1 Acute Kidney Injury. 2 I. Anatomy II. Epidemiology III. Mortality & Cost IV. Diagnosis, Assessment, & Management V. Treatment VI. Limitations and Unmet

1

Acute Kidney Injury

2

I. Anatomy

II. Epidemiology

III. Mortality & Cost

IV. Diagnosis, Assessment, & Management

V. Treatment

VI. Limitations and Unmet Clinical Needs

Outline: Acute Kidney Injury

3

Anatomy

4

• The urinary tract consists of kidneys, adrenal glands, ureters, bladder, urethra and all associated blood vessels.

Renal System Anatomy

• Kidneys are often donated.

• It is not uncommon for an individual to be able to live without one kidney.

KIDNEYS

URETERS

BLADDERURETHRA

ADRENAL GLANDS

4

5

• The kidney is supplied with blood by the renal artery.

Kidney Anatomy

• Each renal artery branches and eventually the blood feeds into the medulla and the nephrons, or functional units of the kidney.

RENAL PELVIS

CORTEX

RENAL MEDULLA

RENAL ARTERY

RENAL VEIN

URETER

5

6

• A tubular structure called the nephron filters blood to form urine.

Nephron

• Blood is filtered through the glomerulus into the Bowman's capsule which empties into a tubule that is also part of the nephron.

• A glomerulus and its surrounding Bowman's capsule constitute a renal corpuscle, the basic filtration unit of the kidney.

• The glomerulus is a group of capillaries that perform the first step of filtering blood.

URINE FORMATION

Blood Flow

Afferent Arteriole

Efferent Arteriole

EXCRETION

Renal Tubule

FILTRATION

NEPH

RO

N

Glomerulus

Additional Waste

Solutes and Waste

SECRETION

REABSORPTION Renal Corpuscle

7

Epidemiology

8

Acute Kidney Injury

• Acute kidney injury (AKI) is a rapid loss of kidney function including:

– Rapid time course (less than 48 hours)

– Rise in serum creatinine

– Reduction in urine output (oliguria)

Mehta RL, Kellum JA, Shah SV et al. Crit Care. 2007;11(2):R31.

9

Number of AKI Hospitalizations: 1979 to 2002

National Center for Health Statistics, National Hospital Discharge Survey.Centers for Disease Control and Prevention.

700,000

600,000

500,000

400,000

300,000

200,000

100,000

45,000,000

40,000,000

35,000,000

25,000,000

15,000,000

30,000,000

20,000,000

10,000,000

5,000,000

001980 1982 1984 1986 1988 19981996199419921990 2000 2002

All Hospitalizations AKI

10

A Dramatic Rise in Kidney Injury

60

50

40

30

20

10

0

Rat

e (P

er 1

0,00

0 Po

pula

tion)

Year

1980 1985 1990 1995 2000 2005

Total (all types)

Chronic

Unspecified

Acute

Adapted from International Classification of Diseases, 9 th Rev., Center for Disease Control and Prevention. 2008.

11

Patients at Risk for Kidney Injury

• Adults with diabetes or hypertension are at an increased risk of developing chronic kidney disease (CKD) or injury.

• Other risk factors include cardiovascular disease, obesity, elevated cholesterol, and a family history of CKD.

National Chronic Kidney Disease Fact Sheet 2010. U.S. Department of Health and Human Services. Centers for Disease Control and Prevention.

Overall

20-44 Years45-65 Years

65+ Years

MaleFemale

Non-Hispanic WhiteNon-Hispanic Black

Mexican American

0 10 20 30 40 50

Percent (%)

12

AKI Risk Factors

• Sepsis

• Age > 65 years

• Presence of infection

• Low cardiac output

• Major surgery

• Trauma

• Cancer

• Hypervolemia (fluid overload)

• Cirrhosis

• Certain medications

Dennen P, Douglas IS, Anderson R. Crit Care Med. 2010;38:261-75.Kidney Disease: Improving Global Outcomes (KDIGO). 2008.

13

AKI Causes

Environmental exposures • Trauma• Medications

Sepsis • Increases LOS• 32.4% of AKI

Ischemia • Inflammatory mediators in tubules

Physiological • Pre-renal• Intrinsic• Post-renal

Unknown • Consider renal biopsy

14

HOSPITAL LENGTH OF STAY ICU LENGTH OF STAY

AKI Causes: Sepsis

Bagshaw SM, George C, Bellomo R et al. Crit Care. 2008;12:R47.

Sepsis accounted for 32.4% of all hospitalized patients with AKI.

Over 42% of all sepsis diagnoses also had an AKI diagnosis.

Sepsis is the most common cause of AKI in the ICU.

Day

s

Day

s

RIFLE Category RIFLE Category

None Risk Injury FailureNone Risk Injury Failure

6

5

4

3

2

1

0

25

20

15

10

5

0

Non-Septic AKISeptic AKI

Non-Septic AKISeptic AKI

15

INFLAMMATORY MEDIATORS OF ISCHEMIC AKI

AKI Causes: Ischemia

• Ischemia can lead to AKI through the induction of inflammatory mediators that induce cell death in the kidney tubules– Reactive oxygen species

– Cytokines

– Chemokines

– Macrophages

Adapted from Aiello S and Noris M. Kidney Int. 2010;78:1208-10.

Lymphocytes

Neutrophils

Chemokines

Macrophages

ROS

Vasoconstrictors

Dendritic Cells

Interstitium

Endothelium

Tubular Urinary Lumen

Proximal Tutules

Adhesion Molecules

Apoptosis, Cell Injury, Oxidative Stress

16

PRE-RENAL

AKI Causes: Physiological

• Low blood pressure

• Low blood volume

• Heart failure

• Arterial changes leading to kidney

• Glomerulonephritis

• Acute tubular necrosis (ATN)

• Acute interstitial nephritis (AIN)

• Benign prostatic hyperplasia

• Kidney stones

• Obstructed urinary catheter

• Bladder stone

• Bladder, ureteral or renal malignancy

Thadhani R, Pascual M, Bonventre JV. N Engl J Med. 1996;334(22):1448-60.

Decreased blood flow to the kidney

INTRINSIC (RENAL)

Damage to the kidney itself

POST-RENAL

Urinary tract obstruction

17

CONSIDER RENAL BIOPSY

There are cases of AKI with no known cause

Uncertain or competing diagnoses where treatment differs with definitive diagnosis

Young patients

AKI Causes: Unknown

18

GFR assessed from measured or estimated GFR. Estimated GFR does not reflect measured GFR in AKI as accurately as in CKD. Kidney damage assessed by pathology, urine, or blood markers, imaging, and – for CKD – presence of a kidney transplant. AKD, acute kidney diseases and disorders; AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate; NKD, no known kidney disease; SCr, serum creatinine.

Definitions of AKI, CKD, and AKD

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012; Volume 2, Issue 1:1–126.

Functional Criteria Structural Criteria

AKI Increase in SCr by 50% within 7 days, OR Increase in SCr by 0.3 mg/dL (26.5 μmol/L) within 2 days OR oliguria

No criteria

CKD GFR < 60 mL/min for > 3 months Kidney damage > 3 months

AKD AKI, OR GFR < 60 mL/min for < 3 months, ORDecrease in GFR by ≥ 35% or increase in SCr by > 50% for < 3 months

Kidney damage for < 3 months

NDK GFR ≥ 60 mL/minStable SCr

No damage

19

Chronic Kidney Disease

• CKD is a slow loss of kidney function over time.

STAGE CHARACTERISTICS

Slightly diminished function; kidney damage* with normal or relatively high GFR (≥ 90 mL/min/1.73 m2).

Mild reduction in GFR (60–89 mL/min/1.73 m2) with kidney damage*.

Moderate reduction in GFR (30–59 mL/min/1.73 m2).

Severe reduction in GFR (15–29 mL/min/1.73 m2). Preparation for renal replacement therapy.

Established kidney failure (GFR <15 mL/min/1.73 m2), or permanent renal replacement therapy.

* Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalitiesin blood or urine test or imaging studies.

• Many elderly patients have CKD despite creatinine values that are “normal” (~1.0).

1

2

3

4

ESRD

20

• AKI can occur on top of CKD– Many patients have CKD at baseline

– AKI can increase severity of CKD

CKD vs. AKI

Adapted from Dear JW and Yuen PST. Kidney Int. 2008;74:7-9.

CKD

AKI

ESRDESRD

CKD

21

AKI With or Without Chronic Kidney Disease

• AKI can be diagnosed in patients with chronic kidney disease (CKD).

• AKI can also increase the incidence of CKD.

Cerda´ J, Lameire N, Eggers P et al. Clin J Am Soc Nephrol. 2008;3:881-6.

Ren

al F

unct

ion

100

80

60

40

20

0

AKI to ESRD

AKI on CKD

AKI to CKD

Full Recovery

Insult

Time

22

Cumulative Incidence of CKD by Exposure Status (Recovered AKI vs. Controls) in Patients With Normal Baseline Kidney Function

Bucaloiu ID, Kirchner HL, Norfolk ER et al. Kidney Int. 2012 Mar;81(5):477-85.

1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n of

Pat

ient

s W

ithou

t CK

D

Months Since Index Hospitalization

0 6 12 18 24 30 36 42 48 54 60 66 72

AKIControls

23

Additional Comorbid Pathologies

• Diabetes mellitus

• Ischemic heart disease

• Congestive heart failure

• Hypertension

Bagshaw SM. Nephrol Dial Transplant. 2008;23(7):2126-8.

MOST COMORBID CONDITIONS ARE INFLAMMATORY OR CARDIOVASCULAR

MOST COMORBID CONDITIONS ARE INFLAMMATORY OR CARDIOVASCULAR

24

Mortality & Cost

25

AKI Increases Hospital Length of Stay and Associated Costs

AKI = INCREASING COST AND LENGTH OF STAY

26

AKI Associated Length of Stay (LOS)

Barrantes F, Tian J, Vazquez R, Amoateng-Adjepong Y et al. Crit Care Med. 2008;36:1397-403.

OUTCOME TOTAL AKI NON-AKI P VALUE

RRT rate, N (%) 18 (4.7) 18 (15.0) 0 (0.0) < 0.01

Hospital LOS, Median

Survived 8.0 14.0 7.0 < 0.01

Died 11.0 14.0 9.0 0.25

Total 9.0 14.0 7.0 < 0.01

MICU LOS, Median

Survived 3.0 6.0 3.0 < 0.01

Died 5.0 5.0 4.5 0.71

Total 3.0 5.0 3.0 < 0.01

RRT, renal replacement therapy; MICU, medical intensive care unit; NROF, non-renal organ failure.

27

OUTCOME TOTAL AKI NON-AKI P VALUE

Mortality, N (%)

≥ 2 NROFs 66 (31.9) 41 (50.6) 25 (19.8) < 0.01

< 2 NROFs 32 (18.4) 14 (35.8) 18 (13.3) < 0.01

1 NROF 19 (15.8) 9 (34.6) 10 (10.6) < 0.01

2 NROFs 25 (22.5) 16 (44.4) 9 (12.0) < 0.01

3 NROFs 27 (40.9) 19 (59.4) 8 (23.1) < 0.01

4 NROFs 11 (44.0) 6 (54.5) 5 (35.7) < 0.01

Total 98 (25.7) 55 (45.8) 43 (16.4) < 0.01

Barrantes F, Tian J, Vazquez R, Amoateng-Adjepong Y et al. Crit Care Med. 2008;36:1397-403.


AKI Associated Length of Stay (LOS)

28

AKI Cost by Creatinine Level

N = 2892, 1236, 351, 105, 4060, 1967, 714, 352, and 1160 for respective AKI criteria. Results are relative to those without the change indicated. Multivariable analyses were adjusted for age, gender, DRG weight, and ICD-9-CM categories of cardiovascular, respiratory, malignant, and infectious diseases.

Chertow GM, Burdick E, Honour M et al. J Am Soc Nephrol. 2005;16:3365–70.

↑ SCr ≥ 0.5 + baseline SCr < 2.0 mg/dl

29

AKI Costs Can Increase Following Surgery

No AKI Mild AKI Moderate AKI Severe AKI

RIFLE Criteria None R I F

Mortality (%) 2.3 5.1 12.9 26.0

ICU Costs $13,836 $21,775 $28,872 $49,328

ICU Length of Stay (Days)

1.4 2.4 3.5 5.4

Dasta JF, Kane-Gill SL, Durtschi AJ et al. Nephrol Dial Transplant. 2008;23:1970-74.

INCREASING SEVERITY FOLLOWING CARDIAC SURGERY

30

Mortality Associated With Changes in SCr

Criterion Unadjusted OR (95% CI)

Age- and Gender-Adjusted OR (95%

CI)Multivariable OR

(95% CI)b

Area under ROC Curve

↑ SCr ≥ 0.3 mg/dl 6.9 (5.2 to 9.0) 6.6 (5.0 to 8.7) 4.1 (3.1 to 5.5) 0.84

↑ SCr ≥ 0.5 mg/dl 11.1 (8.7 to 14.2) 10.6 (8.3 to 13.6) 6.5 (5.0 to 8.5) 0.86

↑ SCr ≥ 1.0 mg/dl 19.9 (15.1 to 26.1) 19.0 (14.4 to 25.0) 9.7 (7.1 to 13.2) 0.84

↑ SCr ≥ 2.0 mg/dl 36.4 (24.3 to 54.6) 37.7 (25.0 to 56.9) 16.4 (10.3 to 26.0) 0.83

↑ SCr by 25% 4.0 (3.0 to 5.2) 3.9 (3.0 to 5.2) 2.0 (1.2 to 3.9) 0.83

↑ SCr by 50% 5.9 (4.6 to 7.5) 5.8 (4.6 to 7.5) 4.4 (3.4 to 5.7) 0.84

↑ SCr by 100% 8.9 (6.9 to 11.4) 9.2 (7.1 to 11.8) 6.5 (4.9 to 8.6) 0.84

↑ SCr by 50% to a minimum peak of 2.0 mg/dl

16.9 (12.8 to 22.3) 15.9 (12.0 to 21.0) 7.9 (5.8 to 10.9) 0.84

↑ SCr ≥ 0.5 mg/dl with baseline SCr < 2.0 mg/dl or ↑ SCr ≥ 1.0 mg/dl with baseline SCr ≥ 2.0 and < 5.0 mg/dl

11.0 (8.6 to 14.0) 10.5 (8.2 to 13.4) 6.5 (5.0 to 8.5) 0.86

N = 2892, 1236, 351, 105, 4060, 1967, 714, 352, and 1160 for respective AKI criteria. Results are relative to those without the change indicated. Multivariable analyses were adjusted for age, gender, DRG weight, and ICD-9-CM categories of cardiovascular, respiratory, malignant, and infectious diseases.

Chertow GM, Burdick E, Honour M et al. J Am Soc Nephrol. 2005;16:3365–70.

31

ICU MORTALITY2ICU MORTALITY1

Morbidity and Mortality

60

50

40

30

20

10

0

60

50

40

30

20

10

0No AKI AKI Sepsis Sepsis +

AKI

1. Clermont G, Acker CG, Angus DC et al. Kidney Int. 2002;62(3):986-96.2. Hoste EA, Lameire NH, Vanholder RC et al. J Am Soc Nephrol. 2003;14(4):1022-30.

Perc

ent

Perc

ent

32

Diagnosis, Assessment, & Management

33

Traditional Methods of Measurement

34

15 60

Normal

1200

Kidney Failure Kidney Disease

Creatinine and GFR

• Creatinine– Breakdown product of creatine

– Exclusively filtered out by the kidneys (no resorption)

– Estimates renal function

• GFR– Glomerular filtration rate

– Volume of creatinine cleared per unit time

– Some equations also take age and sex into account

eGFR Value

35

AKI Diagnosis

Serum Creatinine (mg/dL) Diagnosis AKI

CaseBaselin

eDay

1Day

2Day 3

Day 7

Criterion 1:

50% from Baseline

Criterion 2: ≥ 0.3 mg/dL

Rise in ≤ 48 Hours

A 1.0 1.3 1.5 2.0 1.0 Yes Yes

B 1.0 1.1 1.2 1.4 1.0 No Yes

C 0.4 0.5 0.6 0.7 0.4 Yes No

D 1.0 1.1 1.2 1.3 1.5 Yes No

E 1.0 1.3 1.5 1.8 2.2 Yes Yes

F ? 3.0 2.6 2.2 1.0 Yes No

G ? 1.8 2.0 2.2 1.6 ? Yes

H ? 3.0 3.1 3.0 2.9 ? No


36

Estimated Baseline SCr

Age (Years) Black Males (mg/dL

[μmol/L])

Other Males (mg/dL

[μmol/L])

Black Females (mg/dL

[μmol/L])

Other Females (mg/dL

[μmol/L])

20-24 1.5 (133) 1.3 (155) 1.2 (106) 1.0 (88)

25-29 1.5 (133) 1.2 (106) 1.1 (97) 1.0 (88)

30-39 1.4 (124) 1.2 (106) 1.1 (97) 0.9 (80)

40-54 1.3 (115) 1.1 (97) 1.0 (88) 0.9 (80)

55-65 1.3 (155) 1.1 (97) 1.0 (88) 0.8 (71)

> 65 1.2 (106) 1.0 (88) 0.9 (80) 0.8 (71)


37

AKI Staging

Serum Creatinine (mg/dL)

CaseBaselin

eDay

1Day

2Day 3

Day 7

Reference Creatinine

Max AKI Stage

A 1.0 1.3 1.5 2.0 1.0 1.0 2

B 1.0 1.1 1.2 1.4 1.0 1.0 1

C 0.4 0.5 0.6 0.7 0.4 0.4 1

D 1.0 1.1 1.2 1.3 1.5 1.0 1

E 1.0 1.3 1.5 1.8 2.2 1.0 2

F ? 3.0 2.6 2.2 1.0 1.0 3

G ? 1.8 2.0 2.2 1.6 ? ≥ 1

H ? 3.0 3.1 3.0 2.9 ? ?


38


GFR/SCr Algorithm

Is GFR decreased or is serum creatinine increased?

Is SCr increasing or GFR decreasing?

Does the decrease in GFR or increase in SCr resolve within 3 months?

Yes > 3 monthsNoYes < 3 months

NKD AKD without AKI AKI AKD

without AKI AKIAKD without AKI

CKD + AKD without AKI

CKD + AKICKD

No Yes-D Yes-I

No Yes-D Yes-I

No Yes-D Yes-I

Yes-D, change in SCr meets AKD criteria but not AKI criteria

CKD worse

CKD stable

CKD worse

CKD stable

CKD new NKD CKD

new NKD

No Yes No Yes No Yes No Yes

AKD, acute kidney disease/disorder; AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate; NKD, no known kidney disease; SCr, serum creatinine

GFR/SCr

NKD AKD CKD

CKD + AKD without AKI

CKD + AKI

AKD without AKI AKI


39

GFR Over the Course of AKI

Injury

Diagnosis (Future with Biomarkers)

Diagnosis (2011)

Prerenal Azotemia

Time (Days)

GFR

Maladaptive Response

Repair Response

• Prerenal azotemia can progress to kidney injury.

• After the initial sharp drop in GFR, there is further injury from secondary effects.

• Early immune response can be maladaptive and contribute to further injury.

• After injury, GFR does not recover immediately after return of renal blood flow.

Winterberg PD and Lu CY. Am J Med Sci. 2011 Aug 3.

40

Other Methods of Diagnosis

• Serum– Urea nitrogen

• Pathology– Kidney biopsy

• Imaging– Ultrasound, CT, MRI, nuclear renal scan

• Urine– Fractional excretion (sodium, urea), protein/creatinine ratio,

sediment (casts, WBCs, eosinophils), enzyme activity

41

KDIGO is a global non-profit foundation dedicated to improving the care and outcomes of kidney disease patients worldwide.

Assembled working group of eighteen thought leaders to establish global clinical practice guidelines for AKI

New guidelines just published.

Physicians Can Take Action With Early Assessment of AKI

KDIGO Initiative to Set Guidelines KDIGO AKI Guidelines

41

High Risk 1 2 3

Avoid subclavian catheters

Consider ICU admission

Consider Renal Replacement Therapy

Check for changes in drug dosing



Consider alternatives to radiocontrast procedures

Avoid hyperglycemia

Monitor serum creatinine and urine output

Consider functional hemodynamic monitoring

Ensure volume status and perfusion pressure

Discontinue all nephrotoxic agents when possible


42

Physicians Can Take Action With Early Assessment of AKI

42

KDIGO AKI Guidelines

High Risk 1 2 3

Avoid subclavian catheters if possible

Consider ICU admission





Consider alternatives to radiocontrast procedures

Avoid hyperglycemia

Monitor serum creatinine and urine output

Consider functional hemodynamic monitoring

Ensure volume status and perfusion pressure

Discontinue all nephrotoxic agents when possible


43

Current Thinking

• Focus is now on inflammation-mediated organ injury in addition to renal blood flow.

• AKI leads to progressive injury and a spectrum of functional kidney problems.– Serial AKI leading to CKD

• Injury vs. decreased filtration

• New terminology– AKI rather than acute renal failure (ARF)

44

• The care of patients with acute kidney injury is very poor.

Key Findings in Assessment of AKI Care

Hussein HK, Lewington AJP, Kanagasundaram NS. Brit J Hosp Med. 2009;70:M104–7.Stewart JAD. Brit J Hosp Med. 2009;70(7):372-3.

• Acutely unwell patients are not being recognized.

• Education about acute kidney injury must improve.

• Patients are dying from predictable and avoidable renal failure.

• The failings in the care of patients are largely clinical.– Poor assessment of risk

– Inadequate basic intervention

– Missed complication

45

Deficiencies in the Diagnosis and Care of AKI Patients

69%

31%

Care of AKI patient

Good Practice

Room for Improvement

Over 60% had room for improvement

31%

34%

35%

AKI outcome

UnavoidableAKI

Avoidable AKI

Over 30% had avoidable AKI

Not Specified

54%46%

AKI risk assessment

AdequateInadequate

> 50% had inadequate risk assessment

43%57%

Delay in recognition of AKI

AcceptableUnacceptable

Delay

43% had unacceptable recognition delay

Acute Kidney Injury: Adding Insult to Injury. NCEPOD. 2009.

FINDINGS FOR ADMITTED PATIENTS THAT DIED FROM HOSPITAL ACQUIRED AKI

46

Lack of AKI Recognition Resulted in Inadequate Consultations

31%

69%

Referral to nephrologist

No

Yes

Only 31% referred to nephrologist

21%

79%

Was referral to nephrologist timely?

1 in 5 are referred late

Yes

No

21%

79%

Patients that would have benefitedfrom critical care

Several should have been moved to critical care

No

Yes20%

80%

Need for nephrologist in group not referred

Yes

Another 20% should have been referred

No


FINDINGS FOR ADMITTED PATIENTS THAT DIED FROM COMMUNITY AND HOSPITAL ACQUIRED AKI

47

Many Omissions in AKI Management


48

Classification and Assessment

• RIFLE– Classifies AKI into three levels of severity (Risk, Injury, and Failure)

and includes two clinical endpoints (Loss and End-stage renal disease)

– Severity is determined from the increase in CR and decrease in UO

Bellomo R, Ronco C, Kellum JA et al. Crit Care. 2004;8(4):R204–12.

No AKI

Risk (Minor AKI)Cr x 1.5 or GFR decreases > 25% or UO < 0.5 ml/kg/hr x 6 hr

Injury (Moderate AKI)CR x 2.0 or GFR decreases > 50% or < 0.5 ml/kg/hr x 12 hr

Failure (Severe AKI)Cr x 3.0 or GFR decreases > 75% or Cr ≥ 4 mg/dl or < 0.3 ml/kg/hr x 24 hr or anuria x 12 hr

LossOn dialysis > 1 month

ESRDOn dialysis > months

49


• Acute Kidney Injury Network (AKIN)– Stage 1 is similar to RIFLE-R but includes abrupt reduction in function.

– RIFLE-I and F are the same as stages 2 and 3.

– Stage 3 includes patients who need any renal replacement therapy.

No AKI

Stage 1Cr x 1.5 or ≥ 0.3 mg/dl or UO < 0.5 ml/kg/hr x 6 hr

Stage 2CR x 2.0 or UO < 0.5 ml/kg/hr x 12 hr

Stage 3Cr x 3.0 or UO < 0.3 ml/kg/hr x 24 hr or anuria x 12 hr

Mehta RL, Kellum JA, Shah SV et al. Crit Care. 2007;11(2):R31.

NOT in AKIN classification

NOT in AKIN classification

50


• Kidney Disease: Improving Global Outcomes (KDIGO)– Similar to AKIN

– Adds values to creatinine levels as well as fold increase

– Stage 3 also includes patients who need renal replacement therapy.

No AKI

Stage 1Cr ≥ 26 μmol/L within 48 hrs or ≥ 1.5 to 1.9 or UO < 0.5 mL/kg/hr for > 6 hr

Stage 2CR ≥ 2 to 2.9 or UO < 0.5 ml/kg/hr x 12 hr

Stage 3Cr ≥ 354 μmol/L or ≥3 or UO < 0.3 ml/kg/hr x 24 hr or anuria x 12 hr

NOT in KDIGO classification

NOT in KDIGO classification


51

Renal Disease Landscape

Renal disease landscape developed at the 2006 Acute Kidney Injury Network Congress in Vancouver, British Columbia, Canada. AKI, acute kidney injury; R, RIFLE risk (AKI stage I); I, RIFLE injury (AKI stage II); F, RIFLE failure (AKI stage III); AKD, acute kidney disease; ARF, acute renal failure; RRT, renal replacement therapy; CKD, chronic kidney disease; ESRD, end-stage renal disease.

Kellum JA. Crit Care Med. 2008;36[Suppl]:S141–5.

StagesI II III IV V

CKDAKD

I (R)

II (I)

III (F)

?

Biomarkers?

Exists for < or > 90 Days

Fulfills Criteria within 48 Hours?

RRT

“ARF”

Dialysis

ESRDAKI

52

The concept of AKI includes both volume-responsive and volume-unresponsive conditions.

Conceptual Model for Development and Clinical Course of AKI

High Risk

Volume Responsive AKI Volume Unresponsive AKI

Hypovolemia

Hypervolemia

Therapeutic Window

Kidney Function

Eurolemia

Biomarkers

Mortality

TraditionalSensitive


53

• Kidney damage is not required for diagnosis of AKI.

Markers of Kidney Damage in AKD and CKD

Markers AKD CKD

Pathology X X

Urinary markers

RBC/casts X X

WBC/casts X X

RTE/casts X X

Fine and coarse granular casts X X

Proteinuria X X

Blood markers (tubular syndromes) X X

Imaging

Large kidneys X X

Small kidneys - X

Size discrepancy - X

Hydronephrosis X X

Cysts X X

Stones X X

History of kidney transplantation - XAKD, acute kidney diseases and disorders; CKD, chronic kidney disease; RBC, red blood cells; RTE, renal tubular epithelial cells; WBC, white blood cells.

• In the presence of AKI, findings of kidney damage do not indicate a separate AKD diagnosis.


54

Treatment

55

Treatment Options

• Treatment options are limited– Fluid therapy

– Vasopressors or inotropes

– Treatment of underlying sepsis

– Renal replacement therapy

• Further limited by inadequate diagnostic tools

56

Dialysis Solution

Waste Fluid

Peritoneal Catheter

External Catheter

Renal Replacement Therapy

• Hemodialysis

• Peritoneal dialysis

• Hybrid therapies– Sustained low-efficiency dialysis

• Kidney transplantation

ArteryVein

Blood from Dialysis Machine

Blood to Dialysis MachineGraft

57

Dialysis

• Intermittent renal replacement therapy (IRRT)– Less than 24 hours in each 24 hour period

– Two to seven times per week

• Continuous renal replacement therapies (CRRT)– Continuous without any interruption throughout each day

IRRT CRRT

Dwell

Volu

me

Time

Outflow

Inflow

Volume

Time (Minutes)

Residual Volume

0 15 30 45 60

[Inflow = Outflow]

Last Drain

Tota

l Exc

hang

e Vo

lum

e (V

ip)

58Vesconi S, Cruz DN, Fumagalli R et al. Crit Care. 2009;13(2):R57.

Dose of RRT and Mortality in AKI

TOTAL CRRT

< 35 ml/kg/hour ≥ 35 ml/kg/hour P

Length of ICU stay (days) 13 (6.5 to 26) 15 (9 to 28) 8 (4 to 18) < 0.001

Patients who survived 19 (11 to 32) 19.5 (12 to 33.5) 15 (8 to 26) 0.063

Patients who died 10 (4 to 19) 12 (6 to 20) 4.5 (3 to 9.5) < 0.001

Duration of MV (days) 10 (4 to 19) 12 (5 to 21) 5 (2.5 to 13) < 0.001

Patients who survived 14 (4.5 to 22) 14 (5 to 24) 7 (4 to 17) 0.031

Patients who died 8.5 (3 to 17) 10 (5 to 18) 4 (2 to 9.5) < 0.001

TOTAL IRRT

< 6 sessions/week ≥ 6 sessions/week P

Length of ICU stay (days) 14 (6.5 to 23) 18 (15 to 31) 9.5 (6 to 18) 0.023

Patients who survived 11 (6 to 20) 18 (13 to 35) 8 (5.5 to 14) 0.008

Patients who died 17 (12 to 23) 18 (17 to 23) 15 (12 to 22) 0.597

Duration of MV (days) 8 (1 to 17) 14 (5 to 21) 6 (0 to 14) 0.030

Patients who survived 5 (0 to 13) 12 (3 to 24) 2.5 (0 to 10) 0.026

Patients who died 17 (11 to 21) 18 (17 to 21) 14 (8 to 18) 0.252

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Limitations & Unmet Needs

60

Serum Creatinine

• Gold standard, but far from ideal

• Not sensitive to kidney insults that don’t affect filtration

• Creatinine is affected by non-renal factors:– Protein intake

– Muscle mass

– Age

– Race

– Sex

• In AKI it takes 24-48 hours for serum creatinine to rise.– As much as 50% of kidney function can be lost in that time

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Urine Output

• May be misleading

Legrand M and Payen D. Ann Intensive Care. 2011;1:13.

• A minimum of 6 hours must pass to determine urine output.

• Nonsustained decreases of urine output do not necessarily imply decreased GFR.– Can represent a physiological

renal adaptation for homeostasis

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NO. OF PATIENTS

REFERENCE TP FP FN TN NGAL CUTOFF (NG/ML)

SENSITIVITY (%; 95% CI)

SPECIFICITY (%; 95% CI)

Mishra et al, 2005 (p) 14 3 6 48 > 25 70.0 (45.7-87.2) 94.1 (82.8-98.5)

Mishra et al, 2005 (u) 20 1 0 50 > 50 100.0 (80.0-100.0) 98.0 (88.2-99.9)

Wagener et al, 2006 11 23 5 42 > 400 68.8 (41.5-87.9) 64.6 (51.7-75.8)

Dent et al, 2007 38 5 7 73 > 150 84.4 (69.9-93.0) 93.6 (85.0-97.6)

Zappitelli et al, 2007 12 7 4 16 > 10 75.0 (47.4-91.7) 69.6 (47.0-85.9)

Hirsch et al, 2007 (p) 8 1 3 79 >100 72.7 (39.3-92.7) 98.8 (92.3-99.9)

Hirsch et al, 2007 (u) 8 0 3 80 > 100 72.7 (39.3-92.7) 100.0 (94.3-100.0)

Wagener et al, 2008 44 172 24 186 > 450 64.7 (52.1-75.6) 52.0 (46.7-57.2)

Bennett et al, 2008 78 8 21 89 >150 78.8 (69.2-86.1) 91.8 (83.9-96.1)

Ling et al, 2008 10 8 3 19 -- 76.9 (46.0-93.8) 70.4 (49.7-85.5)

Koyner et al, 2008 (p) 8 13 10 41 > 280 44.4 (22.4-68.7) 75.9 (62.1-86.1)

Koyner et al, 2008 (u) 12 19 6 35 > 550 66.7 (41.2-85.6) 64.8 (50.6-77.0)

Nickolas et al, 2008 20 16 3 502 > 80 87.0 (65.3-96.6) 96.9 (94.9-98.2)

Lima et al, 2008 5 12 1 34 -- 83.3 (36.5-99.1) 73.9 (58.6-85.3)

Wheeler et al, 2008 19 74 3 47 > 140 86.4 (64.0-96.4) 38.8 (30.3-48.2)

Xin et al, 2008 2 8 1 22 > 250 66.7 (12.5-98.2) 73.3 (53.8-87.0)

Cruz et al, 2009 47 46 17 191 > 150 73.4 (60.7-83.3) 80.6 (74.9-85.3)

Makris et al, 2009 (CIN) 5 6 1 44 60 90.0 (54.1-99.5) 88.0 (75.0-95.0)

Makris et al, 2009 (ICU) 6 7 1 17 > 190 85.7 (42.0-99.3) 70.8 (48.8-86.6)

Constantin et al, 2009 43 1 9 35 > 155 82.7 (69.2-91.3) 97.2 (83.8-99.9)

Tuladhar et al, 2009 (p) 7 13 2 28 > 420 77.8 (40.2-96.1) 68.3 (51.8-81.4)

Tuladhar et al, 2009 (u) 8 9 1 32 > 390 88.9 (50.7-99.4) 78.1 (62.0-88.9)

Haase-Fielitz et al, 2009 18 17 5 60 > 150 78.3 (55.8-91.7) 77.9 (66.8-86.3)

Sensitivity and Specificity of Studies for NGAL to Predict AKI

Haase M, Bellomo R, Devarajan R et al. Am J Kidney Dis. 2009;54:1012-24.

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BIOMARKER NEEDS

AKI Biomarkers

BIOMARKERS

• IL-18

• NGAL

• KIM1

• L-FABP

• Cystatin C

• Early detection

• Differential diagnosis

• Prognosis

MOST AKI MARKERS ARE NOT FDA APPROVED

AND AVAILABLE ONES DO NOT MEET CURRENT CLINICAL NEEDS.

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Possible Utility of New Biomarkers

• Early detection

• Differential diagnosis

• Prognosis– Predict need for dialysis

– Reversibility

– Risk of death

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Unmet Clinical Needs

• AKI is difficult to assess.

• Mortality is high and it carries a very high cost.

• Currently available methodologies and biomarkers are not meeting clinical needs.

• New biomarkers are on the horizon to assistwith AKI risk assessment.

Documents

1 Acute Kidney Injury. 2 I. Anatomy II. Epidemiology III. Mortality & Cost IV. Diagnosis, Assessment, & Management V. Treatment VI. Limitations and Unmet