglycemia, No. (%) 104 (75.4) 70 (50.7) < 0.001

ACEi and ARBs, No. (%) 42 (30.4) 15 (10.9) < 0.001

Nephrotoxic agents, No. (%) 22 (15.9) 18 (13.0) 0.494

Contrast agents 19 (13.8) 11 (8.0) 0.122

Vancomycin, Gentamicin 6 (4.3) 9 (6.5) 0.426

Diuretics, No. (%) 113 (81.9) 103 (74.6) 0.144

Urine [TIMP-2]•[IGFBP7] at 12 h, ng/ml2/1000, median (Q1,

Q3)

0.84 (0.35, 1.57) 0.58 (0.26, 1.20) 0.045*

Intervention In [TIMP-2]*[IGFBP7] Positive Patients Was Associated With Significant Differences In Dobutamine, ACE/ARB,

Hyperglycemia and 12h [TIMP-2]*[IGFBP7]

*Relative change from baseline of 12h [TIMP-2]*[IGFBP7] was not statistically different between the two arms (p > 0.05)

KDIGO Bundle Intervention Significantly Reduced AKI

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• Although the KDIGO CT bundle significantly reduced the incidence of AKI within 72 hours following surgery, it did not impact morbidity or mortality and secondary outcomes

•ICU LOS•Hospital LOS•MAKE30,60,90

• POTENTIAL REASONS FOR THESE FINDINGS:1.PrevAKI was NOT powered to show a difference in these secondary outcomes,2.The rate of complications was low3.90 days may be too short a period of time to observe a potential benefit (especially in patients with health kidneys and ample renal reserve)4.Mild to moderate AKI (as defined by the KDIGO criteria) may not cause substantial CKD:• Patients who developed AKI in most other observation studies, as compared to those who did

not, have usually been sicker with more underlying comorbidities. 5.The KDIGO criteria were used to diagnose AKI, and most AKIs were diagnosed on the basic of decreased Urine Output (UO). The association of oliguria with patient-centered outcomes has been shown in a general ICU population (largely in higher stages of AKI) but not in a cardiac surgery population. This observation may be due to the relatively higher incidence of prerenal causes.

Secondary outcomes:

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• The implementation of a bundle of supportive measures (KDIGO CT surgery bundle) in high risk patients, identified by an elevated Nephrocheck® test, reduced the occurrence of AKI within 72 hours compared to standard care.

• Patients treated with the KDIGO CT surgery bundle used more dobutamine, had a reduced rater of hyperglycemia, and a higher rate of discontinuing ACEi’s and ARBs. These patients also received better hemodynamic monitoring, which likely resulted in a more individually tailored approach to their care.

• Patient randomized to the KDIGO CT surgical bundle also had lower Nephrocheck® levels at 12 hours following randomization, supporting he hypothesis that this bundle dampens tubular damage and protects against AKI

• Nephrocheck® therefore allows the bedside clinician to implement effective preventative and protective interventions well before clinical AKI develops. Physicians now have an evidence-based clinical strategy that uses commonly employed clinical therapies in high risk patients for AKI who are proactively identified by an elevated Nephrocheck® level, to prevent AKI from occurring.

Key Conclusions:

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Case # 3 –A negative result that matters

• 48 yr old woman with poorly controlled diabetes mellitus who presents with severe necrotizing fasciitis of the perineal region.

• She is in septic shock preoperatively on 2 vasopressors and requires source control operation.

• Postoperatively the patient has oliguria and remains in septic shock on vasopressors.

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Case # 3 – A negative result that matters

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Case # 3

• Patient needed Vancomycin and a dose of Tobramycin both potentially nephrotoxic

• Patient also needed repeat CT scans with dye

• The negative Nephrocheck gave us more confidence to proceed with these interventions

Case # 4

• 81 year old male with PMHx of CAD s/p CABG x 2 (1987, redo in 1999), angioplasty to LAD in 2013, aortic valve/ascending aorta repair in 2004, sick sinus syndrome s/p pacemaker placement in 2004, admitted after infected pacemaker lead removal attempt.

• There was difficulty removing the leads secondary to severe calcification and temporary pacer was placed.

• On ICU day #1 pt exhibited signs of sepsis with low grade temperature, WBC of 21,000 and PCT was 53.

• On ICU day #2 he developed septic shock and was fluid resuscitated yet required moderate dose Norepi.

• Nephrocheck was assessed on morning rounds.

Case # 4

What is your prediction regarding this patient’s risk of developing Acute Kidney Injury within the next 12 hours?

1.<25%

2.25-50%

3.50-75%

4.75-100%

AKI risk prediction is positive

Meets AKI criteria

Meets AKI criteria

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Conclusions

• Acute kidney injury is common, costly and deadly.

• There is now a new tool to help you predict which patients are at an increased risk for acute kidney injury.

• A focused effort to implement Acute Kidney Injury bundles can lead to significant quality improvement in this disease state.

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