1. Brophy University of Iowa Acute Kidney Injury & Sepsis Patrick Brophy MD Director Pediatric Nephrology University of Iowa- Children’s Hospital PCRRT Orlando June 2008

2. 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

3. Brophy University of Iowa Pediatric AKI: Changing Epidemiology Stickle SH et al: Am J Kid Dis 45:96-101, 2005

4. 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

5. Brophy University of Iowa Sepsis Associated AKI  Not solely due to hypoperfusion  Mounting evidence suggests it is multifactorial (particularly inflammation)  Complexity of development and treatment are present

6. Brophy University of Iowa Animal Models of AKI  Classic Renal artery cross clamping Nephrotoxic models  HgCl 2  D-Serine  Aminoglycoside  None of these single insult models replicates the sepsis syndrome well Animal models of sepsis utilize LPS or a peritonitis model

7. Brophy University of Iowa Operating Hypothesis  SA-AKI is unique form of kidney injury  SA-AKI is a direct and organ specific mediated injury of the sepsis syndrome  Inflammation plays a critical role in this injury  Mitigation of this direct sepsis mediated injury should attenuate the effects of SA-AKI as measured by improvement in renal composite endpoints and mortality

8. Brophy University of Iowa Human Correlates  If Animal models indicate that SA- AKI is is multifactorial and not simply due to renal hypoperfusion  What about human evidence?

9. 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

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13. AKI –associated Sepsis  Both animal and human data support a multifactorial etiology  Inflammatory cytokines have been proposed as mediators of these processes (IL-6)

14. Brophy University of Iowa Cytokine profiles appear elevated in 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

15. 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

16. Brophy University of Iowa Cytokine Profile Post-Code Adrie et al Circulation 2002

17. Brophy University of Iowa Ronco et al CJASN 2008

18. Brophy University of Iowa If Inflammation Causes AKI, Interventions That Decrease Inflammation Should Be Associated With Less AKI What strategies/interventions are available?

19. Brophy University of Iowa Death Conceptual Model for AKI Complications Normal Increased risk Kidney failure Damage  GFR Antecedents Intermediate Stage AKI Outcomes EGDT Current Point of Intervention GDT

20. 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

21. 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

22. 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?

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24. EGDT and Renal Outcomes Lin et al – Shock - 2006

25. Brophy University of Iowa Ranieri, V. M. et al. JAMA 2000;284:43-44.

26. Brophy University of Iowa Copyright restrictions may apply. Ranieri, V. M. et al. JAMA 2000;284:43-44. Organ Failure

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28. Less Inflammation with low TV Log IL-6Day 0Day 3 Traditional TV2.5 + 0.7 pg/ml2.3 + 0.7 pg/ml Low TV2.5 + 0.7 pg/ml 2.0 + 0.5 pg/ml ** ** p <0.001

29. Brophy University of Iowa ARDsnet Organ Failure Organ Failure TraditionalLow TVP value Circulatory19 + 10 days 17 + 11 days 0.004 Coagulation21 + 1019 + 110.004 Renal20 + 1118 + 110.005

30. 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

31. Brophy University of Iowa Rationale for Current Treatment 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?

32. Brophy University of Iowa Extracorporeal therapies  Hemodialytic techniques  CRRT- convective vs diffusive  Plasma exchange/plasmapheresis  Adsorption techniques

33. Brophy University of Iowa Ronco et al CJASN 2008

34. Brophy University of Iowa Summary  Prophylactic fenoldopam may have a role in the prevention of AKI  Early resuscitation is associated with less inflammation and improved renal outcomes  Pro-inflammatory mediators predict AKI  Deranged fibrinolsyis predicts AKI in patients with ARDS  Interventions that decrease inflammation are associated with improved renal outcomes

35. Brophy University of Iowa Death Role for the Nephrologist When do you get consulted? Normal Increased risk Kidney failure Damage  GFR Antecedents Intermediate Stage AKI Outcomes EGDT Defend Blood Pressure Restore & Optimize Perfusion Use inotropes with care Mitigate Inflammatory Injury Optimize RRT

36. 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  Interventions and drugs targeted at inflammation and deranged fibrinolysis may prove to be robust agents for the treatment of AKI

37. Brophy University of Iowa Acknowledgments  Mink Chawla MD  ppCRRT members  The organizers