Exemplary Care Cutting-edge Research World-class Education Raghavan Murugan MD, MS, FRCP...

Exemplary Care Cutting-edge Research World-class Education

Raghavan Murugan MD, MS, FRCPAssociate Professor Dept. of Critical Care Medicine Clinical and Translational ScienceCore Faculty, Center for Critical Care Nephrology, CRISMAUniversity of Pittsburgh School of Medicine

Intensivist, Abdominal Organ Transplant ICUUniversity of Pittsburgh Medical Center

Understanding Mechanisms in Acute Kidney Injury


AcknowledgementsJohn 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)


ObjectivesMechanisms related to AKI susceptibility

Mechanisms related to AKI outcomesRenal RecoveryMortality

CohortSepsis-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)


Severe sepsis is a leading cause of AKI in critically ill patients

120,123 patients in 57 ICUs in Australia 28% had sepsis related diagnosisAmong septic patients 42% developed AKIHospital mortality (AKI vs. no AKI:19% vs.13%,P <0.001)

BEST Kidney study: 54 centers in 28 countries4.3% received renal replacement therapy47% sepsis60% hospital mortality

Acute renal failure Trial Network (ATN) Study: 27 centers in the US receiving renal replacement therapy

54.9% had septic AKI60 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


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


Risk of death following AKI in pneumonia

Days after pneumonia hospitalization

0

0.5

1.0

1.5

2.0

2.5

3.0

0 50 100 150 200 250 300 350 400

Haz

ard

rat

ios

wit

h 9

5% C

I

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

0 50 100 150 200 250 300 350 400

adjusted hazard ratio range = 1.10-2.10, P <0.001



AKI mortality in non-severe pneumonia0

51

01

52

0

0 100 200 300 400

Days after pneumonia

Mo

rtali

ty (

%)

AKI (n= 209)

No AKI (n= 821)

Pneumonia Severity Index classes I-III

P = 0.009

Mo

rtali

ty (

%)

05

10

15

20

0 100 200 300 400


CURB-65 group I

AKI (n=132)

No AKI (n=674)

P = 0.002

05

10

15

20

25

0 100 200 300 400


Non-severe sepsis subgroup

AKI (n=302)

No AKI (n=962)

P < 0.001

05

10

15

20

25

30

35

0 100 200 300 400


Non-ICU subgroup

P <0.001

No AKI (n=1158)

AKI (n=386)

Mo

rtali

ty (

%)

05

10

15

20

0 100 200 300 400


Mo

rtali

ty (

%)

AKI (n= 209)

No AKI (n= 821)

Pneumonia Severity Index classes I-III

P = 0.009

Mo

rtali

ty (

%)

05

10

15

20

05

10

15

20

0 100 200 300 400


CURB-65 group I

AKI (n=132)

No AKI (n=674)

P = 0.002

05

10

15

20

25

05

10

15

20

25

0 100 200 300 4000 100 200 300 400


Non-severe sepsis subgroup

AKI (n=302)

No AKI (n=962)

P < 0.001

05

10

15

20

25

30

35

05

10

15

20

25

30

35

0 100 200 300 4000 100 200 300 400


Non-ICU subgroup

P <0.001

No AKI (n=1158)

AKI (n=386)

Mo

rtali

ty (

%)



0

1

2

3

4

5

6

1 2 3 4 5 6 7

Hospital day

Lo

g m

ean

s CAP, severe sepsis, died

CAP, severe sepsis, alive

CAP, no organ failure

Kellum JA et al. Arch Intern Med 2007; 167(15):1655-63

IL-6 and severe sepsis


Inflammatory and Coagulation Markers in AKI and CAP

Day 1 BiomarkerConcentration in

CAP *AKI No AKI P Value

Interleukin-6 73.97 36 0.001

Tumor necrosis factor 7.46 4.82 0.001

Interleukin-10 7.03 5.14 0.002

Factor IX 122 121.5 NS

Anti-thrombin 85 89 NS

Thrombin-antithrombin 4.4 3.4 < 0.001Plasminogen activator inhibitor-1 6.71 4.95 < 0.001

D-Dimer 787.76 525 < 0.001

* Median values in pg/ml


Interleukin-6 and AKIIn

terl

euki

n-6

, p

g/m

l

0

20

40

60

80

100

120

1 2 3 4 5 6 7Days after pneumonia

AKI, Severe sepsis

AKI, No severe sepsis

No AKI, Severe sepsis

No AKI, No severe sepsis



Variable Odds Ratio 95% CI P-value

age 1.0461 1.0384 to 1.0538 < 0.001

IL-6 1.1283 1.0522 to 1.2098 < 0.001

TNF 1.5776 1.3258 to 1.8773 < 0.001

Baseline Cr 6.1672 2.7679 to 13.7416 < 0.001

Female 0.7007 0.5304 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 AKI Risk Injury Failure

Day

1 I

L-6

(p

g/m

l)


Risk of renal replacement therapy during CAP hospitalization

2.6% in patients with AKI9% in patients with severe AKI (RIFLE-F)

Renal recovery by hospital dischargeComplete: 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 AKI5.6% in patients with severe AKI (RIFLE-F)37.5% in patients who receive inpatient RRT

Renal Recovery after AKI in CAP


1-year mortality by renal recovery

50

263 167 151 141Non-recovery71 55 48 46Partial

287 245 239 224Complete1205 1078 1014 977No AKI

Number at risk

025

0 100 200 300 400

Days after pneumonia hospitalization

Mo

rtal

ity

(%)

No AKIComplete

Partial

Non-recovery

P = <0.001


Cause of death after AKI

Cardiovascular Infection Malignancy Respiratory Renal/metabolic

Others0

5

10

15

20

25

30

35

40

No AKI

AKI

Cau

se-s

pec

ific

mo

rtal

ity

(%)

Murugan, R et. al.; Clin J Am Soc Nep 2012


Cardiovascular deaths by renal recovery

No AKI Complete Partial Nonrecovery0

5

10

15

20

25

30

No pre-existing CVD

Pre-existing CVD

Car

dio

vasc

ula

r d

eath

s (%

)


Statins and 1-yr Mortality in Patients with CAP-induced AKI

Murugan, R et. al.; Clin J Am Soc Nep 2012


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-60Renal recovery (alive and independent from RRT): 36%Mortality: 50%


Day-1 biomarkers and renal recovery


Inflammatory and apoptotic pathwaysand 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)


Inflammatory and apoptosis biomarkers and 60-day mortality


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)


Biomarker concentration and intensity of RRT


Interaction between biomarkers and RRT intensity

0

2

4

6

8

10

0 2 4 6 8 10

Da

y 8

(p

g/m

l)

Day 1 (pg/ml)

IL-6

P<0.01

0

2

4

6

8

10

12

0 2 4 6 8 10 12

Da

y 8

(p

g/m

l)

Day 1 (pg/ml)

IL-8

P=0.14

0

2

4

6

8

10

0 2 4 6 8 10

Day

8 (

pg

/ml)

Day 1 (pg/ml)

IL-1β

P<0.01

0

2

4

6

8

10

12

0 2 4 6 8 10 12

Day

8

(pg

/ml)

Day 1 (pg/ml)

IL-10

P=0.30

0

2

4

6

8

10

0 2 4 6 8 10

Day

8 (

pg

/ml)

Day 1 (pg/ml)

IL-18

P=0.44

0

2

4

6

8

10

0 2 4 6 8 10

Day

8 (

pg

/ml)

Day 1 (pg/ml)

TNF

P=0.05

0

2

4

6

8

10

12

14

0 2 4 6 8 10 12 14D

ay 8

(p

g/m

l)

Day 1 (pg/ml)

MIF

P<0.01

A

0

2

4

6

8

10

12

0 2 4 6 8 10 12

Day

8 (

pg

/ml)

Day 1 (pg/ml)

TNFR-I

P<0.01

0

2

4

6

8

10

12

0 2 4 6 8 10 12

Day

8 (

pg

/ml)

Day 1 (pg/ml)

TNFR-II

P=0.15

0

2

4

6

8

10

0 2 4 6 8 10

Da

y 8

(p

g/m

l)

Day 1 (pg/ml)

DR-5

P=0.05

B C

0

2

4

6

8

0 2 4 6 8D

ay

8 (

pg

/ml)

Day 1 (pg/ml)

GM-CSF

P=0.27

Intensive RRT

Conventional RRT


Association between intensive RRT and outcomes by day 1 marker levels

BiomarkerAdjusted Odds Ratio (95% CI)

Renal Recovery Mortality

IL-6 0.78 (0.55 - 1.10) 1.14 (0.81 – 1.59)

IL-8 0.82 (0.58 – 1.16) 1.09 (0.78 – 1.54)

IL-10 0.78 (0.56 – 1.11) 1.14 (0.82 – 1.60)

IL-18 0.76 (0.54 – 1.08) 1.20 (0.86 – 1.68)

MIF 0.77 (0.54 – 1.09) 1.20 (0.85 – 1.68)

TNFR-I 0.78 (0.55 – 1.11) 1.15 (0.82 – 1.60)

TNFR-II 0.79 (0.56 – 1.11) 1.15 (0.82 – 1.60)

DR-5 0.78 (0.55 – 1.10) 1.18 (0.84 – 1.65)


Association between day 8 marker concentration and clinical outcomes

BiomarkerAdjusted Odds Ratio (95% CI)

Renal Recovery Mortality

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)


ConclusionsIn CAP

inflammation is associated with AKI susceptibilityAKI is associated with increased short and long term mortalityone-third of patients receiving RRT during hospitalization following CAP develop ESRDcardiovascular disease accounts for one-third of all deaths in patients with AKI

In critically Ill patients receiving RRTincreased 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 mortalityoverall

no association between RRT intensity and biomarkers and outcomessignificant 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

Exemplary Care Cutting-edge Research World-class Education Raghavan Murugan MD, MS, FRCP...

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