JPediatr(RioJ).2017;93(1):1---3
www.jped.com.br
EDITORIAL
Sepsis-associated
acute
kidney
injury
---
is
it
possible
to
move
the
needle
against
this
syndrome?
夽
,
夽夽
Lesão
renal
aguda
associada
a
sepse
---
é
possível
fazer
a
diferenc
¸a
contra
essa
síndrome?
Prasad
Devarajan,
Rajit
K.
Basu
∗UniversityofCincinnati,CincinnatiChildren’sHospitalMedicalCenter,CenterforAcuteCareNephrology,Cincinnati, UnitedStates
Ontheonehand,sepsisistheleadingcauseofnon-trauma relateddeathinpediatricpatientsacrosstheworld,inboth developedanddevelopingnations.1Ontheotherhand,
epi-demiologicdatademonstratetheindependentcontribution of acutekidney injury(AKI) tomorbidity andmortalityin both adultsand children.2,3 The mortality,morbidity, and
financialcostofAKIissignificantandhasledtodedicated globalinitiativestoeliminatepreventableAKIandmitigate theeffectsofexistentAKI.4Together,unfortunately,sepsis
andAKIsynergizeintothe‘‘worstofbothworlds’’---inciting alitany ofnegativehost responsesand ultimatelyleading topoorpatientoutcome. Inthisissue ofJornalde Pedia-tria,Riyuzoetal.5reportdataonthepredictivefactorsof
deathinpatientswithsepsisassociatedAKI.Intheir retro-spectiveevaluationof77childrenwithsepsisandAKI,the rateofsevereAKI(pRIFLEstageI---Fand/orstage2---3were bothover75%)andtheoverallmortalityratewassubstantial (33.7%).
The driversof injury and progressionin sepsis andAKI aresimilar.Sepsisispropagatedbythecardinalmediators
夽
Please cite this article as: Devarajan P, Basu RK. Sepsis-associatedacutekidneyinjury---isitpossibletomovetheneedle againstthissyndrome?JPediatr(RioJ).2017;93:1---3.
夽夽
SeepaperbyRiyuzoetal.inpages28---34. ∗Correspondingauthor.
E-mail:Rajit.basu@cchmc.org(R.K.Basu).
of ischemia, hypoxia, inflammation, and cell death. The multi-dimensionalpathophysiologyof sepsisexerts pertur-bationsfromthecellularleveltooverallhosthomeostasis. Datafrombothanimalandhumanmodelssupports dysreg-ulation of the innate immune system, imbalance of pro-and anti-inflammatory cytokine production/degradation, destabilization of apoptotic pathways, and disruption of endothelial stability. In a parallel fashion, AKI is typified byasetofhostresponsesincludingischemia,dysregulated inflammation,hypoxia,andrenaltubularinjury.6
Addition-ally, AKI results in deleterious autocrine, paracrine, and endocrinecytokine effects onextra-renal vitalstructures suchasthebrain,heart,lungs,andliver.7Therefore,sepsis
andAKI,individually,aremoreappropriatelycharacterized as syndromes (versus ‘‘diseases’’ or ‘‘injuries’’) as they leadtodestabilizationofhomeostasisbyavarietyofglobal mechanisms.
Severe sepsis-associated acute kidney injury (SSAKI) is common,costly, andharmful. Sepsis is the leadingcause of AKI in adults and children, accounting for 33---50% of all AKI in adults and 25---50% of those in children.8 As
a unified syndrome, SSAKI contributes to high mortality, greaterresourceutilization (ventilatorysupport, dialysis), andincreased morbidity for patients (increased length of stay).Additionally,thelong-termsequelaeofSSAKIare sig-nificant;anotableproportionofsurvivingpatients (adults andchildren)sufferchronickidneydisease,earlyend-stage kidney disease, and earlier death.9,10 Unfortunately, the
pathophysiology of SSAKI is poorly understood. Similar to
http://dx.doi.org/10.1016/j.jped.2016.09.001
2 DevarajanP,BasuRK
both sepsis andAKI (takenindependently), the drivers of SSAKI include intrarenal hemodynamic changes, endothe-lialdysfunction,dysregulationofinflammatoryhomeostasis, necrosis/apoptosis,andischemic-hypoxicinjury.11Onahost
level, sepsis and AKI concurrently propagate one another by independent effects on systemic vascular tone, inter-stitialvolume,altereddistributionof serumalbumin,and inductionofnitricoxideproduction.Separationofthe inde-pendenteffectsofAKIfromsepsishasproventobedifficult, asthetwosharecommonpathwaysinvolvingcirculatory dys-function,adisconnectionofbio-energetics,andstresseson thenitrosativeandoxidativepathways.12Limitationsinthe
abilityofanimalmodelstoreplicatehumandisease,anda paucityofhumantissuedata,discredittheassumptionsof sepsisautomaticallydecreasingrenalbloodflowandleading totubularnecrosis.13Inboth‘‘miceandmen’’,the
multidi-mensionalinjuryispotentiatedintheveryyoungandvery old,andthosewithchronicillness.3Forthesereasons,
sep-sisand AKIgo‘‘hand-in-hand’’ ---andlikelysynergistically contribute tothe quick, downward spiralof patients suf-feringboth injurysyndromes. Riyuzoetal.5in theirstudy
ofchildrenwithSSAKI,observedaclinicalparalleltothese pathophysiologicfindings.Intheirstudy,thechildren with SSAKIwereyoung(median4months),werediagnosedearly (firstdayofadmissiontotheintensivecareunit),and suf-feredsevereinjury(>75%pRIFLEclassI---Fandstage2---3). Theindependentriskfactorsassociatedwithdeathincluded characteristicsofseverelyillpatients(mechanical ventila-tion,dialytictherapy,andhypoalbuminemia).Intheirstudy, AKI was not independently associated with mortality, an unsurprisingfindinginthecontextoftheoverallsevere ill-nessofpatientsincludedforstudy.Importantly,noseverity ofillnessmetric(PediatricRiskofMortality,PediatricIndex ofMortality)wasincludedintheirstudytocomparesurviving patientsfromthosewhodied.Anobviousassociationexists, however,betweenadvancedkidney injuryinpatientswith sepsis(stage 2---3 and/or therequirement of dialysis)and death---supportedbythesignificantdecreasedemonstrated intheKaplan---Meiersurvivalestimates.
How then, giventhe synergisticcontributionsof sepsis andAKI,dowemove theneedletoimproveoutcomesfor patientswithSSAKI?Amulti-faceted,timely,rational,and systematicapproachisneeded(Table1).Thefirststepisthe timelyidentificationofpatientsat-riskforSSAKI.Obviously ---treat the sepsis!Early initiationof antibiotics is associ-atedwithreducedmortality---afindingthatisonlyslowly beingappreciatedandincorporatedintoroutinecareof crit-icallyillpatients.14 Incidentalpopulationstudiesidentified
putativebiomarkersforthepurposeofidentifyingpatients at-risk of developing AKI (and the progression of AKI) in the context of sepsis.15 Genome-wide association studies
(GWAS)carrythepotentialtoidentifypatientsathighriskof SSAKI.16 Meanwhile,ongoinganimalstudiesidentifynewer
biomarkersfor SSAKI, specificallythosewithpotential for therapeutic targeting. Appropriateutilization of biomark-ersinthecontextofSSAKIisparamountfortheinclusionof thisnext-waveofprecisionmedicineintoroutinepractice. To mitigatecapricious use of novel diagnosticbiomarkers andtooptimizethepost-testprobabilityofprediction,the renal angina methodology of risk stratification has been derivedandvalidatedinmultiplepediatricpopulations.This methodology,ascitedbyRiyuzoetal.,5stratifiespatients
Table1 MovingtheneedleforSSAKImanagement.
1. Identificationofpatientsandearlydetectionofinjury
A.Recognizeandtreatsepsis(earlyantibiotics!) B.Genome-wideassociationstudies(priortoillness) C.Renalanginaindexdrivenbiomarkertesting
2. Adjudicationofinjuryprogression
A.Biomarkerprogression B.Assessmentof‘‘FluidPhase’’
3. SupportivecareandAKIbundles
A.Regular,daily,andhourlyassessmentsofrenal function
B.Optimizetherapyforsepsis/hemodynamics C.AKIbundles
i.Reduceoreliminatenephrotoxins
ii.Adjustmedicationsforrenalclearance
4. Nextgenerationtherapy/targetedtherapeutics
A.Immunomodulation
B.Cell-specifictargeting(ironchelation) C.Extracorporealdevices
i.Selectivecytophereticdevice
by risk and is a facile system for prediction of AKI at a time after ICU admission (72h) carrying significant rami-fications for patientmanagement.17---19 The second step is
earlyadjudicationoftheprogressionofinjury.Biomarkers for theprogressionof SSAKImaybeanimportantfacet of management, particularly in the early stabilization phase ofpatients.14Attentiontofluidaccumulationisparamount.
Increasingevidencefrombothadultsandchildrensupports thefindingofthedeleteriousindependentcontribution of fluid accumulation in critically ill patients.20 To this end,
fluidmanagementintheSSAKIpatientpopulation,inclusive ofrenalreplacementtherapy,isimportanttomitigatethe effects of end-organ tissue edema.21 An important
delin-eationmustbemadewithregardstothe‘‘stage’’offluid resuscitation for a givenpatient;treating allpatients the same and with the same approach to fluid resuscitation, stabilization, and maintenance is nonsensical.22,23 Third,
consistent and systematic supportive care is paramount. Earlygoaldirectedtherapyforsepsishasbecome common-placeincriticallyillpatients,butthenotionofsupportive careforAKI(regularassessmentsofcreatinine,attentionto urineoutputandweight,limitationsofnephrotoxins,renal dosing of medications,avoidanceof contrast,etc.) is not consistentacrosstheglobe.Earlyevidenceofthe introduc-tion of AKI care bundles into managementis promising.24
Finally,targetedtherapy isonthehorizon.Attenuation of early inflammation usingendocannabinoidsandcell-based therapies, cellular-specific targeting using iron chelation agents, and heme-oxygenase mediators are in advanced stages ofclinicalstudy.25 Extracorporealtherapiessuchas
theselectivecytophereticdeviceforattenuationof inflam-mation may be the next wave of therapy for the most criticallyillpatientswithSSAKI.26
Severe sepsis associated AKI is a combination of inde-pendent and synergistic disease syndromes with notable negativeeffectsonpatientoutcome.Inthiseditionofthe JornaldePediatria,Riyuzoetal.5reportjusthowsignificant
Sepsis-associatedacutekidneyinjury 3
mitigationfor these patientsparamount. Caring for these patients requires an understanding of the importance of a timely, consistent, and multi-dimensional approach to management.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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