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

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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

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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

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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

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Human Correlates

If Animal models indicate that SA- AKI is multifactorial and not simply due to renal hypoperfusion

What about human evidence?

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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

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AKI –associated Sepsis Both animal and human data support a multifactorial etiology Inflammatory cytokines have been proposed as mediators of

these processes (IL-6)

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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

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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?

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Death

Conceptual Model for AKI

Complications

NormalIncreased

riskKidneyfailure

Damage GFR

AntecedentsIntermediate StageAKIOutcomes

EGDT

Current Point of

Intervention

GDT

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Approaching SA-AKI

Prevention Early goal directed fluid management

Biomarkers Cytokines, Fluid overload as a biomarker

Pharmacological support Extracorporeal Blood Support Facilitating Renal Recovery

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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

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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?

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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

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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?

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Extracorporeal therapies

Hemodialytic techniques CRRT- convective vs diffusive Plasma exchange/plasmapheresis Adsorption techniques

Dr. Durwald will review!

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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

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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

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Acknowledgments

Mink Chawla MD ppCRRT members The organizers