diagnostic and nomenclature controversies for aki€¦ · aki, akd, ckd continuum criteria aki akd...

©2013 MFMER | 3322132-1©2013 MFMER | 3322132-1

Diagnostic and nomenclature controversies for AKI

Kianoush B. Kashani, MD, MSc, FASN, FCCP

37th Vicenza Course on CRRT & AKI

Vicenza, ItalyMay 29th, 2019

©2013 MFMER | 3322132-2

Disclosures

• KK

• My institution has received research funds from Astute Medical Inc.

• I have no personal financial relationship

©2013 MFMER | 3322132-3

KDIGO ConferenceAKI controversies

©2013 MFMER | 3322132-4

OutlinesDefinitions

• AKI, AKD, CKD continuum

• Subclinical AKI and Kidney stress

• Persistence vs. transient vs. relapsing AKI

• Kidney recovery

• Role of etiology/setting

• Urine output vs. serum creatinine criteria

• Role of biomarkers, biopsy, and imaging

• Fluid imbalance

• Community vs. hospital-acquired AKI

• Pediatrics vs. adult AKI

©2013 MFMER | 3322132-5

OutlinesDefinition implementation: Bedside and research

• Baseline kidney function • Baseline creatinine• eGFR• Renal reserve• Imaging

• How should urine output be evaluated • Body composition• Fluid balance or use of diuretics• Setting/context

• What is the role for real time or kinetic GFR?

• How and how often should monitor kidney?

• Role of expert interpretation/judgment

©2013 MFMER | 3322132-7

AKI, AKD, CKD Continuum

KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138

Stages defined

by creatinine

and urine output

are surrogates

AntecedentsIntermediate StageAKIOutcomes

Markers such as

NGAL, KIM-1

and IL-18 are

surrogates

Damage

GFR

NormalIncreased

risk Damage GFRKidney

failureDeath

Complications

©2013 MFMER | 3322132-8


Criteria AKI

Duration Within 7 days

Function Alteration

Oliguria for ≥6 hours

OR↑ Scr by ≥0.3 mg/dL

in 48 hoursOR

↑ Scr by ≥50% in 7 days

Structural Alteration

Not defined


©2013 MFMER | 3322132-9


Criteria AKI AKD

Duration Within 7 days 3 months

Function Alteration



in 48 hoursOR


AKIOR

GFR <60 mL/min/1.73 m2

OR↓ GFR by ≥35%

OR↑Scr by ≥50% in

7-90 days


Not defined Marker of kidney damage

(albuminuria)


©2013 MFMER | 3322132-10


Criteria AKI AKD CKD

Duration Within 7 days 3 months >3 months

Function Alteration



in 48 hoursOR


AKIOR


OR↓ GFR by ≥35%


7-90 days




(albuminuria)

Marker of kidney damage

(albuminuria)


©2013 MFMER | 3322132-11


Criteria AKI AKD CKD NKD*

Duration Within 7 days 3 months >3 months

Function Alteration



in 48 hoursOR


AKIOR


OR↓ GFR by ≥35%


7-90 days


GFR ≥60 mL/min/1.73 m2

AND

Stable Scr



(albuminuria)

Marker of kidney damage

(albuminuria)

No marker of kidney damage


©2013 MFMER | 3322132-12


Chawla, L. S., et al. (2017). Nat Rev Nephrol 13(4): 241-257

0 2

(48h)

7 90 180

Injury

AKI AKD CKD

Days post injury

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1

No Yes >3 mo

Yes<3 mo orunknown

GFR/Scr

AKD

↓ GFR or ↑ Scr?

NKD CKD


©2013 MFMER | 3322132-16

NKDAKD w/o

AKIAKI

AKD w/oAKI

AKD w/oAKI

AKI CKDCKD +AKD

w/o AKI

CKD+AKI

No Yes >3 mo

Yes<3 mo orunknown

No Yes-D Yes-I No Yes-D Yes-I No Yes-D Yes-I

GFR/S cr

AKD

↓ GFR or ↑ Scr?

NKD

Ongoing ↓ GFR or ↑ Scr?

CKD

1

2


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3

CKDworse

CKDstable

CKDworse

CKDstable

CKDnew

NKDCKDnew

NKD

No Yes No Yes No Yes No Yes

CKD+AKD w/o

AKI

CKD+AKI

AKD w/o

AKIAKI

↓ GFR or ↑ Scr resolve within 3 months?


©2013 MFMER | 3322132-18


AKD AKI CKD


©2013 MFMER | 3322132-19

AKI, AKD, CKD ContinuumPopulation-based epidemiology study (N=1,109,099)

Category and Criteria No. (%)

No Kidney disease

Total 921,116 (100) [82%]

CKD

Prior eGFR <60 mL/min/1.73 m2 66,955 (51.6)

Preexisting albuminuria 62,764 (48.4)

Identified by albumin to creatinine ratio 17,331 (27.6)

Identified by dipstick 45,433 (72.4)

Total 129,719 (100) [12%]

AKI

Increase in sCr >0.3 mg/dL in 2 d or >50% in 7 d 8,807 (42.4)

Decrease in sCr >50% in 7 d 8,906 (42.8)

Coincident acute care diagnosis associated with AKI 3,079 (14.8)

Total 20,792 (100) [2%]

AKD without AKI

Prior eGFR >60 mL/min/1.73 m2, index eGFR <60 mL/min/1.73 m2 23,049 (47.2)

No prior eGFR measure, index eGFR <60 mL/min/1.73 m2 4,903 (10.0)

Increase sCr >50% in >7 d for <90 d 3,825 (7.8)

Decrease in eGFR >35% in >7 d for <90 d 1,019 (2.1)

Development of albuminuria 15,998 (32.8)

Identified by albumin to creatinine ratio 4,221 (26.4)

Identified by dipstick 11,777 (73.6)

Total 48,794 (100) [4%]

James et al. (2019). JAMA Netw Open 2(4): e191795.

[6%]

©2013 MFMER | 3322132-20

AKI, AKD, CKD ContinuumPopulation-based epidemiology study

0,0

0,2

0,4

0,6

0,8

0 1 2 3 4 5 6 7 8

0,00,10,20,30,40,5

0 1 2 3 4 5 6 7 8

Cum

ula

tive

incid

ence

Cum

ula

tive

incid

ence

Mortality CKD Development

Follow-up time, y Follow-up time, y

0,00,10,20,30,40,50,6

0 1 2 3 4 5 6 7 8

0,00,10,20,30,40,5

0 1 2 3 4 5 6 7 8

Cum

ula

tive

incid

ence

Cum

ula

tive

incid

ence

CKD Progression ESKD

Follow-up time, y Follow-up time, y

CKD and AKD w/o AKI

CKD and AKI

CKD

AKI

AKD w/o AKI

NKD

James et al. (2019). JAMA Netw Open 2(4): e191795.

©2013 MFMER | 3322132-22

Subclinical AKI

“Subclinical

AKI”No functional

changes or

damage

Damage without

loss of function

Loss of function

without damage

Damage with loss

of function

Biomarker

Negative

Biomarker

Positive

Creatinine

Negative

Creatinine

Positive

“Prerenal AKI”

“True AKI”

10th ADQI Consensus Conference. Adapted from Murray PT et al. Kidney International 2013

©2013 MFMER | 3322132-23

Subclinical AKI

Acute Kidney

Injury

No functional

changes or

damage

Damage without

loss of function

Loss of function

without damage

Damage with loss

of function

Biomarker

Negative

Biomarker

Positive

Creatinine

Negative

Creatinine

Positive

Acute kidney

Dysfunction

10th ADQI Consensus Conference. Adapted from Murray PT et al. Kidney International 2013

©2013 MFMER | 3322132-24

Acute kidney stress

Katz et al. (2019). Critical Care Medicine

• Pre-injury

• Cell cycle arrest biomarkers

• Functional load

• Glomerular Stress

• Protein loading

• Tubular Stress

• Furosemide stress test

• Preconditioning

©2013 MFMER | 3322132-25

Acute Kidney StressPre-Injury

Structure

Normal Cells Cell Damage Cell Loss

AKS AKIUnchecked Injury

Affected cells

Whole organ

Function

TimeKatz et al. (2019). Critical Care Medicine

©2013 MFMER | 3322132-26

Cell cycle arrest biomarkers of kidney stressIGFBP7*TIMP2

Kashani et al. Critical Care 2013, 17:R25

©2013 MFMER | 3322132-28

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

Pre-RIPC

Post-RIPC

4 8 12 16 20 24

Acute Kidney StressPreconditioning

Zarbock et al. (2015). JAMA 313(21): 2133-2141

Before

CPB

After

CPB, h

Urine

(T

IMP

-2)

x (

IGF

BP

7),

ng/m

L2/1

000

Urine (TIMP-2) x (IGFBP7)

0

50

100

150

200

250

300

Pre-RIPC

Post-RIPC

4 8 12 16 20 24

Before

CPB

After

CPB, hU

rine

NG

AL

, n

g/m

L

Urine NGAL

RIPC

Control

©2013 MFMER | 3322132-30

Transient vs. Persistent AKI


AKIStage 3

AKIStage 2

AKIStage 1

SubacuteAKI andnormal

renalfunction

AKI AKD

0 2 7 14 28Days

Rapid reversal

123

45

©2013 MFMER | 3322132-31

Transient vs. Persistent AKIIncidence and impact on outcomes

Study Study group (n)Criteria for AKI Definition of RR Outcomes

Uchino et al.(2010)1

All patients admitted to a university-affiliated hospital (20,1260

SCr Reversal to no-AKI RIFLE class within 72h of AKI onset

RR in 14.8% of patients; persistent AKI in 29.1% Patients with TA had a significantly higher odds ratio for hospital mortality (2.26; 95% CI 1.85-2.76) than patients without AKI

Coca et al.(2010)2

Diabetic patients from 123 Veterans Affairs medical centresundergoing their first non-cardiac surgery. (35,302)

SCr Reversal of SCrto <17.7 mol/L (<0.2 mg/dL) above the preoperativevalue within 48 h

Mortality was lowest in those with AKI duration 2 days, regardless of stage Median survival was 3.5 years for patients with short durtionAKI (<2 days), 2.9 years for those with medium-duration AKI (<2 days), 2.9 years for those with medium-duration AKI (3-6 days), and 2.1 years for patients with long-duration AKI (≥7 days)

Kellum et al.(2015)3

Academic medical centre database of critically ill patients who were classified according to the maximum KDIGO criteria met during hospitalization (32,045)

SCrand UO

Reversal to no-AKI KDIGO class within 3 days

Likelihood of death or dialysis at 1 year was higher in patients with persistent AKI than in those with transient AKI (excluding death or RRT during the index hospitalization)

Sood et al. (2014)4

AKI of any RIFLE severity prevalent at shock (5,443)

SCr Reversal of SCr to baseline value within 24 h

RR in 21.2% of patients; persistent AKI in 53.0%

Brown et al. (2010)5

Patients undergoing cardiac surgery (4,987)

SCr Reversal to no-AKI RIFLE class within 72 h of AKI onset

RR within 1-2 days in 18% of patients; persistent AKI (for 3-6 days) in 11% >7 days in 9%

Perinel et al.(2015)6

Critically ill patients with ICU stay >3 days (447)

SCrand UO

Reversal of oliguria (in the absence of diuretic treatment)and/or ≥50% decrease in SCr and/or return to the baseline value

RR in 29.6% of patients; persistent AKI in 38.9%


Rapid reversal 15-30%

Persistent AKI 20-53%

©2013 MFMER | 3322132-35

Etiology/setting

• Anatomical classification

• Renal, pre- and post-renal

• Pros

• Easy to remember

• Cons

• Miss injuries if solely relied on functional biomarkers

• Misdirection in management

©2013 MFMER | 3322132-36

‘Prerenal’ AKIAvoid ‘Lumping’ Conditions Together!

‘Prerenal’ cause Intrarenal blood flow Resuscitate with IV fluids?

Volume depletion Yes

Dehydration

Courtesy of Prof. Zoltan Endre

©2013 MFMER | 3322132-37

‘Prerenal’ AKIAvoid ‘Lumping’ Conditions Together!

‘Prerenal’ cause Intrarenal blood flow Resuscitate with IV fluids?

Volume depletion Yes

Dehydration

Reduced cardiac output ?

Myocardial infarction, LVF

Reduced cardiac output No

Venous congestion

Right heart failure, EDD

Vasoconstriction

Hepatorenal syndrome No

Crush injury With care

Vasculitis Noe

Sepsis Maybe – EGDT results vary

Sepsis with hypotension Regional Yes

Courtesy of Prof. Zoltan Endre

©2013 MFMER | 3322132-40

0,0

0,2

0,4

0,6

0,8

1,0

0 365

Age a

dju

ste

d s

urv

ival

Days from ICU admission to death

Kellum et al. (2015). J Am Soc Nephrol 26(9): 2231-2238

50 100 150 200 250 300

No AKI by either criterion

Stages 1–2 by UO but no AKI by SC or stage 1 by SC and no AKI by UO

Stages 1–2 by UO plus stage 1 by SC or stages 2–3 by SC alone

Stages 1–2 by UO plus stage 2 by SC or stage 3 by UO alone

Stage 3 by UO plus stages 1–2 by SC or stage 3 by SC plus stages1–2 by UO

Stage 3 by both criteria

©2013 MFMER | 3322132-41

0,0

1,0

0 365

Age a

dju

ste

d f

ree o

f E

SR

D

Days from ICU admission to USRDS Admission

Kellum et al. (2015). J Am Soc Nephrol 26(9): 2231-2238

50 100 150 200 250 300

0.80

0.90

Stages 1–2 by UO but no AKI by SC or stage 1 by SC and no AKI by UO

Stages 1–2 by UO plus stage 1 by SC or stages 2–3 by SC alone

Stages 1–2 by UO plus stage 2 by SC or stage 3 by UO alone

Stage 3 by UO plus stages 1–2 by SC or stage 3 by SC plus stages1–2 by UO

Stage 3 by both criteria

No AKI by either criterion

©2013 MFMER | 3322132-43

Therapeutic Window

Changed from: Himmelfarb et al: Clin J Am Soc Nephrol 3:962, 2008

High Risk AKI Stage 1 AKI Stage 3

Preventive/Therapeutic Window

Kidney FunctionMortality

Prediction: Biomarker/Models Detection: Traditional Biomarkers

AKI Stage 2

©2013 MFMER | 3322132-44

Current state

Belcher et al. Am J Kidney Dis. 2011;57(6):930-940

TIMP2*IGFBP7

TIMP2*IGFBP7

TIMP2*IGFBP7

Clinical Utility

Current test

Novel Biomarkers

Differential Diagnosis in

Established AKIEarly Detection Prognosis

Functional FENa

Functional mGFR*

SCr

Functional AKINRIFLE

Structural Biopsy*

Urine microscopy

Structural Biopsy**

Structural Biopsy

Urine microscopy

IL-18KIM-1NGALNAG

Cystatin C GSTIL-18KIM-1NGALNAG

L-FABP

RRTCystatin C

RRTNGALNAG

L-FABP

DeathIL-18NGALNAG

L-FABPBiomarkers of:

Recovery

Etiology specific

©2013 MFMER | 3322132-45

AKI as main Bx indication

14,8

12,2

14,313,1

13,815,2

17,7

15,5

20,8

18,4 18,919,6

24,2

0

5

10

15

20

25

30

P<0.0001López-Gómez et al. (2008). CJASN 3(3): 674-681

%

©2013 MFMER | 3322132-46

Main syndrome required BxN=13,491

0 10 20 30 40

Hypertension

Haematuria

Nephritic syndrome

Chronic renal failure

Acute renal failure

Asymptomatic urinary abnormalities

Nephritic syndrome

López-Gómez et al. (2008). CJASN 3(3): 674-681

©2013 MFMER | 3322132-49

Available measured serum creatinineN=379

Siew at al: Clin J Am Soc Nephrol 7:712–719, 2012

ICC (95% CI) per Days Before Admission

Estimated Method 7-365 days 7-730 days 1-730 days

Most recent

outpatient

0.84

(0.80-0.88)a

0.83

(0.78-0.86)b

0.74

(0.68-0.79)c

Mean outpatient0.91

(0.88-0.92)a

0.81

(0.77-0.84)b

0.71

(0.65-0.76)c

Nadir outpatient0.83

(0.76-0.87)a

0.64

(0.46-0.75)b

0.68

(0.31-0.83)c

Most recent

inpatient or

outpatient

0.88

(0.85-0.91)d

0.88

(0.85-0.91)d

0.80

(0.76-0.84)e

©2013 MFMER | 3322132-51

Observed vs. estimated (MDRD GFR=75)Scr67% had pre-admission creatinine; (n=1314; 46% CKD)

All patients CKD excluded

Bagshaw et al: Nephrol Dial Transplant 24: 2739-2744, 2009

Diffe

rence

Average

-25

-10

0

10

25

.1 5 10 15 20

r = 0.49

Average

-25

-10

0

10

25

.1 5 10 15 20

r = 0.9

©2013 MFMER | 3322132-53

44370 samples

5

4

3

2

1

0

0 1 2 3 4 5

Ba

se

line

cre

atin

ine v

alu

e41162 samples

5

4

3

2

1

0

0 1 2 3 4 5

Ho

sp

ita

l M

in c

rea

tin

ine

23601 samples

5

4

3

2

1

0

0 1 2 3 4 5

First a

dm

issio

n S

cr

44370 samples

5

4

3

2

1

0

0 1 2 3 4 5

MD

RD

75

ba

ck c

alc

ula

tion

Baseline creatinine valueBaseline creatinine value

Underestimation

of AKI

CAKI as CKD

Overestimation

of AKI

CKD as AKI

©2013 MFMER | 3322132-55

0

1

2

3

4

5

0 1 2 3 4 5

Pre

dic

ted c

reatinin

e v

alu

e

Real creatinine value

Pearson r= 0.11; P<.0001

R2= - 0.07

0

1

2

3

4

5

0 1 2 3 4 5

Pre

dic

ted c

reatinin

e v

alu

e

Real creatinine value

Pearson r= 0.66; P<.0001

R2=0.41

Baseline serum creatinineComparative assessments

MDRD Back Calculation Gradient Boosting

©2013 MFMER | 3322132-58

Take Home Points

• Progress in the field of AKI has been tremendous

• Remains many questions and controversies

• Collaborative investigations

• Consensus meetings

• Future tools and measures should shed additional light

diagnostic and nomenclature controversies for aki€¦ · aki, akd, ckd continuum criteria aki akd...

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