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Acute Kidney Injury & Sepsis
Patrick D Brophy, MD, MHCDS
Director Pediatric Nephrology
Professor
The University of Iowa
London 2015
Brophy University of Iowa
Overview
Epidemiolgy (Peds) SA-AKI is a unique entity Sepsis specific animal models of AKI Human epidemiologic data in SA-AKI Potential Interventions and concepts/strategies
Brophy University of Iowa
Pediatric Patient with Acute Kidney Injury: Characteristics
Children are NOT small adults 0 days to 21+ years 2 kg to 200 kg
Primary conditions Congenital heart
disease Inborn errors of
metabolism Sepsis with multi-organ
involvement Bone marrow and solid
organ transplantation NOT RENAL
Children develop MODS early in ICU course Maximum number of organ
failures occurs within 72 hours of ICU admission (87% of patients)
Children die with MODS very early in ICU course 88.4% of deaths occur
within 7 days of MOSF diagnosis
Proulx et al: Crit Care Med 22:1025, 1994
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Sepsis Associated AKI
Not solely due to hypoperfusion Mounting evidence suggests it is multifactorial (particularly
inflammation) Complexity of development and treatment are present
Brophy University of Iowa
Animal Models of AKI Classic
Renal artery cross clamping Nephrotoxic models
HgCl2 D-Serine Aminoglycoside
None of these single insult models replicates the sepsis syndrome well Animal models of sepsis utilize LPS or a peritonitis model
Brophy University of Iowa
Operating Hypothesis
SA-AKI is unique form of kidney injurySA-AKI is a direct and organ specific
mediated injury of the sepsis syndromeInflammation plays a critical role in this
injuryMitigation of this direct sepsis mediated
injury should attenuate the effects of SA-AKI as measured by improvement in renal composite endpoints and mortality
Brophy University of Iowa
Human Correlates
If Animal models indicate that SA- AKI is multifactorial and not simply due to renal hypoperfusion
What about human evidence?
Brophy University of Iowa
Early acute kidney injury and sepsis: a multicentre evaluation Sean M Bagshaw1,2, Carol George3, Rinaldo Bellomo2,4 for the ANZICS Database Management Committee Critical Care 2008, 12:R47
Brophy University of Iowa
Brophy University of Iowa
Brophy University of Iowa
Brophy University of Iowa
AKI –associated Sepsis Both animal and human data support a multifactorial etiology Inflammatory cytokines have been proposed as mediators of
these processes (IL-6)
Brophy University of Iowa
Cytokine profiles appear elevatedin sepsis and post code status
Hemodynamically stable patient codes and is revived
Post-code Pt. requires pressors and
acts like a patient in septic shock
Processes are correlated with whole body ischemia
Brophy University of
Iowa
Cytokines Predict AKI
876 patients Multi-variable analysis
adjusted for age, sex, race, interventions, hypotension, platelet count, bilirubin and infection
Well defined cohort
Liu et al, CCM, 2007
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Cytokine Profile Post-CodeAdrie et al Circulation 2002
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Ronco et al CJASN 2008
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If Inflammation Causes AKI, Interventions That Decrease
Inflammation Should Be Associated With Less AKI?
What strategies/interventions are available?
Brophy University of Iowa
Death
Conceptual Model for AKI
Complications
NormalIncreased
riskKidneyfailure
Damage GFR
AntecedentsIntermediate StageAKIOutcomes
EGDT
Current Point of
Intervention
GDT
Brophy University of Iowa
Approaching SA-AKI
Prevention Early goal directed fluid management
Biomarkers Cytokines, Fluid overload as a biomarker
Pharmacological support Extracorporeal Blood Support Facilitating Renal Recovery
Brophy University of Iowa
Prevention of SA-AKI
Fluid overload has been identified as an independent variable associated with increased mortality in pediatrics
Studies: (% FO and CRRT outcomes) Goldstein et al 2005 KI Foland et al 2004 CCM Gillespie et al 2004 Peds Neph Goldstein et al 2001 Pediatrics
Brophy University of Iowa
Early Intervention is Critical“Golden Hour?”
Trauma Patients – Golden Hour Stroke – 3 hour window Acute MI – 6 hour window SA-AKI - ?
Early shock is often hypo-dynamic The effects GDT are different depending on the severity of
inflammation and shock What do we do once injury is established?
Brophy University of Iowa
Previous Clinical Trials - AKI
Dopamine > Well powered study shows no utility IGF-1 > One small RCT shows no benefit
Drug started late (mean serum creatinine > 6.0 mg.dl)
Anaritide > 2 RCTs, over 700 pts., no benefit Concerns over hypotension
rANP – 61 patient pilot study positive Fenoldopam(treatment) – 155 patients, negative
study, some subsets had benefit Fenoldopam(prophylactic) – 300 pts, positive pilot
study
Brophy University of Iowa
Rationale for CurrentTreatment Strategies
No drugs shown to be helpful for treatment Role for EGDT must developed further Under-resuscitation is inflammatory
Role of Inflammation in Causing AKI?
Brophy University of Iowa
Extracorporeal therapies
Hemodialytic techniques CRRT- convective vs diffusive Plasma exchange/plasmapheresis Adsorption techniques
Dr. Durwald will review!
Brophy University of Iowa
Death
Role for the NephrologistWhen do you get consulted?
NormalIncreased
riskKidneyfailure
Damage GFR
AntecedentsIntermediate StageAKIOutcomes
EGDT
Defend Blood PressureRestore & Optimize PerfusionUse inotropes with careMitigate Inflammatory Injury
Optimize RRT
Brophy University of Iowa
Conclusions
Early resuscitation improves outcomes as measured by mortality and organ failure
Mounting evidence supports the notion that inflammation is an important causal component of AKI
Interventions that safely decrease inflammation should be integrated in good clinical practice in order to maximize benefit- but how?
Interventions and drugs targeted at inflammation and deranged fibrinolysis may prove to be robust agents for the treatment of AKI
Brophy University of Iowa
Acknowledgments
Mink Chawla MD ppCRRT members The organizers
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