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©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 | 3322132-6
©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
AKI, AKD, CKD Continuum
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
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©2013 MFMER | 3322132-9
AKI, AKD, CKD Continuum
Criteria AKI AKD
Duration Within 7 days 3 months
Function Alteration
Oliguria for ≥6 hours
OR↑ Scr by ≥0.3 mg/dL
in 48 hoursOR
↑ Scr by ≥50% in 7 days
AKIOR
GFR <60 mL/min/1.73 m2
OR↓ GFR by ≥35%
OR↑Scr by ≥50% in
7-90 days
Structural Alteration
Not defined Marker of kidney damage
(albuminuria)
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©2013 MFMER | 3322132-10
AKI, AKD, CKD Continuum
Criteria AKI AKD CKD
Duration Within 7 days 3 months >3 months
Function Alteration
Oliguria for ≥6 hours
OR↑ Scr by ≥0.3 mg/dL
in 48 hoursOR
↑ Scr by ≥50% in 7 days
AKIOR
GFR <60 mL/min/1.73 m2
OR↓ GFR by ≥35%
OR↑Scr by ≥50% in
7-90 days
GFR <60 mL/min/1.73 m2
Structural Alteration
Not defined Marker of kidney damage
(albuminuria)
Marker of kidney damage
(albuminuria)
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©2013 MFMER | 3322132-11
AKI, AKD, CKD Continuum
Criteria AKI AKD CKD NKD*
Duration Within 7 days 3 months >3 months
Function Alteration
Oliguria for ≥6 hours
OR↑ Scr by ≥0.3 mg/dL
in 48 hoursOR
↑ Scr by ≥50% in 7 days
AKIOR
GFR <60 mL/min/1.73 m2
OR↓ GFR by ≥35%
OR↑Scr by ≥50% in
7-90 days
GFR <60 mL/min/1.73 m2
GFR ≥60 mL/min/1.73 m2
AND
Stable Scr
Structural Alteration
Not defined Marker of kidney damage
(albuminuria)
Marker of kidney damage
(albuminuria)
No marker of kidney damage
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©2013 MFMER | 3322132-12
AKI, AKD, CKD Continuum
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
©2013 MFMER | 3322132-15
1
No Yes >3 mo
Yes<3 mo orunknown
GFR/Scr
AKD
↓ GFR or ↑ Scr?
NKD CKD
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©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
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©2013 MFMER | 3322132-17
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?
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©2013 MFMER | 3322132-18
AKI, AKD, CKD Continuum
AKD AKI CKD
KDIGO-AKI; Kidney Int Sppl. 2(1): 1-138
©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 | 3322132-21
©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 | 3322132-29
©2013 MFMER | 3322132-30
Transient vs. Persistent AKI
Chawla, L. S., et al. (2017). Nat Rev Nephrol 13(4): 241-257
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%
Chawla, L. S., et al. (2017). Nat Rev Nephrol 13(4): 241-257
Rapid reversal 15-30%
Persistent AKI 20-53%
©2013 MFMER | 3322132-34
©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 | 3322132-39
©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 | 3322132-42
©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 | 3322132-47
©2013 MFMER | 3322132-48
©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 | 3322132-50
©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 | 3322132-52
©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 | 3322132-54
Machine learning for Baseline ScrN=44370
Gradient Boosting Features
©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
©2013 MFMER | 3322132-59
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