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4/9/2018
1
John A. Kellum, MD, MCCM
Professor of Critical Care Medicine, Medicine,
Bioengineering and Clinical & Translational Science
Vice Chair for Research
Director, Center for Critical Care Nephrology
Acute Kidney Injury:
Ending learned
helplessness
Disclosures
•Consulting:
•Adrenomed
•AM Pharma
•Astellas
•Astute Medical
•Atox Bio
•Baxter
•Bioporto
•Cheetah Medical
•Cochlear
•Cytosorbents
•Eliaz Pharma
•Elsevier
•Grifols
•Grant support:
•Astellas
•Astute Medical
•Bard
•Baxter
•Bioporto
•Grifols
•RenalSense
•Intellectual
Property:
•Astute Medical
•Cytosorbents
•PhotoPhage
•Medibeacon
•MedScape
•Mitobridge
•Novartis
•NxStage
•PhotoPhage
•Potrero
•Premier
•Sirtex
•Sphingotech
•Sobi
•Spectral Diagnostics
•Venn Strategies
Updated Jan 2018
Kellum et al. Am J Respir Crit Care Med. 2016 Feb 1;193(3):281-7.
AKI severity
determines
outcome
Patients that
recover do
rather well
Patients that
don’t recover
…do poorly
4/9/2018
2
Differences in Fluid Administered
Usual Care
EGDT
PST
Renal Outcomes
No treatment effect on…
•RRT at any other time point or overall
•New AKI or AKI progression (by KDIGO or Biomarkers)
•AKI Recovery
Kellum et al. Am J Respir Crit Care Med. 2016 Feb 1;193(3):281-7.
N Engl J Med 2014;370:1683-93.
4/9/2018
3
AKI in Sepsis
Cardiac
Dysfunction
Sepsis/Septic Shock
Immune
response
Tissue
Perfusion
Pathogen
Inflammation
Coagulation
Venous
Congestion
Systemic
release: Mb,
UA, HMGB1
LPS and
other PAMPs
DAMPs
O2/ Nutrients
4/9/2018
4
NINJA
NINJA
UPMC
4/9/2018
5
Following First Dose of Vancomycin
Ostermann et al. Crit Care Med. 2017 Nov 20.
AKI
No AKI
•Avoid
nephrotoxins
(NSAIDs,
ACEi/ARBs)
•Avoid
hyperglycemia
•Optimize volume
status and
hemodynamics
4/9/2018
6
SVV
CI
MAP
Goal achieved
Check every 3h up to 12h after
randomization
≤ 11
> 3l/min/m2
> 65 mmHg
No
Yes
Volume: crystallois 500-1000 ml
dobutamine or epinephrine
norepinephrine
> 12
< 3l/min/m2
< 65 mmHg
Meersch et al. ICM 2017
Meersch et al. ICM 2017
Nature Reviews Nephrology 2017
Using biomarker enrichment the authors were
able to achieve an effect with a number
needed to treat of only 6. Without biomarkers
it would have been >33.
4/9/2018
7
UPMC AKI Alert
Odds ratio 0.91, 0.86-0.96, P=0.001
Al-Jaghbeer M, et al.
JASN 2017; Nov 2
Clinical Decision Support for Acute
Kidney Injury and Hospital Survival
doi: 10.1681/ASN.
CONCLUSION
Implementation of a CDSS for AKI resulted in
a small but sustained decrease in hospital
mortality, length of stay and use of dialysis.
Clinical Decision Support System
•Derives reference serum creatinine from
historical values in EMR
•Flags creatinine changes and KDIGO stage
OUTCOMES
Outcomes were measured pre- and post-
implementation of a Clinical Decision
Support System (CDSS) for AKI
[]%
[]
[]% []
6.7%
[]%
[]
[]% [].0
[].0%
0
2
4
6
8
10
12
Mortality LOS in days Mortality* LOS in days* RRT*
No AKI AKI
Outcomes Pre- and Post-CDSS
implementation
Pre CDSS Post CDSS
METHODS
181k patients
11.0% clinically diagnosed AKI
Pre-CDSS (12 months):
Implemented the CDSS
346k patients
12.8% clinically diagnosed AKI
Post-CDSS (24 months):
*P<.001
40%
Balanced Saline
2x Creatinine RRT Death
15.4%
14.3%
P=0.04
N = 15,802
0
2
4
6
8
10
12
14
16
18
20
Balanced Saline
2x Creatinine RRT Death
4.7% 5.6%
P=0.01
N = 13,347
4/9/2018
8
What's in the IV bag? Studies show safer
option than saline
•BY MARILYNN MARCHIONE, AP CHIEF MEDICAL WRITER
Feb 27, 2018, 5:10 PM ET
Conclusions
•Markers of cell-cycle arrest appear to be robust measures of risk
for AKI (manifesting in the next 12-24h)
•Underlying biology suggestive of an “alarm-phase” marker
before actual damage has a occurred.
•A “KDIGO Bundle” can reduce AKI when applied to biomarker
positive patients after cardiac surgery.
•Nephrotoxic drug exposure accounts for as much as 30% of AKI
and may contribute to more than half.
•Improved risk assessment and early detection can prevent Acute
Renal Failure.
•Stop using saline!
www.ccm.pitt.edu
Follow @CCCNPitt
4/9/2018
1
ACUTE KIDNEY INJURY (AKI)
TREATMENT AND MANAGEMENT
PREVENTING AKI INDUCED ADVERSE DRUG
EVENTS
SANDRA KANE-GILL, PHARMD, M SC, FCCM, FCCP
ASSOCIATE PROFESSOR, UNIVERSITY OF PITTSBURGH
CRITICAL CARE MEDICATION SAFETY PHARMACIST, UPM C
FACULTY, CENTER FOR CRITICAL NEPHROLOGY, UPMC AND UNIVERSITY OF PITTSBURGH
CONFLICT OF INTEREST
•NODISCLOSURES
PREVALENCE OF DRUG ASSOCIATED ACUTE KIDNEY
INJURY (D-AKI) IN THE ICU
•5,143 PATIENTS IN 20 ICUS
•20% (74/355) ASSOCIA TED WITH DRUGS
•ICUSAT 5 HOSPITA LS
•25% (157/618) ASSOCIA TED WITH DRUGS
•26,269 CRITICA LLY ILL PATIENTS IN 54 HOSPITA LS IN 23 COUNTRIES
•19% (328/1726) ASSOCIA TED WITH DRUGS
Brivet FG et al. Crit Care Med 1996;24:192; Mehta RL et al. Kid International 2004;66:1613-1621;
Uchino S et al. JAMA 2005;294:813-818.
3rd-5th
4/9/2018
2
D-AKI CONSEQUENCES PEDIATRIC, NON-ICU PATIENTS
Variable
AKI due to
Nephrotoxin
(n=77)
No AKI
Baseline eGFR
(mL/min/1.73m2)
118
120
eGFR at 6 months
(mL/min/1.73m2)
113.8
123.4
Up/C ratio at 6 months,
mg/mg
0.9
.0.27
Hypertension
37.7%
19.3%
≥ 1 sign of CKD
33.7%
8.8%
•70% of patients with drug associated AKI have
evidence (reduced eGFR, hyperfiltration, proteinuria, or
hypertension) of residual kidney damage
Menon S et al. J Pediatr 2014;165:522
D-AKI CONSEQUENCES
Mehta RL et al. Kid Int 2004;66:1613
0%
10%
20%
30%
40%
50%
60%
In-Hospital Mortality In-Hospital Mortality
and/or Dialysis
Dependence
Acute Tubular Necrosis
(ATN)
Nephrotoxicity
ATN + Nephrotoxicity
Other Etiologies
Similar, slightly better, mortality rates and/or dialysis dependence compare to AKI of other
etiologies
TRANSITIONING FROM ACUTE KIDNEY INJURY TO
CHRONIC KIDNEY DISEASE
•PATIENTS WITH AKI HAVE A SUBSTANTIAL RISK OF PROGRESSING TO
CKD
•ABOUT 30% OF PATIENTS WHO HAVE AKI PROGRESS TOCKD
•DIALYSIS DEPENDENCE FOR AKI SURVIVORS IS 40%
AKI - acut e kidney injury
AKD- acute kidney disease
CKD- chronic kidney disease
Chawla LS et al. Nat Rev Nephrol 2017;13:241.
4/9/2018
3
RISK FACTORS FOR AKI/D-AKI
Description
Risk Factors for Critically Ill
Susceptibilities
Age, black race, female,
history of diabetes,
history of hypertension, previous AKI episode,
elevated baseline serum creatinine
Exposures
Nephtoroxin
administration, trauma, burn,
circulatory shock, sepsis, high risk surgery,
hypotension, fluid overload
Drug
-specific
Exposure
Nephrotoxin
treatment duration, cumulative
dose, total daily dose, pharmacokinetic and
pharmacodynamic
drug interactions,
nephrotoxic burden
▪Concomitant nephrotoxin administration was an
independent predictor of AKI
▪53% greater odds of developing A KI for every
nephrotoxic drug received (OR 1.53; CI 1.09-2.14)
▪Significant association between cumulative number of
exposures and risk of AKI (p = 0.02) but no association
between the each type of exposure and A KI (p = 0.22)
Kane-Gill SL, Goldstein SL. Crit Care Clin 2015;31:675
Cotner SE et al. AAC 2017;61:e00871
Cartin-Ceba R et al. Crit Care Res Pract 2012;
article ID 691013
Ostermann M et al. Crit Care Med 2018: ahead of
print
ADVANCE OUR THINKING BEYOND SINGLE NEPHROTOXINS:
DRUG COMBINATIONS
•EV IDENCE FOR DRUG CLASS COM BI NATIONS
ASSOCIAT ED WITH AKI
•COM PLETED A FORM AL GRADE PROCESS FOR
QUALITY OF EV IDENCE ASSESSM ENT
•76 UNIQUE DRUG COM BINATIONS
•74% VERY LOW QUALITY OF EVI DENCE (D)
•16% LOW QUALITY OF EVI DENCE (C)
•10% MODERATE QUALITY OF EVIDENCE (B)
•0% HIGH QUALITY OF EVIDENCE (A)
Rivosecchi RM et al. Ann Pharmacother 2016;50:953-972.
DRUG COMBINATIONS: MODERATE QUALITY OF EVIDENCE
Drug
Class 1
Drug Class II
Mechanism
NSAIDs
Diuretic
pharmacodynamic effect with a decrease in prostaglandin synthesis by
NSAIDs causing afferent vasoconstriction and a decrease in effective
blood volume by diuretics
NSAIDs
Diuretic
plus renin-
angiotensin aldosterone
system “triple whammy”
cumulative pharmacodynamic effect of each drug
- exacerbated by
the efferent arteriolar vasodilation caused by the RAAS
Statins
Macrolide
increased serum statin concentrations as a result of inhibition of the
cytochrome 450 (CYP450) enzyme system by macrolides
Calcium channel
blockers
Clarithromycin
CYP3A4 inhibition of clarithromycin, leading to elevated concentra
-
tions of calcium channel blockers
leads to global hypotension,
affecting the kidney
results in ischemic renal injury resulting in AKI
Statins
Calcium channel blockers
drug
-drug interaction between certain calcium channel blockers
inhibiting CYP3A4 metabolism of statins metabolized through this
pathway
Piperacillin/tazo
-
bactam
Vancomycin
decreased vancomycin clearance caused by piperacillin/tazobactam
potentially leading to a greater degree of vancomycin exposure
Rivosecchi RM et al. Ann Pharmacother 2016;50:953-972.
4/9/2018
4
PREVENTING AKI INDUCED
ADVERSE DRUG EVENTS
EARLY WARNING AND
HYPERVIGILANCE
Biomarker
AUC-ROC 95% CI
SCr
Day 0 0.447 0.222-0.673
SCr
Day 1 0.676 0.461-0.892
SCr
Day 2 0.782 0.582- 0.981
SCr
Day 3 0.799 0.617- 0.981
uKIM
-1 Day 0 0.769 0.629-0.910
uKIM
-1 Day 1 0.724 0.556-0.892
uKIM
-1 Day 2 0.849 0.75-0.948
uKIM
-1 Day3 0.781 0.658-0.904
uNGAL
Day 0 0.703 0.575-0.831
uNGAL
Day 1 0.733 0.59-0.877
uNGAL
Day 2 0.824 0.7260.922
uNGAL
Day 3 0.812 0.698-0.927
uKIM
-1 and uNGAL 0.852 0.754-0.996
KINETICS OF URINARY BIOMARKERS(KIM-1, NGAL) AND
VANCOMYCIN EXPOSURE
Pang HM et al. Eur Rev Med Pharmaocol SCI 2017;21:4203
NGAL = Neutrophil
gelatinase-associated
lipocalin;
KIM-1 = kidney injury
molecule-;
AUC-ROC= area under
the receiver operating
characteristic curve
Ostermann M et al. Crit Care Med 2018: epub ahead of print
BIOMARKER(TIMP2-IGFBP7)KINETICS AND
VANCOMYCIN EXPOSURE
4/9/2018
5
HYPERVIGILANCE/SURVEILLANCE
PREVENTION IN PEDIATRIC, NON-ICU PATIENTS
•DEVELOPMENT AND REFINEMENT OF A PREDI CTIVE AKI TRIGGER WITH T HE GOAL OF REDUCING AKI
SEVERITY
•KNOWLEDGE FOR ALERT
•≥3 NEPHROTOXINS ON THE SAME DAY
•IV AMINOGLYCOSIDE FOR ≥ 3 DAYS
•RECENT: VANCOMYCIN FOR ≥ 3 DAYS
•PHARMACIST MANAGED ALERT -OUTSIDE OF WORKFLOW AND A DVICE PROVIDED TO PRACTITIONER
•EVIDENCE OF AKI
•PEDIATRIC RIFLE CRITERIA; NO URINE EVALUATION
•RISK: ECRCL DEC REASE BY 25%
•INJURY: ECRCL DECREASE BY 50%
•FAILURE: ECRCL DEC REASE BY 75%
•1-YR: 42% DECREASE IN AKI INTENSITY WITH A REDUCTION IN DAYS IN AKI PER 100 EXPOSURE DAYS
•3-YR: RESULTS SUSTAINED WITH A 31% AKI INTENSITY DECREASE AND A 64% AKI RATE DECREASE
Goldstein SL et al. Pediat rics 2013;132:e756
Kirkendall ES et al. Appl Clin Inform 2014;5:313
Goldstien SL Kidney Int 2016;90:212
CHANGE SERUM CREATININE TO BIOMARKER
MONITORING
•ADULTS? ICU PATIENTS?
•WE ALREADY MONITOR SERUM CREA TININE REGULA RLY
Alert
≥3 nephrotoxins
Pharmacists evaluate
alert
-repeat, patient already
has AKI
Pharmacists order
biomarker test and
inform physician
Pharmacists aid in
interpretation and makes
medication
management
recommendations
QI-evaluate
medication
recommendations
made, AKI severity ,
days of AKI and AKI
incidence
Frazee E, Voils S, Kane-Gill SL. Pharmacotherapy (in press).
COST OF AKI
$0
$10,000
$20,000
$30,000
$40,000
$50,000
$60,000
Cost of
AKI in
CTICU
patients
BigpAK - One ICU day LOS reduction in intervention about a $2400
(US) savings
Averting or reducing AKI severity in one patient could result in cost
savings. Budget impact models and economic evaluations are needed
0
5000
10000
15000
20000
25000
30000
No AKI
AKIN 1
AKIN 2
AKIN 3 no…
AKIN 3 dialysis
Total Costs
Increment
al Costs
Dasta JF et al. Nephrol Dial Transplant 2008;23:1970-4
Collister D et al. Clin J Am Soc Nephrol 2017: 12:1733
Gocze I et al. Annals of Surgery 2017; epub ahead of print
4/9/2018
6
ACUTE KIDNEY INJURY (AKI)
TREATMENT AND MANAGEMENT
PREVENTING AKI INDUCED ADVERSE DRUG
EVENTS
SANDRA KANE-GILL, PHARMD, M SC, FCCM, FCCP
ASSOCIATE PROFESSOR, UNIVERSITY OF PITTSBURGH
CRITICAL CARE MEDICATION SAFETY PHARMACIST, UPM C
FACULTY, CENTER FOR CRITICAL NEPHROLOGY, UPMC AND UNIVERSITY OF PITTSBURGH
Disclosures: None
4/16/2018
1
Case of Acute Kidney Injury
•John Videen, M.D.
•Nephrologist with Balboa Nephrology Medical Group
•Sharp Chula Vista Medical Center
Disclosures
•Speaker for Astute Medical
•Speaker for Merck Pharmaceuticals
Case of Acute Kidney Injury
•60 year old male, with massive obesity, chronic
obstructive pulmonary disease and worsening
bilateral lower extremity edema admitted with
cellulitis of the legs.
•He had recurrent cellulitis and previous skin
grafts of this region.
•Comorbidities of obstructive sleep apnea, atrial
fibrillation and schizophrenia.
•Frequently admitted with respiratory issues,
poorly compliant.
4/16/2018
2
Case of Acute Kidney Injury
Initial Evaluation
•HR 120, irregular, 119/60, T 38.5
•Weight estimated at 500 lb. Edema noted
from feet to abdomen several mm in depth,
large pannus, chronic hyperkeratotic lesions of
legs, with lipodermatosclerosis. Draining open
wounds. Awake and alert.
•MRSA nasal screen +, wbc 16k, Crn 0.9.
Bicarbonate 34.
•CXR showed layering effusions.
Case of Acute Kidney Injury
Initial Therapy
•Treated with vancomycin, receiving 7 gm over
the first 48 hr and piperacillin-tazobactam.
•Diuretics started: bumetanide 1 mg IV bid plus
spironolactone 25 mg bid.
•Urine output was about 200 ml over 8 hr.
•Complained of pain, demanding treatment
with narcotics.
Case of Acute Kidney Injury
Deterioration
•Late on day 2 he became drowsy, not responding to
naloxone or bipap.
•Episodes of bradycardia noted.
•Transferred to the ICU.
•ABG: 7.09/pCO2118/pO2124
•Intubated with bronchoscopy showing clear airways.
Hemodynamics stabilized with pressors. HR 110s.
•Crn rose to 1.4 on day 3.
•Foley placed with urine output <10 ml/hr
•Biomarker TIMP2*IGFB7 measured >10
4/16/2018
3
Case of Acute Kidney Injury
ICU Treatment
•Blood cultures remained negative.
Streptococcus grew from wound and
vancomycin was stopped. Cephalosporin
given.
•Bumetanide increased to an intravenous
infusion at 1 mg/hr.
•Urine output improved to 150 ml/hr over 12
hr.
•Metolazone 10 mg given PO.
Case of Acute Kidney Injury
Resolution
•UO increased to 800 ml/hr and diuretics
stopped and a spontaneous diuresis
continued.
•Creatinine peaked at 2.1, returned to baseline
over next 2 weeks.
•Tracheostomy performed.
•Transferred to lower level of care.
Case of Acute Kidney Injury
Teaching Points
•Not a single insult to the kidney
•Despite co-morbidities, his renal function was
normal before admission.
•Period of hemodynamic instability.
•Exposed to nephrotoxic agents: Vancomycin
and Piperacillin-Tazobactam.
•Elevated renal vein pressure.
4/16/2018
4
Oliguric Renal Failure
Heart
Failure Forward
Heart Failure
Backward
Heart Failure
Activation:
Sympathetic NS
Renin/Angiotensin
ADH
Intrinsic
Renal Disease
Renal Venous
Congestion
Sodium
Retention
That’s all folks,
Any Questions?

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