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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

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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

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AKI RIFLE Criteria: ADQI II

Bellomo R et al. Crit Care 2004; 8: R204-212

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Modified RIFLE criteria in critically ill children with acute kidney injury

Estimated CCl Urine output

• Risk eCCl decrease by 25% <0.5 ml/Kg/h for 8 h• Injury eCCl decrease by 50% <0.5 ml/Kg/h for 16 h• Failure eCCl decrease by 75% or <0.3 ml/Kg/h for 24 h or anuric for 12h eCCl <35 ml/min/1.73 m2• Loss persistent failure >4 weeks• End end-stage renal disease

Stage (persistent failure >3 months)

150 pts 82% (n=123) AKI by pRIFLE 18% (n=27) no AKI

48.8%(n=60) R26% (n=32) I25.2% (n=31) F

Akcan-Arikan A. Kidney international 2007; 71: 1028-1035

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Goldstein B et al. International pediatric sepsis consensus conference: definitions forsepsis and organ dysfunction in pediatrics. Pediatric Crit Care Med 2005; 6(1): 2-8

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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

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Is sepsis a frequent cause of AKI in children?

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Study Location year Definition of

AKI

n pt

AKI

n (%)AKI + sepsis

BallNew

Zealand

2001-06

need for dialysis 226 29 (13)

Hui-Stickle USA 98-01

eCCl <75 ml/min/1.73

m2248 27 (11)

Vachvanichsanong

Thailand 82-04

creat >2 mg/dl or doubling

311 68 (21)

Bailey Canada 2000-01

creat doubling

44 4 (9)

Akcan-Arikan USA 2005-

06pRIFLE 123 33 (27)

Shaheen UK 2000-02

need for dialysis

83 28 (34)

Williams USA 79-98 creat doubling

228 41 (18)

Incidence of AKI secondary to sepsis

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Epidemiology of AKI varies between countries

Cause

SepsisHypovolemiaPSAGNSLEInfectious diseaseMalignanciesHearth failureCGNToxinsKUB anomaliesMiscellaneousUnknownDeathTotal

< 1995N(%)23(25)15(16)11(12)7(7)6(6)12(134(4)3(3)2(2)0(0)9(10)1(1)44(47)93

1995-1999N(%)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

2000-2004N(%)20(18)9(8)20(18)7(6)9(8)5(5)17(16)2(2)3(396(5)8(7)3(3)38(35)109

Table 2 Distribution of causes and mortality rates of ARF according to the year of admission

Williams DM et al. Arch. Pediatr. Adolesc Med. 2002; 156:893-900

Vachvanichsanong P et al. Pediatrics 2006; 18: 786-91

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Is the mortality of septic AKI higher than that of AKI secondary

to other causes?

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Septic AKI and mortality

Variable Survivorsn=42

Non-survivorsn=34

Odds ratio

95%CI P value

>20%FOSepsisMODS

8 (19.1%)13 (31%)29 (69%)

20 (58.8%)29 (85.3%)34 (100%)

6.112.9a

(2.2-17.0)(4.1-41.0)a

.0006

.0001

.0003

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

Sepsis group Mortality

Alive, n (%) Dead, n (%)

Without sepsis (73) 58 (79) 15 (21)

With sepsis (76) 46 (61) 30 (39)

Total (149) 104 (70) 45 (30)

P=0.012

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Septic AKI and mortality

Study N pt Overall mortality

%

Sepsis mortality %

VachvanicsanongBallHui-StckleLoza

318226248149

41.5113030

66326939

Study N pt Overall mortality

%

Sepsis mortality

%

Williams 228 27 19.5

“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”

“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”.

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Is the mortality of septic AKI higher than that of sepsis without

AKI?

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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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Watson RS et al. Am J Respir Crit Care Med 2003 Mar 1; 167(5):695-701

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

Sepsis and mortality

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Do patients with septic AKI show evidence of renal

dysfunction at follow up?

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Survivors n

Survivors with abnormalities at discharge n (%)

Post-cardiac surgeryHUSSepsisGNIschemiaNephrotoxicOther Total

12139209535202

18(15)34(87)11(55)9(100)3(60)1(33)5(100)

Short-term outcome of survivors

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

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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

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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

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Bagshaw SM et al. Intensive Care Med 2007; 33: 1285-96

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

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Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children

Washburn KK et al. Nephrol Dial Transplant 2008; 23: 566-72

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

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Zappitelli M et al. Critical Care, 2007; 11: R84

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

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Why do only some septic patients develop AKI?

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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 IL-10 CGG haplotype

protective from sepsis-associated

AKI

Wattanathum

NADPH oxidas

e p22ph

oxcatalas

e

200 incremental increase in serum

creat by 0.5, 1, 1.5 mg/dl

incidence of sepsis not

significantly different

Perianayagam

Genetic polymorphisms in sepsis associated AKI

Haase-Fielitz A et al. Contrib Nephrol 2007; 156: 75-91

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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

Cytokine gene promoter polymorphisms and mortality in AKI

Jaber et al. Cytokine, 2004; 25:212-219

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Can we attenuate or prevent septic AKI?

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Methods of Attenuating or Preventing Sepsis-Related 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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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 ACCM-PALS Guidelines.

Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome

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

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Terlipressin as a rescue therapyfor 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 andPaO2/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

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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

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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