uptodate on acute kidney injury

1. .
DRSHERIFALY
.
DRSHERIFALY
Consultant (A) Nephrology
Assir central hospital
Abha 10/10/10

2. OBJECTIVESOBJECTIVES : :
Introduction Concept of Introduction Concept of
AKIAKI
Introducing RIFIE and Introducing RIFIE and
AKIN staging criteria AKIN staging criteria
for AKIfor AKI
Describe the need for Describe the need for
Biomarkers in AKIBiomarkers in AKI
Describe the role of Describe the role of
Biomarkers in AKIBiomarkers in AKI
Discuss examples of Discuss examples of
promising AKI biomarkerspromising AKI biomarkers
Discuss pharmacological Discuss pharmacological
treatment of AKItreatment of AKI
Discuss new Discuss new
anticoagulantsanticoagulants

4. IntroductionIntroduction
A. ) A. )
AKIVersus ARF

AKIVersus ARF
-AKI refl ects the enti re spectrum of AKI refl ects the enti re spectrum of
the di sease and recogni zes that the di sease and recogni zes that
acute decl i ne i n ki dney functi on i s acute decl i ne i n ki dney functi on i s
often secondary to an i nj ury that often secondary to an i nj ury that
causes functi onal or structural causes functi onal or structural
changes i n the ki dneychanges i n the ki dney
B.) B.) HistoryHistory
- In 2002 , ADQI proposed RIFLE - In 2002 , ADQI proposed RIFLE
cl assi fi cati on systemcl assi fi cati on system
- Categori zes and strati fi es a - Categori zes and strati fi es a
popul ati on of pati ents based on popul ati on of pati ents based on
thei r renal functi on.thei r renal functi on.
- Three severi ty categori es : - Three severi ty categori es : RISKRISK , ,
INJURYINJURY & & FAILUREFAILURE
- Two outcome categori es : - Two outcome categori es : LOSSLOSS & & -
END
-
END

STAGEDISEASE

STAGEDISEASE
- In 2004 Acute Ki dney Inj ury Network - In 2004 Acute Ki dney Inj ury Network
(AKIN) formed(AKIN) formed
- Prposed a di agnosti c cri teri a for - Prposed a di agnosti c cri teri a for
the defi ni ti on of AKIthe defi ni ti on of AKI
- In 2004 ADQI , ISN and ASN met and - In 2004 ADQI , ISN and ASN met and
proposed the term of AKI.proposed the term of AKI.

5. AKI : A Common Serious ProblemAKI : A Common Serious Problem
AKI is present in 5% of AKI is present in 5% of
all hospitalized all hospitalized
patients , and up to 30% patients , and up to 30%
of patients in ICUs.of patients in ICUs.
The incidence is The incidence is
increasing at an alarming increasing at an alarming
rate.rate.
Mortality rate > 50% in Mortality rate > 50% in
dialyzed ICU patients.dialyzed ICU patients.
25% of ICU dialysis 25% of ICU dialysis
survivors progress to ESRD survivors progress to ESRD
within 3 years.within 3 years.

6. Green bars are unadj usted, bl ue bars are age
and gender adj usted, and gray bars are
mul ti vari abl e
adj usted. Mul ti vari abl e anal yses adj usted f or
age, gender, di agnosi s-rel ated group (DRG)
wei ght,
CKD status, and I CD-9-CM codes f or respi ratory,
gastroi ntesti nal , mal i gnant, and i nf ecti ous
di seases;
n = 1564, 885, 246, and 105 f or change i n SCr
0. 3 to 0. 4, 0. 5 to 0. 9, 1. 0 to 1. 9, and 2. 0 mg/
dl .
Chertow et al, JASN
2005
The Effect of AKI on MortalityThe Effect of AKI on Mortality

7. The Effects of AKI on Hospital CostsThe Effects of AKI on Hospital Costs
Green bars are unadj usted, bl ue bars are age and
gender adj usted, and gray bars are
mul ti vari abl e adj usted. Mul ti vari abl e anal yses
adj usted f or age, gender, di agnosi s-rel ated
group (DRG) wei ght, CKD status, and I CD-9-CM
codes f or respi ratory, GI , mal i gnant,
and i nf ecti ous di seases; n = 1564, 885, 246, and
105 f or change i n SCr 0. 3 to 0. 4, 0. 5 to 0. 9,
1. 0 to 1. 9, and 2. 0 mg/dl .
Chertow et al, JASN 2005

8. AKI Definition and Staging AKIN AKI Definition and Staging AKIN
20072007
* * An abrupt (within 48 hrs) An abrupt (within 48 hrs)
reduction in kidney reduction in kidney
function defined as an function defined as an
absolute increase in serum absolute increase in serum
creatinine level of ≥ 26.4 creatinine level of ≥ 26.4
Mmol/L (0.3mg1dl) Mmol/L (0.3mg1dl) oror a a
percentage increase in percentage increase in
serum creatinine level of ≥ serum creatinine level of ≥
50% (1.5 fold from base 50% (1.5 fold from base
line) line) or or a reduction in a reduction in
urine output (documented urine output (documented
oligurea of < 0.5 ml/kg/ hr oligurea of < 0.5 ml/kg/ hr
for > 6 hrs.)for > 6 hrs.)

9. Acute Kidney Injury Network (AKIN) Staging SystemAcute Kidney Injury Network (AKIN) Staging System
for Acute Renal Failure for Acute Renal Failure
Modifiable RIFLE CriteriaModifiable RIFLE Criteria
AKI N AKI N
StageStage
Serum Creati ni ne Serum Creati ni ne
Cri teri aCri teri a
UOPUOP
1)1)Ri skRi sk ↑↑S. Creat ≥ 26.4 S. Creat ≥ 26.4
Mmol /L or 50-100% Mmol /L or 50-100%
above base l i neabove base l i ne
< 0.5 < 0.5
ml /kg/mml /kg/m
22
for > 6 for > 6
hourshours
1)1)I nj uryI nj uryI ncrease of 2-3 fol ds I ncrease of 2-3 fol ds
over base l i neover base l i ne
< 0.5 < 0.5
ml /kg/mml /kg/m
22

for > 12 for > 12
hourshours
1)1)Fai l urFai l ur
ee
I ncrease of > 3 fol ds I ncrease of > 3 fol ds
over base l i ne or S. over base l i ne or S.
Creat > 354 Mmol /L Creat > 354 Mmol /L
acute i ncrease of at acute i ncrease of at
l east 0.5 mg/dl (44 l east 0.5 mg/dl (44
Mmol /L)Mmol /L)
Need RRTNeed RRT
< 0.5 < 0.5
ml /kg/mml /kg/m
22

for > 24 for > 24
hourshours

10. Progression of Early Kidney DiseaseProgression of Early Kidney Disease
Hosl e EAJ , etal Cri t care 2006 , 10 : R Hosl e EAJ , etal Cri t care 2006 , 10 : R
7373

11. Conceptual Model for AKI
Normal
Increased
risk
Damage
↓GF
R

Kidney
Failure
Death

12. Mechanism of Ischemic Mechanism of Ischemic
Acute Kidney InjuryAcute Kidney Injury
1)1)Tubular cell Tubular cell
metabolismmetabolism
2)2)Tubular cell Tubular cell
structurestructure
3)3)Microvasculature Microvasculature
and inflammationand inflammation

15. PeriodPeriod
Acute Myocardial

Acute Myocardial
InfarctionInfarction

Acute Kidney

Acute Kidney
InjuryInjury
1960s1960s LDHLDH Serum Serum
creati ni necreati ni ne
1970s1970s CPK, myogl obi nCPK, myogl obi n Serum Serum
creati ni necreati ni ne
1980s1980s CK-MBCK-MB Serum Serum
creati ni necreati ni ne
1990s1990s Troponi n TTroponi n T Serum Serum
creati ni necreati ni ne
2000s2000s Troponi n ITroponi n I Serum Serum
creati ni necreati ni ne
Mul ti pl e
Therapi e
s
50%
↓
Mortal i t
y
Supporti v
e Care
Hi gh
Mortal i tyNeed early biomarkers of AKI for improved understanding, early
treatment and better outcomes
Biomarkers: AMI versus AKIBiomarkers: AMI versus AKI

16. What is wrong with Serum Creatinine?What is wrong with Serum Creatinine?
The production of creatinine The production of creatinine
is highly variable (age, sex, is highly variable (age, sex,
muscle mass)muscle mass)
Serum creatinine may not show Serum creatinine may not show
significant increased until significant increased until
50% of kidney function is 50% of kidney function is
lost.lost.
Does not depict real-time Does not depict real-time
changes in GFR that occur changes in GFR that occur
with acute reduction in with acute reduction in
kidney function.kidney function.
Require time to accumulate to Require time to accumulate to
prior to being detected.prior to being detected.

17. The Ideal Biomaker of AKIThe Ideal Biomaker of AKI
Easy, rapid and inexpensive Easy, rapid and inexpensive
to measure.to measure.
Precise and reliablePrecise and reliable
Highly sensitive for AKI.Highly sensitive for AKI.
It should be able to It should be able to
monitor the injury and monitor the injury and
predicts the severity.predicts the severity.
It should be specific.It should be specific.

18. Serum and Urinary Biomakers for AKI
. 2008
SGCoca etalkid International
73 , 1008 -1016

19. Validity Criterion Validity Criterion Explanation Explanation Scoring Scoring Comments Comments
Participant recruitmentParticipant recruitment
Was recruitment based on presenting symptoms, results from Was recruitment based on presenting symptoms, results from
previous tests, or fact that participants received index tests?previous tests, or fact that participants received index tests?
Presenting sx=1Presenting sx=1
Previous tests or Previous tests or
index tests=0index tests=0
Based on presenting symptoms in all 31 studies.Based on presenting symptoms in all 31 studies.
Participant samplingParticipant sampling
Was it study population or a convenience sample or a consecutive Was it study population or a convenience sample or a consecutive
series?series?
Consecutive series=1Consecutive series=1
Convenience Convenience
sample=0sample=0
Based on convenience sample in 5Based on convenience sample in 5
10, 19, 20, 22, 25, 3710, 19, 20, 22, 25, 37
studies. studies.
Data collectionData collection
Was data collection planned before the index test and reference Was data collection planned before the index test and reference
standard were performed prospectively or retrospectively?standard were performed prospectively or retrospectively?
Prospective=1Prospective=1
Retrospective=0Retrospective=0
Planned and performed prospectively in all 31 studies.Planned and performed prospectively in all 31 studies.
Reference standardReference standard Was the rationale for the reference standard stated?Was the rationale for the reference standard stated?
Stated=1Stated=1
Not stated=0Not stated=0
Not stated for twoNot stated for two
12, 1812, 18
studies. studies.
Materials and methodsMaterials and methods
Were technical specifications of material and methods stated Were technical specifications of material and methods stated
including how and when measurements were taken?including how and when measurements were taken?
Stated=1Stated=1
Not stated=0Not stated=0
Stated in all but oneStated in all but one
1919
of the articles. of the articles.
Index testIndex test
Were the definitions of and rationales for the units, cutoffs, and/or Were the definitions of and rationales for the units, cutoffs, and/or
categories of the results of the index tests stated?categories of the results of the index tests stated?
Stated=1Stated=1
Not stated=0Not stated=0
Not stated in twoNot stated in two
12, 1912, 19
of the 31 articles. of the 31 articles.
BlindingBlinding Were readers of index test and reference standard blinded?Were readers of index test and reference standard blinded?
Blinded=1Blinded=1
Not blinded or not Not blinded or not
stated=0stated=0
Stated that the readers of index test and reference standard were Stated that the readers of index test and reference standard were
blinded in 17blinded in 17
10, 11, 19, 29, 30, 35, 36, 37, 38, 3910, 11, 19, 29, 30, 35, 36, 37, 38, 39
articles. articles.
CompletionCompletion
Was the number of participants that did not undergo index tests (no. Was the number of participants that did not undergo index tests (no.
of tests vs sample size) stated?of tests vs sample size) stated?
Stated=1Stated=1
Not stated=0Not stated=0
Stated in all but oneStated in all but one
1919
of the studies. of the studies.
Time intervalTime interval Was the time interval from index test to reference standard stated?Was the time interval from index test to reference standard stated?
Stated=1Stated=1
Not stated=0Not stated=0
The time interval between index test and reference standard (clinical The time interval between index test and reference standard (clinical
diagnosis of AKI or severity end point such as dialysis or death) was diagnosis of AKI or severity end point such as dialysis or death) was
not stated in fivenot stated in five
19, 20, 25, 34, 3619, 20, 25, 34, 36
articles. articles.
Distribution of severity Distribution of severity
of diseaseof disease
Was there a representative distribution of severity of disease? (mild, Was there a representative distribution of severity of disease? (mild,
moderate, severe AKI; non-oliguric vs oliguric)moderate, severe AKI; non-oliguric vs oliguric)
Yes=1Yes=1
No=0No=0
A broad distribution of disease severity was found in all but four A broad distribution of disease severity was found in all but four
12, 25, 12, 25,
27, 3727, 37
of the studies. of the studies.
Scoring system for validity used in this systematic review

20. References References Biomarker Biomarker Clinical setting Clinical setting Subjects Subjects Sensitivity/specificity Sensitivity/specificity Area under ROC Area under ROC Positive LR Positive LR Quality score Quality score
SerumSerum
Herget-Rosenthal Herget-Rosenthal et al.et al.
99
Cystatin CCystatin C ICUICU 8585 0.82/0.950.82/0.95 NRNR 16.416.4 99
Ahlstrom Ahlstrom et al.et al.
2424
Cystatin CCystatin C ICUICU 202202 NRNR 0.9010.901 N/AN/A 99
Mazul-Sunko Mazul-Sunko et al.et al.
2525
Cystatin CCystatin C ICUICU 2929 0.5/0.50.5/0.5 NRNR 1.01.0 66
Mazul-Sunko Mazul-Sunko et al.et al.
2525
ProANP(1-98)ProANP(1-98) ICUICU 2929 NR/NRNR/NR NRNR N/AN/A 66
Mishra Mishra et al.et al.
1111
NGALNGAL Cardiac surgery in childrenCardiac surgery in children 7171 0.70/0.940.70/0.94 NRNR 11.611.6 1010
Rinder Rinder et al.et al.
2727
Neutrophil CD11bNeutrophil CD11b Cardiac surgeryCardiac surgery 7575 NRNR NRNR 62.662.6
††
88
UrineUrine
Mishra Mishra et al.et al.
1111
NGALNGAL Cardiac surgery in childrenCardiac surgery in children 7171 1.0/0.981.0/0.98 0.9980.998 50.050.0 1010
Wagener Wagener et al.et al.
2828
NGALNGAL Cardiac surgeryCardiac surgery 8181 0.73/0.780.73/0.78 0.80.8 3.33.3 99
Zappitelli Zappitelli et al.et al.
3838
NGALNGAL Critically ill childrenCritically ill children 140140 0.77/0.720.77/0.72 0.780.78 2.752.75 1010
Parikh Parikh et al.et al.
2929
NGALNGAL Post-transplantPost-transplant 6363 0.9/0.830.9/0.83 0.90.9 5.35.3 1010
Parikh Parikh et al.et al.
1010
IL-18IL-18 ICUICU 138138 0.5/0.850.5/0.85 0.730.73 3.33.3 99
Parikh Parikh et al.et al.
2929
IL-18IL-18 Post-transplantPost-transplant 6363 NRNR 0.90.9 N/AN/A 1010
Parikh Parikh et al.et al.
3030
IL-18IL-18 Cardiac surgeryCardiac surgery 7171 0.5/0.940.5/0.94 0.750.75 8.38.3 1010
Han Han et al.et al.
4040
IL-18IL-18 Critically ill childrenCritically ill children 137137 0.25/0.810.25/0.81 0.540.54 1.31.3 1010
Han Han et al.et al.
3737
KIM-1KIM-1 Cardiac surgeryCardiac surgery 4040 0.74/0.900.74/0.90 0.830.83 3.163.16 88
Han Han et al.et al.
3737
NAGNAG Cardiac surgeryCardiac surgery 4040 1.0/0.31.0/0.3 0.690.69 1.431.43 88
Han Han et al.et al.
3737
MMP-9MMP-9 Cardiac surgeryCardiac surgery 4040 NRNR 0.500.50 N/AN/A 88
Eijkenboom Eijkenboom et al.et al.
3131
GSTGST Cardiac surgeryCardiac surgery 8484 NRNR NRNR N/AN/A 99
Westhuyzen Westhuyzen et al.et al.
3232
-GT-GT ICUICU 2626 1.0/0.91.0/0.9 0.950.95 10.010.0 99
Westhuyzen Westhuyzen et al.et al.
3232
-GST-GST ICUICU 2626 1.0/0.91.0/0.9 0.9290.929 10.010.0 99
Westhuyzen Westhuyzen et al.et al.
3232
-GST-GST ICUICU 2626 0.75/0.90.75/0.9 0.8930.893 7.57.5 99
Westhuyzen Westhuyzen et al.et al.
3232
APAP ICUICU 2626 0.5/0.950.5/0.95 0.8630.863 10.010.0 99
Westhuyzen Westhuyzen et al.et al.
3232
NAGNAG ICUICU 2626 1.0/0.811.0/0.81 0.8450.845 5.35.3 99
Westhuyzen Westhuyzen et al.et al.
3232
LDHLDH ICUICU 2626 0.5/0.950.5/0.95 0.6880.688 10.010.0 99
Studies of biomarkers for the early diagnosis of AKI

21. Promising BiomakersPromising Biomakers
Urinary BiomakersUrinary Biomakers
A.) Inflammatory A.) Inflammatory
BiomakersBiomakers
NGALNGAL
IL - 18 IL - 18
B.) Tubular ProteinsB.) Tubular Proteins
 KIM - IKIM - I

22. NGALNGAL
(Neutrophil Gelatiaase Associated Lipocalin)(Neutrophil Gelatiaase Associated Lipocalin)
- - 25 kd protein up regulated 25 kd protein up regulated
in proximal tubule cells in in proximal tubule cells in
response to Ischemic or response to Ischemic or
nephrotoxic injury.nephrotoxic injury.

23. •

Mouse
Ischemia
• 30
min
ischemia
•
S creat
24
↑ h
•
KidneyNGAL
3
↑ h
•
Colocalize

withPCNA
(
proliferating
cell

nuclear
)
antigen
Kidney NGAL in Ischemic AKIKidney NGAL in Ischemic AKI
Mishra et al, JASN 14:2534-43,
2003
Mishra et al, JASN 15:3073-82,
2004

24. Urine NGAL in Ischemic AKIUrine NGAL in Ischemic AKI
•

Mouse
Ischemia
• 30
min
ischemia
•
S creat
24
↑ h
• 8
Urine NAG↑
h
• 2 8
Urine B M↑
h
•
Urine NGAL↑
2
h
Mishra et al, JASN 14:2534-43, 2003
Mishra et al, JASN 15:3073-82, 2004

25. * In development. Currently not for sale in US
®
*
Phase 3 Transition: Plasma NGAL Kit

26. Urine NGAL PlatformUrine NGAL Platform
Abbott DiagnosticsAbbott Diagnostics
ARCHITECT: Standardized clinical ARCHITECT: Standardized clinical
platformplatform

27. IL - 18IL - 18
Pro inflammatory Cytokine Pro inflammatory Cytokine
induced and cleared in proximal induced and cleared in proximal
tubule after AKI.tubule after AKI.
20 patient developed AKI post 20 patient developed AKI post
CPBCPB
AKI defined as > 50% AKI defined as > 50% in serum
↑
in serum
↑
creatininecreatinine
35 control who did not develop 35 control who did not develop
AKIAKI
Results :Results :
Using serum creatinine , AKI Using serum creatinine , AKI
was detected only 48 – 72 hrs. was detected only 48 – 72 hrs.
after CPB.after CPB.
Urine IL – 18 at 4 – 6 hrs.
↑
Urine IL – 18 at 4 – 6 hrs.
↑after CPB and peaked at 12 hrs.after CPB and peaked at 12 hrs.
Parlikin CR Kid. Int. 2006 , 70 – Parlikin CR Kid. Int. 2006 , 70 –
199 - 203199 - 203

28. Tubular ProteinTubular Protein
KIM – I (Kidney Injury Molecule – I)KIM – I (Kidney Injury Molecule – I)
Trans membrane protein over Trans membrane protein over
expressed in proximal tubule expressed in proximal tubule
cells I ischemic or cells I ischemic or
nephrotoxic AKInephrotoxic AKI

29. ConclusionConclusion
Urinary biomakers allow Urinary biomakers allow
diagnosis of AKI earlier than a diagnosis of AKI earlier than a
rise in serum creatinine.rise in serum creatinine.
Most of recently discovered Most of recently discovered
biomakers are used to detect biomakers are used to detect
proximal tubular injury.proximal tubular injury.
e.g – NGAL , 2-4 hrse.g – NGAL , 2-4 hrs
- IL - 18 , 4 – 6 hrs- IL - 18 , 4 – 6 hrs
- KIM – I , 12 – 24 hrs- KIM – I , 12 – 24 hrs

30. Management of AKIManagement of AKI
Indications for RRT in Patients with AKIIndications for RRT in Patients with AKI
BUN > 27 mmol /LBUN > 27 mmol /L
Rel ati veRel ati ve
BUN > 35.7 mmol /LBUN > 35.7 mmol /L
Absol uteAbsol ute
Hyperkal emi a > 6Hyperkal emi a > 6
Rel ati veRel ati ve
Hyperkal emi a > 6 wi th ECG changeHyperkal emi a > 6 wi th ECG change
Absol uteAbsol ute
Aci dosi s pH > 7.15Aci dosi s pH > 7.15
Rel ati veRel ati ve
Aci dosi s pH < 7.15Aci dosi s pH < 7.15
Absol uteAbsol ute
Fl ui d overl oad (di ureti c Fl ui d overl oad (di ureti c
sensi ti ve)sensi ti ve) Rel ati veRel ati ve
Fl ui d overl oad (di ureti c Fl ui d overl oad (di ureti c
resi stant)resi stant) Absol uteAbsol ute
RIFLE (R.I.F) RIFLE (R.I.F)

Rel ati veRel ati ve

31. Is Early Start of RRT Better ?Is Early Start of RRT Better ?
AA tend toward a better outcome tend toward a better outcome
with early RRT, however , the with early RRT, however , the
quality of this trials quality of this trials
favoring early timing is favoring early timing is
poor.poor.

32. Pharmacological Treatment of AKIPharmacological Treatment of AKI
Recombinant human IGF–1 (rh IGF–I )Recombinant human IGF–1 (rh IGF–I )
- - Reduced kidney injuryReduced kidney injury
- Decrease apoptosis and - Decrease apoptosis and
inflammationinflammation
Atrial naturitic peptideAtrial naturitic peptide
- Dilate afferent - Dilate afferent
arteriolesarterioles
- Constrict efferent - Constrict efferent
arteriolesarterioles
Duo to narrow therapeutic windowDuo to narrow therapeutic window
- Failed to reduce AKI - Failed to reduce AKI
in human trials.in human trials.

33. Drugs on the HorizonDrugs on the Horizon
Anti -apoptosi s/necrosi sAnti -apoptosi s/necrosi s * *
Caspas i nhi bi torsCaspas i nhi bi tors
* PARP i nhi bi tors* PARP i nhi bi tors
Anti -i nfl ammatoryAnti -i nfl ammatory * Acti vated * Acti vated
protei n Cprotei n C
* L-MSH,anti PPAR-yr* L-MSH,anti PPAR-yr
Anti sepsi sAnti sepsi s * Acti vated * Acti vated
protei n eprotei n e
* ethyl pyruvate* ethyl pyruvate
Growth factorsGrowth factors * *
Erythroprotei nErythroprotei n
* HGF* HGF
Vasodi l atersVasodi l aters * *
ANPANP
* Co rel ease* Co rel ease
New anti -coagul antsNew anti -coagul ants * *
anti factor l l a (r-hi ri dum)anti factor l l a (r-hi ri dum)
* Anti factor Xa * Anti factor Xa
(danaparoi d)(danaparoi d)
Combination (nafamostat)To prevent Combination (nafamostat)To prevent
HITinCVVH patients.HITinCVVH patients.

34. Conclusion :Conclusion :
AKI is common complication in AKI is common complication in
hospitalized patients.hospitalized patients.
AKI has strong impact on AKI has strong impact on
morbidity and mortality.morbidity and mortality.
Even mild degree of renal Even mild degree of renal
dysfunction may have a negative dysfunction may have a negative
impact on outcome.impact on outcome.
RIFIE classification is a good RIFIE classification is a good
outcome predictor.outcome predictor.
There are promising biomakers There are promising biomakers
for early diagnosis and outcome for early diagnosis and outcome
predictor.predictor.
Drugs on horizon (no effective Drugs on horizon (no effective
pharmacological therapy).pharmacological therapy).