What did we aim to learn fromthe FINNAKI -study

Maija Kaukonen, MD, PhD, EDICSpecialist in anesthesiology and intensive care

Specialist in clinical phramacologyIntensive Care Units, Division of Anaesthesia

and Intensive Care Medicine,Helsinki University Central Hospital, Helsinki, Finland

Acute Kidney Injury -AKI

• Definition and classification of AKI:RIFLE 2004, AKIN 2007, KDIGO2012

• These criteria are based inmeasurements of serum creatinine orurine output

RIFLE & AKIN & KDIGO

KDIGO 2012

20072004

0.3 mg/dl =26 umol/L

0.5 mg/dl =44 umol/L

4 mg/dl =354 umol/L

AKIN vs. RIFLE

Joannidis et al. ICM 2009

AKIN vs. RIFLE

Joannidis et al. ICM 2009

• RIFLE: 9% of patients unrecognised thatwere recognised by AKIN– 90% of thse were AKIN Stage 1 patients

• AKIN: 26.9% of patients unrecognised thatwere recognised by RIFLE– 30% of these were RIFLE I– 18% of these were RIFLE F

AKI progression

Creatinine as marker for AKI

• Limitations of creatinine• Slow and lateincrease in AKI• Largeinterindividualvariation (age, musclemass etc.)• Is affectedbyfluidbalance

(dehydration&volumeoverload)• Is notspecific for tubularinjury• Increasesonlyaftersignificantloss of GFR• Is a poorprognosticmarker

AKI biomarkers

Bagshaw SM. Bellomo R. Et al. Canadian Journal of Anaesthesia; 2Bagshaw SM. Bellomo R. Et al. Canadian Journal of Anaesthesia; 2010010..

AKI biomarkers

Devarajan, P. Nephrology 2010Devarajan, P. Nephrology 2010

Subclinical AKI

Haase, Devarajan et al.Haase, Devarajan et al. J Am Coll Cardiol. 2011 Apr 26;57(17):1752J Am Coll Cardiol. 2011 Apr 26;57(17):1752--61.61.

Population-based incidence of hospital treated AKI:

Ali, 2007: 2147 / million / year(RIFLE, retrospective, one region, Scotland, population of 523,390)

Population-based incidence of ICU treated AKI:

Cartin-Ceba, 2011: 2900 / million / year(RIFLE, retrospective, one county area USA, population of 124,277)

Population-basedincidence of AKI

AKI incidence –ICU patients

AKI %

Cruz 2007 (2164) 10.8

Thakar 2009 (323 359) 22.0

Joannidis 2009 (16 784) 28.5

Ostermann 2007 (41 972) 35.8

Bagshaw 2008 (120 123) 37.1

Hoste 2006 (5383) 67.2

AKI long-term prognosis

Wald, R., R. R. Quinn, et al. JAMA 2009Wald, R., R. R. Quinn, et al. JAMA 2009..

AKI mortalityAKI mortality

AKIHospital

Mortality%

Stage 3 /RIFLE FHospitalMortality

%

AKILong-termmortality

Hoste 2006 (5383) 13.3 26.3 -

Ostermann 2007 (41 972) 56.8 -

Bagshaw 2008 (120 123) 24.5 32.6 -

Joannidis 2009 (16 784) 36.4 41.2 -

AKI –genetics

• AngiotensinConvertingenzyme I/D geneticpolymorphism– 180 ICU patients, association with AKI (RIFLE –criteria)

• Hypoxia-inducedfactor 1– 241 patientswith AKI– Association withdiseaseseverity and outcome

• TNF alpha and IL 10 genepromotorpolymorphisms– 61 patientswithacuterenalfailurerequiringhemodialysis– Association withincreasedmortality

du Cheyron D, Fradin S, Ramakers M, et al. Angiotensinconvertingenzyme I/D geneticpolymorphism: Itsimpact on renalfunction in criticallyillpatients. CritCareMed2008;36:3178-83Kolyada AY, Tighiouart H et al. A geneticvariant of hypoxia-induced factor-1a is associatedwithadverseoutcomes in acutekidneyinjury. KidneyInt 2009; 75:1322-1329.Jaber BL, RaoMadhumathi, Guo D et al. Cytokinegenepromoterpolymorphisms and mortality in acuterenalfailure. Cytokine 2004; 25:212-219

FINNAKI

• AKI study• RRT –substudy• Finnsepsis II• Genetic substudy• Cardiac surgery substudy

FINNAKI

RRT –substudy

FINNSEPSIS II

Genetic study

Cardiac surgerysubstudy

RRT outsideICU

Study population

ICU admission

AKI study

Excludedpatients

Cardiac surgerysubstudy

Geneticsubstudy RRT -substudy

RRT –treated AKIpatientsoutside ICU

FINNSEPSIS II

Patientflow

• The aims of the study– Incidence of AKI in ICU and in Finnish population– Risk factors for AKI– Outcome of AKI

Renal recoveryMortality (90 –day, 6 month, 12 month, 5 –year)Quality of life after AKICost-utility of the treatment of AKI

– The mechanism of AKI; apoptosis/endothelial damage andinflammatory markers (eg. P-DNA, MMP-2, MMP-8, MMP-9,IL-6, TIMP-1, TIMP-2, PINP, PIIINP ja ICTP, caspases)

– New biomarkers of AKIPredictive value for AKI, RRT –treatment and mortality(e.g. P-/U-NGAL, U-NAG, U-KIM-1, U-IL-18)

FINNAKI

RRT –substudy

• Incidence of RRT treatment in FinnishICUs– Riskfactors for RRT treatment in ICU– Description of RRT– Outcomeof AKI

• Incidence of RRT –treated AKI outside ICUs– All AKI –patientsincludedifnephrologicalconsultation is

asked for the need of renalreplacementtherapy– Description of RRT– Outcome of AKI

• Incidence of septic AKI in ICU and inFinnishpopulation

• Riskfactors for septic AKI• Outcomeof septic AKI

RenalrecoveryMortality (90 –day, 6 month, 12 month, 5 –year)Quality of life afterseptic AKICost-utility of the treatment of septic AKI

• Biomarkers of septic AKI

FINNSEPSIS II -substudy

• Incidence and interrelation of cardiac injuryand AKI measured with new cardiac biomarkers

• Correlation of acute kidney injury biomarkersand cardiac injury biomarkers with risk scoring(Euroscore, Syntax), morbidity and mortality

Cardiac surgery substudy

FINNAKIFINNAKI

Under 18 yearsElective admission < 24hOn chronic RRTOrgan donorInitiation of chronic RRTDeclined / No consentNonresidentPreviously in study with RRTOver 5 days in study in another ICUIntermediate care

Emergency admissionElective admission >24 h

InclusionInclusion ExclusionExclusion

• Demographics• Screening of riskfactors for AKI for 5• Screening of severesepsis/ septicshock for 5 days• DetailledRRT data• Hemodynamic data as 5 min median values for the whole

ICU stay (electronicalcollection)• Laboratoryvalues and vasoactivetreatment for the whole

ICU stay (electronicalcollection)• Laboratorysampling: Bloodand urine sampling0 h, 12 h,

24 h, 36 h, 48 h, day 3, day 5

Collection of data

• Studyprotocolpreparation in 2010• Pilotstudy 3.-4.5.2011• Patientrecruitment 1.9.2011-1.2.2012

– Extension for severesepsispatients and RRT –patients to 30.04.2012

• Cardiacsurgerysubstudyrecuritmentup to21.06.2012

FINNAKI –execution

• 5853 ICUadmissionsduringpatientrecruitmentperiod• 2901 ICU patientsincluded inFINNAKI• 2825 patients in geneticsubstudy• 918 patients in FINNSEPSIS II• 367 patients in RRT substudy

• 296 patients in ICUs• 71 patientstreated outside ICUswith RRT for AKI

• Cardiacsurgerysubstudyrecruitment isongoing (400 patientsrecruited28.05.)

FINNAKI

FINNAKI –near future

• Population –basedincidence of AKI• RRT -substudy• FINNSEPSIS II

FINNAKI - biomarkers

• Earlierdiagnosis of AKI in future– Validationof new biomarkers in unselected ICU

patientcohort– NGAL, IL-18, KIM1

• Biomarkerpanelfor diagnosing AKI inunselected ICU patients?

• Progress and resolutionof AKI in light ofnew biomarkers?

• Biomarker –guided new RCTs?

FINNAKI –long termevaluation

• Long-termmortality: 1 and 5 years• Quality of life after AKI• Cost-effectivenessanalysis of AKI

Central Finland Central Hospital: Raili Laru-Sompa, Anni Pulkkinen, Minna Saarelainen, Mikko Reilama, SinikkaTolmunen, Ulla Rantalainen, Marja Miettinen

East Savo Central Hospital: Markku Suvela, Katrine Pesola, Pekka Saastamoinen, Sirpa KauppinenHelsinki University Central Hospital: Ville Pettilä, Kirsi-Maija Kaukonen, Anna-Maija Korhonen, Sara Nisula, Suvi Vaara,

Raili Suojaranta-Ylinen, Leena Mildh, Mikko Haapio, Laura Nurminen, Sari Sutinen, Leena Pettilä, Helinä Laitinen,Heidi Syrjä, Kirsi Henttonen, Elina Lappi, Hillevi Boman

Jorvi Central Hospital: Tero Varpula, Päivi Porkka, Mirka Sivula Mira Rahkonen, Anne Tsurkka, Taina Nieminen, NiinaPrittinen.

Kanta-Häme Central hospital: Ari Alaspää, Hanna Juntunen, Teija SanisaloKuopio University Hospital: Ilkka Parviainen, Ari Uusaro, Esko Ruokonen, Stepani Bendel, Niina Rissanen, Maarit Lång,

Sari Rahikainen, Saija Rissanen, Merja Ahonen, Elina Halonen, Eija VaskelainenLapland Central Hospital: Meri Poukkanen, Esa Lintula, Sirpa SuominenLänsi Pohja Central Hospital: Jorma Heikkinen, Timo Lavander, Kirsi Heinonen, Anne-Mari Juopperi,Middle Ostrobothnia Central Hospital: Tadeusz Kaminski, Fiia Gäddnäs, Tuija Kuusela, Jane RoikoNorth Karelia Central Hospital: Sari Karlsson, Matti Reinikainen, Tero Surakka, Helena Jyrkönen, Tanja Eiserbeck,

Jaana KallinenSatakunta Hospital district: Vesa Lund, Päivi Tuominen, Pauliina Perkola, Riikka Tuominen, Marika Hietaranta, Satu

JohanssonSouth Karelia Central Hospital: Seppo Hovilehto, Anne Kirsi, Pekka Tiainen, Tuija Myllärinen, Pirjo Leino, Anne

ToropainenTampere University Hospital: Jyrki tenhunen, Anne Kuitunen, Ilona Leppänen, Markus Levoranta, Sanna Hoppu, Jukka

Sauranen, Atte Kukkurainen, Samuli Kortelainen, Simo VarilaTurku University Hospital: Outi Inkinen, Niina Koivuviita, Jutta Kotamäki, Anu LaineOulu University Hospital: Tero Ala-Kokko, Jouko Laurila, Sinikka SälkiöVaasa Central Hospital: Simo-Pekka Koivisto, Raku Hautamäki, Maria Skinnar

Study GroupStudy Group