1
6 th International Pediatric Continuos Renal
Replacement Therapy (pCRRT) Conference
Rome, 8-10 April 2010
Sepsis and AKI
Isabella Guzzo
Department of
Nephrology and Urology
2
AKI definition
More than 30 AKI definitions in
published literature
 hampers comparisons of studies
 limits generalization of data from
single center studies
 prevents patients stratification
Akcan-Arikan A. Kidney international 2007; 71: 1028-1035
3
AKI RIFLE Criteria: ADQI II
Bellomo R et al. Crit Care 2004; 8: R204-212
4
Modified RIFLE criteria in critically ill
children with acute kidney injury
Estimated CCl
•
•
•
Risk
Injury
Failure
•
•
Loss
End
Stage
150 pts
Urine output
eCCl decrease by 25%
<0.5 ml/Kg/h for 8 h
eCCl decrease by 50%
<0.5 ml/Kg/h for 16 h
eCCl decrease by 75% or <0.3 ml/Kg/h for 24 h or anuric for 12h
eCCl <35 ml/min/1.73 m2
persistent failure >4 weeks
end-stage renal disease
(persistent failure >3 months)
82% (n=123) AKI by pRIFLE
48.8%(n=60) R
26% (n=32) I
25.2% (n=31) F
18% (n=27) no AKI
Akcan-Arikan A. Kidney international 2007; 71: 1028-1035
5
Goldstein B et al. International pediatric sepsis consensus conference: definitions for
sepsis and organ dysfunction in pediatrics. Pediatric Crit Care Med 2005; 6(1): 2-8
6
Septic AKI
Septic AKI is defined by the simultaneous
presence both of the RIFLE criteria for AKI
and the consensus criteria for sepsis and
the absence of other clear and established
non-sepsis-related causes of AKI (e.g.
radiocontrast, other nephrotoxins)
Wan L. et al, Crit Care Med 2008; 36:S198-203
7
Is sepsis a frequent cause of
AKI in children?
8
Incidence of AKI secondary to sepsis
Study
Location
year
Definition of
AKI
Ball
New
Zealand
2001-06
need for
dialysis
Hui-Stickle
USA
n pt
n (%)
AKI AKI + sepsis
226
29 (13)
98-01
eCCl <75
248
ml/min/1.73 m2
27 (11)
311
68 (21)
Vachvanichs
anong
Thailand
82-04
creat >2 mg/dl
or doubling
Bailey
Canada
2000-01
creat doubling
44
4 (9)
AkcanArikan
USA
2005-06
pRIFLE
123
33 (27)
Shaheen
UK
2000-02
need for
dialysis
83
28 (34)
Williams
USA
79-98
creat doubling
228
41 (18)
9
Epidemiology of AKI varies between
countries
Table 2 Distribution of causes and mortality rates of
ARF according to the year of admission
Cause
Sepsis
Hypovolemia
PSAGN
SLE
Infectious disease
Malignancies
Hearth failure
CGN
Toxins
KUB anomalies
Miscellaneous
Unknown
Death
Total
< 1995
N(%)
23(25)
15(16)
11(12)
7(7)
6(6)
12(13
4(4)
3(3)
2(2)
0(0)
9(10)
1(1)
44(47)
93
Williams DM et al. Arch. Pediatr. Adolesc Med. 2002; 156:893-900
Vachvanichsanong P et al. Pediatrics 2006; 18: 786-91
1995-1999
N(%)
25(22)
15(13)
7(6)
18(15)
15(13)
12(10)
5(4)
6(5)
2(2)
0(0)
7(6)
4(3)
50(43)
116
2000-2004
N(%)
20(18)
9(8)
20(18)
7(6)
9(8)
5(5)
17(16)
2(2)
3(39
6(5)
8(7)
3(3)
38(35)
109
10
Is the mortality of septic AKI
higher than that of AKI secondary
to other causes?
11
Septic AKI and mortality
Sepsis group
Mortality
Alive, n (%)
Dead, n (%)
Without sepsis (73) 58 (79)
15 (21)
With sepsis (76)
30 (39)
46 (61)
Total (149)104 (70)
45 (30)
P=0.012
Variable
>20%FO
Sepsis
MODS
Survivors
n=42
8 (19.1%)
13 (31%)
29 (69%)
Non-survivors
n=34
20 (58.8%)
29 (85.3%)
34 (100%)
Odds
ratio
6.1
12.9
a
95%CI
(2.2-17.0)
(4.1-41.0)
a
a Unable to calculate odds ratio bacause 100% of non-survivors had MODS
Loza R et al. Pediatr Nephrol 2006; 21: 106-09
Hayes LW et al. Journal of Critical Care 2009; 24: 394-400
P value
.0006
.0001
.0003
12
Septic AKI and mortality
Study
N pt
Overall
mortality %
Sepsis
mortality %
Vachvanicsanong
Ball
Hui-Stckle
Loza
318
226
248
149
41.5
11
30
30
66
32
69
39
Study
Williams
N pt
Overall
mortality %
Sepsis
mortality %
228
27
19.5
“Sepsis was a major cause of
ARF in each era, with the sepsis
mortality rates not improving,
although antibiotics certainly
advanced during this time.”
“Children with sepsis were > 10
times more likely to die as a
result of ARF”.
“Among non-survivors, sepsis
associated acute kidney failure
dropped from 23% in the first decade
to 3% in the second presumably
because of advances in antibiotic
therapy and better management of
fluid volume control”
13
Is the mortality of septic AKI
higher than that of sepsis without
AKI?
14
Acute renal failure in patients with severe sepsis and
septic shock-a significant indipendent risk factor for
mortality: results from German Prevalence Study
3877
screened
patients
415 with
severe
sepsis/septic
shock
14 with CKD
234 patients
w/o ARF
166 patients
with ARF
In-hospital
mortality 42.8%
In-hospital
mortality 67.3%
ARF was the only organ dysfunction that
was predictive for mortality (OR 2.112;
P=0.0001)
Oppert M. Nephrol Dial Transplant 2008; 23: 904-909
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Sepsis and mortality
Mortality of children with severe
sepsis by age and comorbidity
The risk of death increased with
increasing numbers of failing
organs, from 7% for those with
single-organ system failure to
53.1% for those with four organ
systems or more failing
Watson RS et al. Am J Respir Crit Care Med 2003 Mar 1; 167(5):695-701
16
Do patients with septic AKI
show evidence of renal
dysfunction at follow up?
17
Short-term outcome of survivors
Post-cardiac surgery
HUS
Sepsis
GN
Ischemia
Nephrotoxic
Other
Total
Survivors
n
Survivors with
abnormalities
at discharge
n (%)
121
39
20
9
5
3
5
202
18(15)
34(87)
11(55)
9(100)
3(60)
1(33)
5(100)
Hypertension, reduced
eGFR or abnormal
urinalysis were detected in
55% of children with sepsis
at the time of discharge
Ball EF et al. J Ped Child Health 2008; 44: 642-6
18
Long-term outcome of survivors
21 children dialysed with meningococcal sepsis: 12 survivors
After a mean follow-up of 4 years 1/3 developed renal
abnormalities:

2 abnormal GFR, proteinuria and hypertension

1 isolated proteinuria

1 renal parenchimal defect on DMSA scan
Slack R et al. Pediatr. Crit Care 2005; 6: 477-9
19
Are urinary tests useful in
septic AKI?
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In septic AKI biochemical analysis of urine
using standard measurements of sodium,
urea and creatinine calculating various
indices of tubular function is not
diagnostically accurate, prognostically
valuable or clinically useful
Bagshaw SM et al. Am J Kidney Dis 2006; 48: 695-705
21
Urinary biomarkers in septic AKI
Review of 14 studies to assess diagnostic and prognostic value of
urinary biomarkers in septic AKI
Urinary IL-18, PAF and NHE3
 detected early in AKI prior to the development of overt
kidney failure
 higher in septic than in non-septic AKI patients
Several additional low-molecular-weight proteins and enzymes may
be evident early in the urine of patients with AKI. Their value in
sepsis remains unclear
Bagshaw SM et al. Intensive Care Med 2007; 33: 1285-96
22
Urinary interleukin-18 is an acute kidney
injury biomarker in critically ill children
In AKI patients, uIL-18 began to rise at
day -2, peaked at day 0 and then steadely
declined at baseline at day 3, whereas
control uIL-18 concentrations remained
unchanged
AKI uIL-18 was higher in “non septic”
patients than in controls between day 2 and 2.
The sample size was not large enough
to evaluate the role of uIL-18 in the
subgroup of septic patients
Washburn KK et al. Nephrol Dial Transplant 2008; 23: 566-72
23
Urine NGAL is an early marker of acute
kidney injury in critically ill children
Mean uNGAL concentrations by
pRIFLE max strata
Mean concentrations of uNGAL
according to presence or absence of
sepsis
Zappitelli M et al. Critical Care, 2007; 11: R84
24
Why do only some septic patients
develop AKI?
25
Genetic polymorphisms in sepsis associated AKI
Gene
Patients
Definition of AKI
Outcome
References
TNF-α/
IL-6
92
creat > 120 μmol/l,
diuresis < 1 ml/Kg/h
more often present
in AKI (26 vs 6%)
Treszl
TNF-α/
TNF-αR
213
AKI as part of the
SOFA score
no association with
renal function or
mortality
Gordon
IL-10
550
need for dialysis
NADPH
oxidase
p22phox
catalase
200
incremental increase
in serum creat by 0.5,
1, 1.5 mg/dl
IL-10 CGG haplotype Wattanathum
protective from
sepsis-associated AKI
incidence of sepsis
not significantly
different
Haase-Fielitz A et al. Contrib Nephrol 2007; 156: 75-91
Perianayagam
26
Cytokine gene promoter polymorphisms
and mortality in AKI
61 patient with AKI requiring
intermittent hemodialysis
64% had sepsis
Considering combinations of
genotypes, the TNF-α high and IL-10
low producer genotype combination
was associated with a 6 fold
increased risk of death compared to
the TNF-α low and IL-10
intermediate/high producer genotype
combination
Jaber et al. Cytokine, 2004; 25:212-219
27
Can we attenuate or prevent
septic AKI?
28
Methods of Attenuating
or Preventing SepsisRelated Acute Renal
Failure
Arginine vasopressin
Hydrocortisone
Early directed resuscitation
Maintenance of blood glucose
< 145 mg/dl (8.0 mmol/l)
Activated protein C
Schrier RW et al. NEJM 2004; 351: 159-69
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Early reversal of pediatric-neonatal septic shock by
community physicians is associated with improved
outcome
A, Shock reversal resulted in
96% survival versus 63%
survival among patients who
remained in persistent shock
state.
B, Resuscitation consistent with
the new ACCM-PALS Guidelines
resulted in 92% survival versus
62% survival among patients
who did not receive resuscitation
consistent with the new ACCMPALS Guidelines.
Han YY et al. Pediatrics 2003; 112: 793-799
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Steroids
 Hydrocortisone in septic shock → only for children with
catecholamine resistance and suspected or proven
adrenal insufficiency
 No consensus for the best dose
 Dose recommendations vary from 1-2 mg/Kg (stress
dose) to 50 mg/Kg followed by the same dose as a 24 hr
infusion (shock dose)
Dellinger RP et al. Crit Care Med. 2004; 32(3): 858-73
31
Terlipressin as a rescue therapy
for catecholamine-resistant septic
shock in children
58 children with septic shock and
refractary hypotension enrolled to
terlipressin (n=30) or control (n=28).
Mean arterial pressure and
PaO2/FIO2 significantly increased,
and heart rate significantly decreased
30 min after each TP treatment, but
mortality did not differ from control
(67.3% vs. 71.4%).
Yildizdas D et al. Intensive Care Med. 2008; 34: 511-17
32
Drotrecogin alfa in children with
severe sepsis
477 patients enrolled.
237 received placebo and 240
DrotAA
No significant difference
between groups in 28-day
mortality
No difference in overall serious
bleeding events
More CNS bleeding events
occured in the DrotAA group
particularly in children younger
than 60 days
Nadel S et al. Lancet 2007; 369: 836-43
33
Intensive insulin therapy
Intensive insulin therapy did not significantly
reduced in-hospital mortality but significantly
reduced morbidity.
Reduction in newly acquired kidney injury
(8.9 to 5.9%, P=0.04)
Despite the evidence for an association
between hyperglycemia and worsened
outcome in PICU, glycemic control has not
been evaluated in critically ill children
Van den Berghe et al. NEJM, 2006; 354: 449-461
Branco RG et al. Pediatr Crit Care Med, 2005; 6: 470-2
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Conclusions
Sepsis is a frequent cause of AKI in children
Sepsis increases the mortality of AKI
AKI increases the mortality of sepsis
More than half of children with septic AKI presents renal
dysfunction at discharge and 1/3 develops abnormalities in the
long term. Follow-up of these patients is recommended
 Genetic risk factors may be involved in the individual
susceptibility to septic AKI
 Fluid resuscitation avoiding fluid overload, hydrocortisone,
terlipressin, drotrecogin alfa and intensive insulin therapy may be
useful in the management of septic AKI but further studies are
necessary
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Thank you for your attention