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 Exemplary Care  Cutting-edge Research  World-class Education  Raghavan Murugan MD, MS, FRCP Associate Professor Dept. of Critical Care Medicine Clinical.

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Presentation on theme: " Exemplary Care  Cutting-edge Research  World-class Education  Raghavan Murugan MD, MS, FRCP Associate Professor Dept. of Critical Care Medicine Clinical."— Presentation transcript:

1  Exemplary Care  Cutting-edge Research  World-class Education  Raghavan Murugan MD, MS, FRCP Associate Professor Dept. of Critical Care Medicine Clinical and Translational Science Core Faculty, Center for Critical Care Nephrology, CRISMA University of Pittsburgh School of Medicine Intensivist, Abdominal Organ Transplant ICU University of Pittsburgh Medical Center Understanding Mechanisms in Acute Kidney Injury

2  Exemplary Care  Cutting-edge Research  World-class Education  Acknowledgements John Kellum, MD, MCCM Derek Angus, MD, MPH Paul Palevsky, MD Lisa Weissfeld, PhD Michele Elder, RN, MSN Melinda Carter, BS Xiaoyan Wen, PhD Francis Pike, PhD Lan Kong, PhD, Minjae Lee, PhD CRISMA and CCN Staff NIH KL2 (CTSI)

3  Exemplary Care  Cutting-edge Research  World-class Education  Objectives Mechanisms related to AKI susceptibility Mechanisms related to AKI outcomes Renal Recovery Mortality Cohort Sepsis-induced AKI – community-acquired pneumonia Genetic and Inflammatory Markers of Sepsis (GenIMS) Critically ill patients receiving renal replacement therapy (RRT) Acute Renal Failure Trial Network (ATN) and the Biological Markers of Recovery for Kidney (BioMaRK)

4  Exemplary Care  Cutting-edge Research  World-class Education  Severe sepsis is a leading cause of AKI in critically ill patients 120,123 patients in 57 ICUs in Australia 28% had sepsis related diagnosis Among septic patients 42% developed AKI Hospital mortality (AKI vs. no AKI:19% vs.13%,P <0.001) BEST Kidney study: 54 centers in 28 countries 4.3% received renal replacement therapy 47% sepsis 60% hospital mortality Acute renal failure Trial Network (ATN) Study: 27 centers in the US receiving renal replacement therapy 54.9% had septic AKI 60 day mortality: 54% for septic AKI Bagshaw et al; Crit Care. 2008;12(2):R47. Uchino et al; JAMA. 2005 Aug 17;294(7):813-8 Palevsky et al, N Engl J Med 2008;359(1):7-20 Sepsis-induced AKI

5  Exemplary Care  Cutting-edge Research  World-class Education  Risk and outcome of AKI in community-acquired pneumonia (CAP) Murugan, R, et al; Kidney International; 2010;77:527–535 1,836 patients with CAP Risk of AKI = 34% 1 year mortality for AKI: adjusted HR range = 1.10-2.10, P <0.001

6  Exemplary Care  Cutting-edge Research  World-class Education  Risk of death following AKI in pneumonia Days after pneumonia hospitalization 0 0.5 1.0 1.5 2.0 2.5 3.0 050100150200250300350400 Hazard ratios with 95% CI 0 0.5 1.0 1.5 2.0 2.5 3.0 0 0.5 1.0 1.5 2.0 2.5 3.0 050100150200250300350400 adjusted hazard ratio range = 1.10-2.10, P <0.001 Murugan, R, et al; Kidney International; 2010;77:527–535

7  Exemplary Care  Cutting-edge Research  World-class Education  AKI mortality in non-severe pneumonia Murugan, R, et al; Kidney International; 2010;77:527–535

8  Exemplary Care  Cutting-edge Research  World-class Education  Kellum JA et al. Arch Intern Med 2007; 167(15):1655-63 IL-6 and severe sepsis

9  Exemplary Care  Cutting-edge Research  World-class Education  Inflammatory and Coagulation Markers in AKI and CAP Day 1 Biomarker Concentration in CAP * AKINo AKIP Value Interleukin-673.9736 0.001 Tumor necrosis factor 7.464.82 0.001 Interleukin-107.035.140.002 Factor IX122121.5NS Anti-thrombin8589NS Thrombin-antithrombin4.43.4< 0.001 Plasminogen activator inhibitor-1 6.714.95 < 0.001 D-Dimer787.76525< 0.001 * Median values in pg/ml

10  Exemplary Care  Cutting-edge Research  World-class Education  Interleukin-6 and AKI Murugan, R, et al; Kidney International; 2010;77:527–535

11  Exemplary Care  Cutting-edge Research  World-class Education  VariableOdds Ratio95% CIP-value age1.04611.0384 to 1.0538 < 0.001 IL-61.12831.0522 to 1.2098 < 0.001 TNF1.57761.3258 to 1.8773 < 0.001 Baseline Cr6.16722.7679 to 13.7416 < 0.001 Female0.70070.5304 to 0.9256 0.012 AKI in Pneumonia Patients 16%7%10%67% Risk of AKI P < 0.001 0 20 40 60 80 100 120 No AKIRisk Injury Failure Day 1 IL-6 (pg/ml )

12  Exemplary Care  Cutting-edge Research  World-class Education  Risk of renal replacement therapy during CAP hospitalization 2.6% in patients with AKI 9% in patients with severe AKI (RIFLE-F) Renal recovery by hospital discharge Complete: 46.2% Partial: 11.4% Non-recovery: 42.3% Risk of end-stage renal disease by 3 months in survivors of AKI 1.8% in all patients with AKI 5.6% in patients with severe AKI (RIFLE-F) 37.5% in patients who receive inpatient RRT Renal Recovery after AKI in CAP

13  Exemplary Care  Cutting-edge Research  World-class Education  1-year mortality by renal recovery

14  Exemplary Care  Cutting-edge Research  World-class Education  Cause of death after AKI Murugan, R et. al.; Clin J Am Soc Nep 2012

15  Exemplary Care  Cutting-edge Research  World-class Education  Cardiovascular deaths by renal recovery Cardiovascular deaths (%)

16  Exemplary Care  Cutting-edge Research  World-class Education  Statins and 1-yr Mortality in Patients with CAP-induced AKI Murugan, R et. al.; Clin J Am Soc Nep 2012

17  Exemplary Care  Cutting-edge Research  World-class Education  BioMaRK Study Ancillary observational study to VA/ATN trial Enrolled 819 critically ill subjects receiving RRT Plasma biomarkers were sampled on days 1 and 8 after randomization in inflammatory (IL-1 ,6,8,10,18,TNF,MIF) apoptosis (DR-5, TNFR-I, II) growth factor pathways (GM-CSF) Outcome at day-60 Renal recovery (alive and independent from RRT): 36% Mortality: 50%

18  Exemplary Care  Cutting-edge Research  World-class Education  Day-1 biomarkers and renal recovery

19  Exemplary Care  Cutting-edge Research  World-class Education  Inflammatory and apoptotic pathways and renal Recovery Adjusted HR for renal recovery (95%CI) IL-8: 0.84 (0.76-0.93) IL-18: 0.88 (0.79-0.98) TNFR-I: 0.84 (0.71-0.99)

20  Exemplary Care  Cutting-edge Research  World-class Education  Inflammatory and apoptosis biomarkers and 60-day mortality

21  Exemplary Care  Cutting-edge Research  World-class Education  Inflammatory and apoptosis biomarkers and time to death Adjusted HR (95%CI) IL-6: 1.26 (1.18-1.35) IL-8: 1.39 (1.29-1.51) IL-18: 1.27 (1.14 -1.41) TNFR-I: 1.57 (1.22-2.02) MIF: 1.16 (1.08-1.25)

22  Exemplary Care  Cutting-edge Research  World-class Education  Biomarker concentration and intensity of RRT

23  Exemplary Care  Cutting-edge Research  World-class Education  Interaction between biomarkers and RRT intensity

24  Exemplary Care  Cutting-edge Research  World-class Education  Association between intensive RRT and outcomes by day 1 marker levels Biomarker Adjusted Odds Ratio (95% CI) Renal RecoveryMortality IL-60.78 (0.55 - 1.10)1.14 (0.81 – 1.59) IL-80.82 (0.58 – 1.16)1.09 (0.78 – 1.54) IL-100.78 (0.56 – 1.11)1.14 (0.82 – 1.60) IL-180.76 (0.54 – 1.08)1.20 (0.86 – 1.68) MIF0.77 (0.54 – 1.09)1.20 (0.85 – 1.68) TNFR-I0.78 (0.55 – 1.11)1.15 (0.82 – 1.60) TNFR-II0.79 (0.56 – 1.11)1.15 (0.82 – 1.60) DR-50.78 (0.55 – 1.10)1.18 (0.84 – 1.65)

25  Exemplary Care  Cutting-edge Research  World-class Education  Association between day 8 marker concentration and clinical outcomes Biomarker Adjusted Odds Ratio (95% CI) Renal RecoveryMortality IL-6 0.74 (0.62-0.87)1.45 (1.23-1.72) IL-8 0.60 (0.50-0.73)1.90 (1.56-2.32) IL-10 0.73 (0.60-0.89)1.47 (1.21-1.78) IL-18 0.72 (0.60-0.86)1.48 (1.22-1.79) MIF 0.86 (0.74-1.00)1.25 (1.07-1.46) TNFR-I 0.20 (0.12-0.32)3.20 (2.06-4.95) TNFR-II 0.51 (0.35-0.74)1.61 (1.10-2.36) DR-5 0.72 (0.56-0.92)1.48 (1.15-1.91)

26  Exemplary Care  Cutting-edge Research  World-class Education  Conclusions In CAP inflammation is associated with AKI susceptibility AKI is associated with increased short and long term mortality one-third of patients receiving RRT during hospitalization following CAP develop ESRD cardiovascular disease accounts for one-third of all deaths in patients with AKI In critically Ill patients receiving RRT increased day-1 plasma inflammatory (IL-8, IL-18) and apoptosis (TNFR-I) are associated with RRT dependence plasma IL-6, 8, 18, MIF, TNFR-I are associated with mortality overall no association between RRT intensity and biomarkers and outcomes significant interaction exists within subgroup of patients with high and low day-1 concentrations persistently elevated concentrations of these markers are associated with death and RRT dependence

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